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Apr 18, 2011 - adjudicated major bleeding and adjudicated clinically relevant non-major bleeding during 6 months of ...... sertraline .... increased menstrual flow or vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual.

Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thrombo­ embolism. N Engl J Med 2013;369:799-808. DOI: 10.1056/NEJMoa1302507

This Supplement contains the following items: 1) Final protocol with summary of changes from the original protocol 2) Final statistical analysis plan with summary of changes from the original statistical analysis plan

Page: Protocol Number: IND Number: EUDRACT Number Date: Revised Date

1 CV185056 66,106 2007-007867-25 20-Feb-2008 18-Apr-2011

Clinical Protocol CV185056 A Safety and Efficacy Trial Evaluating the Use of Apixaban in the Treatment of Symptomatic Deep Vein Thrombosis and Pulmonary Embolism Revised Protocol Number: 02 Incorporates Amendment(s) 04 and Administrative Letters 02, 03 and 04 Study Director / Central Medical Monitor Raphael Pak, PhD Pfizer Global Research & Development 2800 Plymouth Road Ann Arbor, MI 48105 USA Office Telephone: (734) 887-8011 Mobile Telephone: (734) 548-0260 Fax: (734) 622-5769 [email protected] Steering Committee Chair Prof. Giancarlo Agnelli, MD Sezione di Medicina Interna e Vascolare Ospedale S. Maria della Misericordia Via Gerardo Dottori n° 1 Località S. Andrea delle Fratte 06100 Perugia - Italy

Clinical Protocol Manager Melanie Noble Pfizer Global Research & Development 50 Pequot Ave New London, CT 06320 USA

24-hr Emergency Telephone Number USA/Canada: 888-483-7729 Europe/Rest of World: 44-1223-374-240 Latin America: 55 11 4504 4801 Bristol-Myers Squibb Research and Development (Sponsor) Route 206 & Province Line Road Lawrenceville, NJ 08543 2

Pfizer Global Research & Development 50 Pequot Ave New London, CT 06320 This protocol contains information that is confidential and proprietary to Bristol-Myers Squibb (BMS) and Pfizer Inc.

Replace all previous version(s) of the protocol with this revised protocol and please provide a copy of this revised protocol to all study personnel under your supervision, and archive the previous versions.

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DOCUMENT HISTORY Document

Date of Issue

Revised Protocol 02

18-Apr-2011

Amendment 04

18-Apr-2011

Administrative Letter 04

23-Oct-2009

Summary of Change Incorporates Amendment 04 and Administrative Letters 02, 03 and 04 This amendment was written to: • include the 2008 American College of Chest Physicians (ACCP) recommendations for treatment of VTE. • clarify when to discontinue the use of blinded enoxaparin/placebo. • clarify the duration of follow up for patients who discontinue study treatment early. • clarify the eligibility of subjects with a provoked index event • align the protocol with the eligibility checklist. • clarify the interpretation of various exclusion criteria. • clarify the quantity of warfarin bottles dispensed at randomization. • clarify the labeling of the enoxaparin/placebo syringes. • update the storage conditions of the study medication. • provide additional blinded INR monitoring instructions and clarify the timing of the first blinded INR test. • clarify the potential of unblinding a patient if an unblinded INR is obtained. • prohibit the use of dual antiplatelet therapy and/or aspirin greater than 165 mg while on study medication. • clarify treatment compliance. • include procedures for subjects who transition from AMPLIFY to AMPLIFY-EXT • clarify instructions and procedures for subjects who bridge from blinded study treatment to open-label warfarin. • include an outcome assessment during the follow-up visit. • clarify the definition of a major bleeding event. • establish minimum requirements for local laboratory tests used to qualify a subject for randomization. • clarify the Cockcroft and Gault equation. • clarify timing of dossier submissions. • clarify the purpose of outcomes research for this study. • update the SAE reporting requirements and contact information. • clarify the overdose reporting requirements. • update instructions regarding the return of investigational product. The revisions provided by this amendment do not significantly impact study conduct or data analysis. The amendment applies to all current and future subjects. Change in Serious Adverse Event (SAE) Submission process listed in Adverse Event section of the protocol.

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Document

Date of Issue

Summary of Change

Administrative Letter 03

06-Oct-2009

Change in Serious Adverse Event (SAE) Submission process listed in Adverse Event section of the protocol.

Administrative Letter 02

29-Jan-2009

Correct the number of bottles of warfarin dispensed to subjects at randomization from 2 bottles to 1 bottle.

Revised Protocol 01

21-Apr-2008

Incorporates Amendment 02

Amendment 02

21-Apr-2008

The primary reasons for this amendment are to: •

Clarify and provide additional detail in the secondary objectives and the analysis of the secondary objectives • Ensure appropriate clinical assessment of all randomized study subjects, even if study treatment was discontinued prior to the end of the planned treatment period • Provide instruction on obtaining an unblinded INR after study drug is completed or discontinued in order to prevent unblinding of study treatment • Clarify and include additional study statements or instructions in Table 6.1: Flow Chart/Time and Events Schedule • Provide more frequent hematology assessments as part of the safety assessment of participating subjects • Establish a consistent investigator process for reporting study outcomes • Expand and clarify the description and activities of the Independent Central Adjudication Committee and the adjudication process. Other changes include: • • • • •

Original Protocol

20-Feb-2008

Including Pfizer information on the cover page Providing a better approximation for the number of participating countries Clarifying statements made in Section 1: Introduction and Study Rationale Clarify wording regarding the use of aspirin and dual antiplatelet therapy in Section 5.5.1 Providing the Molecular Profiling Supplement as a separate document instead of integrating it into the protocol.

Not Applicable

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SYNOPSIS Clinical Protocol CV185056 Title of Study: Protocol CV185056: A Safety and Efficacy Trial Evaluating the Use of Apixaban in the Treatment of Symptomatic Deep Vein Thrombosis and Pulmonary Embolism Estimated Number of Study Centers and Countries/Regions: Approximately 300 - 400 centers in approximately 35 countries Study Phase: Phase 3 Research Hypothesis: Apixaban is not inferior to conventional therapy with enoxaparin and warfarin for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). Primary Objective: To determine if apixaban is non-inferior to standard enoxaparin/warfarin therapy in the combined endpoint of adjudicated recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or VTE-related death over 6 months of therapy. Secondary Objectives: •

To determine if apixaban is superior to standard enoxaparin/warfarin therapy in the combined endpoint of adjudicated recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or VTE-related death over 6 months of therapy



To determine if apixaban is superior to standard enoxaparin/warfarin therapy in the combined endpoint of adjudicated recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or all-cause death over 6 months of therapy



To characterize apixaban therapy relative to standard enoxaparin/warfarin therapy in the combined endpoint of adjudicated recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or cardiovascular (CV) death over 6 months of therapy



To characterize apixaban therapy relative to standard enoxaparin/warfarin therapy in the combined endpoint of adjudicated recurrent symptomatic VTE (nonfatal DVT or nonfatal PE), VTE-related death, or major bleeding over 6 months of therapy



To characterize apixaban therapy relative to standard enoxaparin/warfarin therapy in adjudicated major bleeding during 6 months of therapy



To characterize apixaban therapy relative to standard enoxaparin/warfarin therapy in the composite of adjudicated major bleeding and adjudicated clinically relevant non-major bleeding during 6 months of therapy



To characterize the primary efficacy outcome in the subset of subjects with index events of DVT only and in the subset of subjects with index events of PE with or without DVT.

Study Design: This is a randomized, active-controlled, parallel-group, double-blind, triple dummy study. Subjects with an objectively confirmed acute symptomatic proximal DVT or acute symptomatic PE are eligible for this study. Subjects will be stratified based on the type of disease treated (symptomatic proximal DVT or symptomatic PE) at baseline. If a subject has both symptomatic proximal DVT and symptomatic PE, the subject will be stratified as having symptomatic PE. Subjects with cancer who will be treated for 6 months or more with low molecular weight heparin therapy are ineligible for this study.

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Enrollment is projected to include approximately two-thirds DVT and one-third PE subjects, approximating clinical demographics for patients with VTE.1 The number of randomized subjects in each of the DVT and PE categories will be monitored through an interactive voice response system (IVRS) during the study. Depending on how the study progresses, a cap may be utilized to halt enrollment of subjects into one category while continuing enrollment into the other category, in order to ensure a DVT: PE ratio of approximately 2: 1 by the end of the study. Subjects will be randomized (1: 1 ratio) to Groups 1 or 2 using a central interactive voice response system (IVRS). Group 1

2

Treatment

Dose

Duration

Warfarin

Dosing to target INR range between 2.0 - 3.0

6 months

Enoxaparin

1 mg/kg SC Q12h until INR ≥ 2

≥ 5 days

Placebo (Apixaban)

10 mg BID for 7 days followed by 5 mg PO BID

6 months

Placebo (Warfarin)

Dosing to target SHAM INR range between 2.0 – 3.0.

6 months

Placebo (Enoxaparin)

SC Q12h until SHAM INR ≥ 2

≥ 5 days

Apixaban

10 mg BID for 7 days followed by 5 mg PO BID

6 months

Subjects in Group 1 will receive enoxaparin injections, warfarin tablets, and placebo apixaban tablets. Subjects in Group 2 will receive placebo enoxaparin injections, placebo warfarin tablets, and apixaban tablets. Enoxaparin and placebo enoxaparin will be administered for at least 5 days and will be discontinued after the blinded INR is ≥ 2, on one or more occasions. Apixaban, placebo apixaban, warfarin, and placebo warfarin tablets will be administered for 6 months. In order to minimize missing data, subjects who discontinue study drug early will continue to have their regularly scheduled follow-up visits throughout their originally intended treatment period (6 months after randomization) and 30 day follow up period. For subjects who have discontinued study treatment, query of health status (alive, occurrence of efficacy and safety endpoints and AEs/SAEs) by telephone is allowed. Subjects who have new symptoms should undergo further assessment as clinically appropriate, preferably at the study site whenever feasible. This study will utilize a blinded INR monitoring routine. The blinded routine will consist of a point of care INR device that will generate an encrypted code. This code will be reported to a centralized IVRS by the investigator. The IVRS will decrypt the code and report back to the investigator either the actual INR result from subjects randomized to warfarin or a sham INR result from subjects randomized to placebo warfarin. Sham INRs will be based on a predefined computerized algorithm. Dose adjustments will be at the discretion of the investigator. Blinded INR testing frequency will occur approximately every month during the treatment period, and more frequently during titration and when clinically indicated. Subjects randomized to warfarin or placebo warfarin will be titrated to a target blinded INR range between 2 and 3. Study visits will be scheduled at 2, 4, 8, 12, 16, 20 and 24 weeks.

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All subjects will have an additional 30-day observation period after cessation of study treatment. The ICAC will adjudicate all index events (proximal DVT and/or PE). During the study period and the post-treatment observation period, the ICAC will adjudicate all suspected occurrences/recurrences of venous or arterial thromboembolic events, deaths, and the following events of special interest: acute myocardial infarction, acute stroke, and thrombocytopenia. The ICAC will also review all suspected episodes of bleeding, and categorize adjudicated bleeding as major, clinically relevant non-major, or minor bleeding. Adjudication results will be the basis for the final analyses. Adjudication is intended to provide a consistent process for assessing data quality and interpreting study data. Adjudicated outcomes should not be relied upon for subject safety, study treatment decisions, or clinical care. Therefore, adjudication outcomes will not be shared with investigators for subject diagnosis or treatment. A 24-hour emergency telephone service will be provided for sites to call throughout the study. An independent data monitoring committee (DMC) will monitor the subjects’ safety during the study and give recommendations to the steering committee. No interim analysis of efficacy is planned. Ongoing review of the safety of all investigational treatments will be the mandate of the DMC. Subject to IRB/EC approval/favorable opinion, this study will include an additional research component involving collection of biological samples for de-identified exploratory ‘omics analysis. The Molecular Profiling Supplement to this protocol provides a description of this additional research. Subjects may participate in this drug study even if they choose not to participate in the sample banking component. Duration of Study: For all subjects, the study treatment duration will be 6 months followed by a 30-day observation period. Number of Subjects per Group: Approximately 2408 Study Population: Men and women, ages 18 years or greater with: a)

Subjects whose index event was either unprovoked OR provoked with a risk for recurrence as described in the eligibility checklist. b) Acute symptomatic proximal DVT with evidence of proximal thrombosis that involves at least the popliteal vein or a more proximal vein, demonstrated by imaging with: − compression ultrasound (CUS), including grey-scale or color-coded Doppler, or − ascending contrast venography. Or Acute symptomatic PE with evidence of thrombosis demonstrated by imaging as follows: − an intraluminal filling defect in segmental or more proximal branches on spiral CT scan; or − an intraluminal filling defect or a sudden cutoff of vessels more than 2.5 mm in diameter on the pulmonary angiogram; or − a perfusion defect of at least 75% of a segment with a local normal ventilation result (high-probability) on ventilation/perfusion lung scan (VPLS). Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational Product(s): See table above in Study Design section. Study Assessments and Primary Endpoints: The primary efficacy outcome is the incidence of an adjudicated composite of recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or VTE-related death during 6 months of therapy. The primary safety outcome is the incidence of an adjudicated major bleeding.

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Statistical Methods: Sample size The sample size was computed for a non-inferiority margin of 1.8. The rationale for the margin is detailed 2 in the Statistical Analysis Plan (SAP). Using the method of Farrington Manning with the assumption that 3% of subjects in the enoxaparin/warfarin group have VTE/VTE related death over 6 months of therapy, a sample size of 4094 subjects will have 90% power for a one-sided α = 0.025 non-inferiority test. A sample size of 4094 is large enough to adequately power the study for the primary intent-to-treat assessment. However, a second analysis based on a per-protocol data set needs to have adequate power for this non-inferiority study. Therefore the sample size will be adjusted to 4816 (2408 per group) to account for ~15% of subjects discontinuing treatment early and continuing to complete all scheduled treatment visits up to 6 months after randomization. A review of the blinded aggregate rate for the primary efficacy endpoint will be provided to the Steering Committee after 80% of subjects have been randomized. The sample size may be adjusted to provide sufficient power for the non-inferiority test on the primary efficacy endpoint based on both the intent-to-treat and the per-protocol data sets. This blinded review will be performed by an independent statistician. The maximum sample size will be 5400 subjects. Efficacy Analysis The primary objective is to determine whether apixaban is non-inferior to enoxaparin/warfarin for the primary efficacy endpoint (incidence of recurrent VTE and VTE-related death during 6 months of therapy). To conclude non-inferiority for the primary efficacy endpoint, it is necessary to demonstrate that the apixaban event rate is not materially higher than the enoxaparin/warfarin event rate, as measured by both the relative risk (pa/pe) and the risk difference (pa - pe), where pa and pe represent the proportions of subjects with primary efficacy outcomes in the apixaban and enoxaparin/warfarin groups, respectively. Non-inferiority will be concluded if both the following conditions are satisfied; •

The upper bound of the 95% CI for the relative risk must not exceed a non-inferiority margin (NIRR) of 1.8. This condition corresponds to a test of the hypothesis H0RR: pa/pe ≥ 1.8 vs. HaRR: pa/pe < 1.8, performed at the one-sided α = 0.025 level. The hypothesis test will be performed using the Yanagawa, Tango and Hiejima (YTH) relative risk method. Descriptive statistics will include an estimate for the relative risk and 95% CI computed based using Mantel-Haenszel’s method stratified by index event.



The upper bound of the 95% CI for the risk difference must not exceed a non-inferiority margin (NI∆) of 0.035. This corresponds to a test of the hypothesis H0∆: pa - pe ≥ 0.035 against Ha∆: pa - pe < 0.035, performed at the one-sided α = 0.025 level. The hypothesis test will be performed using YTH’s risk difference method. Descriptive statistics will include an estimate for risk difference and 95% CI computed using the inverse variance method.5

The non-inferiority margin for relative risk (NIRR = 1.8) was the minimum value that clinical experts, investigators and Health Authorities thought was clinically meaningful and is less than a margin that would preserve 50% of the treatment effect. The non-inferiority margin for risk difference (NI∆ = 0.035) protects against higher than expected event rates in the control group. Formal justification for these margins is detailed in the SAP. With a 1% to 4% event rate in the enoxaparin/warfarin group, the relative risk margin of 1.8 corresponds to an absolute difference margin of 0.8% to 3.2% which is smaller than the 3.5% absolute difference margin

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in the second criterion. In this case, the first criterion is more stringent than the second criterion and would determine whether non-inferiority has been demonstrated. However, if the event rate in the enoxaparin/warfarin group was higher than expected (eg, 4.5% or more) then the relative risk margin of 1.8 would correspond to an absolute difference margin of at least 3.6% and the second criterion will determine whether non-inferiority has been demonstrated. Analyses of the primary efficacy endpoint will be performed using both the primary efficacy data set using the intent-to treat principle and the per protocol data set. The intent-to-treat analysis of the primary endpoint will include endpoints that occur at any time from randomization until the end of their originally intended treatment period regardless of whether subjects are receiving study medication. For the secondary efficacy endpoints, analyses will be performed using the primary efficacy data set. Sensitivity analyses will be performed to assess robustness of the results of the primary efficacy analysis to missing data. This sensitivity analyses will repeat the primary analysis by varying a hypothetical event rate in the missing data. The sensitivity analysis will explore a range of assumptions including following: •

0% of subjects with missing data on the apixaban and enoxaparin/warfarin treatment groups would achieve the endpoint



100% of subjects with missing data on the apixaban and enoxaparin/warfarin treatment groups would achieve the endpoint



100% of subjects with missing data on apixaban and 0% of subjects on enoxaparin/warfarin would achieve the endpoint



0% of subjects with missing data on apixaban and 100% of subjects on enoxaparin/warfarin would achieve the endpoint

In addition to the extreme cases bulleted above, other scenarios will be explored. These less extreme scenarios will be detailed in the SAP. Key secondary efficacy analyses are the testing of superiority of apixaban over enoxaparin/ warfarin for two composite endpoints: 1) incidence of VTE/VTE-related death, and 2) incidence of VTE/all-cause death. For each of these endpoints, a superiority test will be conducted. Superiority will be tested using the Mantel-Haenszel test stratified by index event using the primary efficacy data set. The hypotheses for superiority are H0: pa = pe tested against the alternative Ha: pa < pe where pa and pe represent the proportions of subjects with the endpoint being tested. To control the overall probability of type I error, the following testing procedure will be used. The hypotheses associated with the non-inferiority and the superiority of apixaban relative to enoxaparin and warfarin therapy (as described above) for a 6 month treatment duration, will be tested at the one-sided α = 0.025 following a hierarchical structure: •

if non-inferiority of apixaban relative to control treatment group with respect to the primary efficacy endpoint (composite of recurrent VTE and VTE-related death) ○ is not demonstrated, then stop ○ is demonstrated, then superiority of apixaban relative to control treatment group for the primary efficacy endpoint (composite of recurrent VTE and VTE-related death) will be tested.



if superiority of apixaban relative to control treatment group with respect to the primary efficacy endpoint (composite of recurrent VTE and VTE-related death) ○ is not demonstrated, then stop ○ is demonstrated, then superiority of apixaban relative to control treatment group for the key secondary efficacy endpoint (composite of recurrent VTE and all- cause death) will be tested. The

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test of this endpoint is intended for regulatory labeling claims of superiority of apixaban over enoxaparin/warfarin. Additional supportive endpoints to be analyzed are incidence of: •

an adjudicated composite of recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) and cardiovascular (CV) death



an adjudicated composite of recurrent symptomatic VTE (nonfatal DVT or nonfatal PE), VTE-related death and major bleeding



an adjudicated nonfatal symptomatic DVT



an adjudicated nonfatal symptomatic PE



an adjudicated VTE-related death



an adjudicated CV death



all-cause death.

The analysis will use methodology described for the analyses of the key secondary endpoints. The procedure to control the Type I error across additional potential regulatory claims associated with other secondary objectives will be documented in the statistical analysis plan. All efficacy analyses will be performed on efficacy outcomes confirmed by adjudication. Point and interval estimates of the incidence rates of the primary and secondary efficacy endpoints (Section 8.3) will be calculated and reported. Relative risk of apixaban versus enoxaparin/warfarin (ratio of proportions) will be reported for the adjudicated primary efficacy composite endpoint, and key secondary endpoints as identified in the SAP.

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TABLE OF CONTENTS

TITLE PAGE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 DOCUMENT HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 SYNOPSIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 TABLE OF CONTENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 1 INTRODUCTION AND STUDY RATIONALE . . . . . . . . . . . 16 1.1 Research Hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . 16 1.2 Investigational Product Development Rationale . . . . . . 16 1.3 Summary of Results of Investigational Program . . . . . 18 1.4 Study Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 1.4.1 Rationale for Study Population . . . . . . . . . . . . . . . . . . . . . . 19 1.4.2 Rationale for Treatment Duration . . . . . . . . . . . . . . . . . . . . 20 1.4.3 Rationale for Apixaban Dose Selection . . . . . . . . . . . . . . . 21

1.5 Overall Risk/Benefit Assessment . . . . . . . . . . . . . . . . . 23 1.5.1 Summary Risk/Benefit Assessment . . . . . . . . . . . . . . . . . . 26

2 STUDY OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 2.1 Primary Objective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 2.2 Secondary Objectives. . . . . . . . . . . . . . . . . . . . . . . . . . 27 3 ETHICAL CONSIDERATIONS . . . . . . . . . . . . . . . . . . . . . . 28 3.1 Good Clinical Practice . . . . . . . . . . . . . . . . . . . . . . . . . 28 3.2 Institutional Review Board/Independent Ethics Committee . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 Revised Protocol No.: 02 Date: 18-Apr-2011 Approved v 5.0

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3.3 Informed Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 4 INVESTIGATIONAL PLAN . . . . . . . . . . . . . . . . . . . . . . . . . 29 4.1 Study Design and Duration. . . . . . . . . . . . . . . . . . . . . . 29 4.1.1 Duration of Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 4.1.2 Steering Committee . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 4.1.3 Independent Central Adjudication Committee . . . . . . . . . . 32 4.1.4 Independent Data Monitoring Committee . . . . . . . . . . . . . . 33

4.2 Study Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 4.2.1 Inclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 4.2.2 Exclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 4.2.3 Discontinuation of Subjects from Treatment . . . . . . . . . . . . 38

5 TREATMENTS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 5.1 Study Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 5.1.1 Investigational Product . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 5.1.2 Noninvestigational Product . . . . . . . . . . . . . . . . . . . . . . . . . 39 5.1.3 Identification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 5.1.4 Packaging and Labeling . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 5.1.5 Handling and Dispensing . . . . . . . . . . . . . . . . . . . . . . . . . . 42

5.2 Method of Assigning Subjects to a Treatment . . . . . . . 42 5.3 Selection and Timing of Dose for Each Subject . . . . . . 43 5.4 Blinding/Unblinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 5.4.1 Invasive Procedures and Surgery. . . . . . . . . . . . . . . . . . . . 49 5.4.1.1 Elective Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . 49 5.4.1.2 Emergency Procedures . . . . . . . . . . . . . . . . . . . . . . . 51

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5.4.1.3 Bridging Strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 5.4.2 Post Treatment Bridging Strategy to Warfarin . . . . . . . . . . 55

5.5 Concomitant Treatments . . . . . . . . . . . . . . . . . . . . . . . 56 5.5.1 Prohibited and/or Restricted Treatments . . . . . . . . . . . . . . 56 5.5.2 Other Restrictions and Precautions . . . . . . . . . . . . . . . . . . 57

5.6 Treatment Compliance . . . . . . . . . . . . . . . . . . . . . . . . . 57 5.7 Transitioning from CV185056 to CV185057 . . . . . . . . . 58 5.7.1 Reporting AEs and SAEs during CV185056 and CV185057 Overlap . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 5.7.2 Blinded INRs For Subjects Transitioning from CV185056 (AMPLIFY) to CV185057 (AMPLIFY-EXT) . . . . . . . . . . . . . . . 60

6 STUDY ASSESSMENTS AND PROCEDURES . . . . . . . . . 61 6.1 Flow Chart/Time and Events Schedule . . . . . . . . . . . . 61 6.1.1 Visit Windows . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 6.1.2 Screening Visit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 6.1.3 Day 1 (Baseline) Visit (which may coincide with screening) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 6.1.4 Weeks 2, 4, 8, 12, 16, 20 Visits . . . . . . . . . . . . . . . . . . . . . 66 6.1.5 End of Treatment (Week 24). . . . . . . . . . . . . . . . . . . . . . . . 66 6.1.6 Follow-up Period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

6.2 Study Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 6.3 Safety Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 6.3.1 Bleeding Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 6.3.1.1 Treatment Guidelines for Bleeding/Suspected Bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 6.3.2 Laboratory Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . 71 Revised Protocol No.: 02 Date: 18-Apr-2011 Approved v 5.0

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6.3.2.1 Pregnancy Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 6.3.2.2 Creatinine Clearance . . . . . . . . . . . . . . . . . . . . . . . . . 74 6.3.2.3 Treatment Guidelines for Jaundice and Elevated LFTs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 6.3.3 Vital Signs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 6.3.4 Electrocardiograms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 6.3.5 Physical Examinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 6.3.6 Physical Measurements . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 6.3.7 Concomitant Medications . . . . . . . . . . . . . . . . . . . . . . . . . . 77 6.3.8 Blinded INR Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

6.4 Efficacy Assessments. . . . . . . . . . . . . . . . . . . . . . . . . . 78 6.4.1 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 6.4.2 Subject Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

6.5 Pharmacokinetic Assessments. . . . . . . . . . . . . . . . . . . 80 6.6 Pharmacodynamics Assessments . . . . . . . . . . . . . . . . 81 6.7 Pharmacogenomics/Pharmacogenetics Assessments. 82 6.8 Outcomes Research Assessments . . . . . . . . . . . . . . . 82 6.9 Other Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 6.9.1 Events of Special Interest . . . . . . . . . . . . . . . . . . . . . . . . . . 83

7 ADVERSE EVENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 7.1 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 7.1.1 Serious Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 7.1.2 Nonserious Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . 86

7.2 Assignment of Adverse Event Intensity and Relationship to Investigational Product . . . . . . . . . . . . . 87 Revised Protocol No.: 02 Date: 18-Apr-2011 Approved v 5.0

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7.3 Collection and Reporting . . . . . . . . . . . . . . . . . . . . . . . 87 7.3.1 Serious Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 7.3.2 Handling of Expedited Safety Reports . . . . . . . . . . . . . . . . 89 7.3.3 Nonserious Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . 91

7.4 Laboratory Test Abnormalities . . . . . . . . . . . . . . . . . . . 91 7.5 Overdose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 7.6 Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 7.6.1 Requirements for Pregnancy Testing . . . . . . . . . . . . . . . . . 92 7.6.2 Reporting of Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

7.7 Other Safety Considerations . . . . . . . . . . . . . . . . . . . . 94 8 STATISTICAL CONSIDERATIONS. . . . . . . . . . . . . . . . . . . 94 8.1 Sample Size Determination . . . . . . . . . . . . . . . . . . . . . 94 8.2 Populations for Analyses . . . . . . . . . . . . . . . . . . . . . . . 95 8.3 Endpoint Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 8.4 Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 8.4.1 Demographics and Baseline Characteristics . . . . . . . . . . . 96 8.4.2 Safety Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 8.4.3 Efficacy Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 8.4.4 Pharmacokinetic Analyses . . . . . . . . . . . . . . . . . . . . . . . . . 101 8.4.5 Pharmacodynamic Analyses. . . . . . . . . . . . . . . . . . . . . . . . 102 8.4.6 Pharmacogenomic Analyses . . . . . . . . . . . . . . . . . . . . . . . 102 8.4.7 Outcomes Research Analyses . . . . . . . . . . . . . . . . . . . . . . 102 8.4.8 Other Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

8.5 Interim Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 Revised Protocol No.: 02 Date: 18-Apr-2011 Approved v 5.0

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9 ADMINISTRATIVE SECTION . . . . . . . . . . . . . . . . . . . . . . . 103 9.1 Compliance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 9.1.1 Compliance with the Protocol and Protocol Revisions . . . . 103 9.1.2 Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 9.1.3 Investigational Site Training . . . . . . . . . . . . . . . . . . . . . . . . 104

9.2 Records Retention . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 9.2.1 Case Report Forms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 9.2.2 Investigational Product Records . . . . . . . . . . . . . . . . . . . . . 106

9.3 Return and Destruction of Investigational Product . . . . 107 9.3.1 Return of Investigational Product . . . . . . . . . . . . . . . . . . . . 107 9.3.2 Destruction of Investigational Product . . . . . . . . . . . . . . . . 107

9.4 Publications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 10 GLOSSARY OF TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . 109 11 LIST OF ABBREVIATIONS . . . . . . . . . . . . . . . . . . . . . . . . 111 12 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 APPENDIX 1 ADDITIONAL ETHICAL CONSIDERATIONS. . 116 APPENDIX 2 US COUMADIN PACKAGE INSERT . . . . . . . . 121 APPENDIX 3 WARFARIN DOSING GUIDELINES. . . . . . . . . 155 APPENDIX 4 DOSE-RESPONSE MODELING . . . . . . . . . . . 179 APPENDIX 5 MAINTENANCE WARFARIN DOSE IN SUBJECTS WITH VENOUS THROMBOEMBOLISM . . . . 185

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1

INTRODUCTION AND STUDY RATIONALE

1.1

Research Hypothesis

Apixaban is not inferior to conventional therapy with enoxaparin and warfarin for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE).

1.2

Investigational Product Development Rationale

Apixaban is a novel, selective, orally active inhibitor of coagulation factor X [FXa] that is being co-developed by Bristol-Myers Squibb (BMS) and Pfizer as an anticoagulant and antithrombotic agent. Apixaban (also referred to as BMS-562247), is a reversible and highly potent inhibitor of human FXa, with an inhibitor constant (Ki) of 0.08 ± 0.01 nM, and a high degree of selectivity over other coagulation proteases and structurally related enzymes involved in digestion and fibrinolysis. FXa occupies a pivotal role in the clotting cascade, converting prothrombin to thrombin (FIIa). Thrombin has multiple functions, converting fibrinogen to fibrin, promoting fibrin cross-linking by activating factor XIII, providing positive feedback activation of coagulation by activating factors V, VIII, and XI, activating the protein C anticoagulant pathway, and activating thrombin-activatable fibrinolysis inhibitor (TAFI) to protect the clot from premature degradation (Figure 1.2). Thrombin is also a powerful platelet agonist, activating platelets and recruiting additional platelets into the platelet-rich thrombus. FXa inhibition decreases conversion of prothrombin to active thrombin, thereby diminishing fibrin formation, and reducing coagulation and platelet activation. Unlike unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and fondaparinux, each of which acts through an antithrombin (AT)-mediated mechanism, apixaban directly inhibits FXa. Compared with UFH, LMWHs (including enoxaparin) have relatively more effect on inhibiting FXa than FIIa, while the pentasaccharide, fondaparinux, selectively inhibits FXa.

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Figure 1.2:

The hemostatic pathway and site of action of inhibitors of activated factor X (FXa). FXa occupies a central position in the pathway, converting prothrombin (FII) to thrombin (FIIa). Thrombin then converts fibrinogen to fibrin.

Tissue Factor Pathway

Contact Pathway FXII

FXIIa

FX

FIX TF/FVIIa

FXIa

FXI

FIXa FVIII

+

FVIIIa

FVa/FXa

FV

Xa inhibitors

APC

FII FIIa Fibrin

Fibrinogen

XIIIa

XIII

TAFI

Venous thromboembolism is a common clinical problem, with an overall incidence of about 0.1%. The incidence rises steeply with advancing age, approaching 1% of those in 1

the seventh decade of life. Nearly half of these episodes involve DVT with the attendant 2

risks of PE, recurrent thromboembolic disease, and the post-thrombotic syndrome. A recent meta-analysis of the prevalence of major coronary artery disease risk factors in VTE subjects and control subjects has suggested that the following coronary artery disease risk factors may be present more often in subjects having venous

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thromboembolism:

cigarette

hypertension, obesity.

smoking,

diabetes

mellitus,

hypercholesterolemia,

6

The present standard of care for treatment of DVT is a 2-stage process. The first involves initiation of treatment parenterally with UFH, LMWH or the pentasaccharide 7,8,9,10,11,12,13

fondaparinux.

The second stage, usually begun at the same time as the first,

is the initiation of oral dosing with a vitamin K antagonist (VKA). Treatment with UFH or LMWH is continued until therapeutic anticoagulation is achieved with the VKA, as evidenced by an INR between 2.0 and 3.0. At this point parenteral therapy is discontinued and oral therapy with the VKA is continued for a duration that depends upon the clinical setting.

1.3

3,14,15,16,17,18

Summary of Results of Investigational Program

Apixaban has been evaluated in a wide variety of preclinical models; these findings are detailed in the Investigator Brochure. Extensive Phase 1 testing revealed apixaban to have dose-proportional exposure up to 10 mg with a bioavailability of approximately 50% and a small volume of distribution (16 to 25 L). Food does not affect apixaban absorption and changes in pH are not likely to have an effect given its physicochemical properties. Apixaban has a half-life of approximately 12 hours. Apixaban is converted to several metabolites; the major circulating metabolite is an inactive phenol sulfate conjugate (M1). Cytochrome P450 3A4 is the primary oxidative enzyme involved in the metabolism of apixaban. Apixaban has multiple elimination pathways, with about 25% renal and 75% non-renal. Drug-drug interaction studies have been conducted in healthy volunteers. Inhibitors of CYP3A4, ketoconazole and diltiazem, increase apixaban exposure by 2 and 1.4-fold, respectively. Rifampin, an inducer of CYP3A4, decreases apixaban exposure by about 50%. Apixaban does not have an effect on the PK of digoxin. Apixaban does not prolong QTc in healthy volunteers. Apixaban's pharmacodynamic effects have been demonstrated by dose-dependent increases in traditional markers of coagulation, such as international normalized ratio (INR) and activated partial thromboplastin time (aPTT), as well as changes in exploratory

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measurements of FXa inhibition such as modified prothrombin time (mPT) and anti-Xa activity. The usefulness of the routine clotting time tests INR and aPTT for measuring apixaban activity is limited by their relative insensitivity and poor inter-method reproducibility. The mPT clotting time test and the chromogenic anti-Xa assay better reflect the plasma concentration of apixaban. BMS has completed a Phase 2 VTE prevention study (CV185010) in subjects undergoing total knee replacement surgery and a Phase 2 DVT treatment study (CV185017). The study design and outcomes are discussed in Section 1.5 (Clinical Phase 1 and 2 Safety). See Investigator Brochure for more detailed information.

