Protocol

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May 5, 2009 - HCV RNA 24 weeks after the last actual dose of study drug. ...... vasectomy or if the female partner has a bilateral oophrectomy, hysterectomy, tubal ..... Discomfort enough to cause a noticeable impact on the subject's daily life.
Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011;364:2405-16.

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VERTEX PHARMACEUTICALS INCORPORATED

TIBOTEC BVBA

Clinical Trial Protocol A Phase 3 Study of 2 Dose Regimens of Telaprevir in Combination With Peginterferon Alfa-2a (Pegasys®) and Ribavirin (Copegus®) in Treatment-Naïve Subjects with Genotype 1 Chronic Hepatitis C Study VX07-950-108 IND Number: 71832 EUDRACT Number: 2007-004720-20 Version 3.0 Date : 05 May 2009 (Replaces Version 2.0 dated 31 January 2008) Vertex Pharmaceuticals Incorporated 130 Waverly Street Cambridge, Massachusetts 02139-4242 Tibotec BVBA Gen De Wittelaan L 11B 3 B-2800 Mechelen, Belgium CONFIDENTIAL This document contains confidential information. Any use, distribution, or disclosure without the prior written consent of Vertex Pharmaceuticals Incorporated and Tibotec BVBA is strictly prohibited except to the extent required under applicable laws or regulations. Persons to whom the information is disclosed must be informed that the information is confidential and may not be further disclosed by them.

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Investigator’s Agreement I have read Version 3.0 of Protocol VX07-950-108 and agree to conduct the study according to its terms. I understand that all information concerning telaprevir supplied to me by Vertex Pharmaceuticals Incorporated and Tibotec BVBA is confidential.

Principal Investigator Signature

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Summary of Changes The previous version of this protocol (Version 2.0, 31 January 2008) was modified to create Version 3.0, dated 05 May 2009. A detailed list of all changes is located in Section 17. Major revisions made in Version 3.0 of the current protocol with rationale for changes are as follows: •

A secondary endpoint was added to assess the proportion of subjects with undetectable HCV RNA 24 weeks after the last actual dose of study drug. To accommodate this endpoint, a new visit was added “24 weeks after last actual dose of study drug” in Table 2-4. Also at this visit, a corresponding sample for viral sequencing will be drawn. In the previous versions of the protocol, HCV RNA was only assessed 24 weeks after the last planned dose of study treatment and the corresponding primary endpoint was SVR, defined as undetectable HCV RNA 24 weeks after the last planned dose of study treatment. This added endpoint and HCV RNA assessment time point will allow for comparisons of efficacy across other telaprevir studies.



In addition, an additional secondary endpoint was added to assess the proportion of subjects who relapse, defined as those who have undetectable HCV RNA at the end of treatment (EOT), and become HCV RNA detectable during antiviral follow-up.



The timing of treatment assignment unblinding was modified. In previous versions of the protocol, unblinding was to occur at Week 72. In the operations of the study, “Week 72” was interpreted as the time point at which all subjects reached Week 72 or discontinued earlier. The timing of treatment unblinding for investigator and sponsor was changed to database lock. In addition, a note was made to clarify that the sponsor’s study team will receive HCV RNA data after all subjects complete the Week 52 visit (post-treatment for all subjects). Also, unblinded virologists, who are not part of the study team, will be aware of treatment group and will receive HCV RNA results throughout the study to conduct the viral sequencing analyses for subjects with treatment failure (Section 11.6). Sequencing results will not be revealed until after database lock. Lastly, select members of the sponsor’s quality assurance team, who are not part of the study team, may be unblinded to study data to allow for the performance of quality assurance activities.



The option for mobile blood sample collection was added in Section 11.4.2. For subjects who are in the follow-up period, and who would otherwise be lost-to-follow-up, a mobile blood sample collection may be used. In these cases, only HCV RNA and viral sequencing samples will be drawn.



Under certain circumstances, confirmatory HCV RNA and viral sequencing samples will be collected. The circumstances that require confirmatory testing are as follows: after HCV RNA results are unblinded at Week 28, and only for the last dosing visit, the safety follow-up, and antiviral follow-up visits, when the original HCV RNA result is “< 25 IU/mL, detectable”. The confirmatory HCV RNA and viral sequencing samples must be drawn within 2 weeks of the visit when the “< 25 IU/mL, detectable” sample was drawn.

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At the Week 40 drug dispensation visit, subjects will have HCV RNA and viral sequencing samples drawn. These assessments will provide an additional data point between the Week 36 and Week 48 visits. In Table 8-2, a treatment stopping rule has been added for subjects who have detectable HCV RNA at Week 40.



In Section 10.12, specific text giving guidance on prior and concomitant medication use was removed and a cross reference to the current version of the Investigator’s Brochure was added. As new data are being generated from drug-drug interaction studies on an ongoing basis, the Investigator’s Brochure is maintained as the most up-to-date source of information and guidance.



The Sponsor has decided to amend the protocol to specifically disallow erythropoiesis-stimulating agents (ESAs) during the trial period. This decision is driven by the recent update, by the U.S. Food and Drug Administration (FDA), of the prescribing information for ESAs. This update introduces a warning of the potential for antibody-mediated pure red cell aplasia (PRCA) in patients with hepatitis C infection when ESAs are administered to treat anemia associated with interferon alfa and ribavirin therapy. The label update applies to all products in the ESA class of medicines registered in the US. The Marketing Authorization Holders do consider this a global issue and it is anticipated that other major health authorities will make changes similar to the FDA within the timelines they have for updating label safety information. Antibody-mediated PRCA is a rare to very rare adverse drug reaction in which patients who are treated with ESAs develop antibodies to the ESA. These antibodies inactivate both the ESA and naturally produced erythropoietin. The resulting anemia does not respond to treatment with an ESA. Antibody-mediated PRCA is treatable and usually resolves over several months and often requires multiple red blood cell transfusions and immunosuppressants. There is no definitive understanding of why PRCA occurs in the setting of hepatitis C treatment. Data regarding the benefit of ESAs when used to manage pegylated interferon alfa and ribavirin treatment induced anemia are not conclusive and they have not definitively been shown to improve hepatitis C viral response.1,2,3,4,5,6 According to the labeled indications, ESAs are not approved in any jurisdiction for the treatment of anemia in the setting of anti-HCV treatment with pegylated interferon alfa and ribavirin, however, in some countries, treatment guidelines do provide for exceptional or off-label use in this setting.7,8,9,10 Section 10.12 (Guidance on Prior and Concomitant Medications and Other Substances) and Section 13.1.3 (Management of Study Drug in Cases of Anemia) were revised to reflect the prohibition of ESAs.



Edits were made throughout the protocol to clarify specific operational aspects of the study (e.g., when investigators would be notified of treatment modifications, the schedule for antiviral follow-up schedule, etc.). Throughout the protocol, the text was revised to clarify that all subjects must attend all study visits through Week 72, regardless of treatment duration and HCV RNA status. The specific revisions are shown in Section 17.

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PROTOCOL SYNOPSIS Titl e

Lea d I nve st igat or

St udy Ce nte rs O bj ec tiv e s

A Phase 3 Study of 2 Dose Regimens of Telaprevir in Combination With Peginterferon Alfa-2a (Pegasys®) and Ribavirin (Copegus®) in Treatment-Naïve Subjects with Genotype 1 Chronic Hepatitis C John McHutchison, MD Director, Gastroenterology and Hepatology Research Duke Clinical Research Institute Durham, NC, USA This multicenter study will be conducted at 125 sites globally Primary: To demonstrate the efficacy of telaprevir in combination with peginterferon alfa-2a (Peg-IFN-alfa-2a) and ribavirin (RBV) in treatment-naïve subjects with genotype 1 chronic hepatitis C Secondary: To evaluate the safety of telaprevir in combination with Peg-IFN-alfa-2a and RBV in treatment-naïve subjects with genotype 1 chronic hepatitis C

St udy De si gn a nd St udy E ndpoi nt s

This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study to be conducted in treatment-naïve subjects with genotype 1, chronic hepatitis C infection. The study is designed to compare 2 dose regimens of telaprevir dosed with Peg-IFN-alfa-2a and RBV against standard of care, Peg-IFN-alfa-2a and RBV. The telaprevir regimens have a planned total treatment duration of 24 or 48 weeks, with telaprevir given in combination with Peg-IFN-alfa-2a and RBV for either the first 8 weeks (T8/PR group) or the first 12 weeks (T12/PR group). For subjects who achieve an extended rapid viral response (eRVR, defined as undetectable hepatitis C virus [HCV] RNA at Week 4 and at Week 12), Peg-IFN-alfa-2a and RBV dosing is planned for 24 weeks. For subjects who do not achieve eRVR, Peg-IFN-alfa-2a and RBV dosing is planned for 48 weeks. The control group has a planned total treatment duration of 48 weeks, with telaprevir-matching placebo given for the first 12 weeks and Peg-IFN-alfa-2a and RBV dosing planned for 48 weeks (Pbo12/PR group). Enrollment is planned for 350 subjects per group. The study drug dosing regimens presented above represent the planned regimens for each group. However, to minimize the risk to subjects who are not demonstrating an adequate antiviral response, and for consistency with standard guidelines for the treatment of genotype 1, chronic hepatitis C, HCV RNA results will be monitored, at specific time points between Week 4 and Week 12, and continually after Week 28, to determine if treatment and procedural modifications should be made for individual subjects based on the prespecified viral response criteria shown in Table 8-2. Individual viral response monitoring will be conducted by an unblinded independent reviewer while the site and sponsor remain blinded to HCV RNA data, and then by the site investigator following HCV RNA data unblinding. Treatment assignments will be double-blinded until database lock. HCV RNA