1.4

Study Rationale

1.4.1

Rationale for Study Population

This study was designed at the time of the 2004 American College of Chest Physicians (ACCP) recommendations for treatment

19

of DVT or PE. The guidelines classified the

clinical population into 5 different sub-groups with regard to various risk-factors and recommended durations of anticoagulant treatment. These recommendations include: 1. Patients with a first episode of DVT or PE secondary to a transient (reversible) risk factor (ie, provoked event, eg, secondary to surgery) - Treatment should include an oral VKA for 3 months. This applies to patients with proximal vein thrombosis and patients with symptomatic DVT confined to the calf veins. 2. Patients with a first episode of proximal DVT or PE and concurrent cancer - Treatment with an LMWH for 3 to 6 months is recommended, and the patient should be considered for indefinite anticoagulant therapy or until the cancer is resolved. 3. Patients with a first episode of idiopathic proximal DVT or PE (ie, unprovoked event) - Treatment with a VKA for at least 6-12 months is recommended, and the patient should be considered for indefinite anticoagulant therapy.

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4. Patients with a first-episode of proximal DVT and a documented pro-thrombotic genotype or a prognostic marker of an increased risk of recurrent thromboembolism (this subgroup includes patients with a deficiency of antithrombin III, protein C, or protein S; or those with a factor V Leiden or prothrombin 20210 gene mutation); or those with homocysteinemia or elevated Factor VIII levels – anticoagulant therapy for 6 to 12 months is recommended; for those with documented anti-phospholipid antibodies or ≥ 2 of the above mentioned thrombophilic conditions, 12 months of anti-coagulant treatment is recommended. Consideration for indefinite anticoagulant therapy is suggested for all with idiopathic thrombosis. 5. Patients with two or more episodes of objectively documented proximal DVT or PE - indefinite anti-coagulant treatment is recommended. The 2008 ACCP guidelines27 have since been published and remain consistent with the 2004 ACCP guidelines. For unprovoked events in patients with certain risk factors and medical conditions, such as cancer, an idiopathic event, presence of pro-thrombotic genotype, or presence of a marker indicative of an increased risk of recurrent thromboembolism treatment for 6 months or longer is supported by the current guidelines. In addition, clinicians sometimes treat patients with a transient risk factor for 6 - 12 months, or longer, when there is an ongoing predisposition for thrombosis (eg, persistent immobility). This study will provide data from a population consisting of subjects with DVT or PE who are similar to those described in the guidelines and treated as per usual and customary care.

1.4.2

Rationale for Treatment Duration

The currently accepted standard for the treatment and secondary prevention of DVT or PE is initial treatment with an intravenous infusion of unfractionated heparin (UFH) or subcutaneous administration of LMWH or fondaparinux combined with an oral VKA 20

such as warfarin.

The parenteral anticoagulant is continued until the oral VKA causes

an increase in INR to ≥ 2.0, with follow-up VKA therapy adjusted to maintain a target INR of 2.0 - 3.0. The duration of parenteral and VKA anticoagulant therapy varies in accordance with the therapeutic objectives for anticoagulation therapy in the management 21

of VTE,

summarized as follows:

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Initial (acute) treatment (5 to 14 days) – usually with a parenteral agent UFH or LMWH, the intent is to rapidly abrogate thrombin generation, prevent thrombus extension, and “bridge” to oral long-term anticoagulation. Chronic treatment [secondary prevention] (3 to 6 months) – usually with an oral VKA (INR 2.0 – 3.0) or LMWH administered subcutaneously; the intent is to stabilize the thrombus, prevent early recurrence, and allow time for endogenous fibrinolysis-mediated recanalization. Based on the above therapeutic objectives, the study treatment duration in recently completed clinical trials of new anticoagulants for VTE treatment and prevention have 7, 8, 9, 10, 11, 12, 13

ranged from 5 – 14 days for acute treatment secondary prevention.

and 3 - 6 months for

3, 14, 15, 16

Currently ongoing Phase 3 clinical trials of new anticoagulants for VTE treatment and prevention posted in ClinicalTrials.gov website also employ similar treatment duration. The 6-month treatment duration for this study is within the range of study treatment durations used in the majority of recently completed clinical trials of new anticoagulants for VTE treatment and prevention.

1.4.3

Rationale for Apixaban Dose Selection

In this study, an apixaban dose of 10 mg BID for initial 7-day treatment, followed by 5 mg BID for 6 months, is used. This dose regimen is supported by clinical experience with apixaban in a DVT population, empiric observations on the use of other anticoagulants, and dose-response modeling. In a 3-month Phase 2 study in DVT treatment (CV185017), 520 patients were randomized to blinded apixaban doses of 5 mg BID, 10 mg BID, and 20 mg QD or open-label LMWH or fondaparinux + VKA. The efficacy endpoint was a composite of symptomatic recurrent VTE and deterioration of the thrombotic burden, as assessed by baseline and Week 12 imaging studies. Bleeding was the primary safety endpoint, and the composite of major and clinically relevant non-major (CRNM) bleeding was assessed.

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Rates of primary efficacy and safety endpoints were low and comparable across the apixaban arms and the comparator. The efficacy endpoint rates were 6.0, 5.6, 2.6 and 4.2% for apixaban 5 mg BID, 10 mg BID, 20 mg QD and the comparator, respectively. The corresponding rates for major/CRNM bleeding were 8.6, 4.5, 7.3 and 7.9%. In a 6-month dose-ranging study of acute coronary syndrome (CV185023), apixaban doses of 20 mg QD and 10 mg BID were discontinued due to excess bleeding with the triple-treatment combination of apixaban + clopidogrel + aspirin when compared to placebo + clopidogrel + aspirin. Excess minor bleeding, but not major or clinically relevant non-major bleeding, was observed with apixaban 10 mg BID + clopidogrel + aspirin when compared to placebo + clopidogrel + aspirin. Apixaban 10 mg BID is anticipated to be safe in the current study, however, for several reasons: (1) In a separate, completed dose-ranging study of DVT (CV185017), apixaban 10 mg BID was very well tolerated for 3 months when administered without concomitant clopidogrel + aspirin. (2) There was no excess bleeding when apixaban was compared to the active control of low molecular weight heparin + vitamin K antagonist in that study. (3) In the current study, apixaban 10 mg BID will be administered for only 7 days. (4) Concomitant treatment with clopidogrel + aspirin is not allowed at the time of randomization in the current study. Thus, apixaban 10 mg BID remains appropriate and expected to be safe as acute (7 day) treatment for DVT or PE. Doses of parenteral anticoagulants (eg, enoxaparin, fondaparinux, dalteparin and tinzaparin) approved for initial VTE treatment are ~2 - 4 times higher than those approved for VTE prevention. An initial apixaban dose of 10 mg BID for 7 days and a subsequent dose of 5 mg BID are 4 and 2 times higher, respectively, than the dose being evaluated for VTE prevention, and thus consistent with dosing of other anticoagulants for VTE treatment. In addition, because the approved dosing of VKA for treatment of VTE (ie adjusted to achieve an INR of 2 - 3) is the same as that for prevention of stroke in AF, an apixaban dose of 5 mg BID during the chronic treatment period is expected to provide comparable efficacy and safety for both indications. Further support for the selection of an apixaban dose of 10 mg BID for 7 days followed by 5 mg BID comes from the results of dose-response modeling that is summarized in Appendix 4.

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Overall Risk/Benefit Assessment

Pre-clinical Safety: Apixaban was well tolerated when administered orally to rats (up to 600 mg/kg/day for 6 months) and to dogs (up to 100 mg/kg/day for 12 months). The animal to human exposure multiple (AUC) at the no observed adverse effect level (NOAEL) for these studies corresponds to 17x and 59x in rats and dogs, respectively, relative to a clinical dose of 5 mg BID. No significant toxicology findings were noted in animals during exposure, or in those subsequently euthanized for histopathologic examination. Apixaban had no adverse fetal effects when given orally to rats (100 to 3000 mg/kg/day) or intravenously to rabbits (1.25 to 5 mg/kg/day). Fetal exposures were confirmed. Maternal toxicity (red perivaginal substance and mucoid feces) was noted in rats but not rabbits. Animal-to-human exposure multiples at the fetal NOAEL were 35x and 3.1x for rats and rabbits, respectively, relative to a clinical dose of 5 mg BID. Although post-implantation loss was slightly increased in pregnant mice given the highest dose of apixaban tested in an oral range finding study (1500 mg/kg/day; 16x human exposure at 5 mg BID), post-implantation loss was not increased in the follow-up definitive study (preliminary data) indicating the previously noted increase was not due to apixaban. Clinical (Phase 1 and 2) Safety: In Phase 1 studies completed as of December 2007, there have been no serious adverse events (SAEs) or major bleeding events; most bleeding-related events were considered mild to moderate in intensity by the Investigator and required little (eg, application of a compress) or no treatment. There were relatively few reports of adjudicated major bleeding events in the Phase 2 DVT prevention study (CV185010). Major bleeding occurred at a low rate in the apixaban arms (0 - 3.3%) and at a rate of 2.6% in the 5 mg BID dosing arm. No major bleeding events were noted in the enoxaparin or warfarin arms. In similar published studies, major bleeding events occur in 1 - 2% of enoxaparin treated patients and < 1% of warfarin treated patients. Total bleeding occurred at a rate of 6.5% in the 5 mg BID

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dosing arm of apixaban, compared with 5.4% in the enoxaparin arm and 5.3% in the warfarin arm. The overall frequencies of adverse events (AEs), serious AEs, deaths, and discontinuation for adverse events were similar across treatment groups in this study (Table 1.5). For AEs other than those related to bleeding, there was no dose-response in the apixaban-treated groups and there were no notable differences from enoxaparin- or warfarin-treated groups. The frequency of liver enzyme elevations was low for all apixaban-treated groups and less than the rate for the enoxaparin-treated group.

Table 1.5:

Summary of Adverse Events in Phase 2 VTE Prevention Study (CV185010) Apixaban Enox

Warf

2.5 mg BID

5 mg QD

5 mg BID

10 mg QD

10 mg BID

20 mg QD

AEs (%)

87.0

85.4

86.3

88.4

86.3

88.1

86.6

88.7

SAEs (%)

7.8

13.2

5.9

9.0

7.8

8.6

6.7

6.0

Deaths (%)

1.3

0

0

0

0

0.7

0

0

D/C due to AEs (%)

5.8

3.3

3.9

4.5

5.2

5.3

2.7

2.6

Liver function testing in the CV185010 trial revealed an incidence of ALT > 3x ULN in 0.9% of apixaban-treated subjects compared with 3.1% of enoxaparin-treated subjects and 0.8% of warfarin-treated subjects. A Phase 2 DVT treatment trial (CV185017) was conducted primarily to assess longer-term safety (study treatment was continued for 12 weeks) and to determine the optimal dose and regimen of apixaban for use in Phase 3. The CV185017 study evaluated 3 doses of apixaban (5 mg BID, 10 mg BID and 20 mg QD) versus standard treatment (LMWH/fondaparinux followed by VKA) over a period of 12 weeks in subjects presenting with acute symptomatic DVT. The efficacy end point was the composite of symptomatic recurrent VTE (recurrent DVT or fatal or nonfatal PE) and deterioration of the thrombotic burden as assessed by repeat bilateral compression ultrasound and perfusion lung scan. The safety end point was the composite of major bleeding and

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clinically relevant non-major bleeding. The study randomized 520 patients with acute symptomatic DVT. Rates of recurrent clinical DVT or PE were low and comparable across apixaban treatment arms and comparator. The primary efficacy outcome rates for apixaban 5 mg BID, 10 mg BID, 20 mg QD, and standard treatment were 6.0%, 5.6%, 2.6%, and 4.2%, respectively; the rates of symptomatic VTE were 2.6%, 3.2%, 1.7%, and 2.5%, respectively. The principal safety outcome (composite of major and clinically relevant non-major bleeding) rates were 8.6%, 4.5%, 7.3%, and 7.9%, respectively, and the major bleeding rates were 0.8%, 0%, 0.8%, and 0%, respectively. The number of subjects with AEs, SAEs, and drug-related AEs in Study CV185017 appeared to be comparable between the apixaban and comparator treatment arms. There appeared to be no obvious dose-dependent increases in event rates for either AEs or SAEs. The number of adverse events leading to discontinuation of study therapy was low and comparable between all treatment arms. Bleeding-related AEs were comparable across the apixaban arms and comparable to or lower than for comparator. There were no cerebrovascular accidents (CVA). Eight deaths were reported in the Study CV185017. All deaths occurred in apixaban treated subjects; except for 1 death (a suicide), the remaining 7 death occurred after discontinuation of study drug (11 to 87 days after last dose with apixaban). All deaths occurred in subjects who had cancer (4 diagnosed prior to randomization), and the adjudication committee considered cancer to be the cause of death in 6 of the subjects. In one subject with cancer who died after sepsis and shock, the Adjudication Committee could not exclude PE as the cause of death (death occurred 11 days following discontinuation of apixaban 20 mg QD, no autopsy performed) and therefore PE was considered the cause of death. Study CV185023, is an ongoing Phase 2 dose-ranging study to evaluate the safety and efficacy of 4 doses of apixaban (2.5 mg BID, 10 mg QD, 10 mg BID, 20 mg QD) as compared to placebo over a 26 week treatment period in selected subjects who have had an ACS within the last 7 days and to guide selection of the optimal dose and regimen of apixaban for evaluation in Phase 3 studies in patients with coronary artery disease (CAD). All subjects will receive acetylsalicylic acid (ASA) ≤ 165 mg/day. The study consists of two phases, Phase A and Phase B. The DMC reviews safety and efficacy data for the study on a bi-weekly basis.

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During Phase A, subjects were randomized to placebo, apixaban 2.5 mg BID or apixaban 10 mg QD. After 547 subjects were randomized in Phase A, the DMC reviewed the data and made a recommendation to expand randomization into the two higher dose arms of apixaban (10 mg BID and 20 mg QD) in Phase B of the protocol. Phase B began on March 8, 2007. In September 2007, following two regular reviews of bi-weekly safety and efficacy data, the DMC recommended that first the 20 mg QD treatment group and subsequently the 10 mg BID treatment group be terminated (stopping randomization and further dosing of subjects already randomized into these 2 treatment groups) for subjects who were also receiving clopidogrel plus aspirin due to an excess in minor bleeding; no concerns were noted regarding major or clinically relevant non-major bleeding. The sponsor, in consultation with the Steering Committee, made the decision to terminate both higher dose apixaban arms of the study (20 mg QD on September 18, 2007 and 10 mg BID on October 1, 2007), halting continued treatment and any new randomization into these treatment groups. The study is still ongoing with subjects being randomized into placebo and the two low apixaban dose groups (2.5 mg BID and 10 mg QD) and no new safety finding have been noted by the DMC.

1.5.1

Summary Risk/Benefit Assessment

Apixaban has a number of potential benefits compared with VKAs. In addition to its potent, predictable, and lasting anticoagulant activity, apixaban does not require laboratory monitoring. It is available for oral administration without an effect of food on absorption and is simple to dose. It has a favorable pharmacokinetic profile, low toxicity, and is cleared primarily via non-renal mechanisms. It does not have the same potential for drug and food interactions as VKAs, and appears to have a wider therapeutic index. These features may make apixaban an attractive alternative to currently available therapies, thus addressing an unmet clinical need.

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2

STUDY OBJECTIVES

2.1

Primary Objective

To determine if apixaban is non-inferior to standard enoxaparin/warfarin therapy in the combined endpoint of adjudicated recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or VTE-related death over 6 months of therapy.

2.2 •







• •



Secondary Objectives

To determine if apixaban is superior to standard enoxaparin/warfarin therapy in the combined endpoint of adjudicated recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or VTE-related death over 6 months of therapy To determine if apixaban is superior to standard enoxaparin/warfarin therapy in the combined endpoint of adjudicated recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or all-cause death over 6 months of therapy To characterize apixaban therapy relative to standard enoxaparin/warfarin therapy in the combined endpoint of adjudicated recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or cardiovascular (CV) death over 6 months of therapy To characterize apixaban therapy relative to standard enoxaparin/warfarin therapy in the combined endpoint of adjudicated recurrent symptomatic VTE (nonfatal DVT or nonfatal PE), VTE-related death, or major bleeding over 6 months of therapy To characterize apixaban therapy relative to standard enoxaparin/warfarin therapy in adjudicated major bleeding during 6 months of therapy To characterize apixaban therapy relative to standard enoxaparin/warfarin therapy in the composite of adjudicated major bleeding and adjudicated clinically relevant nonmajor bleeding during 6 months of therapy To characterize the primary efficacy outcome in the subset of subjects with index events of DVT only and in the subset of subjects with index events of PE with or without DVT.

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3

ETHICAL CONSIDERATIONS

3.1

Good Clinical Practice

This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the International Conference on Harmonisation (ICH) and in accordance with the ethical principles underlying European Union Directive 2001/20/EC and the United States Code of Federal Regulations, Title 21, Part 50 (21CFR50). The study will be conducted in compliance with the protocol. The protocol and any amendments and the subject informed consent will receive Institutional Review Board/Independent Ethics Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study. All potential serious breaches must be reported to BMS immediately. A serious breach is a breach of the conditions and principles of GCP in connection with the study or the protocol, which is likely to affect, to a significant degree, the safety or physical or mental integrity of the subjects of the study or the scientific value of the study. Study personnel involved in conducting this study will be qualified by education, training, and experience to perform their respective task(s). This study will not use the services of study personnel where sanctions have been invoked or where there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). Systems with procedures that assure the quality of every aspect of the study will be implemented.

3.2

Institutional Review Board/Independent Ethics Committee

Before study initiation, the investigator must have written and dated approval/favorable opinion from the IRB/IEC for the protocol, consent form, subject recruitment materials/process (eg, advertisements), and any other written information to be provided to subjects. The investigator or sponsor should also provide the IRB/IEC with a copy of

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the Investigator Brochure or product labeling, information to be provided to subjects and any updates. The investigator or sponsor should provide the IRB/IEC with reports, updates and other information (eg, expedited safety reports, amendments, and administrative letters) according to regulatory requirements or institution procedures.

3.3

Informed Consent

Investigators must ensure that subjects, or, in those situations where consent cannot be given by subjects, their legally acceptable representatives, are clearly and fully informed about the purpose, potential risks, and other critical issues regarding clinical studies in which they volunteer to participate. Freely given written informed consent must be obtained from every subject or, in those situations where consent cannot be given by subjects, their legally acceptable representative, prior to clinical study participation, including informed consent for any screening procedures conducted to establish subject eligibility for the study. The rights, safety, and well-being of the study subjects are the most important considerations and should prevail over interests of science and society. Appendix 1 contains procedures on obtaining informed consent from subjects, or, in those situations where consent cannot be given by subjects, their legally acceptable representative prior to participating in a clinical study. Procedures are described for all subjects, including those who are unable to give informed consent. The relevant procedures must be used whenever they are applicable (See Subject selection criteria in Sections 4.2.1 and 4.2.2).

4

INVESTIGATIONAL PLAN

4.1

Study Design and Duration

This is a randomized, active controlled, parallel-group, double blind, triple dummy study. Subjects with an objectively confirmed acute symptomatic proximal DVT or acute symptomatic PE are eligible for this study.

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Subjects will be stratified based on the type of disease treated (symptomatic proximal DVT or symptomatic PE) at baseline. If a subject has both symptomatic proximal DVT and symptomatic PE, the subject will be stratified as having symptomatic PE. Subjects with cancer who will be treated for 6-months or more with low molecular weight heparin therapy are ineligible for this study. Enrollment is projected to include approximately two-thirds DVT and one-third PE 1

subjects, approximating clinical demographics for patients with VTE. The number of randomized subjects in each of the DVT and PE categories will be monitored through IVRS during the study. Depending on how the study progresses, a cap may be utilized to halt enrollment of subjects into one category while continuing enrollment into the other category, in order to ensure a DVT: PE ratio of approximately 2:1 by the end of the study. Subjects will be randomized (1: 1 ratio) to Groups 1 or 2 using a central interactive voice response system (IVRS).

Group

Treatment

Dose

Duration

1

Warfarin

Dosing to target INR range between 2.0 – 3.0.

6 months

Enoxaparin

1 mg/kg SC Q12h until INR ≥ 2

≥ 5 days

Placebo (Apixaban)

10 mg BID for 7 days followed by 5 mg PO BID

6 months

Placebo (Warfarin)

Dosing to target SHAM INR range between 2.0 – 3.0.

6 months

Placebo (Enoxaparin)

SC Q12h until SHAM INR ≥ 2

≥ 5 days

Apixaban

10 mg BID for 7 days followed by 5 mg PO BID

6 months

2

Subjects in Group 1 will receive enoxaparin injections, warfarin tablets, and placebo apixaban tablets. Subjects in Group 2 will receive placebo enoxaparin injections, placebo warfarin tablets, and apixaban tablets. Enoxaparin and placebo enoxaparin will be administered for at least 5 days and will be discontinued after the blinded INR is ≥ 2, on one or more occasions.

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Apixaban, placebo apixaban, warfarin, and placebo warfarin tablets will be administered for 6 months. In order to minimize missing data, subjects who discontinue study drug early will continue to have their regularly scheduled follow-up visits throughout their originally intended treatment period (6 months after randomization) and 30-day follow up period. For subjects who have discontinued study treatment, query of health status (alive, occurrence of efficacy endpoints and AEs/SAEs) by telephone is allowed. Subjects who have new symptoms should undergo further assessment as clinically appropriate, preferably at the study site whenever feasible. This study will utilize a blinded INR monitoring routine. The blinded routine will consist of a point of care INR device that will generate an encrypted code. This code will be reported to a centralized IVRS by the investigator. The IVRS will decrypt the code and report back to the investigator either the actual INR result from subjects randomized to warfarin or a sham INR result from subjects randomized to placebo warfarin. Sham INRs will be based on a predefined computerized algorithm. Dose adjustments will be at the discretion of the investigator. Blinded INR testing frequency will occur approximately every month during the treatment period, and more frequently during titration and when clinically indicated. Subjects randomized to warfarin or placebo warfarin will be titrated to a target blinded INR range between 2 and 3. Study visits will be scheduled at 2, 4, 8, 12, 16, 20 and 24 weeks. All subjects will have an additional 30-day observation period after cessation of study treatment. Adjudication results will be the basis for the final analyses. Adjudication is intended to provide a consistent process for assessing data quality and interpreting study data. Adjudicated outcomes should not be relied upon for subject safety, study treatment decisions, or clinical care. Therefore, adjudication outcomes will not be shared with investigators for subject diagnosis or treatment.

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An independent data monitoring committee will monitor the subjects’ safety during the study and give recommendations to the steering committee and the sponsor. A 24-hour emergency telephone service will be provided for sites to call throughout the study.

4.1.1

Duration of Study

For all subjects, the study treatment duration will be 6 months followed by a 30-day observation period.

4.1.2

Steering Committee

The Steering Committee will be composed of a group of external clinical experts in thrombosis who are voting members. This group will be responsible for ensuring that study design, execution and management are of the highest quality. The Steering Committee will convene regularly by teleconference and/or face-to-face meetings to discuss and report on the ongoing conduct of the study.

4.1.3

Independent Central Adjudication Committee

Independent Central Adjudication Committee (ICAC) review and adjudication will occur without awareness of treatment allocation, i.e. in a blinded manner. The ICAC will include a chairman and independent reviewers who are physicians with experience in vascular medicine and thrombosis. The ICAC will adjudicate all index events (proximal DVT and/or PE). During the study period and the post-treatment observation period, the ICAC will adjudicate all suspected occurrences/recurrences of venous or arterial thromboembolic events, deaths, and the following events of special interest: acute myocardial infarction, acute stroke, and thrombocytopenia. The ICAC will also review all suspected episodes of bleeding, and categorize adjudicated bleeding as major, clinically relevant non-major, or minor bleeding. The Committee will be provided with all relevant documentation related to the events. The criteria and definitions of the study outcomes as well as the procedures followed by the Committee are described in an adjudication manual which will be finalized prior to the first ICAC event adjudication meeting.

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Independent Data Monitoring Committee

The Independent Data Monitoring Committee (DMC) will comprise external members including clinical experts in the management of VTE and a statistician. Its mandate will be to provide ongoing review of the safety of all investigational treatments and to ensure the study has acquired adequate information to address the primary objectives. A detailed charter for the DMC has been developed.

4.2

Study Population

For entry into the study, the following criteria MUST be met.

4.2.1

Inclusion Criteria

1) Signed Written Informed Consent a) Subjects must be willing and able to give written informed consent. 2) Target Population a) Subjects whose index event was either unprovoked OR provoked with a risk for recurrence as described in the eligibility checklist. b) Acute symptomatic proximal DVT with evidence of proximal thrombosis that involves at least the popliteal vein or a more proximal vein, demonstrated by imaging with: − compression ultrasound (CUS), including grey-scale or color-coded Doppler, or − ascending contrast venography. Or Acute symptomatic PE with evidence of thrombosis demonstrated by imaging as follows: − an intraluminal filling defect in segmental or more proximal branches on spiral CT scan; or − an intraluminal filling defect or a sudden cutoff of vessels more than 2.5 mm in diameter on the pulmonary angiogram; or − a perfusion defect of at least 75% of a segment with a local normal ventilation result (high-probability) on ventilation/perfusion lung scan (VPLS). Note: See Section 5.3 for allowable anticoagulant therapy prior to randomization.

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The index DVT and/or PE will be adjudicated by the ICAC according to the adjudication manual. Investigators are encouraged to assemble and to submit imaging dossiers to the ICAC as soon as possible during the period that extends from the screening period up to 2 weeks after randomization. Please refer to the diagnostic test manual for details regarding the assembly and submission of dossiers to the ICAC.

3) Age and Sex a) Men and women, ages 18 years or greater. Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study in such a manner that the risk of pregnancy is minimized. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea ≥ 12 consecutive months; or women on hormone replacement therapy [HRT] with documented serum follicle stimulating hormone [FSH] level > 35 mIU/mL). Even women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (eg, vasectomy) should be considered to be of childbearing potential. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of investigational product. Women are considered surgically sterile only if they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy. Women are considered postmenopausal only if they have had amenorrhea for ≥ 12 consecutive months, or for women on hormone replacement therapy (HRT), if they have a documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL.

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4.2.2

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Exclusion Criteria

1) Sex and Reproductive Status a) WOCBP who are unwilling or unable to use an acceptable method of birth control [such as oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides)] to avoid pregnancy for the entire study. b) Women who are pregnant or breastfeeding. c) Women with a positive pregnancy test on enrollment or prior to investigational product administration. 2) Target Disease Exceptions a) Subjects with a provoked index event without the existence of a persistent risk factor for recurrence as described in the eligibility checklist. b) Less than 6 months of anticoagulation planned for the most recent DVT or PE (index event). c) Thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent to treat the current episode of VTE. d) Active bleeding or high risk for bleeding contraindicating treatment with LMWH and a VKA. e) Subjects with cancer who will be treated for 6-months or more with low molecular weight heparin therapy. f) Subjects with contraindications according to the local prescribing information of enoxaparin or warfarin. 3) Medical History and Concurrent Diseases a) Subjects with an indication, other than VTE, intended for long-term treatment with a VKA such as: • Mechanical valve • Atrial fibrillation or atrial flutter with moderate to high risk of systemic thromboembolism. Subjects with atrial fibrillation that appears to be associated with acute PE may participate. b) The following chart lists examples of conditions for which serious bleeding may occur and the time of exclusion relative to the time of randomization:

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Condition

6 Months

Intracranial bleeding

X

Intraocular bleeding

X

Gastrointestinal bleeding and/or endoscopically verified ulcer disease

X

1 Month

Head trauma or other major trauma

X

Major surgery

X

2 Weeks

Ischemic stroke

X

Neurosurgery

X

Time of Randomization

Gross hematuria

X

Evidence of poor healing of a major wound or major trauma

X

Planned major surgery during trial

X

Intracranial neoplasm, arteriovenous malformation or aneurysm

X

Overt major bleeding (defined in section 6.3.1)

X

Documented hemorrhagic tendencies or blood dyscrasias

X

c) d) e) f)

Active and clinically significant liver disease (eg, hepatorenal syndrome); Life expectancy < 6 months; Bacterial endocarditis; Uncontrolled hypertension: systolic blood pressure > 180 mm Hg or diastolic blood pressure > 100 mm Hg; (subjects who have a transient, higher blood pressure elevation associated with acute PE [upper limit: systolic blood pressure 200 mm Hg or diastolic blood pressure 100 mm Hg] may enter the study;) elevated blood pressure that is persistent 1 - 2 days after the index DVT or PE should be treated according to local guidelines);

4) Physical and Laboratory Test Findings 3

a) Platelet count < 100,000/mm ; b) Hemoglobin < 9 g/dL; c) Serum creatinine > 2.5 mg/dL [221 umol/L]

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d) Calculated creatinine clearance < 25 ml/min (see Section 6.3.2.2.); e) ALT or AST > 2 times upper limit of normal; f) Total bilirubin > 1.5 times upper limit of normal (unless an alternative causative factor is identified [eg, Gilbert’s syndrome]).

5) Allergies and Adverse Drug Reactions a) Heparin induced thrombocytopenia; b) Allergic reaction to unfractionated heparin, LMWH, fondaparinux or any VKA. 6) Prohibited Treatments and/or Therapies a) DVT or PE treatment with more than two doses of fondaparinux or a LMWH that is labeled for once daily dosing, or more than three doses of a LMWH that is labeled for twice daily dosing, or continuous infusion of unfractionated heparin for more than 36 hours, before the first administration of study drug; and/or b) DVT or PE treatment with more than two doses of oral VKA therapy before the first administration of study drug. c) Treatment with apixaban in a previous clinical trial. d) Subjects requiring ASA > 165 mg/day at randomization. e) Subjects requiring dual anti-platelet therapy (ASA plus clopidogrel or ASA plus ticlopidine) at randomization. Subjects who transition from dual anti-platelet therapy to monotherapy prior to randomization will be eligible for the trial. 7) Other Exclusion Criteria a) Prisoners or subjects who are involuntarily incarcerated b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness; c) Receiving concurrent investigational agents or has received an investigational agent within the past 30 days prior to the first dose of study treatment (with the exception of approved medications being used for an approved indication, eg, investigating a new dosing regimen for an approved indication.); d) Any condition, which in the opinion of the investigator, would put the subject at an unacceptable risk from participating in the study; or e) Any other medical, social, logistical, or psychological reason, which in the opinion of the investigator, would preclude compliance with, or successful completion of, the study protocol.

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Eligibility criteria for this study have been carefully considered to ensure the safety of the study subjects and to ensure that the results of the study can be used. It is imperative that subjects fully meet all eligibility criteria.

4.2.3

Discontinuation of Subjects from Treatment

Subjects MUST discontinue study treatment (investigational or non-investigational treatment) for any of the following reasons:

• •

• • •





Withdrawal of informed consent (subject’s decision to withdraw for any reason) Any clinical adverse event (AE), laboratory abnormality, or intercurrent illness which, in the opinion of the investigator, indicates that continued participation in the study is not in the best interest of the subject Pregnancy (See Section 7.6.2) Termination of the study by Bristol-Myers Squibb (BMS) or Pfizer Loss of ability to freely provide consent through imprisonment or involuntary incarceration for treatment of either a psychiatric or physical (eg, infectious disease) illness See Section 6.3.2.3 (Treatment Guidelines for Jaundice and Elevated LFTs) for requirements for interruption or discontinuation of study drug related to jaundice or elevated liver function tests Investigators should use their clinical discretion in deciding whether to discontinue study treatment temporarily or permanently for a clinical condition that arises after randomization and requires fibrinolytic therapy, or elective, urgent, or emergent surgery, or elective, urgent, or emergent percutaneous procedure (eg, coronary arteriography, angioplasty, etc.)

All subjects who discontinue study treatment should comply with protocol specified follow-up procedures as outlined in Section 6. The only exception to this requirement is when a subject withdraws consent for all study procedures or loses the ability to consent freely (eg, due to lost of cognitive function). If a subject was withdrawn before completing the study, the reason for withdrawal must be entered on the appropriate case report form (CRF) page.

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In order to minimize missing data, subjects who discontinue study drug early will continue to have their regularly scheduled follow-up visits throughout their originally intended treatment period (6 months after randomization) and 30-day follow up period. For subjects who have discontinued study treatment, query of health status (alive, occurrence of efficacy endpoints and AEs/SAEs) by telephone is allowed. Subjects who have new symptoms should undergo further assessment as clinically appropriate, preferably at the study site whenever feasible.

5

TREATMENTS

5.1

Study Treatment

5.1.1

Investigational Product

An investigational product, also known as investigational medicinal product in some regions, is defined as follows: A pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical study, including products already with a marketing authorization but used or assembled (formulated or packaged) in a way different from the authorized form, or used for an unauthorized indication, or when used to gain further information about the authorized form. In this protocol, investigational products are: Apixaban 5 mg tablets and matching placebo tablets; enoxaparin prefilled syringes (100 mg/1 ml and 150 mg/1 ml) and matching placebo syringes; and warfarin 2 mg tablets and matching placebo.

5.1.2

Noninvestigational Product

Other medications used in the study as support or escape medication for preventative, diagnostic, or therapeutic reasons, as components of the standard of care for a given diagnosis, are considered noninvestigational products.