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results will be double-blinded up to, but not including, Week 28. From Week 28 onward, the HCV RNA results will be available to the investigator. Note: HCV RNA results from tests prior to Week 28 will not be available to the investigator until database lock. A detailed guideline for the assessment, management, and treatment of rash is included in the protocol to support investigators and to protect subjects’ safety (see Section 13.1.2). Primary Endpoint: Proportion of subjects achieving sustained viral response (SVR), demonstrated by achieving undetectable HCV RNA 24 weeks after last planned dose of study treatment Key Secondary Endpoint: Proportion of subjects who have undetectable HCV RNA at Week 72 (i.e., 24 weeks after last planned dose for subjects with a planned treatment duration of 48 weeks, and 48 weeks after last planned dose for subjects with a planned treatment duration of 24 weeks) Other Secondary Endpoints: • Proportion of subjects achieving rapid viral response (RVR), demonstrated by achieving undetectable HCV RNA 4 weeks after starting study treatment • Proportion of subjects achieving eRVR, demonstrated by achieving undetectable HCV RNA at Week 4 and at Week 12 • Proportion of subjects who have undetectable HCV RNA at Week 12 • Proportion of subjects who have undetectable HCV RNA at the end of treatment (EOT) • Proportion of subjects who have undetectable HCV RNA 12 weeks after last planned dose of study treatment • Proportion of subjects who have undetectable HCV RNA 24 weeks after last actual dose of study treatment • Proportion of subjects who relapse, defined as those who complete treatment as assigned, have undetectable HCV RNA at EOT, and become HCV RNA detectable during antiviral follow-up • Proportion of subjects who relapse, defined as those who have undetectable HCV RNA at the EOT, and become HCV RNA detectable during antiviral follow-up • Biochemical response including transaminase levels • Noninvasive markers of fibrosis • Total Fatigue Score from the Fatigue Severity Scale (FSS) • Adverse events, physical examination findings, and clinical laboratory, vital sign, and electrocardiogram (ECG) assessments Tertiary Endpoints: • Amino acid sequence of the HCV NS3 protease domain • Pharmacokinetics and pharmacokinetic-pharmacodynamic relationships of telaprevir, VRT-127394, Peg-IFN-alfa-2a, and RBV • Patient-reported outcomes including EQ-5D, assessment of work productivity, and assessment of healthcare utilization St udy Drug

Active substance: Telaprevir Strength: 375 mg

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Activity: HCV NS3•4A protease inhibitor Dosage form: Tablets for oral administration

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Study Assessment Flow Charts

The schedules of events are shown in the following tables: Table 2-1

Schedule of Events for Screening Through Week 6

Table 2-2

Schedule of Events for Week 8 Through Week 26

Table 2-3

Schedule of Events for Week 28 Through Week 72

Table 2-4

Follow-up Assessments 4 and 24 Weeks After the Last Actual Dose of Study Drug

Table 2-5

Schedule of Visits for Study Drug Dispensing

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Table 2-1

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Schedule of Events for Screening Throu gh Week 6 Screen

Events/Assessments Screening Events/Assessments • Informed Consent Signed • Demographics, eligibility criteria, medical history, height, weight, urinalysis, HCV genotyping and subtyping, HBsAg, HIV 1 and 2 Ab, AFP, ANA, HbA1Ca, liver biopsy if not performed within 1 yearb Randomization Study Drug Dosing

(Day -28 to Day -10)

Day 1 --

Wk 1 ±2 days

Wk 2 ±2 days

Wk 3 ±2 days

Wk 4 ±2 days

Wk 6 ±2 days

X

X Continues based on viral response assessment and treatment assignment (see Table 8-2). Blinded investigator will be informed how to proceed.

Safety Assessments Serious Adverse Events Adverse Events At all study visits, and spontaneously if reported between visits Medication Review Physical Examination/Vital Signs Full physical examination (including A symptom-directed physical examination and vital signs should be conducted as needed (temperature, pulse, respirations, blood an eye examination as per standard based on reported signs and symptoms. pressure) practice at the site) and vital signs Clinical Laboratory Assessments Predose, includes Paxgene & X X X X X X immune response markers (see Section 11.4.2) ECG (12-lead, manually read at the X site) Serum β-hCG (only women of X childbearing potential) Urine Pregnancy Test (only women of Predose X childbearing potential) Viral Assessments X Predose X X X X X HCV RNA Viral Sequencing Samples Predose X X X X X Patient Reported Outcomes FSS (Fatigue Severity Scale), EQ-5D, Productivity Predose X Pharmacokinetic Assessmentsc Predose Telaprevir, VRT-127394, Xd Xd X Peg-IFN-alfa-2a, RBV Sampling a Only for subjects with a history of diabetes b To avoid unnecessary biopsies for ineligible subjects, it is recommended that the biopsy be performed after the subject successfully completes all other screening assessments. c Only at sites with the technical capability to process pharmacokinetic samples d For approximately 45 subjects at a subset of sites, intensive pharmacokinetic sampling will be conducted at either Week 2 or Week 4 as per the schedule described in Section 11.5.

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Table 2-2

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Schedule of Events for Week 8 Through Week 26 Wk 8

Wk 10

Wk 12

Wk 14

Wk 16

Wk 20

Wk 24

Wk 26 (Only applies to subjects who are continuing treatment beyond Week 24)a

Events/Assessments Study Drug Dosing Safety Assessments Serious Adverse Events Adverse Events Medication Review Physical Examination/Vital signs (temperature, pulse, respirations, blood pressure) Clinical Laboratory Assessments (see Section 11.4.2)

Urine Pregnancy Test (only women of childbearing potential) Viral Assessments HCV RNA Viral Sequencing Samples Patient Reported Outcomes FSS, EQ-5D, Productivity

±2 days

±2 days ±2 days ±2 days ±2 days ±2 days ±2 days Continues based on viral response assessment and treatment assignment (see Table 8-2). Blinded investigator will be informed how to proceed. At all study visits, and spontaneously if reported between visits

A symptom-directed physical examination and vital signs should be conducted as needed based on reported signs and symptoms. X

X

X X X

X X

X

X

X

X

X

X

X

X

X X

X X

X X

X X X, Questionnaire must be completed before investigator’s inform subject of planned treatment duration/SVR assessment time point

X

Investigator Notified of Subject’s Planned Treatment Duration Investigator-Subject Consultation on Future Treatment/Study Visit Plans Pharmacokinetic Assessmentsb Telaprevir, VRT-127394, Peg-IFN-alfa-2a, RBV Sampling a

b

±2 days

X (See Section 8.2.2) X (See Table 8-2) May be in-person visit or via telephone

X

X (See Section 8.2.2)

X (See Table 8-2) May be in-person visit or via telephone

X

Subjects with a planned treatment duration of 48 Weeks and an SVR assessment time point at Week 72 (All Pbo12/PR subjects, and the T8/PR and T12/PR subjects who do not achieve eRVR and who do not have virologic failure at Week 4 or Week 12) Only at sites with the technical capability to process pharmacokinetic samples.

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Table 2-3

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Schedule of Events for Week 28 Through Week 72 Wk 28

Wk 36

Wk 40

Wk 48

Wk 52

Wk 60

Wk 72

Events/Assessments +2 weeks ±2 weeks ±2 weeks ±2 weeks +2 weeks ±2 weeks ±2 weeks Subjects with a Planned Treatment Duration of 24 Weeks and SVR Assessment at Week 48 (T8/PR and T12/PR subjects who achieve eRVR) After Safety Follow-up Assessment, only SAEs considered related to the study drug regimen should continue to be reported. Serious Adverse Events HCV RNA Xa Xa Xa Xa Xa a a a a Viral Sequencing Samples X X X X Xa Safety Follow-up Urine Pregnancy Test (only women of Assessment. No planned study visit for childbearing potential, may be a home Weeks 32, 36, 40, 44, and 48 See Table 2-4 these subject test when no study visit occurs) Patient Reported Outcomes FSS, EQ-5D, Productivity Xb Xb Xb Subjects with a Planned Treatment Duration of 48 Weeks and SVR Assessment at Week 72 (All Pbo12/PR subjects and T8/PR and T12/PR subjects who do not achieve eRVR) Continues based on viral response assessment Study Drug Dosing Last planned dosing. (see Table 8-2).

Safety Assessments Serious Adverse Events Adverse Events Medication Review Physical Examination/Vital Signs (temperature, pulse, respirations, blood pressure) Clinical Laboratory Assessmentsc (See Section 11.4.2)

Urine Pregnancy Test (only women of childbearing potential, may be a home test when no study visit occurs) Viral Assessments HCV RNA Viral Sequencing Samples Patient-Reported Outcomes FSS, EQ-5D, Productivity a

b

Only related SAEs are reported after the Safety Follow-up Visit

At all study visits, and spontaneously if reported between visits

A symptom-directed physical examination and vital signs should be conducted as needed based on reported signs and symptoms. X

X

X

Weeks 28, 32, 36, 40, 44, 48 X X

a a

X X

a a

Xb

X X

a a

X X

a a

Safety Follow-up Assessment. See Table 2-4

Weeks 52, 56, 60, 64, 68, 72 X X

a a

Xb

X X

a a

Xb

All subjects will remain on study through Week 72, regardless of treatment duration and HCV RNA status. If HCV RNA becomes detectable, HCV RNA and viral sequencing samples must be collected 4 and 24 weeks after the subject becomes detectable, which may result in additional study visits unless these visits fall within ±1 week of a scheduled study visit, and possibly out to Week 96 if the detectable result occurs at Week 72. After HCV RNA results are unblinded at Week 28, and only for the last dosing visit, the safety follow-up, and antiviral follow-up visits, a confirmatory HCV RNA and viral sequencing sample must be drawn if the result is “< 25 IU/mL, detectable”. This confirmatory HCV RNA and viral sequencing sample must be drawn within 2 weeks of the visit when the “< 25 IU/mL, detectable” sample was drawn. See Section 8.2.2 and 8.2.3. Questionnaires must be completed before the disclosure of HCV RNA results.

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Table 2-4

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Follow-up Assessments 4 and 24 Weeks After the Last Actual Dose of Study Drug Safety Follow-up 4 weeks after each subject’s last actual dose of study drug

Events/Assessments Safety Assessments Serious Adverse Events Adverse Events Medication Review Physical Examination/Vital Signs (temperature, pulse, respirations, blood pressure)

Clinical Laboratory Assessments (see Section 11.4.2) ECG (12-lead, manually read at the site) Urine Pregnancy Test (only women of childbearing potential) Viral Assessments HCV RNA Viral Sequencing Samples a

b

Antiviral Follow-up 24 weeks after each subject’s last actual dose of study druga

± 1 week X X X full physical examination and vital signs X X X Xb

Xb

Xb

Xb

If this visit falls within ±1 week of a scheduled study visit in which HCV RNA and viral sequencing samples are collected (as shown in Table 2-1, Table 2-2, or Table 2-3), it does not need to be performed. After HCV RNA results are unblinded at Week 28, a confirmatory HCV RNA and viral sequencing sample must be drawn if the result is “< 25 IU/mL, detectable”. This confirmatory HCV RNA and viral sequencing sample must be drawn within 2 weeks of the visit when the “< 25 IU/mL, detectable” sample was drawn.