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CV185056 Clinical Protocol

Identification

The following investigational products will be provided by Bristol-Myers Squibb, Global Research and Development: PRODUCT

POTENCY

APPEARANCE

5 mg

Reddish brown, plain, oval shaped, shallow biconvex film coated tablet

Placebo for apixaban (BMS-562247) film coated tablets

-

Reddish brown, plain, oval shaped, shallow biconvex film coated tablet

Warfarin Sodium (BMS-565793) tablets

2 mg

Lavender, round, biconvex tablet with one face bisected and the other face plain

Placebo for Warfarin Sodium (BMS-565793) tablets

-

Lavender, round, biconvex tablet with one face bisected and the other face plain

Enoxaparin prefilled syringes

100 mg/1.0 mL

Prefilled 1.0 ml syringe containing 1.0 ml clear and colorless solution

-

Prefilled 1.0 ml syringe containing 1.0 ml clear and colorless solution

150 mg/1.0 mL

Prefilled 1.0 ml syringe containing 1.0 ml clear and colorless solution

-

Prefilled 1.0 ml syringe containing 1.0 ml clear and colorless solution

Warfarin tablets

1 mg

Pink, single scored with one face imprinted with 1 superimposed and inscribed with “Coumadin” and with the opposite face plain.

Warfarin tablets

5 mg

Peach, single scored with one face imprinted with 5 superimposed and inscribed with “Coumadin” and with the opposite face plain.

Apixaban (BMS-562247) film coated tablets

Placebo for enoxaparin prefilled syringes Enoxaparin prefilled syringes Placebo for enoxaparin prefilled syringes

5.1.4

Packaging and Labeling

At randomization, each subject will receive a Week 1 blister card containing tablets of apixaban 5 mg or matching placebo as well as one dispensing kit containing 13 blister cards of apixaban or placebo tablets. Additionally they will receive 1 bottle of warfarin or placebo tablets as well as one kit containing 16 syringes prefilled with Enoxaparin Sodium (100 mg/1 ml or 150 mg/1 ml) or placebo (0.9% NaCl).

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The Week 1 blister card will contain 28 tablets and will be labeled with a three-panel, double-blind label. On this label, the protocol number, drug name, container number, blinded batch number, tablet quantity, storage conditions, subject number, Investigator number, route of administration, and directions for use will be indicated. Each warfarin/placebo bottle will be labeled with a 3-panel, double-blind white label printed in black ink. On this label the protocol number, blinded batch number, container number, blinded drug name tablet quantity, storage conditions, directions for use and route of administration will be indicated. Subjects will be resupplied with a new bottle of warfarin/placebo tablets as needed based on their dose titration and will be managed through the Interactive Voice Response System. The dispensing kits for both apixaban and Enoxaparin will be labeled with 3-panel, double-blind labels printed in black ink. On this label the protocol number, blinded batch numbers, container number, tablet quantities, syringe or tablet quantity, storage conditions, subject number, Investigator name, directions for use and route of administration will be indicated. The third panel contains the unblinding information. In the event of a medical emergency, the panel may be opened by the treating physician. The Investigator must record the nature of the emergency that required breaking the code and must notify the Medical Monitor (see Section 5.4). Each apixaban blister card, for use after week 1, will contain 14 tablets and will be labeled with a one-panel, double-blind label. On this label, the protocol number, drug name, container number, blinded batch number, tablet quantity, storage conditions, subject number, Investigator number, route of administration, and directions for use will be indicated. Each syringe will be labeled in accordance with local regulations. Symbols will be used to reference the caution statement, and route of administration with full translated text contained on an insert card within each patient kit for Enoxaparin. Each subject will be resupplied with a kit of apixaban/placebo 5 mg tablets at their 3 month visit and warfarin/placebo 2 mg tablets as needed based on their dose titrations. If required, patients may also receive a resupply of enoxaparin/placebo at week 2.

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Subjects who require additional treatment beyond the 6 months of double-blind therapy, will receive open-label bottles of commercial warfarin sodium. Commercially available open-label warfarin 1 mg and 5 mg will be provided in bottles of 100s and labeled with a 1-panel, open label printed in black ink.. On this label the protocol number, drug name, batch numbers, container number, tablet quantity, storage conditions, and route of administration will be indicated.

5.1.5

Handling and Dispensing

The investigational product should be stored in a secure area according to local regulations. It is the responsibility of the investigator to ensure that investigational product is only dispensed to study subjects. The investigational product must be dispensed only from official study sites by authorized personnel according to local regulations. The investigator should ensure that the investigational product is stored in accordance with the environmental conditions (temperature, light, and humidity) as determined by the sponsor and defined in the Investigator Brochure or SmPC/reference label. If concerns regarding the quality or appearance of the investigational product arise, do not dispense the investigational product and contact the sponsor immediately. Please refer to Section 9.2.2 for information on investigational product record retention and 9.3 for return and destruction instructions.

5.2

Method of Assigning Subjects to a Treatment

The subject identification (ID) and treatment kit numbers will be provided by the central randomization service through an automated interactive voice response system (IVRS) available 24 hours per day, 7 days a week. Subsequent treatment kit numbers for drug resupply will be provided through IVRS.

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5.3

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Selection and Timing of Dose for Each Subject

All study groups DVT or PE treatment before the first administration of study drug is allowed with:

• • •

≤ 2 doses of fondaparinux (or an approved LMWH that is labeled for once daily dosing); or ≤ 3 doses of an approved LMWH that is labeled for twice daily dosing; or Continuous infusion of unfractionated heparin for ≤ 36 hours.

In addition, ≤ 2 doses of VKA are allowed before the first administration of study drug (See Sections 4.1 and 4.2.2). It is recommended that:

• • •

the last dose of UFH be given ≥ 2 hours prior to administration of first study treatment; the last dose of LMWH labeled for twice daily administration be given ≥ 6 hours prior to administration of first study treatment; or the last dose of LMWH labeled for once daily administration (or fondaparinux) be given ≥ 12 hours prior to administration of first study treatment.

All study medication should be started as soon as possible but not later than 24 hours after randomization. After the study treatment period is completed, an unblinded INR should not be obtained within 7 days of the last dose of study medication unless there is a medical emergency that requires knowledge of an unblinded INR, or within 4 days of the last dose of study medication if the subject is bridging to open label warfarin as described in Section 5.4.2. If the study drug is discontinued before the study treatment period is completed, an unblinded INR should not be obtained within 7 days of the last dose of study medication unless there is a medical emergency that requires knowledge of an unblinded INR, or within 4 days if the subject is bridging to an open label VKA.

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Enoxaparin or Placebo Enoxaparin Enoxaparin is indicated for the treatment of DVT and PE.

21

In global pivotal studies

where enoxaparin has been an active comparator, 1 mg/kg BID subcutaneously has been 10

an acceptable standard for comparison.

For the treatment of deep vein thrombosis or pulmonary embolism, enoxaparin (or enoxaparin placebo) is to be administered subcutaneously in a dose of 1 mg/kg every 12 hours. For subjects with a calculated creatinine clearance of < 30 ml/min, enoxaparin should be administered subcutaneously in a dose of 1 mg/kg every 24 hours. Subjects (or their care giver) will be provided with prefilled syringes containing either enoxaparin or placebo and instructions on how to administer the prescribed twice daily VTE treatment dose. The minimal duration of treatment with enoxaparin (or enoxaparin placebo) is 5 days. This 5-day treatment period could include the period up to 24 hr before randomization. Treatment with enoxaparin (or placebo) should continue until the blinded INR is ≥ 2.0 with an advised overlap with VKA for at least 5 days.

Warfarin or Placebo Warfarin Warfarin/Placebo Warfarin Dosing and INR Monitoring: In order to maintain consistency across this investigational study, investigators are encouraged to administer warfarin or placebo warfarin in a manner that is consistent with ®

clinical practice as described in the COUMADIN (warfarin) United States Package Insert (version August 2007) (Appendix 2). The following is guidance provided to physicians in the Package Insert. Initial Dosage: The dosing of warfarin must be individualized according to patient's sensitivity to the drug as indicated by the INR. Use of a large loading dose may increase the incidence of hemorrhagic and other complications, does not offer more rapid protection against thrombi formation, and is not recommended. Lower initiation and maintenance doses are recommended for elderly and/or debilitated patients and patients with potential to exhibit greater than expected INR response to warfarin. Based on limited data, Asian patients may also require lower initiation and maintenance doses of

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warfarin. It is recommended that warfarin therapy be initiated with a dose of 2 to 5 mg per day with dosage adjustments based on the results of INR determinations. Maintenance: Most patients are satisfactorily maintained at a dose of 2 to 10 mg daily. The individual dose and interval should be gauged by the patient's prothrombin response. INR Monitoring: Available clinical evidence indicates that an INR of 2.0 - 3.0 is sufficient for prophylaxis and treatment of venous thromboembolism and minimizes the risk of hemorrhage associated with higher INRs. The INR should be determined daily after the administration of the initial dose until INR results stabilize in the therapeutic range. Intervals between subsequent INR determinations should be based upon the physician's judgment of the patient's reliability and response to warfarin in order to maintain the individual within the therapeutic range. Acceptable intervals for INR determinations are normally within the range of one to four weeks after a stable dosage has been determined.

Study Limits for Warfarin Dosing and Blinded INR Monitoring Frequency: Investigators should not exceed the limits for warfarin dosing or blinded INR monitoring frequency as described in Appendix 3. These limits are summarized as follows: For this protocol, an initiation algorithm of both dosing and blinded INR measurements is shown in Table 5.3. Dosing decisions on Day 5 should incorporate the subject’s response to previous warfarin doses, in addition to the Day 5 test result. A similar algorithm, applied prospectively to elderly subjects (mean age 85 ± 6 years), achieved a therapeutic 22

INR within 7 days and a maintenance dose within 10 days; no patient had an INR > 4.0.

Since INR measurements have a variability that approaches 10%, frequent dosing changes based upon small differences in the measured INR are likely to be counterproductive.

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Table 5.3: Age (years) < 80

≥ 80

An Algorithm for the Initiation of Warfarin and Testing of Blinded INR. Day 1: Dose

Day 2: Dose

Day 3: blinded INR Test

Day 3: Dose

Day 4: Dose

Day 5: blinded INR Test

Day 5: Dose

6 mg

6 mg

INR < 1.5

8 mg

8 mg

INR < 1.5

10 mg

INR 1.5 - 1.9

6 mg

4 mg

INR 1.5 - 1.9

6 mg

INR 2.0 - 3.0

2 mg

2 mg

INR 2.0 - 3.0

4 mg

INR > 3.0

Hold

Hold

INR > 3.0

Hold

INR < 1.5

6 mg

6 mg

INR < 1.5

8 mg

INR 1.5 - 1.9

2 mg

2 mg

INR 1.5 - 1.9

6 mg

INR 2.0 - 3.0

Hold

2 mg

INR 2.0 - 3.0

2 mg

INR > 3.0

Hold

Hold

INR > 3.0

Hold

4 mg

4 mg

Warfarin may be initiated on an outpatient basis. When initiating warfarin, “loading doses” greater than 6 mg should be avoided. Previous studies have shown that lower initiation doses (~5 mg) achieve the therapeutic range as quickly as higher doses, but with less risk of overshoot. Moreover, initiating with doses that are likely to be much larger than the daily maintenance dose unnecessarily complicates management. Particular care should be taken when initiating elderly patients, who tend to have a lower 24

maintenance dose. In work performed by Garcia and colleagues,

the median daily

maintenance dose of warfarin for men and women 80 years of age or older was between 3 and 4 mg. Patients over the age of 80 have an increased risk of major hemorrhage that may exceed 10% at one year following initiation of therapy in those who are naïve to warfarin.

25

Apixaban or Placebo Apixaban Two tablets of apixaban 5 mg tablets (or placebo) twice daily for 7 days followed by 1 tablet of apixaban 5 mg (or placebo) twice daily will be administered. Dosing should start as soon as possible.

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Special Considerations: Vomiting: If a subject were to vomit within 30 minutes of ingestion of the study drug, the full dose of oral study drug should be repeated. If the subject vomits more than 30 minutes after study drug ingestion, no additional study drug should be taken and the subject should resume study drug ingestion according to the usual schedule.

5.4

Blinding/Unblinding

This study will be conducted in a blinded fashion. To maintain blinding of study treatment, study medications will be prepared in a triple-dummy design using placebo matching the active treatments. Subjects, Investigators, members of any of the administrative and adjudicating committees, and the sponsor’s staff conducting the study, will not have access to individual subject treatment assignments. The Randomization Center will have access to such assignments. Blinding is critical to the integrity of this clinical study. However, in the event of a medical emergency or pregnancy in an individual subject, in which knowledge of the investigational product is critical to the subject's management, the blind for that subject may be broken by the treating investigator. Before breaking the blind of an individual subject's treatment, the investigator should have determined that the information is necessary, ie, that it will alter the subject's immediate management. The study investigator should ensure that health care professionals who may provide any elective, urgent or emergent medical or surgical care for a subject after randomization are informed that: (1) The subject is enrolled in a clinical study and is receiving blinded oral study treatment, consisting of:

• •

Oral factor Xa inhibitor + injectable placebo + oral placebo, or Oral warfarin + injectable enoxaparin + oral placebo

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(2) The factor Xa inhibitor is an anticoagulant, with a half-life of approximately 12 hours, which can not be monitored using standard laboratory tests, such as PT, PTT, ACT, and INR; there is no antidote for this compound. Enoxaparin is a low molecular weight heparin; there is no antidote for this compound. Warfarin is a vitamin K antagonist that can be reversed with vitamin K administration. (3) In the event of an emergency, this person should be treated symptomatically as would any other person being treated with anticoagulants. Treatment in an emergency may include discontinuation of all study treatment, and the use of standard resuscitative management such as fresh frozen plasma and/or vitamin K, if appropriate. (4) Assessing this person’s INR may unblind the study treatment and may compromise the integrity of the clinical study. Should an INR be essential to this person’s management, every effort should be made to ensure the results are not shared with this person, the study physician, the study site personnel, or anyone associated with this person or the clinical study.

Unblinding When knowledge of the subject’s randomized treatment assignment would have a meaningful impact on individual management, for example in many cases of clinically significant bleeding or the need for urgent invasive procedures, the subject’s treatment assignment should be unblinded. This information should be provided to those who are caring for the subject and as few other people as possible. In these cases, we will minimize bias by assuring that the clinical events committee remains blinded to treatment assignment, even if the investigator has been unblinded. Every subject will be provided with an alert card. The alert card:

• • • •

Will indicate that the subject is participating in a double-blind clinical trial Provides the sponsor’s name (Pfizer) and trial number (CV185056) Will note that the subject may be receiving either enoxaparin/warfarin or an investigational anticoagulant drug (a factor Xa inhibitor) Will instruct the treating physician that assessing this person’s INR may unblind the study treatment and may compromise the integrity of the clinical study. Should an INR be essential to this person’s management, every effort should be made to ensure

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the results are not shared with this person, the study physician, the study site personnel, or anyone associated with this person or the clinical study Includes contact numbers for the subject’s investigator to provide information to emergency medical personnel.

The need to break the blind must first be discussed, if at all possible, with the responsible Medical Monitor. A trial help line may also be used be for this purpose.

5.4.1

Invasive Procedures and Surgery

Several factors govern the management of anticoagulation in this study with respect to surgery and invasive procedures, as well as the management of bleeding that may occur in subjects on study drugs. These are:

• • • • •

The risk of thromboembolism in an individual subject (low, intermediate or high) The risk of bleeding associated with the procedure or surgery Whether the surgery or invasive procedure is elective or emergent in nature The desirability of maintaining blinding, if at all possible, without creating risk for the subject The different times of onset and offset of anticoagulant effect for warfarin and apixaban (warfarin needs to be discontinued earlier than apixaban to permit its effects to abate, and needs to be started in advance of apixaban to achieve a stable anticoagulant effect).

5.4.1.1

Elective Procedures

In general, local standards of care for discontinuation of anticoagulation prior to elective procedures/surgery should be employed; these may be informed by current guidelines. These are summarized below based upon the risk of thromboembolism: A. For subjects with a low risk of thromboembolism: • Stop warfarin/warfarin-placebo and apixaban/apixaban-placebo 4 days before the planned procedure • Monitor the INR using the encrypted POC device as necessary* • Once the POC INR has attained a value deemed appropriate for the proposed procedure, the procedure/surgery may proceed

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If the procedure is associated with an increased risk of thrombosis, brief postoperative protection with UFH or LMWH at a prophylactic dose may be considered, using doses that conform with labeling and local standard of care Restart warfarin/warfarin-placebo (usually the night of the day of surgery) and apixaban/apixaban-placebo postoperatively (usually the day after surgery) when it is deemed safe to do so. When the POC INR is therapeutic, stop UFH/LMWH. It is recommended that: ○ the last dose of UFH be given ≥ 2 hours prior to administration of apixaban/apixaban-placebo ○ the last dose of LMWH labeled for twice daily administration be given ≥ 6 hours prior to administration of apixaban/apixaban-placebo or ○ the last dose of LMWH labeled for once daily administration (or fondaparinux) be given ≥ 12 hours prior to administration of apixaban/apixaban-placebo.

* Note that the encrypted POC device will provide the true INR for subjects receiving warfarin, and a sham INR for those receiving apixaban. The sham value will decline, as it is based on the most recent warfarin placebo “doses”, which will be nil (since they are being held prior to the planned procedure). Thus the POC INR will reflect the true INR for subjects randomized to warfarin, while preserving the blind in all subjects.

B. • • •

For subjects with an intermediate risk of thromboembolism: Stop warfarin/warfarin-placebo 4 days before the planned procedure Monitor the INR using the encrypted POC device as necessary Two days before the planned procedure, stop the apixaban/apixaban-placebo and begin UFH or LMWH. The doses employed should conform to labeling and the local standard of care. The full anticoagulant dose is recommended • Once the POC INR has attained a value deemed appropriate for the proposed procedure, the procedure/surgery may proceed • Maintain on UFH/LMWH • Restart warfarin/warfarin-placebo and apixaban/apixaban-placebo postoperatively and when it is deemed safe to do so (usually the night of the day of surgery). When the POC INR is therapeutic, stop UFH/LMWH. It is recommended that: ○ the last dose of UFH be given ≥ 2 hours prior to administration of apixaban/apixaban-placebo ○ the last dose of LMWH labeled for twice daily administration be given ≥ 6 hours prior to administration of apixaban/apixaban-placebo or ○ the last dose of LMWH labeled for once daily administration (or fondaparinux) be given ≥ 12 hours prior to administration of apixaban/apixaban-placebo.

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C. • • •

• • •

CV185056 Clinical Protocol

For subjects with a high risk of thromboembolism: Stop warfarin/warfarin-placebo 4 days before the planned procedure Monitor the INR using the encrypted POC device as necessary Begin UFH or LMWH as the INR falls (approximately 2 days before the planned procedure). The doses employed should conform to labeling and the local standard of care. The full anticoagulant dose is recommended. Stop apixaban/apixaban-placebo Once the POC INR has attained a value deemed appropriate for the proposed procedure, the procedure/surgery may proceed After hemostasis has been achieved, resume UFH or LMWH in the postoperative period Restart warfarin/warfarin-placebo (usually the night of the day of surgery) and apixaban/apixaban-placebo postoperatively (when the INR is therapeutic) when it is deemed safe to do so. Stop UFH/LMWH. It is recommended that: ○ the last dose of UFH be given ≥ 2 hours prior to administration of apixaban/apixaban-placebo ○ the last dose of LMWH labeled for twice daily administration be given ≥ 6 hours prior to administration of apixaban/apixaban-placebo or ○ the last dose of LMWH labeled for once daily administration (or fondaparinux) be given ≥ 12 hours prior to administration of apixaban/apixaban-placebo.

5.4.1.2

Emergency Procedures

For urgent or emergent invasive procedures, when waiting 4 - 5 days is not an option, management will in part depend on the randomized treatment assignment (enoxaparin/warfarin or apixaban) and unblinding may be necessary (see Section 5.4 Blinding/Unblinding). Regardless of treatment, study drugs should be discontinued and standard laboratory coagulation tests (PT/INR, aPTT, platelet count, etc.) performed. The procedure should be carried out and in such a way to minimize the risk of bleeding. Subjects receiving enoxaparin/warfarin should be managed according to the local standard of care. The anticoagulant effects of warfarin will be reflected in the PT and INR and, after discontinuation, will take several days (3 - 5) to return to normal. Warfarin can be reversed more quickly by giving oral or intravenous vitamin K (depending on circumstances and the local standard of care) and/or with fresh frozen plasma (FFP).

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For subjects receiving apixaban, the risk of bleeding with invasive procedures is unknown. At therapeutic doses, the anticoagulant effects of apixaban will not be reflected in standard coagulation tests; there is no reversal agent for apixaban. Vitamin K and protamine sulfate are not expected to affect the anticoagulant effect of apixaban, and may carry some risk. Given its half-life (12 hours), however, the anticoagulant effect of apixaban abates in 24 - 48 hours. Depending on the subject’s risk of bleeding with the procedure, subjects receiving apixaban who require an invasive or surgical procedure within 24 hours of their last dose may be treated with prophylactic peri-procedural FFP (2 units IV every 6 hours) at the discretion of the local physician and investigator. If treatment with an alternative open label anticoagulant/antithrombotic is indicated for the procedure, it should be used at the lowest therapeutic dose (if at all) in the 12 hours following last dose of apixaban. Interactions between apixaban and other antithrombotics (with the exception of aspirin and clopidogrel) have not been evaluated.

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CV185056 Clinical Protocol

Bridging Strategy

Figure 5.4.1.3A:

Bridging Strategy for Low Risk Subjects Begin warfarin/warfarin placebo (usually night of day of surgery or procedure)

Bridging Strategy for Low Risk AF Patients Stop Warfarin/Warfarin Placebo

Stop Apixaban/ Apixaban Placebo

INR Therapeutic

Start apixaban/apixaban placebo if post-op UFH/LMWH used

Monitor INR with POC

Day

-4

-3

-2

Day of surgery/procedure

Start apixaban/apixaban placebo if no post-op UFH/LMWH (usually day after surgery or procedure)

-1

0

Monitor INR with POC ±UFH/LMWH (if

Stop UFH/LMWH

prophylaxis needed)

1

2

3

4

A suggested strategy (based on present guidelines) for bridging subjects at low risk for thromboembolism through surgery or an invasive procedure is depicted in Figure 5.4.1.3A. Both study drugs are discontinued four days prior to the planned procedure. INR monitoring is performed using the encrypted POC device. When the INR falls to a value low enough to permit the procedure, an open INR is obtained at a local laboratory to confirm the result prior to the procedure. After the procedure, warfarin (or its placebo) is restarted, generally on the evening of the day of surgery. POC monitoring of the INR is initiated. If bridging with UFH/LMWH is desired (for example, after PCI), it is begun at this time, and apixaban (or its placebo) is not begun until after the POC INR is ≥ 2.0, when the UFH/LMWH is discontinued. If no UFH/LMWH is used, then apixaban (or its placebo) is begun at the time that warfarin (or its placebo) is restarted.

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Figure 5.4.1.3B:

Bridging Strategy for Intermediate and High Risk Subjects

Stop Warfarin/Warfarin Placebo

Begin warfarin/warfarin placebo (usually night of day of surgery or procedure)

Stop Apixaban/ Apixaban Placebo

INR Therapeutic

Monitor INR with POC

Begin UFH/LMWH prophylactic or full dose

Stop UFH/LMWH

Day

-4

-3

-2

-1

Day of surgery/procedure

Begin apixaban/apixaban placebo 1 hour after UFH/LMWH stopped

Monitor INR with POC

Begin UFH/LMWH prophylactic or full dose

0

1

Stop UFH/LMWH

2

3

4

A diagram of the suggested approach to elective invasive procedures/surgery in subjects deemed at intermediate or high risk of thromboembolism is shown in Figure 5.4.1.3B. Warfarin/warfarin-placebo is discontinued 4 days prior to the planned procedure and the INR monitored with the encrypted POC device. When the INR falls below 2.0 (about 2 days prior to the procedure) full dose UFH or LMWH is begun, and apixaban/apixabanplacebo discontinued. An open INR is obtained prior to the procedure at a local laboratory. After the procedure, warfarin (or its placebo) is restarted, generally on the evening of the day of surgery. POC monitoring of the INR is initiated. Bridging with UFH/LWH is begun, generally at full dose. When the POC INR ≥ 2.0, UFH/LWH is discontinued, and apixaban (or its placebo) is restarted.

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5.4.2

CV185056 Clinical Protocol

Post Treatment Bridging Strategy to Warfarin

For those subjects requiring treatment with warfarin beyond the 6-month study treatment period, a bridging strategy will be used. Warfarin must be used for post-treatment anticoagulation during the safety follow-up period for those subjects requiring continuing treatment. For this bridging period, the sponsor will provide 30-days of treatment using 1- and 5-mg warfarin tablets. After completion of the safety follow-up, further anticoagulation is at the discretion of the treating physician. The post treatment bridging strategy is depicted below:

Table 5.4.2:

Post Treatment Bridging Strategy

Study Day

End of Treatment

Blinded Warfarin/ Placebo

Blinded Apixaban/ Placebo

Current Dose

BID

Open Label Warfarin

Blinded INR a

Bridging - Day 1

BID

5-mg QD

Bridging - Day 2

BID

5-mg QD

a

Bridging - Day 3

3-mg QD

Bridging - Day 4

Per INR

a

INR

Unblinded INR

3-mg QD for subjects with age 80 or more years.

On Bridging – Day 1 and Day 2, subjects will continue taking blinded apixaban/placebo twice daily along with 5-mg warfarin once daily. On Bridging – Day 3, subjects will only take 3-mg warfarin once daily. On Bridging – Day 4, an unblinded INR will be determined and subsequent warfarin dosing and INR measurements will be up to the discretion of the treating physician. An unblinded INR should not be performed during the first 3 days of bridging in order to maintain blinding of the study. To assist in the selection of warfarin dosing after day 4, Appendix 5 contains a table summarizing the median, 25th percentile, and 75th percentile for daily warfarin maintenance doses by age, gender, and weight in subjects with venous thromboembolism.

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5.5

Concomitant Treatments

5.5.1

Prohibited and/or Restricted Treatments

Prohibited Treatments The following medications or therapies are prohibited:



• • •



Potent inhibitors of CYP3A4 (eg, azole antifungals [itraconazole and ketoconazole], macrolide antibiotics [clarithromycin and telithromycin], protease inhibitors [ritonavir, indinavir, nelfinavir, atazanavir, and saquinavir], and nefazadone) Aspirin > 165 mg/day Dual antiplatelet therapy such as concomitant (simultaneous) use of both aspirin and a thienopyridine (eg, clopidogrel, ticlopidine) Other antithrombotic agents (eg, UFH, LMWH, direct thrombin inhibitors, fondaparinux) [Note: UFH and LMWH may be used as part of a bridging strategy, see Section 5.4.1.3 Bridging Strategy.] GP IIb/IIIa inhibitors (eg, abciximab, eptifibatide, tirofiban).

If treatment with a prohibited agent becomes necessary, study drug should be temporarily interrupted, and restarted as soon as possible following discontinuation of the prohibited medication or therapy. Restricted Treatments: The administration of the following agents in subjects on study drug should be done cautiously given the increased risk of bleeding. In such cases, consideration of interruption of the study drug may be warranted; this decision should be made after a careful assessment of the risks and potential benefits.

• •

Chronic (> 3 months) daily NSAIDs. NSAIDs should not be administered in doses that exceed those in the approved label Cytotoxic/myelosuppressive therapy

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In addition, if a subject is currently receiving an agent that is a potent inducer of CYP3A4 (eg, rifampin), the investigator should carefully evaluate that subject’s risk of thromboembolism, as the plasma concentration of apixaban may be lower than that in subjects not receiving a potent inducer of CYP3A4.

5.5.2

Other Restrictions and Precautions

The following precautions and restrictions must be followed to preserve study integrity and subject safety:

• •

Subjects should comply with the prescribed dosing and visit schedule Subjects should be instructed that prior to taking any new prescriptions and/or over the-counter medications, they should discuss this thoroughly with the Investigator to ensure the new medication is not prohibited by the study protocol.

Since apixaban is a direct inhibitor of FXa, it acts as an anticoagulant. The safety of apixaban in combination with other anticoagulants such as unfractionated heparin, low molecular weight heparin, or fondaparinux, has not been evaluated. Thus, it is preferable to stop blinded study drug to allow for its clearance from the body prior to initiating treatment with another anticoagulant or performing invasive procedures. In normal human volunteers, apixaban has a half-life of approximately 12 hours. Investigators should contact the Medical Monitor/24 Hour Contact to discuss initiation of other anticoagulants for a study subject (see SAE Telephone Contact Information in Section 7.3.1: Serious Adverse Events).

5.6

Treatment Compliance

Compliance based on study drug pill and syringe count will be performed at each scheduled visit for all subjects. Compliance will be reinforced at each study visit. Patients must maintain adequate compliance with the study medication regimen based upon pill and syringe counts. If a discrepancy of more than 20% of doses exists since the last scheduled visit, the site staff should re-instruct the patient on the importance of medical treatment for their disease and on the dosing regimen. Patients should not be discontinued from the trial based solely on compliance.

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5.7

CV185056 Clinical Protocol

Transitioning from CV185056 to CV185057

In order for subjects to be considered for transition from CV185056 to CV185057, they must:

• • • • •

be compliant with the CV185056 protocol; complete the entire 6-months of CV185056 study treatment as described in the CV185056 protocol; after the completion of the 6-month treatment period, randomize into CV185057 as soon as possible when their blinded INR is 2 or less. complete the final CV185056 study treatment visit as described in the CV185056 protocol; and fulfill the CV185057 inclusion and exclusion criteria and screening/baseline procedures

In addition:

• •

all AEs and SAEs must be reported, as appropriate, during the transition and overlap periods (see Section 5.7.1). all INR procedures must be blinded during the transition from the CV185056 study to the CV185057 study, using the approved blinded INR methods. No unblinded INRs should be obtained (see Section 5.7.2).

5.7.1

Reporting AEs and SAEs during CV185056 and CV185057 Overlap

Subjects who transition from CV185056 to CV185057 will automatically be assigned a unique identifier that indicates their participation in both studies. New SAEs that occur prior to the first dose of CV185057 study treatment will be reported to the CV185056 study only, as depicted in Figure 5.7.1. New SAEs and AEs that occur after the first dose of CV185057 study treatment will be reported to the CV185057 study only, as depicted in Figure 5.7.1. SAEs and AEs that are ongoing at the time of the first dose of CV185057 study treatment will be reported to the CV185056 study only, as depicted in Figure 5.7.1.

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Figure 5.7.1:

CV185056 Clinical Protocol

SAE and AE Reporting during CV185056 and CV185057

056 TREATMENT PERIOD

056 FOLLOW UP PERIOD

Approved v 5.0

057 SCREENING AND BASELINE NEW SAE

057 TREATMENT PERIOD

057 TREATMENT PERIOD

057 FOLLOW UP PERIOD

a

056 SAE Form

b

057 SAE Form

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a

056 AE Form

b

057 AE Form

Consent for 057

First dose of 057 study treatment

a

New SAEs and AEs that occur prior to the first dose of CV185057 study treatment will be reported to the CV185056 study only. SAEs and AEs that are ongoing at the time of the first dose of CV185057 study treatment will be followed in the CV185056 study only. b

New SAEs and AEs that occur after the first dose of CV185057 study treatment will be reported to the CV185057 study only. SAEs and AEs that are ongoing at the time of the first dose of CV185057 study treatment will be followed in the CV185056 study only.

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Blinded INRs For Subjects Transitioning from CV185056 (AMPLIFY) to CV185057 (AMPLIFY-EXT)

In order to protect the CV185056 blind, only blinded INRs will be conducted on all subjects transitioning from CV185056 to CV185057. Blinded INRs can be obtained by one of two methods: 1. 2.

Analyzing a blood sample using the study specific encrypted point of care device and procedures; or Submitting a blood sample to the central laboratory for a blinded INR measurement

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6

STUDY ASSESSMENTS AND PROCEDURES

6.1

Flow Chart/Time and Events Schedule

Approved v 5.0

Table 6.1:

Flow Chart/Time and Events Schedule

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Procedure

a Screening (≤ 48 hours prior to Randomization)

Informed Consent

X

Inclusion/Exclusion Criteria

X

Medical History

X

Physical Examination

X

6.3.5

Height and Weight

X

6.3.6

Vital Signs: BP, HR

X

12-Lead Electrocardiogram

X

Provide Documentation of Index c

a Baseline (Day 1)

Weeks 2, 4, 8, 12, 16, & 20

Week 24 End of Treatment

b Follow-up

Protocol Section

3.3 X

4.2

X

6.3.3 6.3.4

X-----------------------------------------------X

Event to ICAC

Adverse Events Assessment d

Outcome Assessment

X

X

X

X

7

X

X

X

X

6.3, 6.4

X

X

Required Blinded INR e

Measurements

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Table 6.1:

Flow Chart/Time and Events Schedule Procedure

Approved v 5.0

f

Hematology

Chemistry Panel Urinalysis

f

f

Pregnancy Test (WOCBP only)

a Screening (≤ 48 hours prior to Randomization)

a Baseline (Day 1)

Weeks 2, 4, 8, 12, 16, & 20

X

X

X

X

X

X

X

X

X

X

Randomization through IVRS

Week 24 End of Treatment

b Follow-up

g

X

6.3.2

g

X

6.3.2

X

6.3.2

X

6.3.2.1

X

X

5.2

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h

Pharmacodynamic Samples h

Biomarker Samples

X

Sample Banking for Exploratory

X

h, j

Protocol Section

X

i

6.5

X

i

6.6

i

6.8

X

Research

Outcomes Research Dispense Study Treatment

X

Assessment of Study Medication Use Assessment of Concomitant Medication Use

X

X

Collect Study Medication

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X

X

6.8

X

k

X

5.1

X

X

5

X

X

5.5, 6.3.7

X

X

k

X

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Screening may coincide with Baseline (Day 1). All randomized subjects, including subjects who have discontinued study treatment, will be contacted (eg, study site visit or by telephone). Investigators are encouraged to provide documentation for the index event to the adjudication committee as soon as possible during the period that extends from screening period up to two weeks after randomization. See the diagnostic test manual for additional details. Including subjects who have discontinued study treatment Reference Section 5.3 for general guidance on overall INR monitoring. All protocol specific laboratory tests should be analyzed by the central laboratory. A hematology and chemistry panel will be performed at Weeks 2, 4, and 12 only. Participation is voluntary and does not affect study eligibility. Only during week 2 and week 4 visits. Detailed in the Molecular Profiling Supplement to the protocol. Only for those subjects using the post treatment bridging strategy to warfarin as described in Section 5.4.2.

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6.1.1

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Visit Windows

The procedures scheduled at each visit may be performed on days other than the nominal days specified in the table in Section 6.1 (Flow Chart/Time and Events Schedule). The allowed deviations from the nominal visit days are tabulated below:

Table 6.1.1:

Visit Window

Nominal Visit

Visit Days/Allowed Window

Screening

Within 48 hours prior to first dose

Day 1 (Baseline, which may coincide with screening)

Day 1

Week 2 (Day 14)

± 4 days

Week 4 (Day 28)

± 4 days

Week 8 (Day 56)

± 4 days

Week 12 (Day 84)

± 4 days

Week 16 (Day 112)

± 4 days

Week 20 (Day 140)

± 4 days

Week 24 (End of Treatment) (Day 168)

± 4 days

Follow-up (30 days after Week 24 Visit)

± 5 days

6.1.2

Screening Visit

The Investigator or designee will:

• • • • • • • • • •

Obtain written informed consent Obtain relevant medical history Perform physical exam Measure Height and Weight Obtain 12-lead electrocardiogram Measure vital signs (BP, HR) Conduct pregnancy test (WOCBP only) Obtain blood samples for central clinical laboratory tests Obtain urine samples for urinalysis Assess concomitant medication use (within 30 days prior to screening visit)

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• •

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Determine if subject meets inclusion/exclusion criteria Investigators are encouraged to provide documentation for the index event to the adjudication committee as soon as possible during the period that extends from screening period up to two weeks after randomization. See the diagnostic test manual for additional details.

6.1.3

Day 1 (Baseline) Visit (which may coincide with screening)

The Investigator or designee will:

• • • • • • • • • •



Conduct pregnancy test (WOCBP only) Obtain blood samples for central clinical laboratory tests Obtain urine samples for urinalysis Assess concomitant medication use Determine if subject continues to meet inclusion/exclusion criteria Stratify and Randomize subject to study medication using IVRS (See section 5.2 Method of Assigning Subjects to a Treatment Dispense Study Treatment Progress to blinded POC INR monitoring as described in Section 5.3 Start adverse event assessment Investigators are encouraged to provide documentation for the index event to the adjudication committee as soon as possible during the period that extends from screening period up to two weeks after randomization. See the diagnostic test manual for additional details. Outcome assessment (ie suspected recurrent VTE, bleeding) and query of health status.

For subjects participating in the pharmacokinetic assessment:



Obtain blood for biomarker analysis.

*Note: Only Investigators licensed to conduct physical examinations and who are listed on the Delegation of Authority Form are approved to perform physical examinations.

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Weeks 2, 4, 8, 12, 16, 20 Visits

The Investigator or designee will:

• • • • • • • • • •



Assess for AE/SAE(s) Perform blinded POC INR Obtain blood samples for central clinical laboratory tests at Weeks 2, 4, and 12 only. Conduct pregnancy test (WOCBP only) Obtain outcomes research information Collect study medication dispensed at previous visit Assess study medication use Dispense study medication assigned for the current visit Assess concomitant medication use Investigators are encouraged to provide documentation for the index event to the adjudication committee as soon as possible during the period that extends from screening period up to two weeks after randomization. See the diagnostic test manual for additional details Outcome assessment (ie suspected recurrent VTE, bleeding), including subjects who have discontinued study treatment. For subjects who have discontinued study treatment, query of health status (alive, occurrence of efficacy and safety endpoints and AEs/SAEs) by telephone is allowed. Subjects who have new symptoms should undergo further assessment as clinically appropriate, preferably at the study site whenever feasible.

For subjects participating in the pharmacokinetic assessment:

• • •

Obtain blood for pharmacokinetic analysis during visits at Week 2 and Week 4 Obtain blood for pharmacodynamic analysis during visits at Week 2 and Week 4 Obtain blood for biomarker analysis during visits at Week 2 and Week 4.

6.1.5

End of Treatment (Week 24)

The Investigator or designee will:

• •

Measure vital signs (BP, HR) Assess for AE/SAE(s)

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• • • • • • • • •



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Perform blinded POC INR Obtain blood samples for central clinical laboratory tests Obtain urine samples for urinalysis Conduct pregnancy test (WOCBP only) Obtain outcomes research information Collect study medication dispensed at previous visit Assess study medication use Assess concomitant medication use Outcome assessment (ie suspected recurrent VTE, bleeding), including subjects who have discontinued study treatment. For subjects who have discontinued study treatment, query of health status (alive, occurrence of efficacy and safety endpoints and AEs/SAEs) by telephone is allowed. Subjects who have new symptoms should undergo further assessment as clinically appropriate, preferably at the study site whenever feasible. For those subjects using the post treatment bridging strategy to warfarin as described in Section 5.4.2, dispense study medication assigned for the current visit

*Note: After the study treatment period is completed or if the study drug is discontinued, an unblinded INR should not be obtained within 7 days of the last dose of study medication, unless medically necessary or the subject is bridging to open label warfarin.

6.1.6

Follow-up Period

Subjects will receive a telephone contact call 30 days after their Week 24 visit. At this call, the investigator or designee will:

• •



Assess for AE/SAE(s) Outcome assessment (ie recurrent VTE, major bleeding), including subjects who have discontinued study treatment. For subjects who have discontinued study treatment, query of health status (alive, occurrence of efficacy endpoints and SAEs) by telephone is sufficient. For those subjects using the post treatment bridging strategy to warfarin as described in Section 5.4.2, collect study medication dispensed at the previous visit.

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6.2

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Study Materials

The following material will be provided:

• • • • •

Electronic Case Report Form A diagnostic test manual Emergency Cards Laboratory Supplies including Pregnancy Kits Warfarin dosing guidelines (Appendix 3).

6.3

Safety Assessments

6.3.1

Bleeding Assessment

Acute clinically overt bleeding is defined as:

• •

new onset, visible bleeding; or signs or symptoms suggestive of bleeding with confirmatory imaging techniques which can detect the presence of blood (eg, US, CT, MRI).

The definition of major bleeding described below is adapted from the International Society on Thrombosis and Hemostasis (ISTH) definition.

Major bleeding event is defined as a bleeding event that is: •

Acute clinically overt bleeding accompanied by one or more of the following: ○ A decrease in hemoglobin (Hgb) of 2 g/dL or more ○ A transfusion of 2 or more units of packed red blood cells ○ Bleeding that occurs in at least one of the following critical sites: ƒ Intracranial ƒ Intra-spinal ƒ Intraocular (within the corpus of the eye; thus, a conjunctival bleed is not an intraocular bleed) ƒ Pericardial ƒ Intra-articular

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ƒ Intramuscular with compartment syndrome ƒ Retroperitoneal Bleeding that is fatal.

Clinically relevant non-major bleeding event: The definition of clinically relevant non-major bleeding will be acute clinically overt bleeding that consists of:

• • • • •

• • • • • •

Any bleeding compromising hemodynamics Any bleeding leading to hospitalization Subcutaneous hematoma larger than 25 cm2, or 100 cm2 if there was a traumatic cause Intramuscular hematoma documented by ultrasonography Epistaxis that lasted for more than 5 minutes, was repetitive (ie, two or more episodes of bleeding more extensive than spots on a handkerchief within 24 hours), or led to an intervention (eg, packing or electrocoagulation) Gingival bleeding occurring spontaneously (ie, unrelated to eating or tooth brushing) or lasting for more than 5 minutes Hematuria that was macroscopic and was spontaneous or lasted for more than 24 hours after instrumentation (eg, catheter placement or surgery) of the urogenital tract Macroscopic gastrointestinal hemorrhage, including at least one episode of melena or hematemesis, if clinically apparent with positive results on a fecal occult-blood test Rectal blood loss, if more than a few spots on toilet paper Hemoptysis, if more than a few speckles in the sputum and not occurring within the context of pulmonary embolism or Any other bleeding type considered to have clinical consequences for a subject ○ such as medical intervention, the need for unscheduled contact (visit or telephone call) with a physician, or temporary cessation of a study drug; or ○ associated with pain or impairment of activities of daily life.

Minor bleeding events: All acute clinically overt bleeding events not meeting the criteria for either major bleeding or clinically relevant non-major bleeding will be classified as minor bleeding.

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Fatal bleeding event is defined as a bleeding event that the independent adjudication committee determines is the primary cause of death or contributes directly to death. 6.3.1.1

Treatment Guidelines for Bleeding/Suspected Bleeding

Subjects with bleeding or suspected bleeding will undergo confirmatory laboratory or other testing (eg, US, CT, MRI) and a (S)AE CRF must be completed. The date and time of the onset of the bleeding event will be recorded on the CRF. For subjects with minor bleeding, study drug may or may not be held at the discretion of the local physician and investigator. A risk / benefit determination should be made (as would be normally done with warfarin) weighing the subject’s risk of further bleeding against the subject’s risk of thromboembolism and benefit from continued anticoagulation. Minor bleeding should otherwise be managed according to local standard of care. For subjects with clinically significant bleeding, the study drugs should generally be held. Bleeding should be managed according to local standard of care and may include measures such as:

• • •

Local measures to stop the bleeding Volume resuscitation, and transfusion of blood products as appropriate Standard laboratory tests eg hemoglobin, hematocrit, platelet count, etc. Note: Because warfarin affects PT/INR but apixaban does not affect PT/INR or other standard coagulation tests, obtaining a PT/INR may unblind the study treatment and may compromise the integrity of the clinical study. Should a PT/INR be essential to the subject’s management, the results should not be shared with this person, the study physician, or anyone associated with this person or the clinical study.

The management of clinically significant bleeding will in part depend on the randomized treatment assignment (warfarin or apixaban) so unblinding may be necessary (see Section 5.4 on Blinding/Unblinding). Should unblinding occur, subjects receiving warfarin should be managed according to the local standard of care. The anticoagulant effects of warfarin will be reflected in the PT/INR and will generally take 3 - 5 days to return to normal. Warfarin can be reversed more quickly by giving oral or intravenous vitamin K, and/or with fresh frozen plasma (FFP, 2 units IV every 6 hours). Revised Protocol No.: 02 Date: 18-Apr-2011 Approved v 5.0

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There is no reversal agent for apixaban. Given its half-life (12 - 15 hours), however, the anticoagulant effect of apixaban abates in 24 - 48 hours. Subjects receiving apixaban with clinically significant bleeding that does not respond to local measures may be treated with FFP (2 units IV every 6 hours) for 24 - 48 hours or until the bleeding has stopped. For subjects with life threatening bleeding and significant thrombocytopenia or those receiving antiplatelet drugs, transfusion of platelets can be considered. There are few ®

randomized clinical trials of recombinant Factor VIIa (rFVIIa, NovoSeven ) and warfarin induced hemorrhage, and there are pro-thrombotic risks. A recent phase 3 clinical trial employing rFVIIA for treatment of acute spontaneous intracerebral hemorrhage yielded disappointing results (Factor Seven for Acute Hemorrhagic Stroke (FAST) Trial, in press). There is no experience with rFVIIa and apixaban. Some experts have recommended the use of prothrombin complex concentrate (PCC, also referred to as Factor IX concentrate) for reversal of warfarin associated coagulopathy and hemorrhage. There are few randomized clinical trials in this area, but observational studies and some guidelines are cited in support of this approach. There are a variety of PCC formulations available, they differ in their concentration of clotting factors (II, VII, IX and X). Dosing depends on body weight, the formulation of PCC employed, the degree of anticoagulation (INR), the clinical picture and whether concomitant FFP is also administered. Thrombotic events have been reported with PCC use. Given the complexity of the dosing and the risks involved, it is recommended that the decision to employ a PCC for warfarin associated hemorrhage be made by an experienced clinician with careful evaluation of the risks and benefits. There is no data regarding the use of PCC for treatment of apixaban related hemorrhage.

6.3.2

Laboratory Assessments

Blood and urine samples will be obtained on selected visits for clinical laboratory evaluations as outlined in Section 6.1 (Flow Chart/Time and Events Schedule). A central laboratory will perform the analyses and will provide reference ranges for these tests. The following laboratory tests are required for this study, and will be analyzed by a Central Laboratory:

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Hematology Profile: • • • • • • • • • • • • •

Hematocrit Hemoglobin Red Blood Cell Count MCV MCHC MCH White Blood Cell Count Lymphocytes Monocytes Basophils Eosinophils Neutrophils Platelet Count

Chem 21 Panel: • • • • • • • • • • • • • • • • •

Albumin BUN (Urea) Calcium Chloride Bicarbonate CK Creatinine Glucose Potassium Sodium ALP ALT AST Direct Bilirubin Total Bilirubin GGT Phosphate

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• • • •

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Total Protein Uric acid (Urate) Total Cholesterol LDH

Urinalysis: • • • • • • • • • •

Protein Glucose Leukocyte Esterase Nitrite Blood pH Ketones Specific Gravity Bilirubin Urobilinogen

Microscopic Urinalysis: • • • • • • •

RBC WBC Casts Crystals Epithelial Cells Yeast Bacteria

For the central laboratory assessments, materials and detailed instructions for specimen collection, processing, storage and shipment will be provided in special kits and will be described in a separate laboratory manual. Pharmacokinetic, pharmacodynamic and biomarker blood samples may be drawn at the same time as scheduled collections for clinical laboratory tests.

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The central laboratory specimens obtained at the screening visit will be used to determine eligibility for randomization into the study. The central laboratory specimens obtained at the Day 1 (Baseline) visit will serve as the basis for all comparisons during treatment and follow-up. In the event where the screening visit and the Day 1 visit coincide, laboratory specimens must be analyzed by the central laboratory and recorded as the Day 1 visit. In the event when central laboratory results from the screening visit are not received in time for randomization, certified local laboratory results may be used to determine eligibility for randomization. At a minimum, platelet count, hemoglobin, AST, ALT, total bilirubin, serum creatinine, and calculated creatinine clearance are required to determine eligibility for randomization. In addition, sufficient laboratory tests, as deemed by the investigator, to assess the overall health status of the patient for inclusion into the trial should be measured and evaluated at the time of randomization. The source of the lab results (local or central) that are used to determine eligibility for randomization must be stipulated in the source documents.

6.3.2.1

Pregnancy Tests

A pregnancy test is to be conducted in WOCBP (See Sections 4.2.2: Exclusion Criteria for definition of WOCBP):

• •

Within 24 hours of beginning study treatment At all visits

6.3.2.2

Creatinine Clearance

Based on the results of the screening visit clinical laboratory tests, the enrollment criterion for creatinine clearance will be estimated by the method of Cockcroft and Gault: When serum creatinine is measured in mg/dL: Clcr (mL/min) =

(140 - age in years) x (weight in kg) x (0.85 for females only) divided by (serum creatinine in mg/dL) x 72

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When serum creatinine is measured in µmol/L: Clcr (mL/min) =

6.3.2.3

(140 - age) x (weight in kg) x (1.23 for males or 1.04 for females) divided by (serum creatinine in µmol/L)

Treatment Guidelines for Jaundice and Elevated LFTs

The following guidelines are intended to identify and manage subjects with potential hepatotoxicity. Specific laboratory test criteria and instructions for further follow-up are provided. All tests are to be sent to and determined by a Central Laboratory. If at any time during the treatment period a subject’s liver function test (LFT) results show:





An isolated elevation of either ALT ≥ 3 x ULN OR a total bilirubin ≥ 2 x ULN, obtain the following laboratories: ALT, AST, total bilirubin, direct bilirubin, alkaline phosphatase, GGT, CK within one week An elevation of BOTH ALT ≥3 x ULN AND total bilirubin ≥ 2 x ULN, obtain the following laboratories: ALT, AST, total bilirubin, direct bilirubin, alkaline phosphatase, GGT, CK as soon as possible (ie, within ≤ 3 days)

If the repeat tests indicate:

• •



ALT < 3 x ULN and total bilirubin < 2 x ULN, study medication may continue ALT ≥ 3 x ULN but < 5 x ULN and total bilirubin < 2 x ULN study medication may continue but repeat LFTs weekly until ALT returns to < 1.5 x ULN or returns to baseline level if subjects entered the study with an ALT ≥ 1.5 x ULN If the repeat ALT ≥ 3 x ULN AND the total bilirubin is ≥ 2 x ULN, study medication must be discontinued unless, in consultation with the Medical Monitor/Trial Helpline, an alternative causative factor (eg, Gilbert’s syndrome) is identified.

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Study medication must be discontinued if: •

Clinical jaundice is present for a subject at any time

OR



ALT ≥ 3 x ULN plus total bilirubin ≥ 2.0 x ULN and the ratio of direct to total bilirubin is ≥ 50% on any single occasion

OR



If ALT ≥ 5 x ULN on any two consecutive occasions

OR



Total bilirubin ≥ 2.0 x ULN on any two consecutive occasions in the absence of an alternative causative factor [eg, Gilbert’s syndrome] is identified

All subjects with an ALT ≥ 3x ULN or total bilirubin ≥ 2x ULN will be followed weekly until ALT and total bilirubin return to < 1.5x ULN or to baseline levels if subjects entered the study with an ALT ≥ 1.5x ULN. If study medication is discontinued due to elevated ALT or bilirubin, as defined above, inform the Medical Monitor and perform the following:

• •

Hepatitis screen (anti-HAV, HbsAg, anti-HBc, anti-HBs and anti-HCV) Abdominal ultrasound, including liver and hepatobiliary system

If liver function returns to normal, another (not related to study drug) clearly reversible cause is identified (eg, gallstones), and the cause of abnormal liver function is treated or eliminated, consideration may be given to restarting study medication after consulting with the Medical Monitor.

6.3.3

Vital Signs

Vital signs (blood pressure and heart rate) will be recorded at screening and end of treatment visits.

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Electrocardiograms

A 12 lead ECG will be recorded at the screening visit.

6.3.5

Physical Examinations

Targeted physical examinations will be performed at the screening visit and as clinically indicated at other visits.

6.3.6

Physical Measurements

Physical measurements, including height and weight will be measured at the Day 1 (baseline) visit.

6.3.7

Concomitant Medications

Concomitant medications will be recorded at screening, baseline (any medications during the last 30 days), at each visit and end of the intended treatment period visit.

6.3.8

Blinded INR Monitoring

Blinded INR monitoring will be conducted using the encrypted point of care device as described in the protocol. In the event that the encrypted point of care device is unavailable, a blood sample should be submitted to the central laboratory. The central laboratory will perform an INR measurement and provide an INR value to the IVRS vendor. The IVRS vendor will then provide an encrypted code to the site for entry into the IVRS system using the same procedures for encrypted codes obtained by the encrypted point of care device. The central laboratory will not provide the INR value directly to the site and, therefore, the site should not contact the central laboratory regarding the INR measurement. In the event that neither the point of care device nor the central laboratory are viable options, then the medical monitor should be contacted to discuss procedures to protect the blind of the study.

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Section 5.3 and Appendix 2 provide general guidance to blinded INR monitoring but are not intended to overrule good medical judgment or standard of care.

6.4

Efficacy Assessments

6.4.1

Definitions

The adjudication manual will serve as the definitive source for adjudicating all outcome events and AEs of special interest. Guidance to define these events is as follows: 1. Suspected (new or recurrent) PE with one of the following findings:

• • • •

a new intraluminal filling defect in segmental or more proximal branches on spiral CT scan; a new intraluminal filling defect, or an extension of an existing defect, or a new sudden cutoff of vessels more than 2.5 mm in diameter on the pulmonary angiogram; a new perfusion defect of at least 75% of a segment with a local normal ventilation result (high-probability) on ventilation/perfusion lung scan (VPLS); or inconclusive sCT, pulmonary angiography or VPLS evidence of new or recurrent PE, with demonstration of a new or extended DVT in the lower extremities by compression ultrasound or venography.

2. Suspected (new or recurrent) DVT with one of the following findings: (a) For a NEW DVT, criteria include:

• •

abnormal compression ultrasound (CUS), including grey-scale or color-coded Doppler; or an intraluminal filling defect on venography. (b) For a RECURRENT DVT, criteria include:





abnormal CUS where compression had been normal or, if non-compressible previously, a substantial increase (4 mm or more) in diameter of the thrombus during full compression; or an extension of an intraluminal filling defect, or a new intraluminal filling defect or an extension of non-visualization of veins in the presence of a sudden cut-off on venography.

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3. Death: All deaths will be adjudicated by the ICAC and classified as either VTE-related, cardiovascular or other. Deaths are defined as follows: a) VTE-related death

• •

PE based on objective diagnostic testing, autopsy, or Death which can not be attributed to a documented cause (unexplained death) and for which PE/DVT can not be ruled out as the cause. b) Cardiovascular death



This category includes cardiac deaths (eg, cardiogenic shock, fatal arrrhythmia, cardiac rupture) and vascular deaths (eg, VTE-related, fatal stroke, ruptured aortic aneurysm, aortic dissection). c) Other



This category includes all deaths due to a clearly documented other cause, such as respiratory failure (eg, terminal emphysema), hemorrhage (other than intracranial), infections/sepsis, neoplasm, trauma, suicide, or homicide.

6.4.2

Subject Assessments

Subjects will be assessed for signs or symptoms of DVT (ie, swelling, localized pain, redness, heat, localized warmth) and PE (ie, unexplained shortness of breath, chest pain that gets worse with a deep breath, coughing or chest movement or coughing up blood) throughout the course of the study (inclusive of treatment and follow-up periods). If signs and symptoms are present, then subjects will undergo a diagnostic examination to confirm recurrence of VTE. Suspected DVT or PE that occur at anytime after enrollment should also be reported as an AE or a SAE. All VTE will be adjudicated by an independent central adjudication committee in a blinded manner. For the assessment of symptoms of suspected DVT, acceptable diagnostic tests in this study include compression ultrasound (CUS) or ascending venography. In the event that CUS is indeterminate, ascending venography should be used to confirm the presence of DVT.

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For assessment of symptoms of suspected PE, acceptable diagnostic assessments include perfusion lung scan (PLS), a pulmonary angiogram, a high-speed, high-resolution computed tomographic (CT) scan of the chest with an appropriate contrast injection, or a magnetic resonance image (MRI). Documentation to be sent to the adjudication committee will contain copies of images of the tests which were used to confirm the diagnosis. Detailed description of the procedures for these tests will be provided in the diagnostic test manual. During the study, the clinical site should notify Pharmaceutical Product Development Inc (PPD) within 24 hours of awareness of any suspected outcomes (including any suspected venous or arterial thromboembolic events, deaths, or suspected episodes of bleeding) or any of the following events of special interest: acute myocardial infarction, acute stroke, or thrombocytopenia. PPD will in turn notify the ICAC. Documentation for adjudication should be assembled as described in the diagnostic test manual. Investigators are encouraged to send the dossier to the adjudication committee for assessment within 2 weeks of awareness of suspected outcome occurrence. Documentation needed for adjudication of suspected recurrent PE or DVT will be specified in the diagnostic test manual, and will include but will not be limited to clinical summary and copies of films/images of objective testing, eg, CUS or venography for DVT, spiral CT, V/Q scan, angiography and or CUS for PE.

6.5

Pharmacokinetic Assessments

Subject participation in the pharmacokinetic assessments is voluntary and refusal to participate will not affect eligibility for this study. Pharmacokinetic sample collection will be performed on approximately 600 randomized subjects, from a select number of sites, in order to provide apixaban blood samples from approximately 300 subjects. For those sites that participate in PK sample collection, blood specimens will be collected at the week 2 and week 4 visits from all participating subjects in order to maintain the study blind at that site; however, specimens from subjects randomized to active control will not be routinely analyzed. The sampling schedule will depend on the randomization number of the subject, as shown in Table 6.5.

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Samples should be collected as close to the nominal sampling times as possible, but no less than 1 hour apart.

Table 6.5:

Pharmacokinetic Sampling Schedule

Randomization Number

Week 2 Visit

Week 4 Visit

Even

-2 hr predose and predose (0 hr)

2 and 4 hr postdose

Odd

2 and 4 hr postdose

-2 hr predose and predose (0 hr)

For each blood sample collected, the exact date and time of sample collection will be recorded. In addition, the date and time of administration for the last 6 doses of apixaban will be recorded. Additional detailed instructions will be provided separately. Blood samples for pharmacokinetic analysis (approximately 4.5 mL per sample) will be collected by direct venipuncture. Immediately after collection, each blood sample will be gently inverted several times for complete mixing with the anticoagulant (3.2% sodium citrate) and then placed on chipped ice. Within 15 minutes of collection, each blood sample will be centrifuged for 15 minutes at approximately 1500 x g at room temperature to separate plasma. Separated plasma will be transferred to two cryogenic vials (half for measurement of apixaban concentrations and half for measurement of Anti-FXa activity) and immediately stored in an

upright

position

at

approximately

-20°C

for

PK

plasma

aliquot

and

approximately -70°C for Anti-FXa plasma aliquot. If red blood cells are inadvertently drawn into the plasma, the sample will be re-centrifuged immediately. The re-centrifuged sample will be documented on the sample shipment form. All tubes will be clearly and indelibly identified with the labels provided by the central laboratory.

6.6

Pharmacodynamics Assessments

Anti-FXa activity may be measured as an exploratory assessment using an aliquot from the PK plasma sample (see Section 6.5).

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Pharmacogenomics/Pharmacogenetics Assessments

Not Applicable.

6.8

Outcomes Research Assessments

Information related to unplanned hospitalizations, rehabilitations, nursing home admissions, and visits to the emergency department or doctor’s office will be assessed as part of health care utilization. Information related to health care utilization (eg, discharge diagnosis for a hospitalization or the reason or diagnosis of a clinic visit) during the course of the study will be collected. Associated costs will be imputed from outside sources and descriptive and comparative analyses completed with respect to utilization and cost.

6.9

Other Assessments

Biomarker Assessment For subjects participating in the pharmacokinetic assessment, two additional blood samples will be collected at the baseline, week 2 and week 4 visits, and may be analyzed for biomarkers of hemostasis and inflammation, such as, but not limited to, D-dimer or C-reactive protein (CRP). These samples may be collected at any time during the visit. Assessment of D-dimer One blood sample for D-dimer analysis (approximately 4.5 mL per sample) will be collected by direct venipuncture at the baseline, week 2, and week 4 visits. Immediately after collection, each blood sample will be gently inverted several times for complete mixing with the anticoagulant (3.2% sodium citrate) and then placed on chipped ice. Within 15 minutes of collection, each blood sample will be centrifuged for 15 minutes at approximately 1500 x g at room temperature to separate plasma. Separated plasma will be transferred to a cryogenic vial and immediately stored in an upright position at approximately -70°C. If red blood cells are inadvertently drawn into the plasma, the sample will be re-centrifuged immediately. The need for re-centrifugation

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will be documented on the sample shipment form. All tubes will be clearly and indelibly identified with the labels provided by the central laboratory. Assessment of C-reactive protein (CRP) One blood sample for C-reactive protein analysis (approximately 5 mL per sample) will be collected into tubes containing no preservative or additive. Samples will be collected by direct venipuncture at the baseline, week 2, and week 4 visits. Immediately after collection, samples will remain at room temperature until clotted (approximately 30 minutes). Samples will then be centrifuged for 15 minutes at approximately 1500 x g at room temperature to separate serum. Separated serum will be transferred to a cryogenic vial and immediately stored in an upright position at approximately -70°C. If red blood cells are inadvertently drawn into the serum, the sample will be re-centrifuged immediately. The need for re-centrifugation will be documented on the sample shipment form. All tubes will be clearly and indelibly identified with the labels provided by the central laboratory.

6.9.1

Events of Special Interest

In addition to bleeding, the following clinical events have been prospectively identified as events of special interest for the apixaban clinical program. In addition to routine reporting as an AE or SAE, detailed information on these events will be collected. The cause for these events of special interest will be adjudicated.

Thrombocytopenia Thrombocytopenia will be determined by the independent adjudication committee based on evidence in a clinical dossier (eg, hospital records). In addition, the independent adjudication committee will determine whether the event is associated with a disseminated thrombosis syndrome. Thrombocytopenia is defined as follows: A decline in platelet count to < 100,000/mm3 for subjects with a baseline value > 150,000/mm3 or a > 50% decline if the baseline value is ≤ 150,000/mm3.

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Elevated liver function tests Liver function tests will be performed at pre-specified time points and at unscheduled times according to standard patient care. Follow-up testing and treatment guidelines will be provided for jaundice and elevated LFTs.

Neuropathy All AE reports will be compared to a list of terms from the Medical Dictionary for Regulatory Activities (MedDRA) that are suggestive of possible neuropathies or other neurological events. AEs matching any of these terms that persist for at least 7 days or result in a neurology consultation will be followed by collection of additional specific information on specialized case report forms for these types of events. Neurological consultations will be recommended for any SAEs matching the list of terms suggestive of possible neuropathies or other neurological events.

Acute myocardial infarction (MI) Acute MI will be determined by the independent adjudication committee based on evidence in the clinical dossier. An acute MI requires the presence of at least 2 out of the 3 following conditions:

• • •

an appropriate clinical situation suggestive of an MI (eg, abnormal history, physical examination or new ECG changes) elevation of CK-MB or Troponin T or I ≥ 2 x ULN; if no CK-MB or troponin values are available, a total CK ≥2x ULN new, significant (≥0.04 seconds) Q waves in ≥ 2 contiguous leads.

Acute stroke Acute stroke is to be determined by the independent adjudication committee based on evidence in the clinical dossier. An acute stroke is defined as a new, focal neurological deficit of sudden onset, lasting at least 24 hours, that is not due to a readily identifiable non-vascular cause (ie, brain tumor, trauma). All strokes during the study will be assessed by imaging or autopsy and classified as primary hemorrhagic, non-hemorrhagic,

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infarction with hemorrhagic conversion, or unknown, as defined by the American College of Cardiology (ACC):

26

8) Primary hemorrhagic: a stroke with documentation on imaging [eg computed tomographic (CT) scan or magnetic resonance imaging (MRI)] of hemorrhage in the cerebral parenchyma, or a subdural or subarachnoid hemorrhage. Evidence of hemorrhagic stroke obtained from lumbar puncture, neurosurgery, or autopsy can also confirm the diagnosis. 9) Non-hemorrhagic: a focal neurological deficit that results from a thrombus or embolus (and not due to hemorrhage) that appears and is still partially evident at 24 hours. 10) Infarction with hemorrhagic conversion: no evidence of hemorrhage on an initial scan but appeared on a subsequent scan. 11) Unknown type/no imaging performed: the type of stroke could not be determined by imaging or other means (lumbar puncture, neurosurgery).

7

ADVERSE EVENTS

7.1

Definitions

An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a patient or clinical investigation subject administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of investigational product, whether or not considered related to the investigational product.

7.1.1

Serious Adverse Events

A serious AE (SAE) is any untoward medical occurrence that at any dose:

• •

results in death is life-threatening (defined as an event in which the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe)

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requires inpatient hospitalization or causes prolongation of existing hospitalization (see note below for exceptions) results in persistent or significant disability/incapacity is a congenital anomaly/birth defect (note: reports of congenital anomalies/birth defects must also be reported on the Pregnancy Surveillance Form [See Section 7.6]) is an important medical event (defined as a medical event(s) that may not be immediately life-threatening or result in death or hospitalization but, based upon appropriate medical and scientific judgment, may jeopardize the subject or may require intervention [eg, medical, surgical] to prevent one of the other serious outcomes listed in the definition above). Examples of such events include, but are not limited to, intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization). For reporting purposes, BMS also considers the occurrence of pregnancy (See Section 7.6), overdose (regardless of association with an AE), and cancer as important medical events. An overdose is defined as the accidental or intentional ingestion of any dose of a product that is considered both excessive and medically important.

The following hospitalizations are not considered SAEs in BMS clinical studies:

− a visit to the emergency room or other hospital department < 24 hours, that does not result in admission (unless considered "important medical event" or event life threatening) − elective surgery, planned prior to signing consent − admissions as per protocol for a planned medical/surgical procedure − routine health assessment requiring admission for baseline/trending of health status (eg, routine colonoscopy) − medical/surgical admission for purpose other than remedying ill health state and was planned prior to entry into the study. Appropriate documentation is required in these cases − admission encountered for another life circumstance that carries no bearing on health status and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, care-giver respite, family circumstances, administrative)

7.1.2

Nonserious Adverse Events

All AEs that are not classified as serious are considered nonserious.

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Assignment of Adverse Event Intensity and Relationship to Investigational Product

The following categories and definitions of intensity as determined by a physician should be used for all BMS clinical study AEs:

• • • •

Mild (Grade 1) - Awareness of event but easily tolerated Moderate (Grade 2) - Discomfort enough to cause some interference with usual activity Severe (Grade 3) - Inability to carry out usual activity Very Severe (Grade 4) - Debilitating, significantly incapacitates subject despite symptomatic therapy.

The following categories and definitions of causal relationship to investigational product as determined by a physician should be used for all BMS clinical study AEs:



• • •



Certain: There is a reasonable causal relationship between the investigational product and the AE. The event responds to withdrawal of investigational product (dechallenge), and recurs with rechallenge when clinically feasible. Probable: There is a reasonable causal relationship between the investigational product and the AE. The event responds to dechallenge. Rechallenge is not required. Possible: There is reasonable causal relationship between the investigational product and the AE. Dechallenge information is lacking or unclear. Not likely: There is a temporal relationship to investigational product administration, but there is not a reasonable causal relationship between the investigational product and the AE. Not related: There is not a temporal relationship to investigational product administration (too early, or late, or investigational product not taken), or there is a reasonable causal relationship between noninvestigational product, concurrent disease, or circumstance and the AE.