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Table 2-5 Study Week # Screening Day 1 Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 Week 16 Week 20 Week 24 Week 28 Week 32 Week 36 Week 40 Week 44

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Schedule of Visits for Study Drug Dispensing and Drug Accountability Study Drug to Dispense NONE 3 Telaprevir/Placebo Cards 2 Bottles Copegus 2 kits Pegasys 2 Telaprevir/Placebo Cards 2 Telaprevir/Placebo Cards 1 Bottle Copegus 1 kit Pegasys 2 Telaprevir/Placebo Cards 3 Telaprevir/Placebo Cards 1 Bottle Copegus 1 kit Pegasys 2 Telaprevir/Placebo Cards 1 Bottle Copegus 1 kit Pegasys 1 Bottle Copegus 1 kit Pegasys 1 Bottle Copegus 1 kit Pegasys 1 Bottle Copegus 1 kit Pegasys 1 Bottles Copegus 1 kit Pegasys 1 Bottle Copegus 1 kit Pegasys 1 Bottle Copegus 1 kit Pegasys 1 Bottle Copegus 1 kit Pegasys 1 Bottle Copegus 1 kit Pegasys

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TABLE OF CONTENTS

1 2 3 4 5 6

Protocol Synopsis ............................................................................ 5 Study Assessment Flow Charts ........................................................ 7 Table of Contents .......................................................................... 13 List of Abbreviations .................................................................... 17 Introduction ................................................................................. 20 Study Objectives ........................................................................... 21 6.1 Primary Objective..................................................................................................21 6.2 Secondary Objectives ............................................................................................21 7 Study Endpoints ........................................................................... 22 7.1 Primary Endpoint ..................................................................................................22 7.2 Secondary Endpoints .............................................................................................22 7.2.1 Key Secondary Endpoint................................................................................22 7.2.2 Other Secondary Endpoints............................................................................22 7.3 Tertiary Endpoints.................................................................................................22 8 Investigational Plan ...................................................................... 23 8.1 Treatment Groups..................................................................................................23 8.2 Study Overview.....................................................................................................24 8.2.1 Screening.......................................................................................................24 8.2.2 On-Treatment Period .....................................................................................24 8.2.3 Follow-up Period ...........................................................................................32 8.3 Rationale for Selection of Treatment Regimens .....................................................33 8.3.1 Rationale for Selection of Treatment Regimens..............................................33 8.3.2 Rationale for Treatment and Procedural Modifications Based on Viral Response .......................................................................................................35 9 Selection of Study Population ........................................................ 35 9.1 Inclusion Criteria...................................................................................................35 9.2 Exclusion Criteria..................................................................................................36 9.3 Removal of Subjects in the Study ..........................................................................38 9.4 Replacement of Subjects........................................................................................39 10 Study Drug Administration and Management ................................. 39 10.1 Dose and Administration .......................................................................................39 10.2 Approved Products in Clinical Trials .....................................................................40 10.3 Dose Modification for Toxicity .............................................................................40 10.4 Premature Discontinuation of Study Drugs ............................................................41 10.5 Method of Assigning Subjects to Treatment Groups ..............................................41 10.6 Packaging and Labeling.........................................................................................41 10.7 Study Drug Supply, Storage, and Handling............................................................42 10.8 Drug Accountability ..............................................................................................42 10.9 Assessment of Treatment Compliance ...................................................................42 10.10 Disposal ................................................................................................................42 10.11 Blinding and Unblinding .......................................................................................43 10.11.1 Blinding.........................................................................................................43

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10.11.2 Unblinding.....................................................................................................43 10.12 Guidance on Prior and Concomitant Medications and Other Substances ................43 10.12.1 General Guidance ..........................................................................................43 10.12.2 Timing of Prior and Concomitant Medication Data Collection .......................44 11 Assessments .................................................................................. 45 11.1 Timing of Assessments..........................................................................................45 11.2 Subject and Disease Characteristics .......................................................................45 11.3 Efficacy.................................................................................................................45 11.4 Safety ....................................................................................................................45 11.4.1 Adverse Events ..............................................................................................45 11.4.2 Clinical Laboratory Assessments ...................................................................45 11.4.3 Physical Examinations and Vital Signs ..........................................................47 11.4.4 Electrocardiograms ........................................................................................48 11.5 Pharmacokinetics...................................................................................................48 11.6 Viral Sequencing ...................................................................................................48 11.6.1 Sequencing Method .......................................................................................48 11.6.2 Samples Analyzed..........................................................................................48 11.7 Contraception and Pregnancy ................................................................................49 11.8 Patient-Reported Outcomes and Health Economics ...............................................50 12 Statistical and Analytical Plans ..................................................... 50 12.1 Determination of Sample Size ...............................................................................50 12.2 Analytical Plans.....................................................................................................50 12.2.1 Efficacy and Safety Analyses.........................................................................50 12.2.2 Pharmacokinetic and Pharmacodynamic Analyses .........................................54 12.2.3 Viral Sequencing Analyses ............................................................................55 13 Procedural, Ethical, Regulatory, and Administrative Considerations 56 13.1 Adverse Event and Serious Adverse Event Documentation, Grading, and Reporting 56 13.1.1 Adverse Events ..............................................................................................56 13.1.2 Assessment, Treatment and Management of Rash ..........................................60 13.1.3 Management of Study Drug in Cases of Anemia ............................................64 13.1.4 Reporting of Serious Adverse Events and Rash Events of Special Interest .....64 13.2 Administrative Requirements ................................................................................65 13.2.1 Ethical Considerations ...................................................................................65 13.2.2 Subject Information and Informed Consent ....................................................66 13.2.3 Investigator Compliance ................................................................................66 13.2.4 Access to Records..........................................................................................66 13.2.5 Subject Privacy..............................................................................................66 13.2.6 Record Retention ...........................................................................................67 13.2.7 Study Termination .........................................................................................67 13.3 Data Quality Assurance .........................................................................................67 13.4 Monitoring ............................................................................................................67 13.5 Electronic Data Capture.........................................................................................68 13.6 Report and Publications.........................................................................................68 13.6.1 Publication of Study Results ..........................................................................68

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13.6.2 Clinical Study Report.....................................................................................69 References .................................................................................... 70 Appendix 1: Grading Scale For the Severity Of Adverse Events In Hepatitis C Clinical Trials ............................................................ 71 Appendix 2: Summary of Changes to the Protocol (Version 2.0) ..... 78 Appendix 3: Summary of Changes to the Protocol (Version 3.0) ..... 82

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List of Tables Table 2-1 Table 2-2 Table 2-3 Table 2-4 Table 2-5 Table 8-1 Table 8-2 Table 13-1 Table 13-2 Table 13-3 Table 13-4 Table 15-1

Schedule of Events for Screening Through Week 6.............................................8 Schedule of Events for Week 8 Through Week 26 ..............................................9 Schedule of Events for Week 28 Through Week 72 ..........................................10 Follow-up Assessments 4 and 24 Weeks After the Last Actual Dose of Study Drug .................................................................................................................11 Schedule of Visits for Study Drug Dispensing and Drug Accountability ...........12 Treatment Groups .............................................................................................24 Treatment and Procedural Modifications Based on Viral Response Assessments .........................................................................................................................26 Grading of Adverse Event Severity...................................................................58 Classifications for Adverse Event Causality......................................................58 Classifications for Study Drug Action Taken with Regard to an Adverse Event 59 Classifications for Outcome of an Adverse Event..............................................59 Grading Scale For the Severity Of Adverse Events In Hepatitis C Clinical Trials .........................................................................................................................71

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LIST OF ABBREVIATIONS

Abbreviation

Term

β-HCG

beta-human chorionic gonadotropin

Ab

antibodies

AFP

alfa-fetoprotein

ALT

alanine aminotransferase

ANA

antinuclear antibody

AST

aspartate aminotransferase

CPAP

Clinical Pharmacology Analysis Plan

CPK

creatine phosphokinase

CRO

contract research organization

CYP

cytochrome P450

DRESS

drug-related eosinophilia with systemic symptoms

DSMP

Data Safety Monitoring Plan

ECG

electrocardiogram

eCRF

electronic case report form

EDC

electronic data capture

EM

erythema multiforme

EOT

end of treatment

eRVR ESA

extended rapid viral response, defined as undetectable HCV RNA at Week 4 and at Week 12 erythropoiesis-stimulating agent