7.3

Collection and Reporting

Adverse events can be spontaneously reported or elicited during open-ended questioning, examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be questioned regarding the specific occurrence of one or more AEs).

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If known, the diagnosis of the underlying illness or disorder should be recorded, rather than its individual symptoms. The following information should be captured for all AEs: onset, duration, intensity, seriousness, relationship to investigational product, action taken and treatment required. If treatment for the AE was administered, it should be recorded on the appropriate CRF page. The investigator shall supply the sponsor and Ethics Committee with any additional requested information, notably for reported deaths of subjects. Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities that are reported/identified during the course of the study.

7.3.1

Serious Adverse Events

Following the subject’s written consent to participate in the study, which must be obtained before any screening procedures, all SAEs must be collected, including those thought to be associated with clinical study procedures. All SAEs must be collected that occur within 30 days from the end of the intended treatment period. If applicable, SAEs must be collected that relate to any later protocol-specified procedure (eg, a follow-up skin biopsy). The investigator should notify PPD of any SAE occurring after this time period that is believed to be certainly, probably, or possibly related to the investigational product. Serious adverse events, whether related or unrelated to investigational product, must be recorded on the SAE page of the CRF and reported expeditiously to BMS (or designee) to comply with regulatory requirements. An SAE report should be completed for any event where doubt exists regarding its status of seriousness. All SAEs must be reported within 24 hours of awareness by completing the paper Bristol-Myers Squibb Company Serious Adverse Event form and transmitting it by facsimile (confirmed facsimile transmission is required) or by scanning and sending it by electronic mail. Completing the SAE eCRF in OC-RDC does not fulfill this requirement. If only limited information is initially available, follow-up reports are required. (Note: Follow-up SAE reports should include the same investigator term(s) initially reported). In selected circumstances, the protocol may specify conditions that require additional telephone reporting. Revised Protocol No.: 02 Date: 18-Apr-2011 Approved v 5.0

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If the investigator believes that an SAE is not related to the investigational product, but is potentially related to the conditions of the study (such as withdrawal of previous therapy, or a complication of a study procedure), the relationship should be specified in the narrative section of the SAE page of the CRF. If an ongoing SAE changes in its intensity or relationship to the investigational product, a follow-up SAE report should be sent immediately to the sponsor. As follow-up information becomes available it should be sent immediately using the same procedure used for transmitting the initial SAE report. Supporting documentation such as hospital discharge summaries and autopsy reports should be forwarded to BMS in the same manner. All SAEs should be followed to resolution or stabilization.

SAE Email Addresses: Europe and Asia-Pacific: [email protected] Latin America (including Central and South America): [email protected] North America: [email protected]

SAE TELEPHONE CONTACT Name: Keven Griffith, MD Office: PPD Inc. 1800 Perimeter Park, Suite 275 Morrisville, NC 27560 USA 24 Hour Contact and Fax numbers:

• • •

US/Canada Medical and Safety Hotline: 888-483-7729 and Fax: 888-529-3580 EU/ROW Medical and Safety Hotline: 44-1223-374-240 and Fax: 44-1223-374-102 LA Medical and Safety Hotline: +55 11 4504 4801 and Fax: +55 11 4504 4802

7.3.2

Handling of Expedited Safety Reports

In accordance with local regulations, BMS will notify investigators of all SAEs that are suspected (certainly, probably, or possibly related to the investigational product) and unexpected (ie, not previously described in the Investigator Brochure). In the European Union (EU), an event meeting these criteria is termed a Suspected, Unexpected Serious Revised Protocol No.: 02 Date: 18-Apr-2011 Approved v 5.0

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Adverse Reaction (SUSAR). Investigator notification of these events will be in the form of an expedited safety report (ESR). Other important findings which may be reported by the sponsor as an ESR include: increased frequency of a clinically significant expected SAE, an SAE considered associated with study procedures that could modify the conduct of the study, lack of efficacy that poses significant hazard to study subjects, clinically significant safety finding from a nonclinical (eg, animal) study, important safety recommendations from a study data monitoring committee, or sponsor decision to end or temporarily halt a clinical study for safety reasons. Upon receiving an ESR from BMS, the investigator must review and retain the ESR with the Investigator Brochure. Where required by local regulations or when there is a central IRB/IEC for the study, the sponsor will submit the ESR to the appropriate IRB/IEC. The investigator and IRB/IEC will determine if the informed consent requires revision. The investigator should also comply with the IRB/IEC procedures for reporting any other safety information. In this trial, SAEs that are thromboembolic events will be treated as disease-related and not subject to routine expedited reporting. Bleeding SAEs must be reported by the investigator to the sponsor but BMS will not report these events as ESRs because these events are being monitored by a DMC. The primary safety and efficacy outcome events (eg DVT, PE and major bleeding), will not be subject to expedited safety reporting; however, all deaths considered by the study investigator as possibly related to the investigational product/study drug) will be handled according to expedited reporting procedures. Specifically related unexpected SAEs and related deaths will be submitted by BMS to the relevant competent health authorities in all concerned countries according to local regulations (either as expedited and/or in aggregate reports). In addition, suspected serious adverse reactions (whether expected or unexpected) shall be reported by BMS to the relevant competent health authorities in all concerned countries according to local regulations (either as expedited and/or in aggregate reports).

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Nonserious Adverse Events

The collection of nonserious AE information should begin at initiation of investigational product. Nonserious AE information should also be collected from the start of a placebo lead-in period or other observational period intended to establish a baseline status for the subjects. If an ongoing AE changes in its intensity or in its perceived relationship to investigational product, a new AE entry for the event should be completed. Adverse events should be followed to resolution or stabilization, or reported as SAEs if they become serious (See Section 7.3.1). Follow-up is also required for AEs that cause interruption or discontinuation of investigational product, or those that are present at the end of study participation. Subjects with AEs at study completion should receive post-treatment follow-up as appropriate. All identified nonserious AEs must be recorded and described on the appropriate nonserious AE page of the CRF (paper or electronic).

7.4

Laboratory Test Abnormalities

All laboratory test values captured as part of the study should be recorded on the appropriate laboratory test results pages of the CRF, or be submitted electronically from a central laboratory. In addition, the following laboratory abnormalities should also be captured on the nonserious AE CRF page (paper or electronic) or SAE paper CRF page as appropriate:

• • •

Any laboratory test result that is clinically significant or meets the definition of an SAE Any laboratory abnormality that required the subject to have the investigational product discontinued or interrupted Any laboratory abnormality that required the subject to receive specific corrective therapy.

It is expected that wherever possible, the clinical, rather than the laboratory term would be used by the reporting investigator (eg, anemia versus low hemoglobin value).

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Overdose

An overdose is defined as the accidental or intentional ingestion of any dose of a product that is considered both excessive and medically important. All occurrences of overdose that are considered both excessive and medically important must be reported as an SAE (See Section 7.3.1 for reporting details).

7.6

Pregnancy

Sexually active WOCBP must use an effective method of birth control during the course of the study, in a manner such that risk of failure is minimized (See Section 4.2.1 for the definition of WOCBP). Before enrolling WOCBP in this clinical study, investigators must review the sponsorprovided information about study participation for WOCBP. The topics include the following:

• • • • • •

General Information Informed Consent Form Pregnancy Prevention Information Sheet Drug Interactions with Hormonal Contraceptives Contraceptives in Current Use Guidelines for the Follow-up of a Reported Pregnancy

Prior to study enrollment, WOCBP must be advised of the importance of avoiding pregnancy during study participation and the potential risk factors for an unintentional pregnancy. The subject must sign an informed consent form documenting this discussion.

7.6.1

Requirements for Pregnancy Testing

All WOCBP MUST have a negative pregnancy test within 24 hours as specified in Section 6.1 prior to receiving the investigational product. The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent units of HCG. If the pregnancy test is positive, the subject must not receive the investigational product and must not continue in the study. Revised Protocol No.: 02 Date: 18-Apr-2011 Approved v 5.0

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Pregnancy testing must also be performed throughout the study as specified in Section 6.1 (See flow chart/time and events schedule) and the results of all pregnancy tests (positive or negative) recorded on the CRF or transferred electronically. In addition, all WOCBP should be instructed to contact the investigator immediately if they suspect they might be pregnant (eg, missed or late menstrual period) at any time during study participation.

7.6.2

Reporting of Pregnancy

If, following initiation of the investigational product, it is subsequently discovered that a study subject is pregnant or may have been pregnant at the time of investigational product exposure, including during at least 6 half-lives after product administration, the investigational product will be permanently discontinued in an appropriate manner (eg, dose tapering if necessary for subject safety). Exceptions to the investigational product discontinuation may be considered for life-threatening conditions only after consultation with the medical monitor or as otherwise specified in this protocol. The investigator must immediately notify the medical monitor of this event, record the pregnancy on the Pregnancy Surveillance Form. Initial information on a pregnancy must be reported immediately to BMS and the outcome information provided once the outcome is known. Forward these forms to BMS according to SAE reporting procedures described in Section 7.3.1. Protocol-required procedures for study discontinuation and follow-up must be performed on the subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy follow-up procedures should be considered if indicated. Follow-up information regarding the course of the pregnancy, including perinatal and neonatal outcome must be reported on the Pregnancy Surveillance Form. If any male subject's partner becomes or is found to be pregnant during the male subject's treatment with the investigational product, the investigator must submit this information to BMS on a Pregnancy Surveillance Form as described above.

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Other Safety Considerations

Any significant changes noted during interim or final physical examinations, electrocardiograms, x-rays, and any other potential safety assessments, whether or not these procedures are required by the protocol, should also be recorded on the appropriate nonserious AE page of the CRF (paper or electronic) or SAE paper CRF page.

8

STATISTICAL CONSIDERATIONS

8.1

Sample Size Determination

The sample size was computed for a non-inferiority margin of 1.8. The rationale for the margin is detailed in the Statistical Analysis Plan (SAP). Using the method of Farrington 22

Manning

with the assumption that 3% of subjects in the enoxaparin/warfarin group

have VTE/VTE related death over 6 months of therapy, a sample size of 4094 subjects will have 90% power for a one-sided α = 0.025 non-inferiority test. A sample size of 4094 is large enough to adequately power the study for the primary intent-to-treat assessment. However, a second analysis based on a per-protocol data set needs to have adequate power for this non-inferiority study. Therefore the sample size will be adjusted to 4816 (2408 per group) to account for ~15% of subjects discontinuing treatment early and continuing to complete all scheduled treatment visits up to 6 months after randomization. A review of the blinded aggregate rate for the primary efficacy endpoint will be provided to the Steering Committee after 80% of subjects have been randomized. The sample size may be adjusted to provide sufficient power for the non-inferiority test on the primary efficacy endpoint based on both the intent to treat and the per-protocol data sets. This blinded review will be performed by an independent statistician. The maximum sample size will be 5400 subjects.

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Populations for Analyses

The primary efficacy data set will consist of all randomized subjects with a primary endpoint. Subjects will be categorized to the group to which they were assigned by the IVRS, regardless of the treatment actually received. A secondary efficacy data set, to be used for the per-protocol analysis of the primary efficacy endpoint, is the evaluable subject data set (defined in the SAP). The safety data set (as-treated) will consist of all treated subjects (randomized subjects who received at least one dose of study drug). For the purpose of safety analyses, subjects will be categorized to the group to which they were assigned by the IVRS unless incorrect study treatment was received throughout the study, in which case the subject will be categorized according to the treatment received.

8.3

Endpoint Definitions

Primary Efficacy Endpoint: The primary efficacy outcome is the incidence of an adjudicated composite of recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or VTE-related death during 6 months of therapy.

Secondary Efficacy Endpoints: The incidence of:

• • • • • • • •

adjudicated composite of recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) and all-cause death adjudicated composite of recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) and CV death adjudicated composite of recurrent symptomatic VTE (nonfatal DVT or nonfatal PE), VTE-related death and major bleeding adjudicated symptomatic nonfatal DVT adjudicated symptomatic nonfatal PE adjudicated VTE-related death adjudicated CV death all-cause death.

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Primary Safety Endpoint The primary safety outcome is the incidence of adjudicated major bleeding (defined in Section 6.3.1) during the treatment period.

Secondary Safety Endpoints The incidence of:



an adjudicated composite of major and clinically relevant non-major bleeding

Other safety outcome measures will also be assessed, including adjudicated minor bleeding, adjudicated total bleeding, serious and non-serious AEs, and changes in standard clinical laboratory test results.

Other Endpoints: Estimates of apixaban population pharmacokinetic parameters.

8.4

Analyses

Detailed methodology for summary and statistical analyses of the data collected in this trial will be documented in a Statistical Analysis Plan (SAP), which will be finalized and dated and maintained by the sponsor prior to unblinding the data. The SAP may modify the plans outlined in the protocol; however, any major modifications of significant change to the primary endpoint definition and/or its or analysis will also be reflected in a protocol amendment. Analysis of efficacy endpoints will be based only on events that were confirmed by adjudication. All endpoint events reported by the investigator as AEs (serious or nonserious) will be reported in the safety analyses regardless of whether the event was confirmed by adjudication.

8.4.1

Demographics and Baseline Characteristics

Frequency distribution and summary statistics for demographic and baseline variables will be presented by treatment group and for all subjects combined. Key demographic and baseline variables to be summarized include: geographic region, age, gender, race,

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height, weight, body mass index, vital signs (systolic blood pressure, diastolic blood pressure, and heart rate), creatinine clearance; presence/absence of any 2 or more of the following: advanced age (≥ 80 years), low weight (≤ 60 kg), low creatinine clearance (Serum creatinine ≥ 1.5 mg/dL); conditions associated with VTE (cancer [history of cancer; active cancer], persistent or permanent immobility; previous VTE (DVT, PE), prothrombotic genotype, idiopathic cause, and other), cardiovascular risk factors (cigarette smoking, diabetes mellitus, hypercholesterolemia, hypertension, obesity), primary anti-coagulant therapy prior to randomization (eg, VKA) and type of index disease (proximal DVT, PE; provoked or unprovoked).

8.4.2

Safety Analyses

All safety analyses will be conducted on the as-treated population, as defined in Section 8.2. The term “treatment period” refers to the period between the first administration of study drug and 48 hours after the last administration of study drug. This period will be the basis for the summaries of safety.

Primary Safety Analyses The primary safety endpoint will be incidence of adjudicated major bleeding during the treatment period. Point estimates and two-sided 95% CIs for the proportion of subjects in each treatment group with an adjudicated major bleed as well as for the risk difference (difference of proportions) will be presented.

Secondary Safety Analyses The incidence of the adjudicated composite of major and clinically relevant non-major bleeding and adjudicated total bleeding will be analyzed using the methods described above for analysis of major bleeding. Adverse events (AE) and marked abnormalities in clinical laboratory tests will be summarized by treatment group. All AEs that are serious or that result in discontinuation of study drug will be described in depth.

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Other safety outcome measures will also be assessed including changes from baseline in laboratory parameters, abnormal standard clinical laboratory test and vital signs. Details of these analyses will be presented in the SAP.

8.4.3

Efficacy Analyses

The primary objective is to determine whether apixaban is non-inferior to enoxaparin/warfarin for the primary efficacy endpoint (incidence of recurrent VTE and VTE-related death during 6 months of therapy). To conclude non-inferiority for the primary efficacy endpoint, it is necessary to demonstrate that the apixaban event rate is not materially higher than the enoxaparin/warfarin event rate, as measured by both the relative risk (pa/pe) and the risk difference (pa - pe), where pa and pe represent the proportions of subjects with primary efficacy outcomes in the apixaban and enoxaparin/warfarin groups, respectively. Non-inferiority will be concluded if both the following conditions are satisfied;





The upper bound of the 95% CI for the relative risk must not exceed a non-inferiority margin (NIRR) of 1.8. This condition corresponds to a test of the hypothesis H0RR: pa /pe ≥ 1.8 vs. HaRR: pa / pe < 1.8, performed at the one-sided α = 0.025 level. The hypothesis test will be performed using the Yanagawa, Tango and Hiejima (YTH) relative risk method. Descriptive statistics will include an estimate for the relative risk and 95% CI computed based using Mantel-Haenszel’s method stratified by index event. The upper bound of the 95% CI for the risk difference must not exceed a non-inferiority margin (NI∆) of 0.035. This corresponds to a test of the hypothesis H0∆: pa - pe ≥ 0.035 against Ha∆: pa - pe < 0.035, performed at the one-sided α = 0.025 level. The hypothesis test will be performed using YTH’s risk difference method. Descriptive statistics will include an estimate for risk difference and 95% CI 5 computed using the inverse variance method.

The non-inferiority margin for relative risk (NIRR = 1.8) was the minimum value that clinical experts, investigators and Health Authorities thought was clinically meaningful and is less than a margin that would preserve 50% of the treatment effect. The non-inferiority margin for risk difference (NI∆ = 0.035) protects against higher than expected event rates in the control group. Formal justification for these margins is detailed in the SAP. Revised Protocol No.: 02 Date: 18-Apr-2011 Approved v 5.0

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With a 1% to 4% event rate in the enoxaparin/warfarin group, the relative risk margin of 1.8 corresponds to an absolute difference margin of 0.8% to 3.2% which is smaller than the 3.5% absolute difference margin in the second criterion. In this case, the first criterion is more stringent than the second criterion and would determine whether non-inferiority has been demonstrated. However, if the event rate in the enoxaparin/warfarin group was higher than expected (eg, 4.5% or more) then the relative risk margin of 1.8 would correspond to an absolute difference margin of at least 3.6% and the second criterion will determine whether non-inferiority has been demonstrated. Analyses of the primary efficacy endpoint will be performed using both the primary efficacy data set using the intent-to treat principle and the per protocol data set. The per protocol population will be defined in the SAP. The intent-to-treat analysis of the primary endpoint will include endpoints that occur at any time from randomization until the end of their originally intended treatment period regardless of whether subjects are receiving study medication. For the secondary efficacy endpoints, analyses will be performed using the primary efficacy data set. Sensitivity analyses will be performed to assess robustness of the results of the primary efficacy analysis to missing data. This sensitivity analyses will repeat the primary analysis by varying a hypothetical event rate in the missing data. The sensitivity analysis will explore a range of assumptions including following;

• • • •

0% of subjects with missing data on the apixaban and enoxaparin/warfarin treatment groups would achieve the endpoint 100% of subjects with missing data on the apixaban and enoxaparin/warfarin treatment groups would achieve the endpoint 100% of subjects with missing data on apixaban and 0% of subjects on enoxaparin/warfarin would achieve the endpoint 0% of subjects with missing data on apixaban and 100% of subjects on enoxaparin/warfarin would achieve the endpoint.

In addition to the extreme cases bulleted above, other scenarios will be explored. These less extreme scenarios will be detailed in the SAP.

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Key secondary efficacy analyses are the testing of superiority of apixaban over enoxaparin/ warfarin for two composite endpoints: 1) incidence of VTE/VTE-related death, and 2) incidence of VTE/all-cause death. For each of these endpoints a superiority test will be conducted. Superiority will be tested using the Mantel-Haenszel test stratified by index event using the primary efficacy data set. The hypotheses for superiority are H0: pa = pe tested against the alternative Ha: pa < pe where pa and pe represent the proportions of subjects with the endpoint being tested. To control the overall probability of type I error, the following testing procedure will be used. The hypotheses associated with the non-inferiority and the superiority of apixaban relative to enoxaparin and warfarin therapy (as described above) for a 6 month treatment duration, will be tested at the one-sided α = 0.025 following a hierarchical structure:





if non-inferiority of apixaban relative to control treatment group with respect to the primary efficacy endpoint (composite of recurrent VTE and VTE-related death) ○ is not demonstrated, then stop ○ is demonstrated, then superiority of apixaban relative to control treatment group for the primary efficacy endpoint (composite of recurrent VTE and VTE-related death) will be tested. if superiority of apixaban relative to control treatment group with respect to the primary efficacy endpoint (composite of recurrent VTE and VTE-related death) ○ is not demonstrated, then stop ○ is demonstrated, then superiority of apixaban relative to control treatment group for the key secondary efficacy endpoint (composite of recurrent VTE and all- cause death) will be tested. The test of this endpoint is intended for regulatory labeling claims of superiority of apixaban over enoxaparin/warfarin.

Additional supportive endpoints to be analyzed are incidence of:

• • • •

an adjudicated composite of recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) and cardiovascular (CV) death an adjudicated composite of recurrent symptomatic VTE (nonfatal DVT or nonfatal PE), VTE-related death and major bleeding an adjudicated nonfatal symptomatic DVT an adjudicated nonfatal symptomatic PE

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an adjudicated VTE-related death an adjudicated CV death all-cause death.

The analysis will use methodology described for the analyses of the key secondary endpoints. The procedure to control the Type I error across additional potential regulatory claims associated with other secondary objectives will be documented in the statistical analysis plan. All efficacy analyses will be performed on efficacy outcomes confirmed by adjudication. Point and interval estimates of the incidence rates of the primary and secondary efficacy endpoints (Section 8.3) will be calculated and reported. Relative risk of apixaban versus enoxaparin/warfarin (ratio of proportions) will be reported for the adjudicated primary efficacy composite endpoint, and key secondary endpoints as identified in the SAP.

8.4.4

Pharmacokinetic Analyses

Population pharmacokinetic analysis of plasma apixaban concentration versus time data will be conducted using nonlinear mixed effects modeling (NONMEM, University of California, San Francisco, CA). The pharmacokinetic data from this study may be combined with data from other studies for analysis and reporting. The population pharmacokinetic analysis will include all subjects with at least one measured apixaban concentration and adequate dose and sample time information. Based on prior analyses, it is expected that a linear 1-compartment model with first order absorption will adequately describe the data. Estimates of population pharmacokinetic parameters such as CL/F and volume of distribution (V/F), as well as estimates of interindividual and residual variability will be determined. In addition, effects of demographic or physiologic factors (eg, age, race, weight, gender, CLcr) on pharmacokinetic parameters will be assessed. Models will be selected on the basis of goodness-of-fit to the data. This will be assessed using the minimum objective function value obtained from NONMEM, as well as standard diagnostic plots, precision of parameter estimates, and values for interindividual and residual variability. These criteria will be used only when the minimization step is successful and standard errors of parameter estimates are obtained using the

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COVARIANCE step in NONMEM. Additional details on the pharmacokinetic analyses may be found in the SAP.

8.4.5

Pharmacodynamic Analyses

The relationship between anti-Xa activity and plasma apixaban concentration may be explored using appropriate nonlinear mixed effects model-based methods. Based on preclinical and in vitro data, it is expected that linear, Emax and sigmoidal Emax models would be tested. If these analyses are carried out, model fits will be summarized graphically and population parameter estimates will be reported. If D-dimer and CRP are measured, results will be listed and summarized descriptively by sampling time and treatment. Additional details may be found in the SAP.

8.4.6

Pharmacogenomic Analyses

Not Applicable.

8.4.7

Outcomes Research Analyses

Mean healthcare costs associated with study outcomes will be compared between the two arms, and the 95% CIs will be constructed. A multivariate regression model will also be used to compare mean costs adjusting for covariates. Descriptive analyses of utilization will be completed between the two arms.

8.4.8

Other Analyses

Not Applicable.

8.5

Interim Analyses

No interim analysis of efficacy is planned. Ongoing review of the safety of all investigational treatments will be the mandate of the data monitoring committee (DMC). Details are provided in the DMC charter which will be finalized before the first subject visit.

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9

ADMINISTRATIVE SECTION

9.1

Compliance

9.1.1

Compliance with the Protocol and Protocol Revisions

The study shall be conducted as described in this approved protocol. All revisions to the protocol must be discussed with, and be prepared by, Pfizer. The investigator should not implement any deviation or change to the protocol without prior review and documented approval/favorable opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) to study subjects. Any significant deviation must be documented and reflected in the CRF. If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change will be submitted to:

• • •

IRB/IEC for review and approval/favorable opinion Pfizer Regulatory Authority(ies), if required by local regulations.

Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be sent to Pfizer. If an amendment substantially alters the study design or increases the potential risk to the subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects currently enrolled in the study if they are affected by the amendment; and (3) the new form must be used to obtain consent from new subjects prior to enrollment. If the revision is an administrative letter, investigators must inform their IRB(s)/IEC(s).

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Monitoring

Representatives of Pfizer and/or BMS must be allowed to visit all study site locations periodically to assess the data quality and study integrity. The primary efficacy outcome endpoints (ie, DVT, PE and all-cause death), major bleeding, and all other deaths will be included in any random sampling of data integrity performed by monitors. On site monitors will review study records and directly compare them with source documents, discuss the conduct of the study with the investigator, and verify that the facilities remain acceptable. In addition, the study may be evaluated by Pfizer and/or BMS internal auditors and government inspectors who must be allowed access to CRFs, source documents, other study files, and study facilities. Pfizer and BMS audit reports will be kept confidential. THE INVESTIGATOR MUST NOTIFY PFIZER PROMPTLY OF INSPECTIONS SCHEDULED BY REGULATORY AUTHORITIES, PROMPTLY FORWARD COPIES OF INSPECTION REPORTS TO PFIZER.

9.1.3

ANY AND

Investigational Site Training

Pfizer or Pfizer’s designee will provide quality investigational staff training prior to study initiation. Training topics will include but are not limited to: GCP, AE reporting, study details and procedure, study documentation, informed consent, and enrollment of WOCBP. For sites using the Pfizer’s electronic data capture tool of choice, each individual making entries and/or corrections on electronic CRFs must meet predefined training requirements and must only access the electronic data capture tool using the unique user account provided by the sponsor. User accounts are not to be shared or reassigned to other individuals. For electronic CRFs, corrections are made through the electronic data capture tool that generates an automated audit trail including date and timestamp, full name of the person making the correction and original entry. The system also prompts the user to document reason for change that is also maintained in the audit trail.

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Each individual electronically signing electronic CRFs must meet predefined training requirements and must only access the electronic data capture tool using the unique user account provided by the sponsor. User accounts are not to be shared or reassigned to other individuals.

9.2

Records Retention

The investigator must retain investigational product disposition records, copies of CRFs (or electronic files), and source documents for the maximum period required by applicable regulations and guidelines, or institution procedures, or for the period specified by the sponsor, whichever is longer. The investigator must contact Pfizer prior to destroying any records associated with the study. Pfizer will notify the investigator when the study records are no longer needed. If the investigator withdraws from the study (eg, relocation, retirement), the records shall be transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such transfer will be given in writing to Pfizer.

9.2.1

Case Report Forms

An investigator is required to prepare and maintain adequate and accurate case histories designed to record all observations and other data pertinent to the investigation on each individual treated or entered as a control in the investigation. Data reported on the CRF that are derived from source documents must be consistent with the source documents or the discrepancies must be explained. Electronic CRFs will be prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will be reported on SAE pages and the Pregnancy Surveillance Form, respectively. Paper CRFs must be completed legibly in ink. Subjects are to be identified by birth date and subject number, if applicable. All requested information must be entered on the CRF in the spaces provided. If an item is not available or is not applicable, it must be documented as such; do not leave a space blank. Spaces may be left blank only in those circumstances permitted by study-specific CRF completion guidelines provided by the sponsor. Electronic data transfer is acceptable.

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The confidentiality of records that could identify subjects must be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s). The investigator will maintain a signature sheet to document signatures and initials of all persons authorized to make entries and/or corrections on CRFs. For paper CRFs, a correction must be made by striking through the incorrect entry with a single line and entering the correct information adjacent to the incorrect entry. The correction must be dated, initialed and explained (if necessary) by the person making the correction and must not obscure the original entry. The completed CRF, including any paper SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by a qualified physician who is an investigator or subinvestigator. For electronic CRFs, review and approval/signature is completed electronically through the electronic data capture tool. The investigator must retain a copy of the CRFs including records of the changes and corrections.

9.2.2

Investigational Product Records

It is the responsibility of the investigator to ensure that a current record of investigational product disposition is maintained at each study site where investigational product, which also includes open label warfarin, is inventoried and disposed. Records or logs must comply with applicable regulations and guidelines and should include:

• • • • • • • •

amount received and placed in storage area amount currently in storage area label ID number or batch number and use date or expiry date dates and initials of person responsible for each investigational product inventory entry/movement amount dispensed to and returned by each subject, including unique subject identifiers amount transferred to another area/site for dispensing or storage non-study disposition (eg, lost, wasted, broken) amount returned to the sponsor

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amount destroyed at study site, if applicable retain samples sent to third party for bioavailability/bioequivalence, if applicable

The sponsor will provide forms to facilitate inventory control if the staff at the investigational site does not have an established system that meets these requirements.

9.3

Return and Destruction of Investigational Product

9.3.1

Return of Investigational Product

Upon completion or termination of the study, all unused and/or partially used investigational product must be returned to the designated facility, unless authorized to destroy the investigational product at the site. All investigational product returned to the designated facility must be accompanied by the appropriate documentation and be clearly identified by protocol number and study site number on the outermost shipping container. Returned supplies should be in the original containers (eg, patient kits that have clinical labels attached). Empty containers should not be returned to the designated facility. It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that procedures for proper disposal have been established according to applicable federal, state, local, and institutional guidelines and procedures, and provided that appropriate records of disposal are kept. The return of unused investigational product(s) should be arranged by the responsible Study Monitor.

9.3.2

Destruction of Investigational Product

If investigational products are to be destroyed on site, it is the investigator’s responsibility to ensure that arrangements have been made for the disposal, written authorization has been granted by BMS, procedures for proper disposal have been established according to applicable regulation and guidelines and institutional procedures, and appropriate records of the disposal have been documented. The unused investigational products can only be destroyed after being inspected and reconciled by the responsible Study Monitor.

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Publications

The data collected during this study are confidential and proprietary to the sponsor. Any publications or abstracts arising from this study require approval by the sponsor prior to publication or presentation and must adhere to the sponsor’s publication requirements as set forth in the approved clinical trial agreement (CTA). All draft publications, including abstracts or detailed summaries of any proposed presentations, must be submitted to the sponsor at the earliest practicable time for review, but at any event not less than 30 days before submission or presentation unless otherwise set forth in the CTA. sponsor shall have the right to delete any confidential or proprietary information contained in any proposed presentation or abstract and may delay publication for up to 60 days for purposes of filing a patent application.

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GLOSSARY OF TERMS

Term

Definition

Adverse Event

Any new untoward medical occurrence or worsening of a pre-existing medical condition in a patient or clinical investigation subject administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of investigational product, whether or not considered related to the investigational product.

Adverse Reaction

An adverse event that is considered by either the investigator or the sponsor as certainly, probably, or possibly to the investigational product

Expedited Safety Report

Rapid notification to investigators of all SAEs that are suspected (certainly, probably, or possibly related to the investigational product) and unexpected (ie, not previously described in the Investigator Brochure), or that could be associated with the study procedures.

Serious Adverse Event

Serious adverse event defined as any untoward medical occurrence that at any dose: results in death; is lifethreatening (defined as an event in which the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe), requires inpatient hospitalization or causes prolongation of existing hospitalization; results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect; is an important medical event (defined as a medical event(s) that may not be immediately lifethreatening or result in death or hospitalization but, based upon appropriate medical and scientific judgment, may jeopardize the subject or may require intervention [eg, medical, surgical] to prevent one of the other serious outcomes listed in the definition above). Examples of such events include, but are not limited to, intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do

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Term

Definition not result in hospitalization.). For reporting purposes only, BMS also considers the occurrence of pregnancy, overdose (regardless of association with an AE), and cancer as important medical events.

SUSAR

Suspected, Unexpected, Serious Adverse Reaction as termed by the European Clinical Trial Directive (2001/20/EC).

Unexpected Adverse Reaction

An adverse reaction, the nature or severity of which is not consistent with the applicable product information (eg, Investigator Brochure for an unapproved investigational product)

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LIST OF ABBREVIATIONS

Term AE ALT aPTT ASA AST AUC BID BMS BP ICAC CK CRF CUS

Definition adverse event alanine aminotransferase activated partial thromboplastin time acetylsalicylic acid aspartate aminotransferase Area under the curve twice daily Bristol-Myers Squibb blood pressure Central independent adjudication committee creatine kinase case report form compression ultrasound, including grey-scale or color-coded Doppler cytochrome P-450 Data Monitoring Committee Deep-vein thrombosis electrocardiogram follicle-stimulating hormone Gamma-glutamyl transpeptidase human chorionic gonadotropin hormone replacement therapy International Ethics Committee international normalized ratio institutional review board international units Interactive Voice Response System liver function tests Low molecular weight low molecular weight heparin Macro-aggregates of albumin Medical Dictionary for Regulatory Activities nanomolar non-steroidal anti-inflammatory drugs pulmonary embolism

CYP DMC DVT ECG FSH GGT HCG HRT IEC INR IRB IU IVRS LFT LMW LMWH MAA MedDRA nM NSAIDs PE Revised Protocol No.: 02 Date: 18-Apr-2011

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PLS PO PPD PT SAE SC UFH ULN VKA VPLS VTE WOCBP

perfusion lung scan per os (Latin) by mouth Pharmaceutical Product Development Inc prothrombin time serious adverse event subcutaneous unfractionated heparin high limit of normal Vitamin K antagonist Ventilation/perfusion lung scintigraphy venous thromboembolism women of childbearing potential

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REFERENCES

1. Clinical Investigation of Medicinal Products for the Treatment of Venous Thromboembolic Disease. CPMP/EWP/563/98. 16 December 1999. 2. Farrington, CP, Manning, G. Test Statistics and Sample Size Formulae for Comparative Binomial Trials with the Null Hypothesis of Non-zero Risk Difference or Non-unity Relative Risk. Statistics in Medicine, 1990; 9:1447-1454. 3. Fiessinger, JN, Huisman, MV, Davidson, BL, Bounameaux, H, Francis, CW, Eriksson, H, Lundstrom, T, Berkowitz, SD, Nystrom, P, Thorsen, M Ginsberg, JS, for the THRIVE treatment Study Investigators, Ximelagatran vs Low-Molecular-Weight Heparin and Warfarin for the Treatment of Deep Vein Thrombosis, A Randomized Trial. JAMA, 2005; 293(6):681-689. 4. The van Gogh Investigators. Idraparinux versus Standard Therapy for Venous Thromboembolic Disease. NEJM, 2007; 357(11):1094-1104. 5. Mehrotra, D., Raikar, R.: Minimum risk weights for comparing treatments in stratified binomial trials. Statistics in Medicine 19, 811-25, 2000. 6. Ageno, W., Becattini, C., Brighton, T, Selby, R, Kamphuisen, PW. Cardiovascular Risk Factors and Venous Thromboembolism: A Meta-Analysis. Circulation. 2008;117:93-102. 7. Eriksson, H, Wahlander, K, Gustafsson, D, et al. A randomized, controlled, doseguiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I. J Thromb Haemost 2003;1,41-47. 8. The Rembrandt Investigators. Treatment of proximal deep vein thrombosis with a novel synthetic compound (SR90107A/ORG31540) with pure anti-factor Xa activity. A phase II evaluation. Circulation. 2000;102; 2726-2731. 9. Buller, HR, Davidson, BL, Decousus, H, et al. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial. Ann Intern Med 2004;140,867-873. 10. The MATISSE Investigators. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med 2003;349,1695-1702. 11. Harenberg J, Schmidt JA, Koppenhagen K, Tolle A, Huisman MV, Buller HR. Fixeddose, body weight-independent subcutaneous LMW heparin versus adjusted dose unfractionated intravenous heparin in the initial treatment of proximal venous thrombosis. EASTERN Investigators. Thromb Haemost. 2000 May;83(5):652-6.