ESI

events of special interest

EVR

early virologic response

FA

Full Analysis

HBsAg

hepatitis B surface antigen

HCV

hepatitis C virus

HIV

human immunodeficiency virus

IDMC

Independent Data Monitoring Committee

INR

international normalized ratio

IRB

Institutional Review Board

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Abbreviation

Term

IEC

Independent Ethics Committee

IWRS

interactive web-based response system

LDH

lactate dehydrogenase

LOCF

last observation carried forward

LOD

limit of detection

LLOQ

lower limit of quantification

LV

variants with low levels of telaprevir resistance

NASH

nonalcoholic steatohepatitis

Peg-IFN

pegylated interferon

Peg-IFN-alfa-2a

peginterferon alfa-2a

PK-PD

pharmacokinetic-pharmacodynamic

PPA

Per Protocol Analysis

PRCA

pure red cell aplasia

PT

prothrombin time

PTT

partial thromboplastin time

q8h

every 8 hours

QTcB

Bazett-corrected QT interval

QTcF

Fridericia-corrected QT interval

RBV

ribavirin

RT-PCR

reverse transcription-polymerase chain reaction

RVR

rapid viral response

SAE

serious adverse event

SAP

Statistical Analysis Plan

SJS

Stevens-Johnson Syndrome

SmPC

Summary of Product Characteristics

STAT-C

specifically-targeted antiviral treatments for hepatitis C

SUSAR

suspected, unexpected, serious adverse reactions

SVR

sustained viral response

TEN

toxic epidermal necrolysis

TSH

thyroid stimulating hormone

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Abbreviation

Term

ULN

upper limit of normal

WBC

white blood cell

WT

wild type

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INTRODUCTION

One hundred and seventy million people in the world, approximately 3% of the global population, are infected with hepatitis C virus (HCV).11,12 The majority of these patients are above the age of 50 and have been infected for at least 30 years, putting them at risk for severe liver disease. The current standard of care for patients with chronic hepatitis C, a 48-week regimen of pegylated interferon (Peg-IFN) combined with ribavirin (RBV), results in sustained clearance of HCV RNA in 40% or less for patients with genotype 1 chronic hepatitis C.13 This combination therapy has numerous adverse effects, including flu-like symptoms (fatigue, fever, malaise, nausea, myalgia, and arthralgia) and neuropsychiatric effects (anxiety, increased irritability, and depression).14,15 As a result of the low efficacy and poor tolerability, the treatment rates of diagnosed patients with HCV are suboptimal. Telaprevir is being developed to meet the unmet medical need for more effective therapies to treat patients with chronic, genotype 1 hepatitis C. Telaprevir (VX-950), being developed by Vertex Pharmaceuticals Incorporated (Vertex) in collaboration with Tibotec BVBA, is a member of a new class of drugs being developed for chronic hepatitis C: specifically-targeted antiviral treatments for hepatitis C (STAT-C). Unlike Peg-IFN and RBV, STAT-C compounds act directly on HCV. Telaprevir is a specific, reversible, covalent, tight- and slow-binding NS3•4A inhibitor that was derived through structure-based drug design. Telaprevir prevents HCV replication by inhibiting the HCV NS3•4A protease, an enzyme that is essential for HCV replication. The nonclinical and clinical data available to date support further clinical development of telaprevir as a treatment for chronic hepatitis C. The results of nonclinical, Phase 1, and Phase 2a studies are summarized in the Investigator’s Brochure.16 Interim results from 2 complementary Phase 2 studies (104 and 104EU) are summarized below, and additional details are provided in the Investigator’s Brochure.16 Studies 104 and 104EU, conducted in treatment-naïve subjects with chronic, genotype 1 hepatitis C, evaluated the safety and efficacy of 12 weeks of telaprevir treatment (750 mg every 8 hours [q8h]) in combination with 12, 24, or 48 weeks of peginterferon alfa-2a (Peg-IFN-alfa-2a), with and without RBV. To date, interim results show a benefit for telaprevir-treated subjects. The treatment arms receiving 12 weeks of telaprevir in combination with 24 weeks of Peg-IFN-alfa-2a and RBV, had a sustained viral response (SVR) rate of 61% (Study 104) and a 12-week post-treatment response rate of 65% (Study 104EU). Given the 48-week treatment duration in the studies’ control arms, those comparative SVR data are not yet available. However, in Study 104, 45% of controlarm subjects had undetectable HCV RNA at the end-of-treatment, and in Study 104EU, 59% of control-arm subjects had undetectable HCV RNA at Week 36 of treatment. Based on a projected relapse rate of 15%, a conservative estimate from historical data on 48-week regimens with Peg-IFN-alfa-2a and RBV, the SVR rates for the 24-week telaprevir, Peg-IFN-alfa-2a, and RBV regimens are predicted to be 15 to 20% higher than those observed in the control arms.17 Viral breakthrough (defined as increase of >1 log in HCV RNA levels during treatment) occurred in 5% of subjects treated with telaprevir, Peg-IFN-alfa-2a, and RBV in the first Vertex Pharmaceuticals Incorporated

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12 weeks in Studies 104 and 104EU. Breakthroughs were associated with telaprevir resistant variants, and the vast majority of breakthroughs occurred early (in the first 4 weeks) in the dosing period, suggesting that breakthrough, in most cases, is the result of selection of preexisting variants. The duration of telaprevir treatment did not affect the incidence of viral breakthrough and therefore is not associated with increasing levels of phenotypic resistance in the great majority of subjects.17 In Phase 2 Studies 104 and 104EU, the safety profile of telaprevir administered for 12 weeks in combination with Peg-IFN alfa-2a has been well characterized. Based on combined interim safety analyses of Study 104 and 104EU, the treatment discontinuation rate due to adverse events through 12 weeks was 13% for the telaprevir, Peg-IFN-alfa-2a, and RBV regimen compared to 3% for the control. The adverse event profile of the telaprevir, Peg-IFN-alfa-2a, and RBV regimen was similar to that observed with control, with the exception of rash and anemia that occurred at a higher incidence and with greater severity in subjects receiving the telaprevir-containing regimens. The data suggest that telaprevir and RBV have overlapping effects on rash and anemia, resulting in some events of greater severity when telaprevir and RBV are administered in combination. Rash and anemia appeared to be reversible after the discontinuation of telaprevir dosing.18 Severe rash has occurred more often in the period from 8 to 12 weeks. In conclusion, the efficacy and virology data demonstrate the potential of a regimen of 12 weeks of telaprevir, in combination with Peg-IFN-alfa-2a and RBV, to be a substantial improvement over current therapy. The current investigation, a definitive Phase 3 clinical trial, is warranted to confirm the results observed for this regimen in the Phase 2 program. The combination of high antiviral activity but with somewhat decreased tolerability observed for the telaprevir, Peg-IFN-alfa-2a, and RBV treatment regimens in Studies 104 and 104EU suggest that further optimization of the benefit:risk ratio of a telaprevir, Peg-IFN-alfa-2a, and RBV regimen may be possible. Therefore, this study will also evaluate a shorter duration of telaprevir treatment (8 weeks) in combination with Peg-IFN-alfa-2a and RBV. 6

STUDY OBJECTIVES

6.1 Primary Objective To demonstrate the efficacy of telaprevir in combination with Peg-IFN-alfa-2a and RBV in treatment-naïve subjects with genotype 1 chronic hepatitis C 6.2 Secondary Objectives To evaluate the safety of telaprevir in combination with Peg-IFN-alfa-2a and RBV in treatment-naïve subjects with genotype 1 chronic hepatitis C

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STUDY ENDPOINTS

7.1 Primary Endpoint Proportion of subjects achieving sustained viral response (SVR), demonstrated by achieving undetectable HCV RNA 24 weeks after last planned dose of study treatment 7.2 Secondary Endpoints 7.2.1

Key Secondary Endpoint

Proportion of subjects who have undetectable HCV RNA at Week 72 (i.e., 24 weeks after last planned dose for subjects with a planned treatment duration of 48 weeks, and 48 weeks after last planned dose for subjects with a planned treatment duration of 24 weeks) 7.2.2

Other Secondary Endpoints



Proportion of subjects achieving a rapid viral response (RVR), demonstrated by achieving undetectable HCV RNA 4 weeks after starting study treatment.



Proportion of subjects achieving extended rapid viral response (eRVR), demonstrated by achieving undetectable HCV RNA at Week 4 and at Week 12



Proportion of subjects who have undetectable HCV RNA at Week 12



Proportion of subjects who have undetectable HCV RNA at the end of treatment (EOT)



Proportion of subjects who have undetectable HCV RNA 12 weeks after last planned dose of study treatment





Proportion of subjects who have undetectable HCV RNA 24 weeks after last actual dose of study treatment Proportion of subjects who relapse, defined as those who complete treatment as assigned, have undetectable HCV RNA at EOT, and become HCV RNA detectable during antiviral follow-up



Proportion of subjects who relapse, defined as those who have undetectable HCV RNA at the EOT, and become HCV RNA detectable during antiviral follow-up



Biochemical response including transaminase levels



Noninvasive markers of fibrosis



Total Fatigue Score from the Fatigue Severity Scale (FSS)19



Adverse events, physical examination findings, and clinical laboratory, vital sign, and electrocardiogram (ECG) assessments

7.3 Tertiary Endpoints •

Amino acid sequence of the HCV NS3 protease domain



Pharmacokinetics and pharmacokinetic-pharmacodynamic relationships of telaprevir, VRT-127394, Peg-IFN-alfa-2a, and RBV

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Patient-reported outcomes including EQ-5D20, assessments of work productivity21, and assessments of healthcare utilization

8

INVESTIGATIONAL PLAN

This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study to be conducted in treatment-naïve subjects with genotype 1, chronic hepatitis C infection. The study is designed to compare each of 2 dose regimens of telaprevir dosed with Peg-IFN-alfa-2a and RBV against standard of care, Peg-IFN-alfa-2a and RBV. The treatment groups, study overview, and rationale are described below. Enrollment is planned for 350 subjects per group. 8.1 Treatment Groups Subjects will be randomized to 1 of 3 treatment groups. Two of the groups will receive a regimen of telaprevir, Peg-IFN-alfa-2a, and RBV. The third group (the control) will receive a regimen of telaprevir-matching placebo, Peg-IFN-alfa-2a, and RBV. Subjects will be randomized to these treatment groups in a 1:1:1 ratio stratified by genotype 1 subtype and baseline viral load (see Section 10.5). The treatment groups and planned dosing periods are listed in Table 8-1. Details on blinding are provided in Section 10.11. The telaprevir regimens have a planned total treatment duration of 24 or 48 weeks, with telaprevir given in combination with Peg-IFN-alfa-2a and RBV for either the first 8 weeks (T8/PR group) or the first 12 weeks (T12/PR group). For subjects who achieve an extended rapid viral response (eRVR, defined as undetectable HCV RNA at Week 4 and at Week 12), Peg-IFN-alfa-2a and RBV dosing is planned for 24 weeks. For subjects who do not achieve eRVR, Peg-IFN-alfa-2a and RBV dosing is planned for 48 weeks. The control group has a planned total treatment duration of 48 weeks, with telaprevirmatching placebo given for the first 12 weeks and Peg-IFN-alfa-2a and RBV dosing planned for the entire 48 weeks (Pbo12/PR group). Note: The treatment regimens described below are the planned regimens. As described in Section 8.2.2, the actual duration of a subject’s dosing period may change based on viral response assessments throughout the study.