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12. Breddin, HK, Hach-Wunderle, V, Nakov, R, et al. Effects of a low-molecular-weight heparin on thrombus regression and recurrent thromboembolism in patients with deep-vein thrombosis. N Engl J Med 2001;344,626-631. 13. Ongoing study. Oral Direct Factor Xa-Inhibitor Apixaban in Patients With Acute Symptomatic Deep-Vein Thrombosis-The Botticelli DVT Study. http://www.clinicaltrials.gov/ct/show/NCT00252005 14. The PERSIST Investigators. A novel long-acting synthetic Xa inhibitor (SanOrg34006) to replace warfarin for secondary prevention in deep vein thrombosis. A phase II evaluation. J Thromb Haemostast 2004; 2: 47-53. 15. Kakkar VV; Bemiparin Investigators. Treatment of venous thromboembolism: experience with bemiparin. Pathophysiol Haemost Thromb. 2002; 32(5-6):406-7. 16. Buller HR, et al on behalf of the Van Gogh investigators. Idraparinux versus Standard Therapy for Venous Thromboembolic Disease. N Engl J Med 2007;357:1094-104. 17. Schulman S, Wahlander K, Lundstrom T, et al. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med 2003;349,1713-1721. 18. Prins M, et al. On Behalf of the Van Gogh Investigators. The Van Gogh-Extension Trial, a Multicenter, International, Randomized, Double-Blind, Study Comparing the Efficacy and Safety of Once-Weekly Subcutaneous SR34006 With Placebo in the Long-Term Prevention of Symptomatic Venous Thromboembolism in Patients With Symptomatic Pulmonary Embolism or Deep-Vein Thrombosis Who Completed 6 Months of Treatment With Vitamin K Antagonist or SR34006. Oral presentation presented at the 48th Annual Meeting of the American Society of Hematology, in Orlando, Florida, 2006. 19. Buller HR, Agnelli G, Hull RD, Hyers TM, Prins MH, Raskob GE. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:Suppl 3:401S-428S. 20. European Medicines Agency. Op. cit. CPMP/EWP/563/98, 16 December 1999. 21. Deitcher SR. Management of Venous Thromboembolic Disease. In Harrison's Online featuring the complete contents of Harrison's Principles of Internal Medicine, 16th Edition. Dennis L. Kasper, Eugene Braunwald, Anthony S. Fauci, Stephen L. Hauser, Dan L. Longo, J. Larry Jameson, and Kurt J. Isselbacher, Eds. Part 5, Oncology and Hematology, Section 3, Disorders of Hemostasis, Chapter 103. Antiplatelet, Anticoagulant, and Fibrinolytic Therapy. Access webpage on September 8, 2006. http://www.accessmedicine.com/content.aspx?aID=66875&searchStr=thromboembol ism 22. Enoxaparin US Package Insert and EMEA Package Insert.

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23. Siguret V, Gouin I, Debray M, et al. Initiation of warfarin therapy in elderly medical inpatients: a safe and accurate regimen. American Journal of Medicine 2005;118(2):137-42. 24. Garcia D, Regan S, Crowther M, Hughes RA, Hylek EM. Warfarin maintenance dosing patterns in clinical practice: implications for safer anticoagulation in the elderly population. Chest 2005;127(6):2049-56. 25. Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation 2007;115(21):2689-96. 26. Cannon, CP, Battler A, Brindiset RG, et al. American College of Cardiology key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes. JACC 2001; 38:2114-2130. 27. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE Comerota AJ. Antithrombotic therapy for venous thromboembolic disease. Chest 2008; 133: 454S-545S.

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APPENDIX 1 1

ADDITIONAL ETHICAL CONSIDERATIONS

INFORMED CONSENT PROCEDURES

BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed consent form which will include all elements required by ICH, GCP and applicable regulatory requirements. The sample informed consent form will adhere to the ethical principles that have their origin in the Declaration of Helsinki. If the investigator makes changes to the informed consent form sample, BMS will ensure all required elements and local regulatory and legal requirements are met. The consent form must also include a statement that BMS and regulatory authorities have direct access to subject records. Prior to the beginning of the study, the investigator must have the IRB/IEC’s written approval/favorable opinion of the written informed consent form and any other information to be provided to the subjects. The investigator must provide the subject, or, in those situations where consent cannot be given by subjects, their legally acceptable representative with a copy of the consent form and written information about the study in the language in which the subject is most proficient. The language must be non-technical and easily understood. The investigator should allow time necessary for subject or subject's legally acceptable representative to inquire about the details of the study, then informed consent must be signed and personally dated by the subject or the subject's legally acceptable representative and by the person who conducted the informed consent discussion. The subject or legally acceptable representative should receive a copy of the signed informed consent and any other written information provided to study subjects prior to subject's participation in the study.

1.1

Subjects Unable to Give Written Informed Consent

1.1.1

Minors

For minors, according to local legislation, one or both parents or a legally acceptable representative must be informed of the study procedures and must sign the informed consent form approved for the study prior to clinical study participation. (In the event that

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the parents or legal guardians are unable to read, then an impartial witness should be present during the entire informed consent discussion). Whenever feasible, minors who are judged to be of an age of reason must also give their written assent by signing and dating the completed informed consent. All local laws, rules and regulations regarding informed consent of minors must be followed. 1.1.2

Subjects Experiencing Acute Events or Emergencies

A legally acceptable representative or legal guardian must provide informed consent when consent of the subject is not possible prior to clinical study participation, eg, for subjects experiencing an acute medical event such as myocardial infarction or stroke. Informed consent of the subject must additionally be obtained if they become capable of making and communicating their informed consent during the clinical study. All local laws, rules and regulations regarding informed consent of adult subjects incapable of giving informed consent must be followed. 1.1.3

Mentally Impaired or Incapacitated Subjects

Investigators (or whoever required by local regulations) should determine whether or not a mentally impaired or incapacitated subject is capable of giving informed consent and should sign a statement to that effect. If the subject is deemed mentally competent to give informed consent, the investigator should follow standard procedures. If the subject is deemed not to be mentally competent to give informed consent, a fully informed legal guardian or legally acceptable representative can be asked to give consent for, or on behalf of, the subject. All local laws, rules and regulations regarding informed consent of mentally impaired or incapacitated subjects must be followed. Patients who are involuntarily hospitalized because of mental illness must not be enrolled in clinical studies 1.1.4

Other Circumstances

Subjects who are imprisoned or involuntarily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness must not be enrolled in clinical studies.

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In circumstances where a subject’s only access to treatment is through enrollment in a clinical study, eg, for subjects in developing countries with limited resources or for subjects with no marketed treatment options, the investigator must take special care to explain the potential risks and benefits associated with the study and ensure that the subject is giving informed consent. When a subject may be in a dependent relationship with the investigator, a well-informed physician who is not engaged in the clinical study and is completely independent of the relationship between the subject and investigator should obtain the subject’s informed consent. 1.1.5

Illiterate Subjects

If the subject, or, in those situations where consent cannot be given by the subject, their legally acceptable representative is unable to read, a reliable and independent witness should be present during the entire informed consent discussion. The choice of the witness must not breach the subject’s rights to confidentiality. A reliable independent witness is defined as one not affiliated with the institution or engaged in the investigation. A family member or acquaintance is an appropriate independent witness. After the subject or legally acceptable representative orally consents and has signed, if capable, the witness should sign and personally date the consent form attesting that the information is accurate and that the subject, or, in those situations where consent cannot be given by subjects, their legally acceptable representative has fully understood the content of the informed consent agreement and is giving true informed consent.

1.2

Update of Informed Consent

The informed consent and any other information provided to subjects, or, in those situations where consent cannot be given by subjects, the subject's legally acceptable representative, should be revised whenever important new information becomes available that is relevant to the subject's consent, and should receive IRB/IEC approval/favorable opinion prior to use. The investigator, or a person designated by the investigator should fully inform the subject or the subject's legally acceptable representative of all pertinent aspects of the study and of any new information relevant to the subject's willingness to continue participation in the study. This communication should be documented.

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During a subject's participation in the study, any updates to the consent form and any updates to the written information will be provided to the subject.

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APPENDIX 2 US COUMADIN PACKAGE INSERT

Protocol CV185056 34 page(s) excluding cover page

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Rx only ®

Anticoagulant

COUMADIN TABLETS (Warfarin Sodium Tablets, USP) Crystalline ®

COUMADIN FOR INJECTION (Warfarin Sodium for Injection, USP)

WARNING: BLEEDING RISK Warfarin sodium can cause major or fatal bleeding. Bleeding is more likely to occur during the starting period and with a higher dose (resulting in a higher INR). Risk factors for bleeding include high intensity of anticoagulation (INR >4.0), age ≥65, highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, serious heart disease, anemia, malignancy, trauma, renal insufficiency, concomitant drugs (see PRECAUTIONS) and long duration of warfarin therapy. Regular monitoring of INR should be performed on all treated patients. Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shorter duration of therapy. Patients should be instructed about prevention measures to minimize risk of bleeding and to report immediately to physicians signs and symptoms of bleeding (see PRECAUTIONS: Information for Patients).

DESCRIPTION COUMADIN (crystalline warfarin sodium) is an anticoagulant which acts by inhibiting vitamin Kdependent coagulation factors. Chemically, it is 3-(α-acetonylbenzyl)-4-hydroxycoumarin and is a racemic mixture of the R- and S-enantiomers. Crystalline warfarin sodium is an isopropanol clathrate. The crystallization of warfarin sodium virtually eliminates trace impurities present in amorphous warfarin. Its empirical formula is C19H15NaO4, and its structural formula may be represented by the following: O

O H C

ONa

CH2COCH3

Crystalline warfarin sodium occurs as a white, odorless, crystalline powder, is discolored by light and is very soluble in water; freely soluble in alcohol; very slightly soluble in chloroform and in ether. COUMADIN Tablets for oral use also contain: All strengths:

Lactose, starch and magnesium stearate

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NDA 9-218/S-105 Page 2 1 mg: 2 mg:

D&C Red No. 6 Barium Lake FD&C Blue No. 2 Aluminum Lake and FD&C Red No. 40 Aluminum Lake D&C Yellow No. 10 Aluminum Lake and FD&C Blue No. 1 Aluminum Lake FD&C Yellow No. 6 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake and FD&C Red No. 40 Aluminum Lake FD&C Blue No. 1 Aluminum Lake FD&C Yellow No. 6 Aluminum Lake FD&C Yellow No. 6 Aluminum Lake and FD&C Blue No. 1 Aluminum Lake D&C Yellow No. 10 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake Dye Free

2-1/2 mg: 3 mg:

4 mg: 5 mg: 6 mg: 7-1/2 mg: 10 mg:

COUMADIN for Injection is supplied as a sterile, lyophilized powder, which, after reconstitution with 2.7 mL sterile Water for Injection, contains: Warfarin Sodium Sodium Phosphate, Dibasic, Heptahydrate Sodium Phosphate, Monobasic, Monohydrate Sodium Chloride Mannitol Sodium Hydroxide, as needed for pH adjustment to

2 mg/mL 4.98 mg/mL 0.194 mg/mL 0.1 mg/mL 38.0 mg/mL 8.1 to 8.3

CLINICAL PHARMACOLOGY COUMADIN and other coumarin anticoagulants act by inhibiting the synthesis of vitamin K dependent clotting factors, which include Factors II, VII, IX and X, and the anticoagulant proteins C and S. Half-lives of these clotting factors are as follows: Factor II - 60 hours, VII - 4-6 hours, IX - 24 hours, and X - 48-72 hours. The half-lives of proteins C and S are approximately 8 hours and 30 hours, respectively. The resultant in vivo effect is a sequential depression of Factors VII, Protein C, Factor IX, Protein S, and Factor X and II activities. Vitamin K is an essential cofactor for the post ribosomal synthesis of the vitamin K dependent clotting factors. The vitamin promotes the biosynthesis of γ-carboxyglutamic acid residues in the proteins which are essential for biological activity. Mechanism of Action Warfarin is thought to interfere with clotting factor synthesis by inhibition of the C1 subunit of the vitamin K epoxide reductase (VKORC1) enzyme complex, thereby reducing the regeneration of vitamin K1 epoxide. The degree of depression is dependent upon the dosage administered and, in part, by the patient’s VKORC1 genotype. Therapeutic doses of warfarin decrease the total amount of the active form of each vitamin K dependent clotting factor made by the liver by approximately 30% to 50%. Revised Protocol No.: 02 Date: 18-Apr-2011 Approved v 5.0

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NDA 9-218/S-105 Page 3 An anticoagulation effect generally occurs within 24 hours after drug administration. However, peak anticoagulant effect may be delayed 72 to 96 hours. The duration of action of a single dose of racemic warfarin is 2 to 5 days. The effects of COUMADIN may become more pronounced as effects of daily maintenance doses overlap. Anticoagulants have no direct effect on an established thrombus, nor do they reverse ischemic tissue damage. However, once a thrombus has occurred, the goal of anticoagulant treatment is to prevent further extension of the formed clot and prevent secondary thromboembolic complications which may result in serious and possibly fatal sequelae. Pharmacokinetics COUMADIN is a racemic mixture of the R- and S-enantiomers. The S-enantiomer exhibits 2-5 times more anticoagulant activity than the R-enantiomer in humans, but generally has a more rapid clearance. Absorption COUMADIN is essentially completely absorbed after oral administration with peak concentration generally attained within the first 4 hours. Distribution There are no differences in the apparent volumes of distribution after intravenous and oral administration of single doses of warfarin solution. Warfarin distributes into a relatively small apparent volume of distribution of about 0.14 liter/kg. A distribution phase lasting 6 to 12 hours is distinguishable after rapid intravenous or oral administration of an aqueous solution. Using a one compartment model, and assuming complete bioavailability, estimates of the volumes of distribution of R- and S-warfarin are similar to each other and to that of the racemate. Concentrations in fetal plasma approach the maternal values, but warfarin has not been found in human milk (see WARNINGS: Lactation). Approximately 99% of the drug is bound to plasma proteins. Metabolism The elimination of warfarin is almost entirely by metabolism. COUMADIN is stereoselectively metabolized by hepatic microsomal enzymes (cytochrome P-450) to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites (warfarin alcohols). The warfarin alcohols have minimal anticoagulant activity. The metabolites are principally excreted into the urine; and to a lesser extent into the bile. The metabolites of warfarin that have been identified include dehydrowarfarin, two diastereoisomer alcohols, 4'-, 6-, 7-, 8- and 10-hydroxywarfarin. The cytochrome P-450 isozymes involved in the metabolism of warfarin include 2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. 2C9 is likely to be the principal form of human liver P-450 which modulates the in vivo anticoagulant activity of warfarin.

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NDA 9-218/S-105 Page 4 The S-enantiomer of warfarin is mainly metabolized to 7-hydroxywarfarin by CYP2C9, a polymorphic enzyme. The variant alleles CYP2C9*2 and CYP2C9*3 result in decreased in vitro CYP2C9 enzymatic 7-hydroxylation of S-warfarin. The frequencies of these allelles in Caucasians are approximately 11% and 7% for CYP2C9*2 and CYP2C9*3, respectively1. Patients with one or more of these variant CYP2C9 alleles have decreased S-warfarin clearance (Table 1).2

Table 1.

Relationship Between S-Warfarin Clearance and CYP2C9 Genotype in Caucasian Patients N S-Warfarin Clearance/Lean Body Weight (mL/min/kg) Mean (SD)a 118 0.065 (0.025)b 59 0.041 (0.021)b 11 0.020 (0.011)b 188

CYP2C9 Genotype

*1/*1 *1/*2 or *1/*3 *2/*2, *2/*3 or *3/*3 Total a

SD=standard deviation. p3 during the first 3 weeks of warfarin therapy was determined in 219 Swedish patients retrospectively grouped by CYP2C9 genotype. The relative risk of over anticoagulation as measured by INR >3 during the first 2 weeks of therapy was approximately doubled for those patients classified as *2 or *3 compared to patients who were homozygous for the *1 allele.4

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NDA 9-218/S-105 Page 5 Warfarin reduces the regeneration of vitamin K from vitamin K epoxide in the vitamin K cycle, through inhibition of vitamin K epoxide reductase (VKOR), a multiprotein enzyme complex. Certain single nucleotide polymorphisms in the VKORC1 gene (especially the -1639G>A allele) have been associated with lower dose requirements for warfarin. In 201 Caucasian patients treated with stable warfarin doses, genetic variations in the VKORC1 gene were associated with lower warfarin doses. In this study, about 30% of the variance in warfarin dose could be attributed to variations in the VKORC1 gene alone; about 40% of the variance in warfarin dose could be attributed to variations in VKORC1 and CYP2C9 genes combined.5 About 55% of the variability in warfarin dose could be explained by the combination of VKORC1 and CYP2C9 genotypes, age, height, body weight, interacting drugs, and indication for warfarin therapy in Caucasian patients.5 Similar observations have been reported in Asian patients.6,7 Excretion The terminal half-life of warfarin after a single dose is approximately one week; however, the effective half-life ranges from 20 to 60 hours, with a mean of about 40 hours. The clearance of R-warfarin is generally half that of S-warfarin, thus as the volumes of distribution are similar, the half-life of Rwarfarin is longer than that of S-warfarin. The half-life of R-warfarin ranges from 37 to 89 hours, while that of S-warfarin ranges from 21 to 43 hours. Studies with radiolabeled drug have demonstrated that up to 92% of the orally administered dose is recovered in urine. Very little warfarin is excreted unchanged in urine. Urinary excretion is in the form of metabolites. Elderly Patients 60 years or older appear to exhibit greater than expected PT/INR response to the anticoagulant effects of warfarin. The cause of the increased sensitivity to the anticoagulant effects of warfarin in this age group is unknown. This increased anticoagulant effect from warfarin may be due to a combination of pharmacokinetic and pharmacodynamic factors. Racemic warfarin clearance may be unchanged or reduced with increasing age. Limited information suggests there is no difference in the clearance of S-warfarin in the elderly versus young subjects. However, there may be a slight decrease in the clearance of R-warfarin in the elderly as compared to the young. Therefore, as patient age increases, a lower dose of warfarin is usually required to produce a therapeutic level of anticoagulation.

Asians

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NDA 9-218/S-105 Page 6 Asian patients may require lower initiation and maintenance doses of warfarin. One non-controlled study conducted in 151 Chinese outpatients reported a mean daily warfarin requirement of 3.3±1.4 mg to achieve an INR of 2 to 2.5. These patients were stabilized on warfarin for various indications. Patient age was the most important determinant of warfarin requirement in Chinese patients with a progressively lower warfarin requirement with increasing age. Renal Dysfunction Renal clearance is considered to be a minor determinant of anticoagulant response to warfarin. No dosage adjustment is necessary for patients with renal failure. Hepatic Dysfunction Hepatic dysfunction can potentiate the response to warfarin through impaired synthesis of clotting factors and decreased metabolism of warfarin. The administration of COUMADIN via the intravenous (IV) route should provide the patient with the same concentration of an equal oral dose, but maximum plasma concentration will be reached earlier. However, the full anticoagulant effect of a dose of warfarin may not be achieved until 72-96 hours after dosing, indicating that the administration of IV COUMADIN should not provide any increased biological effect or earlier onset of action. CLINICAL TRIALS Atrial Fibrillation (AF) In five prospective randomized controlled clinical trials involving 3711 patients with non-rheumatic AF, warfarin significantly reduced the risk of systemic thromboembolism including stroke (See Table 2). The risk reduction ranged from 60% to 86% in all except one trial (CAFA: 45%) which stopped early due to published positive results from two of these trials. The incidence of major bleeding in these trials ranged from 0.6 to 2.7% (See Table 2). Meta-analysis findings of these studies revealed that the effects of warfarin in reducing thromboembolic events including stroke were similar at either moderately high INR (2.0-4.5) or low INR (1.4-3.0). There was a significant reduction in minor bleeds at the low INR. Similar data from clinical studies in valvular atrial fibrillation patients are not available. Table 2:

Clinical Studies Of Warfarin In Non-Rheumatic AF Patients* N

Study

WarfarinTreated Patients

Thromboembolism Control Patients

PT Ratio

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% Risk Reductio n

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% Major Bleeding WarfarinTreated Patients

Control Patients

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NDA 9-218/S-105 Page 7 Table 2:

Clinical Studies Of Warfarin In Non-Rheumatic AF Patients* N

Thromboembolism 60 0.027

% Major Bleeding 0.6 0.0

AFASAK

335

336

1.5-2.0

2.8-4.2

SPAF

210

211

1.3-1.8

2.0-4.5

67

0.01

1.9

1.9

BAATAF

212

208

1.2-1.5

1.5-2.7

86

60 hrs). This is in contradistinction to the effect on INR, which is noted when factor VII is depleted, and generally occurs within a few days of initiation of therapy. In general, the full 2

antithrombotic effect of warfarin is developed several days after its effect on INR.

Second, the effects on anticoagulant proteins, such as protein C are likely to be encountered before warfarin exerts its full antithrombotic (ie “anti-prothrombin”) effect. For this reason “loading doses” with warfarin (10 mg or more) should be avoided as they are likely to have a greater impact on protein C than on prothrombin, leading potentially to a “prothrombotic” state. In patients who require early onset of anticoagulant effect-such as those with proximal deep venous thrombosis or pulmonary embolism, warfarin is administered with a bridging therapy such as unfractionated or low molecular 3

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weight heparin, or fondaparinux. Since coding of multiple proteins: clotting and anticoagulation factors, the vitamin K epoxide reductase (VKORC), and metabolism pathways in the liver (CYP2C9, CYP1A1, CYP1A2, CYP3A4) is important in the effect and metabolism of warfarin, genetic variation among patients can have a profound effect on warfarin’s pharmacodynamics and pharmacokinetics. Genetic polymorphisms in both CYP2C9 and VKORC1 have been described that confer either warfarin sensitivity or resistance. For example, polymorphisms in CYP2C9 that result in slower metabolism of warfarin occur in 20% of Caucasians but less than 2% of Asians. Patients expressing these alleles can require about half the daily dose of warfarin for maintenance as those who do not.

3

The above factors mean that dosing with warfarin is affected by a number of important extrinsic factors. These include the patient’s daily intake of vitamin K, use of concomitant drugs, herbal products and/or botanicals that may influence the metabolism of vitamin K, and perhaps most importantly, age. The appendix lists some of the most important agents that affect warfarin’s pharmacodynamics; this listing is also found in the warfarin package insert that is appended to the CV185056 protocol.

2

EFFICACY OF WARFARIN FOR TREATMENT OF DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM

Since the 1960s heparins and vitamin K antagonists have been the mainstays of anticoagulation therapy for venous thromboembolism - the former for immediate treatment and the latter for long-term prevention of recurrence. Risk of bleeding is the chief limitation of the use of anticoagulants. Although the pharmacodynamics of warfarin are subject to genetic and environmental variability, the primary determinants of the risk 4

of bleeding are the duration and intensity of anticoagulation therapy. Clinical trials have focused on refining the optimal doses of heparin and warfarin, the optimal duration of treatment, the optimal routes of administration, and the optimal methods of monitoring 5

treatment. Each of an extensive series of well-controlled, randomized, double-blind studies has contributed to the incremental advances that have shaped current guidelines for prophylaxis against venous thromboembolism.6

4

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Warfarin is the most widely used oral anticoagulant for treating venous thromboembolism. Warfarin monitoring is performed using an International Normalized Ratio (INR). Warfarin interacts with many foods, other drugs, and alcohol. A target INR range of 2 - 3 is standard for treatment of venous thromboembolism. Higher levels tend to increase incidence of bleeding without reducing recurrent thromboembolism. Warfarin should be started in conjunction with low molecular weight heparin when the diagnosis of venous thromboembolism is confirmed. As indicated, low molecular weight heparin should be continued concomitantly for five days and until INR is > 2.

3

7

POINT OF CARE INR TESTING

Since the safety and efficacy of warfarin depends upon proper regulation of its pharmacodynamic properties, regular monitoring of its effect is required. Formerly, this was accomplished by measuring the prothrombin time (PT) and adjusting warfarin dosages based on these results. One significant difficulty with this approach was the highly variability of PT results obtained by different laboratories, and at times within the same laboratory. The use of different thromboplastins, reagents and laboratory standards made proper regulation of warfarin difficult, and led to the development of the international normalized ratio, or INR. The INR is defined as: INR = (patient PT/mean normal PT)ISI Where ISI is the International Sensitivity Index of the thromboplastin used in the testing, INRs tend to have lower variability than the PT, and the use of INR testing has improved both the simplicity and reproducibility of warfarin management. As a result, a substantial amount of clinical research has been done to define the optimal INR range (see above) and to refine warfarin dosing algorithms. Even so, the standard deviation of an INR test has been estimated to be 0.2, so warfarin dose changes based upon small changes in the 8

INR are not warranted.

In the past 10 years, small, self-contained point-of-care (POC) INR testing devices have been developed. These devices have been made possible by both advances in microprocessor design and in biologics. Originally intended for anticoagulation clinics and physician’s offices, these devices have been improved and simplified and have

5

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passed through 5 generations in the past 20 years; at least 6 devices have been approved by the U.S. FDA for patient use at home. A POC device was selected for performing INR testing in the CV185056 study. The ®

decision to employ the ProTime POC device (ITC, Edison, NJ, USA) was made for a number of reasons: •



• •

POC devices offer advantages over central laboratory testing in that results are obtained within minutes, rather than being shipped to a distant laboratory for analysis, awaiting results and then seeking to contact the patient with dosing recommendations POC devices used across the study employ the same thromboplastin, central laboratories in a global study may employ different thromboplastins, making comparison of results from different regions more complex POC INR testing simplifies monitoring and makes it easier to preserve blinding ®

The ProTime POC device is a mature design that has been used in a number of blinded clinical trials in the past

®

The ProTime POC device is self calibrating with built in controls that are run with each patient’s INR test. POC INR testing involves having the patient return to the site for a fingerstick (or venipuncture) blood test. The sample is placed in a cuvette that is ®

presented to the ProTime POC device. Two controls are run and then the sample is analyzed. The result appears on the LED read out of the device as an encrypted number. The number is then reported to the IVRS system that provides an INR. If the patient has been randomized to warfarin, this INR will represent the patient’s true INR. If the patient has been randomized to apixaban, the INR reported by the IVRS system will be a sham INR, based on an algorithm that uses the patient’s last doses of warfarin-placebo as well as other factors. The result of this testing is that within minutes of the patient’s POC test, an INR/sham INR is known and a warfarin dose can be provided. This minimizes the need to track results, contact patients and make changes over the telephone. The frequency of INR testing depends on a number of clinical factors and general 9

guidelines do exist. Outpatient INR testing is usually begun after the third dose of warfarin, repeated every few days until a stable value is attained, then twice weekly for two weeks, and then monthly. More frequent monitoring is advised for patients with 6

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patients who have difficulty in achieving or maintaining a stable response, those with certain comorbid conditions, with compliance issues, who may have the addition or discontinuation of concomitant medications known to affect warfarin and with changes in diet.

4

PRINCIPLES OF INITIATION AND MAINTENANCE OF WARFARIN DOSING

In order to maintain consistency across this investigational study, investigators are encouraged to administer warfarin or placebo warfarin in a manner that is consistent with clinical practice as described in the COUMADIN (warfarin) United States Package Insert (Appendix 2). Investigators should not exceed the limits for warfarin dosing or blinded INR monitoring frequency as described in Table 1. Dosing decisions on Day 5 should incorporate the patient’s response to previous warfarin doses, in addition to the Day 5 test result. A similar algorithm, applied prospectively to elderly patients (mean age 85 ± 6 years), achieved a therapeutic INR within 7 days and a maintenance dose within 10 days; no patient had an INR > 4.0.

12

Since INR measurements have a variability that

approaches 10%, frequent dosing changes based upon small differences in the measured INR are likely to be counterproductive. Table 1:

An algorithm for the initiation of warfarin and testing of INR

Age

Day 1: Dose

Day 2: Dose

Day 3: Test

Day 3: Dose

Day 4: Dose

Day 5: Test

Day 5: Dose

< 80

6

6

INR < 1.5

8

8

INR < 1.5

10

INR 1.5 - 1.9

6

4

INR 1.5 - 1.9

6

INR 2.0 - 3.0

2

2

INR 2.0 - 3.0

4

INR > 3.0

Hold

Hold

INR > 3.0

Hold

INR < 1.5

6

6

INR 3.0

Hold

Hold

INR >3.0

Hold

Warfarin may be initiated on an outpatient basis. In initiating warfarin, “loading doses” greater than 6 mg should be avoided. Previous studies have shown that lower initiation doses (~5 mg) achieve the therapeutic range as quickly as higher doses, but with less risk of overshoot. Moreover, initiating with doses that are likely to be much larger than the daily maintenance dose unnecessarily complicates management. Particular care should be taken when initiating elderly patients, who tend to have a lower maintenance dose (see 10

Figure 1). In work performed by Garcia and colleagues,

the median daily maintenance

dose of warfarin for men and women 80 years of age or older was between 3 and 4 mg. Patients over the age of 80 have an increased risk of major hemorrhage, that may exceed 11

10% at one year following initiation of therapy in those who are naïve to warfarin.

Maintenance dosing depends on the factors discussed above, but principally upon age. A variety of approaches including formulas

13

14

nomograms and computer programs

have

been tested using both standard and Bayesian approaches and have yielded similar results,

15

which are on a par with practitioners experienced in warfarin therapy. Different

approaches have been taken to simplify tablet choice and patient compliance. The use of a single tablet size is less confusing to patients; in this study warfarin (or its placebo) will in the form of a 2 mg scored tablet. Some practitioners favor cutting tablets to arrive at the same daily dose (eg a 2 mg tablet split, and the patient advised to take one whole and one half tablet daily for a total daily dose of 3 mg). Others take advantage of warfarin’s long pharmacodynamic half-life and prescribe alternate tablet numbers (eg for 2 mg tablets, take 2 tablets on odd days, and one tablet on even days). Still others prescribe a fixed number of tablets for each day of the week, to allow caregivers to set out doses in advance (eg for 2 mg tablets, 2 tablets on Monday, Wednesday, Friday, 1 tablet on Tuesday, Thursday, Saturday, and no dose on Sunday). Any of the above systems can work well, a tablet splitter will be provided to patients in this study to facilitate dosing. 8

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To assist in the selection of warfarin dosing after day 4, Appendix 5 contains a table summarizing the median, 25th percentile, and 75th percentile for daily warfarin maintenance doses by age, gender, and weight in subjects with venous thromboembolism. Ultimately, the final warfarin dose chosen will rest with the investigator. Long term combined antiplatelet/warfarin treatment is discouraged as it is associated with 16

an increased risk of hemorrhage. Figure 1:

Weekly median maintenance dose of warfarin by age and gender for patients who achieved an INR of 2.0 to 3.0 from a prospective cohort

50

Male

30

35

40

45

Female

25 20

Weekly Warfarin Dose (mg)

(Prospective Cohort)

Garcia et al, Chest, 2005, 127; 2049-2056.

9, up to 5 mg of oral vitamin K may be used, or alternatively, intravenous vitamin K 1.0 to 2.5 mg may be given by slow infusion: rare but serious anaphylactoid reactions to vitamin K have been reported following intravenous administration, so its use must be made with caution. In any event, frequent monitoring of the INR subsequent to its correction is mandatory to minimize further risk.

5.2

Treatment of Bleeding

For subjects with minor bleeding, study drug may or may not be held at the discretion of the local physician and investigator. A risk/benefit determination should be made (as would be normally done with warfarin) weighing the subject’s risk of further bleeding 10

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against the subject’s risk of thromboembolism and benefit from continued anticoagulation. Minor bleeding should otherwise be managed according to local standard of care. For subjects with clinically significant bleeding, the study drugs should generally be held. Bleeding should be managed according to local standard of care and may include measures such as: • • •

Local measures to stop the bleeding Volume resuscitation, and transfusion of blood products as appropriate Standard laboratory tests eg hemoglobin, hematocrit, PT/INR, aPTT, platelet count, etc. (recognizing that the anticoagulant effects of apixaban will not be reflected in standard coagulation tests).