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Table 8-1 Treatment Group T8/PR

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Treatment Groups Planned Telaprevir Dosing Period Day 1 through Week 8

Treatments Planned Telaprevir-matching Placebo Dosing Period Weeks 9 through 12

Planned Peg-IFN-alfa-2a and RBV Dosing Period Day 1 through Week 24–with eRVR Day 1 through Week 48–without eRVR

T12/PR

Day 1 through Week 12 ---

Day 1 through Week 24–with eRVR Day 1 through Week 48–without eRVR

Pbo12/PR --Weeks 1 through 12 Day 1 through Week 48 T = telaprevir, PR = Peg-IFN-alfa-2a and RBV, Pbo=placebo, eRVR=extended rapid viral response (undetectable HCV RNA at Week 4 and Week 12)

8.2 Study Overview 8.2.1

Screening

Subjects will be evaluated for eligibility during a screening period from Day -28 to Day -10. 8.2.2

On-Treatment Period

On Day 1, eligible subjects will be randomized to 1 of 3 treatment groups via an interactive web-based response system (IWRS, see Section 10.5). Based on IWRS, a study drug kit number will be assigned and subjects will receive their first dose of study drug. Subjects will receive Peg-IFN-alfa-2a and telaprevir as described in Section 10.1. Peg-IFN-alfa-2a must be administered before the first dose of telaprevir but both must be administered on the same day, and telaprevir must be administered with food. The study drug dosing regimens presented in Table 8-1 represent the planned regimens for each group. However, to minimize the risk to subjects who are not demonstrating an adequate antiviral response, and for consistency with standard guidelines for the treatment of genotype 1, chronic hepatitis C, HCV RNA results will be monitored, starting at Week 4 and continuing throughout the study, to determine if treatment and procedural modifications should be made for individual subjects based on the prespecified viral response criteria shown in Table 8-2. Individual viral response monitoring will be conducted by an unblinded independent reviewer while the site and sponsor remain blinded to HCV RNA, and then by the site investigator following HCV RNA unblinding. For the first 24 weeks, study visits will occur at Weeks 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24. Viral response assessments will be conducted at Weeks 4 and 12, and treatment and procedural modifications will be made in accordance with Table 8-2. Regardless of whether treatment is modified or discontinued, all subjects are expected to attend all study visits through Week 72. Planned treatment duration will be communicated to the investigator between Weeks 23 and 26. The determination of planned treatment duration and SVR assessment time point will be based on the subject’s 1) treatment assignment, 2) eRVR status, and 3) viral response at Week 4 and Week 12. Subjects in the T8/PR and T12/PR treatment arms who achieve eRVR have a planned treatment duration of 24 weeks and SVR assessment time point at Week 48. Vertex Pharmaceuticals Incorporated

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All other subjects have a planned treatment duration of 48 weeks and SVR assessment time point at Week 72. After Week 24, subjects with a planned treatment duration of 24 weeks (SVR assessment time point at Week 48) will enter antiviral follow-up (see Section 8.2.3). Subjects with a planned treatment duration of 48 weeks (SVR assessment time point at Week 72) will continue to attend all study visits through Week 48. Additionally, if these subjects are still receiving Peg-IFN-alfa-2a and RBV treatment past Week 24 (i.e., they have not met a criterion requiring study drug dosing discontinuation as noted in Table 8-2), they will continue dosing pending the viral response assessments from HCV RNA testing at Weeks 24, 28, 36, and 40 (see Table 8-2). Following Week 48, they will enter antiviral follow-up (see Section 8.2.3). Starting with the Week 28 visit, HCV RNA results will be unblinded to the investigator who will use them to determine whether or not dosing should continue based on the criteria shown in Table 8-2. To maintain the treatment assignment blinding amongst subjects continuing treatment beyond 24 weeks only HCV RNA results from Week 28 onward will be made available to the investigator; prior HCV RNA results and eRVR status will not be reported. After Week 28 HCV RNA unblinding, a confirmatory HCV RNA and viral sequencing sample must be drawn if a subject’s result is “< 25 IU/mL, detectable” at the last dosing visit. The confirmatory HCV RNA and viral sequencing sample must be drawn within 2 weeks of the visit when the “< 25 IU/mL, detectable” sample was drawn. At all sites with the technical capability to process pharmacokinetic samples, samples will be drawn at the time points shown in Section 2 (Table 2-1 and Table 2-2). At a subset of sites, a pharmacokinetic sampling substudy will be conducted in 45 subjects. Additional information is provided in Section 11.5.

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Table 8-2

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Treatment and Procedural Modifi cation s Based on Viral Response Assessments

Study Week for Assessment Subjects T8/PR and Week 4 T12/PR subjects

Point of assessment Independent reviewer

HCV RNA Criteria ≤ 1000 IU/mL

Treatment and Procedural Modification At Week 6, subject continues study drug dosing as planned.

> 1000 IU/mL (Virologic Failure)

At Week 6, investigator will be instructed to: • discontinue telaprevir and continue Peg-IFN-alfa-2a and RBV dosing, and • continue subject on study until Week 72. Table continues on next page

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Treatment and Procedural Modifi cation s Based on Viral Response Assessments

Study Week for Assessment Subjects All subjects Week 12 (EVR Assessment)

Point of assessment Independent reviewer

HCV RNA Criteria < 2-log10 decrease in HCV RNA at Week 12 compared to baselinea

Treatment and Procedural Modification At Week 14, investigator will be instructed to: • discontinue all study drug dosing, • continue subject on study until Week 72, • perform Safety Follow-up Visit (including HCV RNA and viral sequencing samples) 4 weeks after last actual dose of study drug, and • test HCV RNA and collect viral sequencing samples at 4 and 24 weeks after becoming detectable.

≥ 2-log10 decrease in HCV RNA at Week 12 compared to baselinea (EVR)

At Week 14, Pbo12/PR subjects continue study drug dosing as planned. If subject is in T8/PR or T12/PR arms, proceed to Week 12 Virologic Failure Assessment.

T8/PR and • HCV RNA ≤ 1000 IU/mL T12/PR subjects who • HCV RNA >1000 IU/mL had (Virologic Failure) HCV RNA ≤ 1000 IU/mL at Week 4 a Baseline is calculated as the median of all predose values. Week 12 (Virologic Failure Assessment)

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At Week 14, subject continues study drug dosing as planned. At Week 14, investigator will be notified and instructed to: • continue Peg-IFN-alfa-2a and RBV dosing, and • continue subject on study until Week 72. Table continues on next page

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Table 8-2

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Treatment and Procedural Modifi cation s Based on Viral Response Assessments

Study Week for Assessment Subjects Subset of Week 24 T8/PR and T12/PR who achieve eRVR

All other subjects

Point of assessment Independent reviewer

HCV RNA Criteria Undetectable at Week 4 and Week 12 (eRVR)

Independent reviewer

Treatment and Procedural Modification Between Weeks 23 and 26, investigator will be informed that planned treatment duration is 24 weeks. Investigator will be instructed to: • discontinue all study drug dosing, • continue subject on study until Week 72, and • perform a Safety Follow-up Visit (as detailed in Table 2-4). After Week 24 (by Week 26), investigator will be informed that planned treatment duration is 48 weeks. Study drug dosing will continue pending the results of Week 24 HCV RNA (available at Week 26).

Undetectable HCV RNA

After Week 24 (by Week 26), the investigator will be instructed to continue the subject on study treatment.

Detectable (HCV RNA >10 IU/mL, Virologic Failure)

After Week 24 (by Week 26), investigator will be instructed to: • discontinue all study drug dosing, • continue subject on study until Week 72, • perform Safety Follow-up Visit (as detailed in Table 2-4), and • test HCV RNA and collect viral sequencing samples at 4 and 24 weeks after becoming detectable.

Table continues on next page

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Table 8-2

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Treatment and Procedural Modifi cation s Based on Viral Response Assessments

Study Week for Assessment Subjects All subjects Week 28 who are still receiving treatment

Point of assessment Site investigator

HCV RNA Criteria Undetectable HCV RNA

Treatment and Procedural Modification As soon as HCV RNA results are available, investigator will instruct subject to continue dosing as planned.

Detectable (HCV RNA > 10 IU/mL, Virologic Failure)

As soon as HCV RNA results are available, investigator will: • discontinue all study drug dosing, • continue subject on study until Week 72, • perform Safety Follow-up Visit (as detailed in Table 2-4) 4 weeks after last actual dose of study drug, and • test HCV RNA and collect viral sequencing samples at 4 and 24 weeks after becoming detectable. Note: If HCV RNA is detectable, but < 1000 IU/mL, the investigator may repeat the HCV RNA assessment to confirm the value before making changes to treatment. Table continues on next page

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Treatment and Procedural Modifi cation s Based on Viral Response Assessments

Study Week for Assessment Subjects All subjects Week 36 who are still receiving treatment

Point of assessment Site investigator

HCV RNA Criteria Undetectable HCV RNA

Treatment and Procedural Modification As soon as HCV RNA results are available, investigator will instruct subject to continue dosing as planned.

Detectable (HCV RNA > 10 IU/mL, Virologic Failure)

As soon as HCV RNA results are available, investigator will: • discontinue all study drug dosing, • continue subject on study until Week 72, • perform Safety Follow-up Visit (as detailed in Table 2-4) 4 weeks after last actual dose of study drug, and • test HCV RNA and collect viral sequencing samples at 4 and 24 weeks after becoming detectable. Note: If HCV RNA is detectable, but < 1000 IU/mL, the investigator may repeat the HCV RNA assessment to confirm the value before making changes to treatment. Table continues on next page

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Table 8-2

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Treatment and Procedural Modifi cation s Based on Viral Response Assessments

Study Week for Assessment Subjects All subjects Week 40 who are still receiving treatment

Point of assessment Site investigator

HCV RNA Criteria Undetectable HCV RNA

Treatment and Procedural Modification As soon as HCV RNA results are available, investigator will instruct subject to continue dosing as planned.

Detectable (HCV RNA > 10 IU/mL, Virologic Failure)

As soon as HCV RNA results are available, investigator will: • discontinue all study drug dosing, • continue subject on study until Week 72, • perform Safety Follow-up Visit (as detailed in Table 2-4) 4 weeks after last actual dose of study drug, and • test HCV RNA and collect viral sequencing samples at 4 and 24 weeks after becoming detectable. Note: If HCV RNA is detectable, but < 1000 IU/mL, the investigator may repeat the HCV RNA assessment to confirm the value before making changes to treatment.

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8.2.3 8.2.3.1

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Follow-up Period Safety Follow-up

All subjects will have a Safety Follow-up visit 4 weeks after receiving their last actual dose of study drug. This may be an additional visit, unless it falls within ± 1 week of a scheduled study visit. The assessments are shown in Table 2-4. 8.2.3.2

Antiviral Follow-up

Antiviral Follow-up Visits Regardless of treatment duration and HCV RNA status, all subjects must attend all study visits and be followed for antiviral response through Week 72, as shown in Table 2-1, Table 2-2, Table 2-3, and Table 2-4. •

For subjects who complete their assigned treatment at Week 24, antiviral follow-up will occur at Weeks 28, 36, 40, 48, 60 and 72.



For subjects who complete their assigned treatment at Week 48, antiviral follow-up will occur at Weeks 60 and 72.



For subjects who discontinue study treatment early, antiviral follow-up will begin at the next scheduled visit that falls after the safety follow-up visit. From that point onward, the subject will follow the same visit schedule as shown in Table 2-1, Table 2-2, Table 2-3, and Table 2-4.

Antiviral Follow-up Visits with Subject-dependent Timing •

Follow-up 24 Weeks After the Last Actual Dose of Study Drug For all subjects, HCV RNA testing and viral sequencing sampling will be performed 24 weeks after the last actual dose of study drug is received. This may result in an additional study visit unless it falls within ±1 week of a scheduled visit. See Table 2-4.