The management of clinically significant bleeding will in part depend on the randomized treatment assignment (warfarin or apixaban) so unblinding may be necessary. Subjects receiving warfarin should be managed according to the local standard of care. The anticoagulant effects of warfarin will be reflected in the PT/INR and will generally take 3 - 5 days to return to normal. Warfarin can be reversed more quickly by giving oral or intravenous vitamin K, and/or with fresh frozen plasma (FFP, 2 units IV every 6 hours). There is no reversal agent for apixaban. Given its half-life (12 - 15 hours), however, the anticoagulant effect of apixaban abates in 24 - 48 hours. Subjects receiving apixaban with clinically significant bleeding that does not respond to local measures may be treated with FFP (2 units IV every 6 hours) for 24 - 48 hours or until the bleeding has stopped. For subjects with life threatening bleeding and significant thrombocytopenia or those receiving antiplatelet drugs, transfusion of platelets can be considered. There are few ®

randomized clinical trials of recombinant Factor VIIa (rFVIIa, NovoSeven ) and warfarin induced hemorrhage, and there are pro-thrombotic risks. A recent phase 3 clinical trial employing rFVIIA for treatment of acute spontaneous intracerebral hemorrhage yielded disappointing results (Factor Seven for Acute Hemorrhagic Stroke (FAST) Trial, in press). There is no experience with rFVIIa and apixaban.

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Some experts have recommended the use of prothrombin complex concentrate (PCC, also referred to as Factor IX concentrate) for reversal of warfarin associated coagulopathy and hemorrhage. There are few randomized clinical trials in this area, but observational 19, 20, 21, 22

studies and some guidelines are cited in support of this approach.

There are a

variety of PCC formulations available, they differ in their concentration of clotting factors (II, VII, IX and X). Dosing depends on body weight, the formulation of PCC employed, the degree of anticoagulation (INR), the clinical picture and whether concomitant FFP is also administered. Thrombotic events have been reported with PCC use. Given the complexity of the dosing and the risks involved, it is recommended that the decision to employ a PCC for warfarin associated hemorrhage be made by an experienced clinician with careful evaluation of the risks and benefits. There is no data regarding the use of PCC for treatment of apixaban related hemorrhage.

6

COMMON WARFARIN-DRUG INTERACTIONS (VERSION 1.04)

6.1

Warfarin-Drug and Botanical Interactions

Drugs that may increase PT/INR: Classes of Drugs: 5-lipoxygenase Inhibitor Adrenergic Stimulants, Central Alcohol Abuse Reduction Preparations Analgesics Anesthetics, Inhalation Antiandrogen Antiarrhythmics Antibiotics Aminoglycosides (oral) Cephalosporins, parenteral Macrolides Miscellaneous Penicillins, intravenous, high dose Quinolones (fluoroquinolones) 12

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Sulfonamides, long acting Tetracyclines Anticoagulants Anticonvulsants Antidepressants Antimalarial Agents Antineoplastics Antiparasitic/Antimicrobials Antiplatelet Drugs/Effects Antithyroid Drugs Beta-Adrenergic Blockers Cholelitholytic Agents Diabetes Agents, Oral Diuretics Fungal Medications, Intravaginal, Systemic Gastric Acidity and Peptic Ulcer Agents Gastrointestinal Prokinetic Agents Ulcerative Colitis Agents Gout Treatment Agents Hemorrheologic Agents Hepatotoxic Drugs Hyperglycemic Agents Hypertensive Emergency Agents Hypnotics Hypolipidemics Bile Acid-Binding Resins Fibric Acid Derivatives HMG-CoA Reductase Inhibitors Leukotriene Receptor Antagonist Monoamine Oxidase Inhibitors Narcotics, prolonged Nonsteroidal Anti-Inflammatory Agents Proton Pump Inhibitors Psychostimulants 13

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Pyrazolones Salicylates Selective Serotonin Reuptake Inhibitors Steroids, Adrenocortical Steroids, Anabolic (17-Alkyl Testosterone Derivatives) Thrombolytics Thyroid Drugs Tuberculosis Agents Uricosuric Agents Vaccines Vitamins Specific Drugs: acetaminophen alcohol allopurinol aminosalicylic acid amiodarone HCl argatroban aspirin atenolol atorvastatin azithromycin bivalirudin capecitabine cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone celecoxib cerivastatin chenodiol chloramphenicol chloral hydrate chlorpropamide cholestyramine cimetidine ciprofloxacin 14

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cisapride clarithromycin clofibrate COUMADIN overdose cyclophosphamide danazol dextran dextrothyroxine diazoxide diclofenac dicumarol diflunisal disulfiram doxycycline erythromycin esomeprazole ethacrynic acid ezetimibe fenofibrate fenoprofen fluconazole fluorouracil fluoxetine flutamide fluvastatin fluvoxamine gefitinib gemfibrozil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole ketoprofen ketorolac lansoprazole lepirudin levamisole levofloxacin 15

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levothyroxine liothyronine lovastatin mefenamic acid methimazole methyldopa methylphenidate methylsalicylate ointment (topical) metronidazole miconazole (intravaginal, oral, systemic) moricizine hydrochloride nalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxandrolone oxaprozin oxymetholone pantoprazole paroxetine penicillin G, intravenous pentoxifylline phenylbutazone phenytoin piperacillin piroxicam pravastatin prednisone propafenone propoxyphene propranolol propylthiouracil quinidine quinine rabeprazole ranitidine rofecoxib 16

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sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide tramadol trimethoprim/sulfamethoxazole urokinase valdecoxib valproate vitamin E zafirlukast zileuton Drugs that may decrease PT/INR: Classes of Drugs: Adrenal Cortical Steroid Inhibitors Antacids Antianxiety Agents Antiarrhythmics Antibiotics Anticonvulsants Antidepressants Antihistamines Antineoplastics Antipsychotic Medications Antithyroid Drugs Barbiturates Diuretics Enteral Nutritional Supplements 17

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Fungal Medications, Systemic Gastric Acidity and Peptic Ulcer Agents Hypnotics Hypolipidemics Bile Acid-Binding Resins HMG-CoA Reductase Inhibitors Immunosuppressives Oral Contraceptives, Estrogen Containing Selective Estrogen Receptor Modulators Steroids, Adrenocortical Tuberculosis Agents Vitamins Specific Drugs: alcohol aminoglutethimide amobarbital atorvastatin azathioprine butabarbital butalbital carbamazepine chloral hydrate chlordiazepoxide chlorthalidone cholestyramine clozapine corticotropin cortisone COUMADIN underdosage cyclophosphamide dicloxacillin ethchlorvynol glutethimide griseofulvin haloperidol meprobamate 6-mercaptopurine methimazole 18

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moricizine hydrochloride nafcillin paraldehyde pentobarbital phenobarbital phenytoin pravastatin prednisone primidone propylthiouracil raloxifene ranitidine rifampin secobarbital spironolactone sucralfate trazodone vitamin C (high dose) vitamin K Botanicals that may influence warfarin’s anticoagulant effects: Botanicals that contain coumarins with potential anticoagulant properties: Agrimony Alfalfa Angelica (Dong Quai) Aniseed Arnica Asafoetida Bogbean Boldo Buchu Capsicum Cassia Celery Chamomile (German and Roman) Dandelion Fenugreek Horse Chestnut Horseradish 19

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Licorice Meadowsweet Nettle Parsley Passion Flower Prickly Ash (Northern) Quassia Red Clover Sweet Clover Sweet Woodruff Tonka Beans Wild Carrot Wild Lettuce Miscellaneous botanicals with anticoagulant properties: Bladder Wrack (Fucus) Pau d’arco Botanicals that contain salicylate and/or have antiplatelet properties: Agrimony Aloe Gel Aspen Black Cohosh Black Haw Bogbean Cassia Clove Dandelion Feverfew Garlic German Sarsaparilla Ginger Ginkgo Biloba Ginseng (Panax) Licorice Meadowsweet Onion Policosanol Poplar Senega Tamarind 20

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Willow Wintergreen Botanicals with fibrinolytic properties: Bromelains Capsicum Garlic Ginseng (Panax) Inositol Nicotinate Onion Botanicals with coagulant properties: Agrimony Goldenseal Mistletoe Yarrow

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REFERENCES 1. Hardman JG, Limbird LE. Goodman and Gilman's the Pharmacologic Basis of Therapeutics. 10th ed. New York: McGraw-Hill; 2001. 2. Hirsh J, Fuster V, Ansell J, Halperin JL. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. Circulation 2003;107(12):1692-711. 3. Gage BF. Pharmacogenetics-based coumarin therapy. Hematology / The Education Program of the American Society of Hematology American Society of Hematology 2006:467-73. 4. Buller HR, Agnelli G, Hull RD et al. Antithrombotic therapy for venous thromboembolic disease. The Seventh ACCP Conference on Antithrombotic and Thombolytic Therapy. Chest 2004; 126: 401S-408S. 5. Kearon C. Drug trials that have influenced our practice in the treatment of venous thromboembolism. Thromb Haemost 1997;78:553-557. 6. Schager AI. Warfarin for venous thromboembolism. New Eng J Med 2003; 348:1478-1480. 7. Turpie AGG, Chin BSP,and Lip GYH.ABC of antithrombotic therapy: Venous thromboembolism: treatment strategies. BMJ 2002; 325:948-950. 8. McCurdy SA, White RH. Accuracy and precision of a portable anticoagulation monitor in a clinical setting. Archives of Internal Medicine 1992;152(3):589-92. 9. Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(3 Suppl):204S-33S. 10. Garcia D, Regan S, Crowther M, Hughes RA, Hylek EM. Warfarin maintenance dosing patterns in clinical practice: implications for safer anticoagulation in the elderly population. Chest 2005;127(6):2049-56. 22

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11. Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation 2007;115(21):2689-96. 12. Siguret V, Gouin I, Debray M, et al. Initiation of warfarin therapy in elderly medical inpatients: a safe and accurate regimen. American Journal of Medicine 2005;118(2):137-42. 13. Ryan PJ, Gilbert M, Rose PE. Computer control of anticoagulant dose for therapeutic management. BMJ 1989;299(6709):1207-9. 14. http://www.clinpharmacologist.bigstep.com. 15. Gage BF, Fihn SD, White RH. Management and dosing of warfarin therapy. American Journal of Medicine 2000;109(6):481-8. 16. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006;114(7):e257-354. 17. Hanslik T, Prinseau J. The use of vitamin K in patients on anticoagulant therapy. Am J Cardiovasc Drugs 2004; 4: 43-55. 18. Ansell J, Hirsh J, Poller L, et al. The pharmacology and management of the vitamin K antagonist: the seventh ACCP conference on antithrombotic and thrombolytic therapy [published correction appears in Chest 2005; 127: 415-416].Chest 2004; 126 (3 suppl): 204S-233S. 19. Kessler CM. Urgent reversal of warfarin with prothrombin complex concentrate: where are the evidence-based data? J Thromb Haemost 2006;4(5):963-6. 20. Lankiewicz MW, Hays J, Friedman KD, Tinkoff G, Blatt PM. Urgent reversal of warfarin with prothrombin complex concentrate. J Thromb Haemost 2006;4(5):967-70. 23

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21. Leissinger CA, Blatt PM, Hoots WK, Ewenstein B. Role of prothrombin complex concentrates in reversing warfarin anticoagulation: A review of the literature. Am J Hematol epub Aug 29,2007. 22. Preston FE, Laidlaw ST, Sampson B, Kitchen S. Rapid reversal of oral anticoagulation with warfarin by a prothrombin complex concentrate (Beriplex): efficacy and safety in 42 patients. British Journal of Haematology 2002;116(3):619-24.

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APPENDIX 4

DOSE-RESPONSE MODELING

Further support for selection of an apixaban dose of 10 mg BID for 7 days followed by 5 mg BID comes from the results of dose-response modeling for other anticoagulants evaluated in VTE studies. Because of low event rates and limited ranges of dose testing, Phase 2 studies for VTE treatment have provided limited dose-response information.

1, 2

However, dose-response relationships for prevention of VTE are available for a number of compounds. Therefore, a model was developed that links efficacy and safety doseresponse for VTE prevention to efficacy (symptomatic VTE) and safety (major bleeding) for VTE treatment and provides estimates of VTE treatment outcomes for any compound with VTE prevention data relative to an active VTE treatment comparator of enoxaparin 1 mg/kg BID + VKA. A summary of the modeling effort to support this approach is described below. Efficacy and safety dose-response data from 20 treatments evaluated in VTE prevention were modeled, representing > 39,000 patients in 63 trials. Both hip- and knee-replacement patients were included, and the data were fit with logistic regression models that specified a similar shape of the dose-response curve across compounds. From the relative potencies estimated from these analyses, doses of all treatments could be expressed in enoxaparin equivalents (doseeq). Key assumptions for this modeling were that relative potencies (ie, relative ED50) are the same for VTE prevention and VTE treatment differences in dose-response between VTE prevention and treatment are similar across compounds Under these assumptions, dose-response analyses of study-level efficacy and safety endpoints for acute (5 - 14 d) and/or chronic (up to 6 months) VTE treatment periods were modeled across compounds as a function of doseeq. Individual study arm data from 14 treatments evaluated for acute outcome (~31,000 patients), and 10 treatments evaluated for acute + chronic outcome (~5,100 patients) were included. Figure 1.4.3A shows modeling results for symptomatic VTE frequency over the acute treatment period and the entire treatment period as a function of doseeq during the acute period. A statistically significant dose-response relationship was obtained for each treatment period. Figure 1.4.3B shows similar plots for frequency of major bleeding. The dose-response relationship between frequency of major bleeding and doseeq was statistically significant for the acute treatment period and the entire (acute + chronic) treatment period. Revised Protocol No.: 02 Date: 18-Apr-2011 Approved v 5.0

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0.05 0.04 0.03 0.0

0.01

0.02

Acute + Chronic Symptomatic VTE frequency

0.04 0.03 0.02 0.0

0.01

Acute Symptomatic VTE frequency

0.05

0.06

Symptomatic VTE frequency across anticoagulants during the acute (5 - 14 d) and entire (up to 6 mo) treatment period as a function of enoxaparin-equivalent dose during the acute period. A statistically significant dose-response relationship is demonstrated for the acute treatment period and the entire (acute + chronic) treatment period.

0.06

Figure 1:

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0

200

400

600

0

200

400

600

Enoxaparin equivalent dose, acute period (mg)

Figure 1: VTE efficacy dose-response data from 20 anti-coagulant treatments evaluated in VTE prevention were modeled, representing > 39,000 subjects in 63 hip- and knee-replacement prevention trials. The data were fit with logistic regression models that specified a similar shape of the dose-response curve across compounds. From the relative potencies estimated from these analyses, doses of all treatments could be expressed in enoxaparin equivalents (doseeq). Modeling results for symptomatic VTE frequency over the acute treatment period and the entire treatment period as a function of doseeq during the acute period are presented. Note: The symbols reflect mean observed frequency for a certain dose bin adjusted for trial-to-trial differences in mean response and the lines represents the model fits. The error bars are 95% CIs.

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Major bleeding frequency across anticoagulants during the acute (5 14 d) and entire (up to 6 mo) treatment period as a function of enoxaparin-equivalent dose in the acute period. A statistically significant dose-response relationship is demonstrated for the acute treatment period and the entire (acute + chronic) treatment period.

0.03

0.04

0.05

0.0

0.0

0.01

0.02

Acute + Chronic Major Bleed VTE frequency

0.04 0.03 0.02 0.01

Acute Major Bleed frequency

0.05

0.06

0.06

Figure 2:

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0

100

200

300

400

500

0

100

200

300

400

500

Enoxaparin equivalent dose, acute period (mg)

Figure 2: VTE major bleeding dose-response data from 20 anti-coagulant treatments evaluated in VTE prevention were modeled, representing > 39,000 subjects in 63 hip- and knee-replacement prevention trials. The data were fit with logistic regression models that specified a similar shape of the dose-response curve across compounds. From the relative potencies estimated from these analyses, doses of all treatments could be expressed in enoxaparin equivalents (doseeq). Modeling results for symptomatic VTE frequency over the acute treatment period and the entire treatment period as a function of doseeq during the acute period are presented. Note: The symbols reflect the mean observed frequency for a certain dose bin adjusted for trial-to-trial differences in mean response and the lines represents the model fits. The error bars are 95% CIs.

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Using Phase 2 VTE prevention data for apixaban along with these models, efficacy and safety outcomes for various dose regimens of apixaban in VTE treatment were estimated (Tables 1 and 2). An apixaban regimen of 10 mg BID for 7 days followed by 5 mg BID is predicted to result in similar or better efficacy and safety vs enoxaparin 1 mg/kg BID + VKA. The higher initial dose of apixaban is predicted to increase efficacy relative to a dose of 5 mg BID for the entire treatment period (Table 1) without substantially increasing the risk for major bleeding (Table 2). Thus, the dose-response modeling based on prior VTE treatment studies supports a dose selection of 10 mg BID for 7 days followed by 5 mg BID for the 6-month treatment of VTE. Table 1:

Model-Predicted Symptomatic VTE Frequency (%) [10th to 90th percentiles] for Apixaban Doses and Enoxaparin 1 mg/kg BID + VKA Treatment

Acute Period

Total (%)

1.2

3.7

1.3 [1.2 to 1.4]

2.8 [2.3 to 3.5]

5 mg Apixaban BID

1.1 [1 to 1.2]

2.3 [1.8 to 3]

10 mg Apixaban BID

1 [0.9 to 1.1]

1.9 [1.4 to 2.6]

5 mg Apixaban BID x 7 days then 2.5 mg Apixaban BID

1.1 [1 to 1.2]

2.5 [ 2.1 to 3.1]

7.5 mg Apixaban BID x 7 days then 5 mg Apixaban BID

1 [0.9 to 1.2]

2.1 [1.7 to 2.8]

10 mg Apixaban BID x 7 days then 5 mg Apixaban BID

1 [0.9 to 1.1]

2 [1.6 to 2.7]

1 mg/kg Enoxaparin BID + VKA 2.5 mg Apixaban BID

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Model-Predicted Major Bleeding Event Frequency (%) [10th to 90th percentiles] for Apixaban Doses and Enoxaparin 1 mg/kg BID + VKA Treatment

Acute Period

Total (%)

0.8

2

2.5 mg Apixaban BID

0.4 [0.4 to 0.5]

1.3 [ 1 to 1.7]

5 mg Apixaban BID

0.5 [0.4 to 0.6]

1.4 [1.2 to 1.9]

10 mg Apixaban BID

0.7 [0.6 to 1]

1.8 [1.4 to 2.8]

5 mg Apixaban BID x 7 days then 2.5 mg Apixaban BID

0.5 [0.4 to 0.6]

1.4 [1.1 to 1.8]

7.5 mg Apixaban BID x 7 days then 5 mg Apixaban BID

0.6 [0.5 to 0.8]

1.5 [1.2 to 2]

10 mg Apixaban BID x 7 days then 5 mg Apixaban BID

0.7 [0.6 to 1]

1.6 [1.3 to 2.2]

1 mg/kg Enoxaparin BID + VKA

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REFERENCES 1. Agnelli G, Gallus A, Goldhaber S, et al. Treatment of acute, symptomatic, proximal DVT with the oral, direct factor Xa inhibitor rivaroxaban (BAY 59-7939) - the ODIXa-DVT dose-ranging study. Eur Heart J. 2006;27 (suppl):761. Abstract P4569. 2. Büller HR, on behalf of the EINSTEIN-DVT study group. Once-daily treatment with an oral, direct factor Xa inhibitor - rivaroxaban (BAY 59-7939) - in patients with acute, symptomatic DVT. The EINSTEIN-DVT dose-finding study. Eur Heart J. 2006;27 (suppl):761. Abstract P4568.

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APPENDIX 5

Approved v 5.0

Table 1:

MAINTENANCE WARFARIN DOSE IN SUBJECTS WITH VENOUS THROMBOEMBOLISM

Median, 25th percentile, and 75th percentile for daily warfarin doses by age and gender in patients with venous thromboembolism.

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Table 2:

Median daily maintenance warfarin dose and median age for men and women by deciles of weight (n = 369).

Table 3:

Percentage of patients with target INR of 2.0 to 3.0 whose maintenance warfarin dose was < 35 mg/wk (< 5 mg/d)*

Source for Tables 1 - 3: Garcia D, Regan SR, Crowther M, Hughes RA, and Hylek E. Warfarin Maintenance Dosing Patterns in Clinical Practice: Implications for Safer Anticoagulation in the Elderly Population. Chest 2005; 27:2049–2056.

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A SAFETY AND EFFICACY TRIAL EVALUATING THE USE OF APIXABAN IN THE TREATMENT OF SYMPTOMATIC DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM

Statistical Analysis Plan (SAP)

Version: 4.0 Authors: Andrei Breazna - Pfizer Primary Care Statistics John Thompson (amendment 4) With input from the Steering Committee Date: 20-March-2013

*

BMS protocol number used by study team. Pfizer protocol number is B0661001 Statistical Analysis Plan

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TABLE OF CONTENTS LIST OF TABLES .....................................................................................................................4  APPENDICES ...........................................................................................................................4  1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................5  2. INTRODUCTION .................................................................................................................7  2.1. Study Design .............................................................................................................7  2.2. Study Objectives .......................................................................................................9  3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING................................10  4. HYPOTHESES AND DECISION RULES .........................................................................10  4.1. Hypotheses and Decision Rules for Primary Objective ..........................................10  4.2. Hypotheses and Decision Rules for Key Secondary Objectives .............................11  5. ANALYSIS SETS ...............................................................................................................12  5.1. Primary and Secondary Efficacy Datasets ..............................................................13  5.2. Per-Protocol Dataset ................................................................................................13  5.3. Safety Dataset ..........................................................................................................14  5.4. Protocol Deviations .................................................................................................14  6. ENDPOINTS AND COVARIATES ...................................................................................14  6.1. Study Period ............................................................................................................14  6.2. Efficacy Endpoint(s) ...............................................................................................15  6.3. Primary Efficacy Endpoints ....................................................................................15  6.4. Secondary Efficacy Endpoints ................................................................................15  6.5. Safety Endpoints .....................................................................................................17  6.6. Primary Safety Endpoint .........................................................................................17  6.7. Secondary Safety Endpoints....................................................................................17  6.8. Covariates ................................................................................................................17  7. HANDLING OF MISSING VALUES ................................................................................18  8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................18  8.1. Statistical Methods ..................................................................................................18  8.1.1. Analyses for Binary Endpoints ...................................................................18  8.1.1.1. Non-inferiority ..........................................................................18  8.1.1.2. Superiority .................................................................................21  8.1.1.3. Descriptive ................................................................................21  Statistical Analysis Plan

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8.1.2. Analyses for Time to Event Data................................................................21  8.2. Statistical Analyses .................................................................................................22  8.2.1. Subject Disposition .....................................................................................22  8.2.2. Demography and Baseline Characteristics .................................................22  8.2.3. Extent of Exposure .....................................................................................23  8.2.3.1. Study Therapy ...........................................................................23  8.2.3.2. INR (international normalized ratio) Control ...........................24  8.2.4. Concomitant Medications ...........................................................................24  8.2.5. Analysis for Primary Objective ..................................................................25  8.2.6. Exploratory Analysis Supportive of Primary Objective .............................25  8.2.7. Analyses for Key Secondary Objectives ....................................................26  8.2.8. Analysis Supporting Additional Secondary Objectives .............................27  8.2.8.1. Characterization of VTE/CV-related death, VTE/all-cause death, and VTE/VTE-related death/MB ............................................27  8.2.8.2. Pre-specified Subgroups Analyses-Efficacy .............................28  8.2.8.3. Analysis of Bleeding Events .....................................................30  8.2.8.4. Characterization of VTE /MI/Stroke/CV-related death/MB/CRNM bleeding ...............................................................30  8.2.8.5. Pre-specified Subgroups Analyses-Safety ................................30  8.2.9. Other Safety Analyses ................................................................................31  8.2.9.1. Adverse Events ..........................................................................31  8.2.9.2. Laboratory Data ........................................................................32  8.2.9.3. Vital Signs .................................................................................34  8.2.9.4. Events of Special Interest ..........................................................34  8.3. Pharmacokinetic/Pharmacodynamic/Pharmacogenomic Analyses .........................35  8.4. Outcomes Research Analyses .................................................................................35  8.5. Conventions .............................................................................................................35  8.5.1. Safety Data Conventions ............................................................................35  8.5.2. Baseline Measurements ..............................................................................35  8.5.3. Day Ranges for Analysis of Time Points ...................................................36  8.5.4. Multiple Measurements ..............................................................................36  9. REFERENCES ....................................................................................................................38  10. APPENDICES ...................................................................................................................40  Statistical Analysis Plan

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LIST OF TABLES Table 1. 

Subgroups of Interest ............................................................................................29 

Table 2. 

Day Ranges for Analysis of Post-Dose Measurements ........................................36 

APPENDICES Appendix 1. LABORATORY MA CRITERIA.......................................................................40  Appendix 2. BMS CT SOP 109 ...............................................................................................42  Appendix 3. JUSTIFICATION OF THE NON-INFERIORITY MARGIN ...........................58  Appendix 4. REGIONS AND COUNTRIES ..........................................................................69 

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1. AMENDMENTS FROM PREVIOUS VERSION(S) Version 4.0: 

Re-defined the strategy for Type I error control utilizing recent scientific advances. The fixed sequence for hierarchical testing was revised to include important safety endpoints and remove less important efficacy endpoints;



Provided a definition for subjects with a non-missing primary endpoint;



Added an endpoint for net clinical benefit consistent with the recently completed protocol CV 185-057;



Acknowledged the adaptive feature of the protocol and discuss the effect of blinded sample size adjustment on experiment-wise Type I error;



Made minor adjustments to the definition of the intended treatment period;



Simplified the sensitivity analyses for the primary endpoint;



Added subgroup analyses based on Time in Therapeutic Range (TTR), fragile subjects, and active cancer based on steering committee request;



Modified the definition of index event in the sub-group analyses section to better reflect medical judgment;



Added p-values and risk difference calculations for all secondary efficacy endpoints along with primary and secondary safety endpoints;



Updated the algorithm for calculation of TTR.

Version 3.0: 

Documented the decision to exclude a small number of subjects (with data integrity issues) from all analyses;



Deleted use of prohibited anticoagulant or antiplatelet therapy during study treatment as a significant protocol deviation that would impact the primary efficacy endpoint (since it rather potentially impacts safety);



Corrected the version of the SAS software that will be used (V9);



Corrected the creatinine clearance cutoffs used to classify level of renal function at baseline;



Changed the lower and upper limits in the INR summary tabulations to align with the Point-of-Care device’s LLQ and ULQ; Statistical Analysis Plan

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Deleted information regarding how values ULQ will be summarized given that the summary cutoffs are now aligned with LLQ and ULQ as described above;



Added a summary of warfarin time in therapeutic range excluding the titration period and a summary further excluding periods of warfarin interruption;



Aligned the common subgroups for primary efficacy and bleeding endpoint analyses with the relevant subgroups across other apixaban indications and added the methodology for the calculation of treatment by subgroup interaction p-values;



Aligned the duration of the Intended Treatment Period and Intended Follow-up Period with the protocol allowed window for the final treatment visit and follow-up visit;



Aligned the criteria on how to handle multiple measurements for INR, other laboratory measurements and vital signs with that used in prior Apixaban studies;



Deleted a redundant section related to a summary of statistical analyses that will be performed;



Updated Appendix 2 (section Appendix 2) and corrected the references to BMS CT SOP 109;



Added the classification of countries into geographic regions in Appendix 4 (section Appendix 4);



Harmonized section numberings with CV185057.

Version 2.0: 

Adjusted the definition of the Intended Treatment Period in section 6.1 to be consistent with the SAP for Protocol CV185057;



Moved all analyses previously specified in the core analysis plan to this document;



Clarified the definitions of primary and secondary efficacy analysis sets and the definition and approach to missing data;



Clarified that the determination of non-inferiority will be based on the upper bounds of 95% confidence intervals for relative risk and risk difference.

Statistical Analysis Plan

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2. INTRODUCTION Apixaban is a novel, selective, orally active inhibitor of coagulation factor X [FXa] that is being co-developed by Bristol-Myers Squibb (BMS) and Pfizer as an anticoagulant and antithrombotic agent. Apixaban (also referred to as BMS-562247), is a reversible and highly potent inhibitor of human FXa, with an inhibitor constant (Ki) of 0.08 ± 0.01nM, and a high degree of selectivity over other coagulation proteases and structurally related enzymes involved in digestion and fibrinolysis. Study CV185056 is one of two phase III studies in the VTE treatment program. The primary objective of study CV185056 is to determine whether apixaban is non-inferior to standard enoxaparin and warfarin therapy (control treatment group) for the primary efficacy endpoint. The primary efficacy endpoint in this study is incidence of recurrent VTE or VTE-related death during 6 months of therapy using events confirmed through adjudication by an independent review committee. The study is a randomized, active controlled, parallel-group, double blind, triple dummy design. The active control will be enoxaparin, SC, 1 mg/kg BID, for ≥5 d and adjusted dose of warfarin to achieve a target INR = 2–3 for a total treatment duration of 6 months. The focus of this analysis plan document is on the pre-specified objectives ie, on analyses unique to this protocol. The analysis for safety, disposition and exposure will be consistent with safety, disposition and exposure of other apixaban studies. Text taken verbatim from the protocol is italicized. 2.1. Study Design Study Design: This is a randomized, active-controlled, parallel-group, double-blind, triple dummy study. Subjects with an objectively confirmed acute symptomatic proximal DVT or acute symptomatic PE are eligible for this study. Subjects will be stratified based on the type of disease treated (symptomatic proximal DVT or symptomatic PE) at baseline. If a subject has both symptomatic proximal DVT and symptomatic PE, the subject will be stratified as having symptomatic PE. Subjects with cancer who will be treated for 6 months or more with low molecular weight heparin therapy are ineligible for this study. Enrollment is projected to include approximately two-thirds DVT and one-third PE subjects, approximating clinical demographics for patients with VTE. The number of randomized subjects in each of the DVT and PE categories will be monitored through an interactive voice response system (IVRS) during the study. Depending on how the study progresses, a cap may be utilized to halt enrollment of subjects into one category while continuing enrollment into the other category, in order to ensure a DVT: PE ratio of approximately 2: 1 by the end of the study. Statistical Analysis Plan

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Subjects will be randomized (1: 1 ratio) to Groups 1 or 2 using a central interactive voice response system (IVRS). Group 1

2

Treatment Warfarin

Dose

Duration

Dosing to target INR range between 2.0 – 3.0. 6 months

Enoxaparin

1 mg/kg SC Q12h until INR ≥2

≥5 days

Placebo (Apixaban)

10 mg PO BID for 7 days followed by 5 mg PO BID

6 months

Placebo (Warfarin)

Dosing to a target SHAM INR range between 2.0 - 3.0

6 months

SC Q12h until SHAM INR ≥2

≥5 days

10 mg PO BID for 7 days followed by 5 mg PO BID

6 months

Placebo (Enoxaparin) Apixaban

Subjects in Group 1 will receive enoxaparin injections, warfarin tablets, and placebo apixaban tablets. Subjects in Group 2 will receive placebo enoxaparin injections, placebo warfarin tablets, and apixaban tablets. Enoxaparin and placebo enoxaparin will be administered for at least 5 days and will be discontinued once the blinded INR is ≥ 2. Apixaban, placebo apixaban, warfarin, and placebo warfarin tablets will be administered for 6 months. In order to minimize missing data, subjects who discontinue study drug early will continue to have their regularly scheduled follow-up visits until the end of their originally intended treatment period (6 months after randomization). For subjects who have discontinued study treatment, query of health status (alive, occurrence of efficacy and safety endpoints and AEs/SAEs) by telephone is allowed. Subjects who have new symptoms should undergo further assessment as clinically appropriate, preferably at the study site whenever feasible. This study will utilize a blinded INR monitoring routine. The blinded routine will consist of a point of care INR device that will generate an encrypted code. This code will be reported to a centralized IVRS by the investigator. The IVRS will decrypt the code and report back to the investigator either the actual INR result from subjects randomized to warfarin or a sham INR result from subjects randomized to placebo warfarin. Sham INRs will be based on a predefined computerized algorithm. Dose adjustments will be at the discretion of the Statistical Analysis Plan

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investigator. Blinded INR testing frequency will occur approximately every month during the treatment period, and more frequently during titration and when clinically indicated. Subjects randomized to warfarin or placebo warfarin will be titrated to a target blinded INR range between 2 and 3. Study visits will be scheduled at 2, 4, 8, 12, 16, 20 and 24 weeks. All subjects will have an additional 30-day observation period after cessation of study treatment. The independent adjudication committee (ICAC) will adjudicate all index events (proximal DVT and/or PE). During the study period and the post-treatment observation period, the ICAC will adjudicate all suspected occurrences/recurrences of venous or arterial thromboembolic events, deaths, and the following events of special interest: acute myocardial infarction, acute stroke, and thrombocytopenia. The ICAC will also review all suspected episodes of bleeding, and categorize adjudicated bleeding as major, clinically relevant non-major, or minor bleeding. Adjudication results will be the basis for the final analyses. Adjudication is intended to provide a consistent process for assessing data quality and interpreting study data. Adjudicated outcomes should not be relied upon for subject safety, study treatment decisions, or clinical care. Therefore, adjudication outcomes will not be shared with investigators for subject diagnosis or treatment. A 24-hour emergency telephone service will be provided for sites to call throughout the study. An independent data monitoring committee (DMC) will monitor the subjects’ safety during the study and give recommendations to the steering committee. No interim analysis of efficacy is planned. Ongoing review of the safety of all investigational treatments will be the mandate of the DMC. Subject to IRB/EC approval/favorable opinion, this study will include an additional research component involving collection of biological samples for de-identified exploratory ‘omics analysis. The Molecular Profiling Supplement to this protocol provides a description of this additional research. Subjects may participate in this drug study even if they choose not to participate in the sample banking component. Duration of Study: For all subjects, the study treatment duration will be 6 months followed by a 30-day observation period. Number of Subjects per Group: Approximately 2408 2.2. Study Objectives Primary Efficacy Objective: To determine if apixaban is non-inferior to standard enoxaparin/warfarin therapy in the combined endpoint of adjudicated recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or VTE-related death over 6 months of therapy. Statistical Analysis Plan

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Secondary Objectives: 

To determine if apixaban is superior to standard enoxaparin/warfarin therapy in the combined endpoint of adjudicated recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or VTE-related death over 6 months of therapy;



To determine if apixaban is superior to standard enoxaparin/warfarin therapy in the combined endpoint of adjudicated recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or all-cause death over 6 months of therapy;



To characterize apixaban therapy relative to standard enoxaparin/warfarin therapy in the combined endpoint of adjudicated recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or cardiovascular (CV) death over 6 months of therapy;



To characterize apixaban therapy relative to standard enoxaparin/warfarin therapy in the combined endpoint of adjudicated recurrent symptomatic VTE (nonfatal DVT or nonfatal PE), VTE-related death, or major bleeding over 6 months of therapy;



To characterize apixaban therapy relative to standard enoxaparin/warfarin therapy in adjudicated major bleeding during 6 months of therapy;



To characterize apixaban therapy relative to standard enoxaparin/warfarin therapy in the composite of adjudicated major bleeding and adjudicated clinically relevant nonmajor bleeding during 6 months of therapy;



To characterize the primary efficacy outcome in the subset of subjects with index events of DVT only and in the subset of subjects with index events of PE with or without DVT.