Follow-up for Subjects who Become HCV RNA Detectable For any subject who becomes HCV RNA detectable, HCV RNA and viral sequencing samples must be collected at 4 and 24 weeks after becoming detectable. These may be additional visits unless they fall within ± 1 week of a scheduled study visit.

Confirmatory HCV RNA Testing and Viral Sequence Sampling After Week 28 After Week 28 HCV RNA unblinding, a confirmatory HCV RNA and viral sequence sample must be drawn if a subject’s result is “< 25 IU/mL, detectable” at the last dosing visit, the safety follow-up visit, or at any antiviral follow-up visit. The confirmatory HCV RNA and viral sequencing sample must be drawn within 2 weeks of the visit when the “< 25 IU/mL, detectable” sample was drawn.

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Long-term Follow-up Any T8/PR or T12/PR subject who has undetectable HCV RNA at Week 72 may be asked to participate in a separate clinical protocol to collect long-term follow-up data.

Any T8/PR or T12/PR subject who has virologic failure will be asked to participate in a separate protocol to collect long-term follow-up data. 8.3 Rationale for Selection of Treatment Regimens 8.3.1

Rationale for Selection of Treatment Regimens

The telaprevir dose and the treatment regimens in this study were selected based on clinical pharmacology analyses, viral sequencing analyses, and efficacy and safety data from prior studies of telaprevir in treatment-naïve subjects with genotype 1 hepatitis C, including the Phase 2 studies VX05-950-104 (Study 104) and VX06-950-104EU (Study 104EU). The following sections describe the rationale for the telaprevir dose, the duration of telaprevir dosing, and the total duration of treatment. 8.3.1.1

Telaprevir Dose

As described in Section 5, interim efficacy data from 2 Phase 2 studies show that 12 weeks of telaprevir, at doses of 750 mg q8h, in combination with Peg-IFN-alfa-2a and RBV produces a high SVR rate (Study 104) and a high 12-week post-treatment response rate (Study 104EU) compared to EOT responses from the control arms. Interim safety data show that the adverse event profile of the 12-week combination treatment with telaprevir, Peg-IFN-alfa-2a, and RBV regimen was similar to that observed with control, with the exception of rash and anemia, which occurred at a higher incidence in subjects receiving the telaprevir-containing regimens. Severe rash, but not anemia, was a frequent cause for treatment discontinuation. Lastly, rash and anemia appeared to be reversible after the discontinuation of telaprevir dosing. 8.3.1.2

Telaprevir Duration

SVR and relapse rates for the treatment regimen of 12 weeks of telaprevir in combination with 24 weeks of Peg-IFN-alfa-2a and RBV in Studies 104 and 104EU support inclusion of this treatment regimen in the present study. Based on the interim analyses conducted in October 2007 for this regimen, the SVR rate in Study 104 was 61% and the 12-week post-treatment response rate in Study 104EU was 65%. Comparative SVR data are not yet available for the control arms. However, in Study 104, 45% of control-arm subjects had undetectable HCV RNA at the end-of treatment, and in Study 104EU, 59% of control-arm subjects had undetectable HCV RNA at Week 36 of treatment. Based on a projected relapse rate of 15%, a conservative estimate from historical data on 48-week regimens with Peg-IFN-alfa-2a and RBV, the SVR rates for the 24-week telaprevir, Peg-IFN-alfa-2a, and RBV regimens are predicted to be 15 to 20% higher than those observed in the control arms. Between the 2 studies, the relapse rate was 7% (6 of 87) for subjects who achieved a rapid viral response (RVR, undetectable HCV RNA at Week 4 of treatment) and completed 24 weeks of treatment. These high SVR rates and low relapse rates support evaluation of this

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24-week regimen in the present clinical study to confirm the results from Studies 104 and 104EU. During the 12 weeks of telaprevir, Peg-IFN-alfa-2a, and RBV treatment in Studies 104 and 104EU, approximately 13% of subjects discontinued prematurely because of adverse events. This discontinuation rate was higher than the rate of 3% in the control groups, which received Peg-IFN-alfa-2a and RBV. The high antiviral activity and decreased tolerability observed for the telaprevir, Peg-IFN-alfa-2a, and RBV treatment regimens in Studies 104 and 104EU led to consideration of whether lower doses of telaprevir or a shorter duration of telaprevir should be evaluated. Data supporting the 750 mg q8h dose have been described above and support this dose level in future trials. However, a shorter telaprevir treatment duration may have improved tolerability, and thus may further improve the benefit:risk ratio of telaprevir. Therefore, to evaluate this hypothesis, the present study was designed to include a treatment group with a duration of telaprevir shorter than 12 weeks. 8.3.1.3

Peg-IFN-alfa-2a and RBV Duration and Use of eRVR Criterion

The efficacy results from Studies 104 and 104EU show that a regimen with a total duration of 24 weeks (12 weeks of telaprevir in combination in combination with 24 weeks of Peg-IFN-alfa-2a and RBV) had a low relapse rate, indicating that this 24-week treatment duration was sufficient for the majority of subjects. However, to ensure that each subject receives an appropriate duration of Peg-IFN-alfa 2a and RBV to maximize their chance of achieving SVR in the present study, relapse results were further analyzed to identify subjects for whom 24 weeks was sufficient, and those who might benefit from 48 weeks of treatment. The combined relapse rate from the 2 studies was 7% (6 of 87) for subjects who achieved a rapid viral response (RVR, undetectable HCV RNA at Week 4 of treatment) and completed 24 weeks treatment. This low relapse rate supports use of a 24-week regimen for subjects who achieve RVR, and indicates that little additional benefit in SVR rates would be likely obtained from an additional 24 weeks of treatment. However, while based on a small number of subjects, the finding that 3 of 10 subjects in Study 104EU who did not achieve RVR relapsed after 24 weeks of treatment suggests that 24 weeks may not be sufficient for these subjects, and the standard 48-week treatment duration may offer additional benefit. Given the data from Studies 104 and 104EU, the use of the RVR criterion has been included in the study design as a determinant to shortening treatment duration for subjects with a low chance of relapse. Even in some subjects who have undetectable HCV RNA at Week 4 of treatment, they may have subsequent measurements that demonstrate detectable HCV RNA indicating that while they are responding to treatment, their response may be slower or less strong. To be conservative, rapid response criteria similar to that used in Study 104 are to be applied in this trial. In this design, to be eligible for a shorter treatment duration (24 weeks), subjects must have undetectable HCV RNA at Week 4 and Week 12, which has been designated as an “extended RVR” or eRVR. A longer treatment duration, 48 weeks, is planned for all other subjects who do not show this type of response, but meet all other response criteria.

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8.3.2

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Rationale for Treatment and Procedural Modifications Based on Viral Response

Evolution of viral population, gaining additional telaprevir-resistant viral variants, was observed when telaprevir dosing was continued in subjects with breakthrough (Study 104EU). However, additional resistant variants were not observed when telaprevir dosing was stopped after breakthrough was detected (Study 104). The majority of breakthroughs (75%) occurred within 4 weeks after the start of telaprevir treatment. These results highlight the importance of monitoring subjects for viral breakthrough and discontinuing telaprevir dosing if viral breakthrough is detected. Therefore, to minimize telaprevir exposure in subjects with viral breakthrough (now referred to as virologic failure) in the present study, all telaprevir subjects will be assessed for viral response at Week 4 and Week 12. At Week 4, telaprevir-treated subjects who have HCV RNA > 1000 IU/mL will discontinue telaprevir, and be eligible to receive a total of 48 weeks of Peg-IFN-alfa-2a and RBV, contingent on subsequent viral response assessments throughout the study. At Week 12, telaprevir-treated who have HCV RNA > 1000 IU/mL (virologic failure) will also be eligible to receive a total of 48 weeks of Peg-IFN-alfa-2a and RBV, assuming HCV RNA is also a ≥ 2-log10 decrease from baseline at Week 12, and contingent on subsequent viral response assessments. The value of 1000 IU/mL was selected as offering good discrimination between subjects who are having breakthrough (virologic failure) as opposed to subjects with just a slower response to the treatment regimen. In accordance with standard treatment practices for Peg-IFN-alfa-2a and RBV, all subjects will also be assessed at Week 12 to determine whether they have ≥ 2-log10 decrease from baseline in HCV RNA (early viral response, EVR). Subjects who do not have an EVR will discontinue treatment. Lastly, all subjects who are receiving treatment beyond Week 24 will be assessed for viral response at the Week 24, 28, or 36 visits. Subjects who have detectable (> 10 IU/mL) HCV RNA at any of these times will discontinue treatment. This is consistent with standard treatment practices for Peg-IFN-alfa-2a and RBV. 9

SELECTION OF STUDY POPULATION

9.1

Inclusion Criteria

1. May not have received any previous treatment with any approved or investigational drug or drug regimen for the treatment of hepatitis C 2. Male and female subjects, 18 to 70 years of age, inclusive 3. Genotype 1, chronic hepatitis C with detectable HCV RNA. Genotype must be confirmed during screening. Confirmation that the disease is chronic (as opposed to acute disease of less than 6 months duration) must be by at least 1 of the following criteria: •

Diagnosis of HCV >6 months before the screening visit

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Abnormal alanine aminotransferase (ALT) levels for >6 months before the screening period (Note: ALT does not have to be elevated to be eligible for the study, but history of elevated ALT can indicate duration of the infection).

4. Screening laboratory values within the following acceptable ranges: Laboratory Variable

Acceptable Range

Hepatitis B surface antigen (HBsAg) Human Immunodeficiency Virus (HIV) 1 and 2 antibodies (Ab)

Seronegative Seronegative

Absolute neutrophil count Platelet count Hemoglobin

≥ 1,500/cmm ≥ 90,000/cmm ≥ 12 g/dL for females ≥ 13 g/dL for males Within normal range

Uric acid TSH and T4

Within normal range, or adequately controlled thyroid function on treatment

All other hematology and clinical chemistry results

Within normal limits or showing no clinically significant abnormalities

5. Subject must have documentation of a liver biopsy within 1 year before the screening visit, or the subject must agree to have a biopsy performed within the screening period. Liver biopsy must show evidence of hepatitis (demonstrated by inflammation and/or fibrosis). If a biopsy more than 1 year prior to screening has already demonstrated histological cirrhosis, the biopsy does not need to be repeated if this biopsy report can be provided. 6. Subjects (or their female partners) must be not pregnant, or planning to become pregnant within the next 72 weeks, or they must be permanently sterile or otherwise of non-childbearing potential. They must also not be breastfeeding. If of child-bearing potential, subjects must agree to use 2 effective methods of contraception from screening through 6 months after the last dose of RBV. Male subjects who have a female partner of childbearing potential must agree to use 2 effective methods of contraception from Screening through 7 months after the last dose of RBV unless vasectomized. (For additional information on pregnancy and contraception requirements, please see Section 11.7.) 7. Willing and able to refrain from the concomitant use of any medications, substances, or foods noted in Section 10.12, from 14 days prior to the first day of dosing through the end of treatment. 8. Able to read and understand, and willing to sign the informed consent form and abide by the study restrictions. 9.2

Exclusion Criteria

1. Subject has any contraindications to Peg-IFN-alfa-2a or RBV therapy, including but not limited to any of the following:

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Hypersensitivity to Peg-IFN –alfa-2a, RBV, or to any component of these products



Hemoglobinopathies (including thalassemia major, sickle-cell disease)



History or other clinical evidence of significant or unstable cardiac disease (e.g. angina, congestive heart failure, recent myocardial infarction, significant arrhythmia) and/or clinically significant ECG abnormalities



Abnormal thyroid function that cannot be controlled effectively by medication



Poorly controlled diabetes mellitus as evidenced by HbA1C ≥ 8.5% at screening



Creatinine clearance ≤ 50mL/min at screening



Antinuclear antibody (ANA) titer ≥1:640 at screening and/or evidence of autoimmune hepatitis on liver biopsy

2. Evidence of hepatic decompensation in cirrhotic subjects: history of ascites, hepatic encephalopathy, or bleeding esophageal varices, and/or screening laboratory results of any of the following: •

International Normalized Ratio (INR) of ≥1.5



Serum albumin 1.8 times the upper limit of normal (ULN), unless history of Gilbert’s disease

3. Any other cause of significant liver disease in addition to hepatitis C, which may include, but is not limited to malignancy with hepatic involvement, hepatitis B, drug or alcohol-related cirrhosis, autoimmune hepatitis, hemochromatosis, Wilson’s disease, nonalcoholic steatohepatitis (NASH), or primary biliary cirrhosis 4. Diagnosed or suspected hepatocellular carcinoma as evidenced by screening alfa-fetoprotein (AFP) of ≥ 50 ng/mL. If AFP is ≥ 50 ng/mL, absence of a mass must be demonstrated by ultrasound within the screening period. 5. Active malignant disease or history of malignant disease within 5 previous years (with the exception of treated basal cell carcinoma) 6. Pre-existing psychiatric condition that could interfere with the subject’s participation in and completion of the study, including but not limited to: •

severe depression or hospitalization for depression,



schizophrenia, bipolar illness, severe anxiety or personality disorder,



a period of disability or impairment due to a psychiatric disease within the past 5 years.

7. History of craniocerebral trauma or active seizure disorders requiring medication 8. History of organ transplant, with the exception of corneal transplants and skin grafts

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9. Medical condition that requires frequent or prolonged use of systemic corticosteroids (e.g., severe asthma, severe arthritis or autoimmune conditions, organ transplantation, adrenal insufficiency, etc.) 10. Autoimmune-mediated disease (e.g., Crohn’s disease, ulcerative colitis, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, autoimmune hemolytic anemia, scleroderma, severe psoriasis) 11. History of acute pancreatitis within 5 years prior to the screening visit 12. History or other evidence of severe retinopathy or clinically significant ophthalmological disorder due to diabetes mellitus or hypertension. For subjects with a history of hypertension or diabetes, written clearance from an ophthalmologist has to be obtained before the start of treatment 13. History or other clinical evidence of chronic pulmonary disease associated with functional impairment 14. History of hemophilia 15. Evidence of serious or severe bacterial or fungal infection(s), including active tuberculosis 16. Currently abusing illicit drugs (narcotics or other controlled substances) or alcohol, or has a history of illicit substance or alcohol abuse within 2 years prior to the screening visit. Subjects who have a history of abuse of illicit drugs or alcohol should have had no incidents of abuse within the 2 years prior to the screening visit. 17. Participation in any investigational drug study within 90 days before study drug dosing, or participation in more than 2 drug studies in the 12 months before study drug dosing, or participation in any concurrent research study including non-drug studies from screening until the end of the subject’s participation in this study 18. Hypersensitivity to tartrazine (yellow dye #5) 9.3 Removal of Subjects in the Study A subject may discontinue study treatment at any time if the subject, investigator, or sponsor determines that it is not in the best interest of the subject to continue treatment. Note: A subject may discontinue from 1, 2, or all 3 of the study drugs as applicable. Additional information regarding treatment discontinuation is provided in Section 10.4. Although a subject may discontinue study treatment, every effort must be made to continue the subject on the study, returning for a Safety Follow-up Visit 4 weeks after the last actual dose of study drug and an antiviral follow-up visit 24 weeks after the last actual dose of study drug as outlined in Table 2-4, and attending all scheduled visits through Week 72. In addition, subjects who discontinue treatment must follow the contraception and pregnancy surveillance procedures outlined in Section 11.7. Subjects will discontinue study treatment(s) if •

they develop a medical condition that requires concomitant therapy with a prohibited medication.

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they develop a medical condition that may adversely affect their health (e.g., seroconversion to HIV positive status) or which is a contraindication to continuing Peg-IFN-alfa-2a or RBV therapy according to the approved package insert, such as ♦

evidence of decompensated liver disease.



signs or symptoms of ulcerative, hemorrhagic/ischemic colitis.



pancreatitis.





clinically significant psychiatric disturbance that, according to the investigator, requires discontinuation. new or worsening ophthalmologic disorders that, according to the investigator, require discontinuation.



they (or, in the case of male study subjects, their female partner) have a positive pregnancy test, or if the subject/partner is noncompliant with contraception requirements.



they are noncompliant with study requirements.



they withdraw informed consent.

In the event that a subject chooses to withdraw from the study (i.e., discontinue study visits), the investigator should make a reasonable effort to ascertain the reason(s) for withdrawal, while fully respecting the subject’s rights. 9.4 Replacement of Subjects No subjects will be replaced. Randomization will continue until the number of subjects exposed to study drug is equal to the prespecified sample size. 10 STUDY DRUG ADMINISTRATION AND MANAGEMENT 10.1 Dose and Administration Telaprevir (750 mg) or telaprevir-matching placebo will be administered orally q8h. The tablets will be administered in the fed state, meaning that subjects should have food intake within 30 minutes before dose administration. Each dose of telaprevir/placebo should be taken with approximately 240 mL (8 oz.) of water. The nutrient content of meals and snacks should be consistent with a regular diet (i.e., does not have to be a high-fat or low-fat meal). Peg-IFN-alfa-2a (Pegasys®, Roche, New Jersey, USA) will be administered by subcutaneous injection once weekly at a dose of 180 µg in accordance with the package insert. On Day 1, the first dose of Peg-IFN-alfa-2a must be administered before telaprevir, which will be given with food as noted above. It will be administered to the subject in the clinic, at which time appropriate site personnel will conduct training regarding self-administration of the injection as needed. Weekly injections of Peg-IFN-alfa-2a should be self-administered, but may be administered by appropriate staff in the clinic if it is determined that specific subjects require additional assistance. The day chosen for weekly injections should be kept constant throughout the treatment period.

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RBV (Copegus®, Roche, New Jersey, USA) will be administered orally at a total daily dose of 1000 mg/day for subjects weighing < 75 kg and 1200 mg/day for subjects weighing ≥ 75 kg. To maximize adherence to dosing regimens and minimize inconvenience for subjects, RBV, which is taken twice daily, may be taken at the same time as the morning and evening telaprevir doses (rather than q12h). If the number of daily RBV tablets is an odd number, the larger number of tablets should be taken with the morning dose (i.e., 3 tablets in the morning and 2 at night, so the larger dose is given before the longer period between doses). If RBV-related insomnia is a concern, then the second dose of RBV may be administered with the afternoon telaprevir dose instead of the evening dose. If the subject accidentally misses a dose of telaprevir and the missed dose is remembered within 4 hours of the scheduled dose time, the dose should be taken as soon as possible. If the subject accidentally misses a dose of telaprevir and the missed dose is remembered more than 4 hours after the scheduled dose time, the dose should be skipped and the next dose taken at the appropriate time. For missed doses of Peg-IFN-alfa-2a and RBV, the site will provide instructions for the subject in the current version of the approved Patient Medication Guide. 10.2 Approved Products in Clinical Trials Investigators participating in the study will assume responsibility for complying with all procedures and guidelines for the use of telaprevir as outlined in this study protocol, the Investigator’s Brochure, and other study-related materials provided by the study sponsor or their designee. In addition to the administration of telaprevir, subjects enrolled in this clinical trial will be administered the approved products Peg-IFN-alfa-2a and RBV. While dosing information has been provided in Section 10.1, it is the responsibility of the investigator to ensure that the guidelines for administration, contraindications, and special warnings and precautions are adhered to as described in the package inserts for Pegasys® and Copegus® and according to clinical practice. A copy of the Package Insert and the Medication Guide for these products are provided in the Pharmacy Manual. 10.3 Dose Modification for Toxicity Dose modifications for telaprevir/placebo are prohibited. Dose modifications that are used to manage toxicities associated Peg-IFN-alfa-2a (Pegasys®) and RBV (Copegus®) should be made in accordance with the applicable package inserts provided in the Pharmacy Manual. Section 13.1.2 provides a guideline for the assessment, treatment, and management of rash. Section 13.1.3 provides a guideline for the management of study drugs in cases of anemia. The investigator must record all information regarding dose modifications in the source documents and in the eCRF.