3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING No interim analysis of efficacy is planned. Ongoing review of the safety of all investigational treatments will be the mandate of the data monitoring committee (DMC). Final analysis of all data will commence after the database has been released with randomization codes. 4. HYPOTHESES AND DECISION RULES 4.1. Hypotheses and Decision Rules for Primary Objective There are two primary hypotheses, one based on relative risk and the second based on risk difference. The hypotheses address the objective of demonstrating the non-inferiority of apixaban compared to enoxaparin/warfarin for the adjudicated composite endpoint VTE or VTE-related death. Statistical inferences will be based on relative risk (pa / pe) and the risk difference (pa - pe), where pa and pe represent the proportions of subjects with primary efficacy outcomes in the apixaban and enoxaparin/warfarin groups, respectively.

Statistical Analysis Plan

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To conclude non-inferiority for the primary efficacy endpoint, it is necessary to demonstrate that the apixaban event rate is not materially higher, as defined by the non-inferiority margin, than the enoxaparin/warfarin event rate. This is accomplished by testing two hypotheses: 

H0RR: pa/pe  1.8 against HaRR: pa/pe< 1.8 and



H0: pa - pe  0.035 against Ha: pa - pe < 0.035.

Non-inferiority will be demonstrated if for each hypothesis (H0RR and H0), the upper bound of the corresponding 95% confidence interval is below the non-inferiority margin. Both upper confidence bounds must be below the margin to demonstrate non-inferiority. The non-inferiority margin for relative risk (NIRR = 1.8) was the value that clinical experts, investigators and Health Authorities thought was clinically meaningful and is less than a margin that would preserve 50% of the treatment effect. The non-inferiority margin for risk difference (NI = 0.035) protects against higher than expected event rates in the control group (eg, > 4.5%). Formal justification for these margins is detailed in Appendix 3 (section Appendix 3). The study was designed with a possible adaptation. After 80% of the subjects were enrolled a protocol defined blinded sample size re-estimation occurred. The sample size was increased to the protocol defined maximum of 5400 (original sample size was 4094) based on the blinded incidence of the primary endpoint. A blinded sample size re-estimation does not require adjustments to the experimentwise Type I error control. 4.2. Hypotheses and Decision Rules for Key Secondary Objectives There are three key secondary objectives looking at the hypotheses that apixaban therapy is superior to enoxaparin/warfarin therapy for the following adjudicated endpoints: 

Incidence of major bleeding



Incidence of VTE/VTE-related death,



Incidence of the composite of major bleeding or Clinically Relevant Non-Major (CRNM) bleeding

The formal hypotheses statements for these endpoints are expressed as; 

Ho: RR ≥ 1 will be tested against



Ha: RR < 1,

where RR represents the relative risk of apixaban relative to the active comparator (enoxaparin/warfarin) for the given endpoint.

Statistical Analysis Plan

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To control the overall probability of type I error, the following hierarchical testing procedure will be used. Step 1: The hypotheses associated with the non-inferiority of apixaban relative to enoxaparin and warfarin therapy (as described above) for a 6 month treatment duration, will be tested at the one-sided =0.025. If non-inferiority of apixaban relative to control with respect to the primary efficacy endpoint (composite of recurrent VTE or VTE-related death: 

Is demonstrated for both relative risk and risk difference, then superiority of apixaban relative to control treatment for the primary safety endpoint (major bleeding) will be tested at 2-sided =0.05.



Otherwise stop.

Step 2: If superiority of apixaban relative to control treatment with respect to the primary safety endpoint (major bleeding): 

Is demonstrated, then superiority of apixaban relative to control treatment for the primary efficacy endpoint (composite of recurrent VTE or VTE-related death) will be tested at 2-sided =0.05.



Is not demonstrated, then stop.

Step 3: If superiority of apixaban relative to control treatment with respect to the primary efficacy endpoint (VTE or VTE-related death): 

Is demonstrated, then superiority of apixaban relative to control treatment for the secondary safety endpoint (composite of major bleeding or CRNM bleeding) will be tested at 2-sided 0.05.



Is not demonstrated, then stop.

5. ANALYSIS SETS On December 02, 2010 the Clinical Research Oversight Committee accepted the clinical team recommendation of closure of both studies (CV185056, CV185057) at the site in Shefali Center, Paldi, Ahmedabad, India. Moreover, data collected from this site (5 and 4 subjects for CV185056-0648 and CV185057-0650, respectively) are to be excluded from all data analyses. However data collected from these sites will be presented in listings with additional footnotes were applicable to indicate that these data will not be summarized in any tables. The motivation for this is "Lack of source documentation despite repeated training. The accuracy, validity and integrity of data collected are questionable and not verifiable." Indian regulatory authorities have been informed of this situation.

Statistical Analysis Plan

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5.1. Primary and Secondary Efficacy Datasets Primary The primary efficacy dataset (Primary Efficacy Evaluable) will consist of all randomized subjects with a non-missing primary endpoint. Subjects will be categorized to the group to which they were assigned by the IVRS, regardless of the treatment actually received. Subjects with the primary endpoint missing because incidence of primary endpoint is unknown (eg, subjects lost to follow-up) will be excluded from the primary efficacy dataset. A missing primary endpoint is defined to be a primary endpoint (adjudicated by ICAC) that is censored before the end of the Intended Treatment Period. A window of 2 weeks will be utilized to define censored events. Thus, a subjects without a primary endpoint will be considered to have completed the intended treatment period for analysis purposes if a Study Outcomes and events of special interests Visit Assessment (SOVA) page indicating the absence of a VTE or VTE related death is present on or after Day 154 (22 weeks). Secondary Secondary efficacy datasets (secondary Efficacy Evaluable) will be defined for each secondary endpoint as consisting of all randomized subjects for whom that secondary endpoint is non-missing. A missing efficacy endpoint is defined to be an efficacy endpoint that is censored before the end of the Intended Treatment Period. For subjects without an event, the same 22 week window will be used to define completion of the intended treatment period for analysis purposes. Subjects will be categorized to the group to which they were assigned by the IVRS, regardless of the treatment actually received. The analysis sets defined above will be used for analyses of event rates. The analysis set for time-to-event analyses (eg, Kaplan-Meier curves) will be all randomized subjects. Subjects will be categorized to the group to which they were assigned by the IVRS, regardless of the treatment actually received. 5.2. Per-Protocol Dataset A secondary efficacy dataset, to be used for the per-protocol analysis of the primary efficacy endpoint, is the per-protocol subject dataset. This dataset contains subjects from the primary efficacy dataset excluding: 

Less than 80% compliance with intended study medications;



Subjects who discontinue treatment before the end of the Intended Treatment Period without having had an incident of the primary efficacy endpoint during the actual treatment period;



Thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent to treat the current episode of VTE;



Use of anti-coagulant therapy exceeding the limit as specified in the protocol before the first administration of study medications; Statistical Analysis Plan

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Error in treatment dispensing resulting in a subject being dosed with an incorrect treatment;



Subject randomized but not dosed;



Subject randomized but index VTE was not objectively confirmed by the adjudication committee.

A listing of subjects excluded from the primary efficacy dataset to form the per-protocol dataset will be provided. 5.3. Safety Dataset The safety dataset (as-treated) will consist of all treated subjects (randomized subjects who received at least one dose of study drug). For the purpose of safety analyses, subjects will be categorized to the group to which they were assigned by the IVRS unless incorrect study treatment was received throughout the study, in which case the subject will be categorized according to the treatment received. 5.4. Protocol Deviations Prior to unblinding, significant protocol deviations will be identified for all subjects who are randomized. All significant protocol deviations including eligibility deviations, use of prohibited concomitant medications, and errors in dosing will be listed and summarized by deviation type and randomized treatment group. 6. ENDPOINTS AND COVARIATES 6.1. Study Period The terms “Treatment Period” and “Follow-up Period” are defined for all randomized subjects who received at least one dose of study drug (the safety analysis set) as follows. In all listings, summaries and statistical analyses, except for SAE tabulations, the term “Treatment Period” will refer to the period from first dose through 2 days after discontinuation of study drug. For SAE tabulations, the term “Treatment Period” will refer to the period from first dose through 30 days after discontinuation of study drug. In all listings, summaries and statistical analyses, the term “Follow-up Period” will refer to the period starting after the end of the “Treatment Period” and extending through 30 days after discontinuation of study drug. The terms “Intended Treatment Period” and “Intended Follow-up Period” are defined for all randomized subjects as follows. In all listings, summaries and statistical analyses, the term “Intended Treatment Period” refers to the period that starts on the day of study drug until:

Statistical Analysis Plan

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For treated subjects, the period ends 2 days after the later of a) last dose of study drug and b) Day 166 where Day 1 is the first day of study drug (24 week dosing period).



For randomized subjects that are not treated, the period ends on Day 168 where Day 1 is the day of randomization.

In all listings, summaries and statistical analyses, the term “Intended Follow-up Period” will refer to the 30-day period starting after the end of the “Intended Treatment Period”. 6.2. Efficacy Endpoint(s) 6.3. Primary Efficacy Endpoints The primary efficacy outcome is the incidence of an adjudicated composite of recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or VTE-related death during 6 months of therapy. The primary endpoint (VTE/VTE-related death) will include events that occur at any time from randomization until the end of the originally Intended Treatment Period regardless of whether subjects are receiving study medication (using the intent to treat principle). Each subject will be scored as having an event if and only if the subject experienced one or more of the elements of the composite. 6.4. Secondary Efficacy Endpoints The incidence of: 

VTE/all-cause death: Defined as the adjudicated composite of recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or all-cause death. This endpoint will include events that occur during the “Intended Treatment Period” regardless of whether subjects are receiving study medication (using the intent to treat principle). Each subject will be scored as having an event if and only if the subject experienced one or more of the elements of the composite;



VTE/CV-related death: Defined as the adjudicated composite of recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or CV-related death. This endpoint will include events that occur during the “Intended Treatment Period” regardless of whether subjects are receiving study medication (using the intent to treat principle). Each subject will be scored as having an event if and only if the subject experienced one or more of the elements of the composite;



VTE/VTE-related death/ MB: Defined as the adjudicated composite of recurrent symptomatic VTE (nonfatal DVT or nonfatal PE), VTE-related death or major bleeding. This endpoint will include events that occur during the “Intended Treatment Period” regardless of whether subjects are receiving study medication (using the intent to treat principle). Each subject will be scored as having an event if and only if the subject experienced one or more of the elements of the composite;

Statistical Analysis Plan

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VTE/MI/Stroke/CV-related death/MB/CRNM: Defined as the adjudicated composite of recurrent symptomatic VTE (nonfatal DVT or nonfatal PE), MI, Stroke, CV-related death, CRNM bleeding or major bleeding. This endpoint will include events that occur during the “Intended Treatment Period” regardless of whether subjects are receiving study medication (using the intent to treat principle). Each subject will be scored as having an event if and only if the subject experienced one or more of the elements of the composite;



nfDVT: Defined as the adjudicated symptomatic nonfatal DVT. This endpoint will include events that occur during the “Intended Treatment Period” regardless of whether subjects are receiving study medication (using the intent to treat principle);



nfPE: Defined as the adjudicated symptomatic nonfatal PE. This endpoint will include events that occur during the “Intended Treatment Period” regardless of whether subjects are receiving study medication (using the intent to treat principle);



VTE-related death: Defined as the adjudicated VTE-related death: This endpoint will include events that occur during the “Intended Treatment Period” regardless of whether subjects are receiving study medication (using the intent to treat principle);



CV-related death: Defined as the adjudicated CV-related death: This endpoint will include events that occur during the “Intended Treatment Period” regardless of whether subjects are receiving study medication (using the intent to treat principle);



All-cause death: This endpoint will include events that occur during the “Intended Treatment Period” regardless of whether subjects are receiving study medication (using the intent to treat principle);



Time to first occurrence of an adjudicated composite of recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) and all-cause death during the Intended Treatment Period;



Time to first occurrence of an adjudicated composite of recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) and VTE-related death during the Intended Treatment Period. Time to event for efficacy endpoints will consist of two variables: 

A variable indicating whether or not an event occurred during the “Intended Treatment Period”;



A variable measuring the time from randomization to the first occurrence of an efficacy event, or for subjects not experiencing an event, a censoring time defined as the earliest of the date of last contact or date of the last day of the Intended Treatment Period;

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Note that these time-to-event variables will be computed without regard to medication adherence (intention-to-treat).

6.5. Safety Endpoints 6.6. Primary Safety Endpoint The primary safety outcome is the incidence of adjudicated major bleeding (MB) during the Treatment Period. 6.7. Secondary Safety Endpoints The incidence of: 

Clinically Relevant Non-Major (CRNM) bleeding during the Treatment Period;



Clinically Relevant Bleeding: Defined as the adjudicated composite of major or clinically relevant non-major bleeding during the Treatment Period. Each subject will be scored as having an event if and only if the subject experienced one or more of the elements of the composite;



Adjudicated minor bleeding during the Treatment Period;



Total adjudicated bleeding defined as adjudicated major, clinically relevant non-major bleeding, or minor bleeding during the Treatment Period;



Time to first adjudicated major bleed during the Treatment Period;



Time to first adjudicated composite of major or clinically relevant non-major bleed during the Treatment Period.

The time to bleeding endpoints will consist of two variables: 

A variable indicating whether or not a bleeding event occurred during the Treatment Period;



A variable measuring the time from first dose to the first occurrence of the bleeding event. Subjects not experiencing a bleeding event during the Treatment Period will be censored at the earlier of their last contact date or two days after the date of last dose.

Other safety outcome measures will also be assessed. The analyses of serious and non-serious AEs, changes in standard clinical laboratory test results, and other standard safety endpoints are detailed in section 8.2.9. 6.8. Covariates The type of index event (PE or proximal DVT) as entered in IVRS when specified, will be included as a covariate. Statistical Analysis Plan

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7. HANDLING OF MISSING VALUES For the primary efficacy analysis subjects will have a missing endpoint if it could not be determined for the initial 22 weeks of the Intended Treatment Period whether or not the primary endpoint occurred (for example, subject withdrew consent or was lost to follow-up). No imputation for missing data is planned for the primary efficacy analysis as the primary efficacy dataset includes only those randomized subjects with a non-missing primary endpoint (section 5.1). Sensitivity analyses will be performed to assess robustness of the results of the primary efficacy analysis to missing data. These sensitivity analyses will repeat the primary analysis by varying a hypothetical event rate in the missing data. The sensitivity analysis will explore a range of assumptions including the following: A. 0% of subjects with missing data on the apixaban and enoxaparin/warfarin treatment groups would achieve the endpoint B. 100% of subjects with missing data on the apixaban and enoxaparin/warfarin treatment groups would achieve the endpoint C. 100% of subjects with missing data on apixaban and 0% of subjects on enoxaparin/warfarin would achieve the endpoint D. 0% of subjects with missing data on apixaban and 100% of subjects on enoxaparin/warfarin would achieve the endpoint. No imputation for missing data is planned for any secondary analysis nor will any sensitivity analysis be conducted for these analyses. 8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES 8.1. Statistical Methods 8.1.1. Analyses for Binary Endpoints 8.1.1.1. Non-inferiority Confidence Intervals 

The 95% CI for the relative risk will be computed based on Mantel-Haenszel’s method stratified by index event. It can be implemented by using PROC FREQ with “CMH” option in SAS version 9.



Construction of CIs for differences between two event rates will be based on the inverse variance method when there is at least one event of interest per treatment group and stratum1: otherwise, the CIs will be based on the harmonic means method. 2-sided p-values for superiority will also be reported using similar methods. The confidence interval can be calculated using Statistical Analysis Plan

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Protocol CV 185-056 Statistical Analysis Plan ______________________________________________________________________________________ K

ˆw  Z  / 2 { wi2Vˆ (ˆi ) } i 1

where i represents i th stratum, and K

ˆ w   wi ˆ i , i 1

ˆi  pˆ i1  pˆ i 0 , pˆ i1  xi1 / ni1 , pˆ i 0  xi 0 / ni 0 ,

pˆ (1  pˆ i 0 ) pˆ i1 (1  pˆ i1 ) Vˆ (ˆi )  i 0  , and ni 0 ni1 wi 

Vi 1

i 1Vi 1 K

, where Vi  V (ˆi )

[inverse variance method; used only when there is at least one event of interest per treatment group and stratum], or (ni 0 ni1 )

wi 

(ni 0  ni1 ) [harmonic means method; used otherwise] k (n n ) i 0 i1 i 1 (ni 0  ni1 )

These CIs will be constructed only if there is enough information to estimate the quantities. Hypothesis Tests (one sided P-values for non-inferiority) The Yanagawa, Tango and Hiejima (YTH) test will be used to test for non-inferiority. With an asymptotically standard normal distribution under H0RR, the YTH statistic, Zratio, can be calculated as follows: 

1

 2  ~ ~ 1 1 2   2  K 2 K ~  n n ( p NI )(1  p0 k NI RR )  1  )  1k 0 k 0 k ~ RR Zratio=  ( x1k  n1k p 0 k NI RR  , ~ 1 1 1  k 1 k  NI RR n1k (1  p 0 k )  n0 k (1  p 0 k NI RR )    where x1k represents the number of observed events in the k th stratum in enoxaparin/warfarin ~

1 group and ( n1k p 0 k NI RR ) the expected number of events in the enoxaparin/warfarin group in

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the k th stratum. In this equation NIRR=1.8, n1k represents the sample size in the kth stratum in enoxaparin treatment group, n0 k represents the sample size in the kth stratum in apixaban pok is the maximum likelihood estimator of p 0 k under H0RR , treatment group, and ~ expressed as

~ p0k 

Where

4N k tk 1/ 2 } NI RR 2N k NI RR ,

d k  {d k2 

d k  n0 k  x1k 

(n1k  x0 k ) NI RR , N  n  n and t  x  x . k ok 1k k 0k 1k

With an asymptotically standard normal distribution under H0, the statistic Zdiff can be calculated as follows:

Z diff 

n1k n0k ( pˆ 0k  NI  ) 2 (1  pˆ 0k  NI  ) 2 [ x1k n1k ( pˆ 0k  NI  )]{ }1/ 2  ˆ 0k (1  pˆ 0k )  n0k ( pˆ ok  NI  )(1  pˆ 0k  NI  ) k 1 k 1 n1k p

K 2

K 2

Here NI   0.035 , and pˆ 0 k is the maximum likelihood estimator of p 0 k under H02 expressed as pˆ 0 k  [2u * cos( w)] 

b 3a

where 1 v w  ( )[  cos 1 ( 3 )] 3 u

v

b3 bc d  2  3 2a (3a) 6a

u  sgn(v)[

b2 c 12  ] 2 (3a) (3a)

And Statistical Analysis Plan

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1

b  [1   k 

x0 k x   k 1k  NI  ( k  2)] n0 k n1k

c  NI 2  NI  ( 2

d 

x0 k x x   k  1)  0 k   k 1k n0 k n0 k n1k

x0 k NI  (1  NI  ) n0 k

8.1.1.2. Superiority

Hypotheses test of superiority for efficacy endpoints will be based on the Cochran-Mantel-Haenszel test stratified by the type of index event (DVT only or PE with/without DVT). This procedure can be implemented by using PROC FREQ with the “CMH” option. 2-sided p-values will be reported. 8.1.1.3. Descriptive

Descriptive statistics will include the event rate in each group, the estimated relative risk with 95% CI, and the estimated risk difference with 95% CI. 

The 95% CI for the relative risk will be computed based on Mantel-Haenszel’s method stratified by index event. It can be implemented by using PROC FREQ with “CMH” option in SAS version 9.



Construction of CIs for single event rates will be based on the Wald asymptotic limits



Construction of CIs for difference between two event rates will be based on the inverse variance method when there is at least one event of interest per treatment group and stratum; otherwise, the CIs will be based on the harmonic means method. The confidence interval can be calculated as described in section 8.1.1. These CIs will be constructed only if there is enough information to estimate the quantities.

8.1.2. Analyses for Time to Event Data

Summaries will include graphical summaries of Kaplan-Meier estimates of cumulative incidence by treatment group along with a log-rank p-value for treatment differences.

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8.2. Statistical Analyses 8.2.1. Subject Disposition

The number of subjects enrolled into the study, and the number of subjects enrolled but not randomized together with the reasons for not being randomized will be summarized. The reasons for not being randomized will be taken from the CRF pre-randomization status page. The summaries of disposition described below will also be presented by randomization stratification factor - index event. For the treatment period, the number of treated subjects, the number of subjects who completed 24 weeks of study treatment, and the number of subjects discontinuing study therapy together with the reasons for discontinuation will be summarized by treatment group. The reasons for discontinuation will be taken from the end-of-treatment status pages of the CRF. Discontinuations from study drug due to AEs will further be summarized by the AE type: DVT, PE, bleeding, myocardial infarction (MI), stroke, thrombocytopenia, venous thromboembolic event, arterial thromboembolic event, and other. For the follow-up period, the number of subjects who complete the Week 24 visit, the number of subjects who completed the study, and the number of subjects discontinuing study together with the reasons for discontinuation will be summarized by treatment group. The reasons for discontinuation will be taken from the end-of-follow-up status pages of the CRF. The frequency of subjects enrolled in each country and in each region will be tabulated by randomized treatment group and for all randomized subjects combined. 8.2.2. Demography and Baseline Characteristics

Demographic and baseline characteristics will be summarized by randomized treatment group using both the randomized dataset and the per-protocol dataset. All demographic and baseline characteristic summaries will be further tabulated by stratification factor – Index event, for randomized dataset. Continuous variables will be summarized using mean and standard deviation. Categorical variables will be summarized using relative frequency. Key demographic and baseline variables to be summarized include: age (age will be calculated as (CONSENTDATE – BIRTHDATE+1) / 365.25 and truncated to the integer value, or age could be populated on the CRF, without date of birth being collected); age category; gender; race; Ethnicity; vital signs (systolic blood pressure, diastolic blood pressure, and heart rate); level of renal impairment as measured by creatinine clearance (severe: ≤30 ml/min, moderate: >30-50ml/min, mild: >50-80 ml/min, normal >80 ml/min); presence/absence of any 2 or more of the following: advanced age ( 80 years), low weight ( 60 kg), low creatinine clearance (Serum creatinine  1.5 mg/dL); conditions associated with VTE (cancer [history of cancer, active cancer], persistent or permanent immobility, previous VTE [DVT, PE], prothrombotic genotype, and other); cardiovascular risk factors (cigarette smoking, diabetes mellitus, hypercholesterolemia, hypertension, obesity); type of index disease (provoked or unprovoked). Statistical Analysis Plan

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The number of subjects in each treatment arm having received anti-coagulant therapy prior to first administration of the study drug will be summarized by medication class: 

Up to 36 hours infusion of UFH, or



Up to 2 doses of a LMWH indicated for QD use, or



Up to 3 doses of a LMWH indicated for BID use, or



Up to 2 doses of fondaparinux, and



Up to 2 doses of a VKA

Height, weight, weight category, body mass index, and body mass index category will be summarized using randomized subjects, randomized subjects by index event, and treated subjects. Type of index disease (proximal DVT, PE with or without DVT), adjudication status (index DVT and/or PE event is confirmed PE or DVT Y/N by adjudication), and randomization stratum (type of index event from IVRS) will be summarized using randomized subjects. The frequency of subjects having received prior anti-platelet medications will be summarized by medication class (eg, aspirin, thienopyridine, combination aspirin+thienopyridine). The frequency of subjects with abnormal baseline physical examination findings will be summarized by examination criteria (as collected in the Physical Examination module of the CRF at baseline). Subjects’ medical history will be summarized by medical history system class. Any imbalances between the groups will be assessed in reviewing the summaries and any differences deemed clinically relevant to the efficacy or safety comparisons may be investigated by controlling for the characteristic in a supplemental analysis. 8.2.3. Extent of Exposure 8.2.3.1. Study Therapy

For each treated subject, treatment compliance (TC) is defined as follows, where number of tablets taken counts are based on Apixaban/Apixaban placebo. (Assuming that on the first or last day subjects will only take one dose of study medication). For patients who received >7 day treatment: TC = [number of tablets taken / (days from first dose to last dose * 2 + 12)] * 100% For patients who received 3



INR33 kg/m2 ≤ 25 kg/m2 >25-≤30 kg/m2 >30-≤35 kg/m >35 kg/m2 Severe or Moderate Mild Normal Severe Moderate Mild Normal age 75, or CrCl ≤50 ml/min, or body wt ≤50 kg) Other Any 2 of: Age 80, or Serum creatinine ≥ 1.5 mg/dL, or body wt ≤60 kg) Other Active Cancer Absence of active cancer Q1 Q2 Q3 Q4

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If the value of the grouping variable cannot be determined for a subject, the subject will be excluded from the corresponding subgroup analysis. Forest plots will be utilized to present all sub-group analyses as a single visual representation for the primary efficacy and safety endpoints. Forest plots will include the number of subjects in the subgroup along with the number and percentage of events. 8.2.8.3. Analysis of Bleeding Events

The secondary objective included to the characterize bleeding is CRNM bleeding. Adjudicated minor bleed and total adjudicated bleeding will also be analyzed to support the characterization of bleeding risk. Analysis of incidence of these endpoints will be based on the safety analysis set. The analysis will include descriptive statistics of event rates with 95% CI, risk difference with 95% CI, relative risk with 95% CI, and a p-value based on the CMH test stratified for index event. The Kaplan-Meier product-limit estimators of the time to first adjudicated major bleeding event and the time to first adjudicated composite of major and clinically relevant non-major bleed will also be presented graphically. All bleeding analyses will be conducted on the safety dataset (section 5.3). Methodology of computing estimates and confidence intervals are presented in section 8.1.1.3. 8.2.8.4. Characterization of VTE /MI/Stroke/CV-related death/MB/CRNM bleeding

Event rates with 95% CI, risk difference with 95% CI, relative risk with 95% CI, and a p-value based on the CMH test stratified for index event will be used to characterize the relative effect of apixaban therapy compared to standard enoxaparin/warfarin therapy for the composite endpoint VTE/MI/Stroke/CV-related death/MB/CRNM Bleeding. The primary efficacy dataset, the secondary efficacy dataset, and the safety dataset will be used for these analyses. Both MI and Stroke will be considered efficacy endpoints for this analysis (secondary efficacy dataset) while bleeding events will be considered as safety events. The analysis will include descriptive statistics of event rates with 95% CI, risk difference with 95% CI, relative risk with 95% CI, and a p-value based on the CMH test stratified for index event. The primary and secondary efficacy datasets are defined in section 5.1; the safety dataset is defined in section 5.3. The CMH test statistic is described in section 8.1.1.2. Methodology of computing estimates and confidence intervals are presented in section 8.1.1.3. 8.2.8.5. Pre-specified Subgroups Analyses-Safety

Analysis of the primary safety endpoint (adjudicated major bleeding) will be performed for the subgroups described in Table 1.

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No hypothesis testing will be conducted on the subgroups. Analyses will be performed using the safety analysis set (section 5.3). Descriptive statistics will be presented including event rates with 95% CI and risk difference with 95% CI using methods described in section 8.1.1.3. 8.2.9. Other Safety Analyses 8.2.9.1. Adverse Events

Analysis of efficacy endpoints will be based only on events that were confirmed by adjudication. All endpoint events reported by the investigator as AEs (serious or non-serious) will be reported in the safety analyses regardless of whether or not the event was confirmed by adjudication. All AEs will be coded and grouped into Preferred Terms (PT) by System Organ Class (SOC), using the Medical Dictionary for Regulatory Activities (MedDRA). Listings and summaries will be based on the resulting SOCs and PTs. Analysis of all safety data will follow the BMS safety data conventions (described in “Analysis of Safety Data - Reference to BMS CT SOP 109” and attached in Appendix 2) with the following exception: according to the standardized safety data conventions, non-serious AEs occurring up to the day of the last dose of study drug are to be included in summaries for the Treatment Period. The apixaban standard is inclusion up to 2 days after the last dose or 30 days after the last dose if the event is considered an SAE. The incidence of bleeding-related AEs during the Treatment Period will be summarized by SOC, PT and treatment group. All reported AEs and SAEs will be listed, indicating the subject id, treatment group, age, gender, race, day of onset relative to start of dosing, resolution date, investigator-assessment of relationship to study drug, investigator-assessment of intensity of event, action taken regarding study drug and whether treatment was required for the event. Summary information (the number and percentage of subjects) regarding AEs (for serious and non-serious events) will be tabulated by SOC, PT and treatment group for: 

All events;



Deaths;



Treatment-related events;



All events categorized by intensity.

The frequency of subjects discontinuing study drug due to AEs will be tabulated by SOC, PT and treatment group.

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Most common AEs (reported in more than 5% of subjects in any treatment group) will also be summarized by PT and treatment group. Laboratory AEs are laboratory results identified by the Investigator as AEs and thus reported on the AE pages of the CRF. Any such AE occurring during the Treatment Period will be included in the respective AE summaries. 8.2.9.2. Laboratory Data

Laboratory measurements and their changes from baseline will be summarized by nominal visit and treatment group, for protocol specified analytes. The frequency of subjects with laboratory marked abnormalities (MAs) during the Treatment Period based on pre-specified criteria (see Appendix 1) will be tabulated by treatment group, for each analyte. Shift analysis will be performed to evaluate qualitative changes that occurred during the Treatment Period. For protocol specified analytes, shift tables will display, by treatment group, the frequency of subjects with the following combination of values at baseline and during the Treatment Period: 

No change (low to low: L-L, normal to normal: N-N, high to high: H-H);



Abnormal to normal (low to normal: L-N, high to normal: H-N);



Normal to abnormal (normal to low: N-L, normal to high: N-H);



Abnormal to abnormal (low to high: L-H, high to low: H-L).

where low refers to values that are ULN and normal refers to values in-between the normal limits. Two shift tables will be presented: 

One for labs with MA criteria based on high values (regardless of whether the MA criteria also considers low values) - the post-dose value considered for the tabulation will be the largest value obtained during the Treatment Period;



Another for labs with MA criteria based on low values (regardless of whether the MA criteria also considers high values) - the post-dose value considered for the tabulation will be the smallest value obtained during the Treatment Period.

In addition, liver-related elevations and discontinuations will be tabulated by treatment group. The tabulation will include the number and proportion of subjects with 

Post-dose elevation of AT > 3 ×ULN (AT refers to either one of ALT or AST);



Post-dose elevation of AT > 5 ×ULN;



Post-dose elevation of AT > 10 ×ULN;



Post-dose elevation of AT > 20 ×ULN; Statistical Analysis Plan

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Post-dose elevation of total bilirubin > 2 ×ULN;



Post-dose elevation of AT > 3 ×ULN and total bilirubin > 2 ×ULN on the same date;



Liver-related discontinuations.

The number and proportion of subjects with post-dose elevations of AST, ALT, total bilirubin, ALP, or CK will also be tabulated by treatment group including: 

AST elevations >3ULN, >5ULN, >10ULN, or >20ULN;



ALT elevations >3ULN, >5ULN, >10ULN, or >20ULN;



AST or ALT elevations >3ULN, >5ULN, >10ULN, or >20ULN;



Both AST and ALT elevations >3ULN, >5ULN, >10ULN, or >20ULN on the same date;



Total bilirubin elevations > 1.5ULN or >2ULN;



ALT elevations > 3ULN and total bilirubin elevations >1.5ULN on the same date, or ALT elevations > 3ULN and total bilirubin elevations > 2ULN on the same date;



AST elevations > 3ULN and total bilirubin elevations >1.5ULN on the same date, or AST elevations > 3ULN and total bilirubin elevations > 2ULN on the same date;



ALP elevations > 1.5ULN;



CK > 10ULN.

Similar tabulations for the number and proportion of subjects with elevations of AST, ALT, total bilirubin, ALP, or CK as described in the previous paragraph will be presented by treatment group and by nominal visit (including baseline). The following considerations apply to all liver-related laboratory tabulations described above: 

AT elevation refers to ALT or AST elevations regardless of whether they occurred concomitantly;



Elevations will be counted if they occur during the Treatment Period; Only values that meet the criteria and are larger than the baseline value will be included in the tabulations. If baseline value is missing then all values for that particular lab that meet the criteria will be included in the tabulations; Statistical Analysis Plan

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Values will be counted towards the categories of “AST and ALT elevations”, or “AT and Total Bilirubin elevation” if both AST and ALT or both AT and Total Bilirubin, respectively, meet the criteria and at least one of the values in the component is larger than the baseline value;



Values will be counted towards the categories of “AST or ALT elevations” if either AST meets the criteria and is larger than the AST baseline value or ALT meets the criteria and is larger than the ALT baseline value;



For each subject and lab or lab combination, the largest value measured during the Treatment Period will be counted for the Treatment Period summaries that do not take into consideration visit;



For each subject and lab or lab combination, the largest value measured within each visit window during the Treatment Period will be counted for the summaries by nominal visit.

The number and proportion of subjects with decreased platelet counts to