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10.4 Premature Discontinuation of Study Drugs 10.4.1.1 Discontinuation of 1 or 2 Study Drugs in the Treatment Regimen Subjects will be considered to be on study treatment as long as they are receiving Peg-IFN-alfa-2a. If Peg-IFN-alfa-2a is discontinued, RBV and telaprevir/placebo must also be discontinued. If RBV is discontinued for reasons other than anemia, subjects may continue treatment with Peg-IFN-alfa-2a and telaprevir/placebo for the duration of their assigned treatment regimen. If telaprevir is discontinued for safety reasons, subjects may continue treatment with Peg-IFN-alfa-2a and RBV for the duration of their assigned treatment regimen. 10.4.1.2 Discontinuation of All 3 Study Drugs in the Treatment Regimen If a subject prematurely discontinues dosing with all 3 study drugs, the subject will remain on study, attending all scheduled visits through Week 72 regardless of HCV RNA status. 10.5 Method of Assigning Subjects to Treatment Groups Subjects will be randomized via an IWRS in a 1:1:1 ratio to the 3 treatment groups; 350 subjects in each of the T8/PR, T12/PR, and Pbo12/PR groups. Randomization will be blocked and stratified to optimize balance among the treatment groups with regard to genotype subtype (1a, 1b, and other) and baseline viral load (HCV RNA < 800,000 IU/mL or ≥ 800,000 IU/mL). 10.6 Packaging and Labeling Telaprevir, telaprevir-matching placebo, Peg-IFN-alfa-2a, and RBV will be supplied by Vertex. Study drug labeling will be in compliance with applicable local and national regulations. Telaprevir (375 mg) tablets and placebo will be packaged into weekly (7-day) child-resistant blister dosing cards. Each dosing card will have a foil overwrap containing desiccants. Telaprevir and matching-telaprevir placebo will be provided and replaced in a blinded manner via IWRS. Subjects will be dispensed drug on Day 1 and will be provided additional drug at subsequent visits as needed. A detailed drug dispensation plan will be provided in the Pharmacy Manual. Peg-IFN-alfa-2a will be provided in a monthly kit. Each kit will contain 4 individual 180 µg single use pre-filled syringes along with appropriate quantities of needles and alcohol swabs. Sites in the United States will be provided a separate package of safety needles for Peg-IFN-alfa-2a. RBV (Copegus) will be provided as 200-mg tablets in a 125 cc size HDPE bulk bottle. Each bottle will contain 180 tablets.

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10.7 Study Drug Supply, Storage, and Handling Telaprevir will be supplied as tablets containing 375 mg telaprevir. Before being opened, each dosing card of telaprevir must be stored according to current specifications. Once the weekly dosing card has been started, it can be kept at room temperature and does not need to be refrigerated. Instructions regarding the storage and handling of telaprevir after dispensation to subjects will be provided to sites. All study drug must be stored in a secure area of limited access. Peg-IFN-alfa-2a will be supplied by Vertex as an injectable solution for subcutaneous administration. Peg-IFN-alfa-2a must be refrigerated at 2 to 8°C. Additional procedures for handling and storage are detailed in the Package Insert and SmPC. RBV will be supplied by Vertex as tablets for oral administration. RBV must be stored at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Procedures for handling and storage are detailed in the Package Insert and Summary of Product Characteristics (SmPC). 10.8 Drug Accountability Study drug (telaprevir, telaprevir-matching placebo, Peg-IFN-alfa-2a, and RBV) may be dispensed only under the supervision of the investigator or delegate and only to study subjects. The pharmacist or designated site staff will maintain information regarding the dates and amounts of study drug received, dispensed to the subjects, and returned by the subjects. Subjects will be instructed to return all used and unused materials associated with the study drug to the site. These materials will be retained at the site according to instructions provided by the study sponsor or designee until inventoried by the study monitor. The study monitor will review study drug records and inventory throughout the study. 10.9 Assessment of Treatment Compliance During the study, treatment compliance will be assessed by reviewing returned drug and dosing diary cards. All discrepancies will be discussed with the subject and recorded in the source documents. If subjects demonstrate continued noncompliance with study drug dosing despite educational efforts the investigator will be required to contact the study medical monitor to discuss discontinuation of the subject from study treatment. 10.10 Disposal The site staff or pharmacy personnel will retain all materials returned by the subjects until the study monitor has performed drug accountability. Following completion of drug accountability by the study monitor, all study drug materials may be destroyed at the site according to applicable local and national regulations. If the site does not have a drug destruction procedure in place, the drug may be returned to the distributor. Detailed instructions will be provided in the Pharmacy Manual.

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10.11 Blinding and Unblinding 10.11.1

Blinding

Treatment assignments will be double-blinded until database lock. HCV RNA results will be double-blinded up to, but not including, Week 28. From Week 28 onward, the HCV RNA results will be available to the investigator. HCV RNA results from tests prior to Week 28 will not be available to the investigator until database lock. The sponsor’s study team will receive HCV RNA data after all subjects complete the Week 52 visit (post-treatment for all subjects). This team will remain blinded to treatment group. In addition, unblinded virologists, who are not part of the study team, will be aware of treatment group and will receive HCV RNA results throughout the study to conduct the viral sequencing analyses for subjects with treatment failure (Section 11.6). Sequencing results will not be revealed until after database lock. Lastly, select members of the sponsor’s quality assurance team, who are not part of the study team, may be unblinded to study data to allow for the performance of quality assurance activities. To maintain double-blinding during the first 12 weeks, Pbo12/PR subjects will receive telaprevir-matching placebo (placebo) from Day 1 through Week 12, T8/PR subjects will receive placebo from Week 9 through Week 12. 10.11.2

Unblinding

Besides unblinding by the sponsor of serious adverse event reports to determine reportability, unblinding should only occur in circumstances when the knowledge of a subject’s treatment assignment is needed to medically manage the subject’s condition or when a pregnancy occurs in a female subject or the partner of a male subject. In the event the investigator feels that the unblinding of a subject is necessary, they should immediately contact the Study Medical Monitor at Duke Clinical Research Institute (DCRI, North and South America) or Paraxel (rest of world) at the numbers listed below. Information relating to unblinding (reason, date, by whom, etc.) will be clearly recorded in the subject’s medical record. 10.12 Guidance on Prior and Concomitant Medications and Other Substances 10.12.1

General Guidance

In vitro studies suggest that telaprevir is metabolized in the liver primarily by cytochrome P450 (CYP) 3A4. Additional in vivo studies indicated telaprevir was a CYP3A4/5 inhibitor when midazolam was the substrate, and this indicates the potential for telaprevir to cause drug-drug interactions when it is co-administered with drugs that are substrates of CYP3A4. In vitro studies indicated telaprevir was a mild inducer of CYP1A activity. Data from human drug-drug interaction studies for telaprevir completed to date are provided in the Investigator’s Brochure.16 Contraception guidance for investigators is provided in the Investigator’s Brochure and Section 11.7.1.1 of this protocol.

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Other drug-drug interaction studies are being conducted to characterize the interaction potential for telaprevir with other drugs. The information provided in the telaprevir Investigator’s Brochure will be updated as data from these ongoing studies become available. Because the interaction of telaprevir with other medications is not yet known, caution should be used when coadministering medications that are substrates, inhibitors, or inducers of CYP3A4. The Investigator’s Brochure provides a listing of medications that may interact with these enzymes.16 Note: the listing provided is not intended to be a complete list. Other medications that would be used in the study population infrequently (such as antipsychotic medications, or medications usually given in the inpatient setting), or for illnesses which are contraindications for enrollment in the study (such as rifampin for the treatment of tuberculosis), are not included in this list. A list of other prohibited medications and medications to be used with caution while receiving treatment with telaprevir are located in the Investigator’s Brochure.16 Intermittent or inadvertent use of a prohibited medication listed in the Investigator’s Brochure will be considered as a protocol deviation (e.g., if a subject used a single dose). A subject who requires repeated treatment with any of the prohibited medications listed in the telaprevir Investigator’s Brochure should be withdrawn from study treatment. Subjects requiring the use of medications that are noted to be used with caution should be monitored by the investigator for adverse events, and the use of these medications will not be considered protocol deviations. If questions arise regarding potential interactions with any medication, the Study Medical Monitor should be contacted. Subjects should also be advised against the consumption of grapefruit juice since it is a known inhibitor of CYP3A. Some herbal medications may result in unknown interactions and thus, all herbal medications should be taken with caution. In addition, subjects must not receive any erythropoiesis-stimulating agents (ESAs) during the course of the study. If telaprevir treatment is stopped, but Peg-IFN-alfa-2a and RBV treatment is continued, the investigator should refer to the package inserts for Pegasys and Copegus for guidance on prohibited medications. During the subjects’ participation in this study, all antiviral treatments for hepatitis C or other RNA viruses with the exception of those administered under this protocol are prohibited. 10.12.2 Timing of Prior and Concomitant Medication Data Collection Prior and concomitant medications will be collected beginning at the time of Screening or 14 days before signing informed consent, whichever is earlier, through the safety follow-up assessment.

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11 ASSESSMENTS 11.1 Timing of Assessments The timing of assessments is shown in the following tables: Table 2-1

Schedule of Events for Screening Through Week 6

Table 2-2

Schedule of Events for Week 8 Through Week 26

Table 2-3

Schedule of Events for Week 28 Through Week 72

Table 2-4

Follow-up Assessments 4 and 24 Weeks After the Last Actual Dose of Study Drug

Table 2-5

Schedule of Visits for Study Drug Dispensing

11.2 Subject and Disease Characteristics Subject and disease characteristics include the following: demographics, medical history, height, weight, HCV genotyping and subtyping, date of HCV infection and/or diagnosis, and liver histology status as reported on the most recent liver biopsy. 11.3 Efficacy All plasma HCV RNA levels will be assessed using the Roche TaqMan HCV RNA assay (Version 2.0, lower limit of quantification [LLOQ] of 25 IU/mL, limit of detection [LOD] of 10 IU/mL). HCV RNA values ≤10 IU/mL are considered undetectable; HCV RNA values >10 IU/mL are considered detectable. 11.4 Safety Safety evaluations will include clinical laboratory assessments, clinical evaluation of vital signs, physical examinations, ECGs, and the subjective reporting of adverse events. 11.4.1 Adverse Events Adverse events, serious adverse events (SAEs), and events of special interest (ESIs) will be assessed, documented, and reported in accordance with ICH-GCP. Section 13.1 details the definitions, collection periods, criteria, and procedures for documenting, grading, and reporting all adverse events, SAEs, and ESIs. 11.4.2 Clinical Laboratory Assessments Blood and urine samples will be analyzed at a central laboratory. Laboratory samples may be collected in a non-fasted state. Laboratory test results that are abnormal and considered clinically significant must be reported as adverse events (see Section 13.1.1.9). For subjects who are off-treatment, in the follow-up period, and who would otherwise be lost-to-follow-up, a mobile blood sample collection may be used. In these cases, only HCV RNA and viral sequencing samples will be drawn.

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Hematology: The following tests will be performed at each clinical laboratory assessment time point as listed in Section 2: hematocrit, hemoglobin, white blood cell (WBC) count, platelet count, reticulocyte count, and red blood cell count with indices (mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration). Note: If the WBC is abnormal, the laboratory will also perform a differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils). Serum Chemistry: The following tests will be performed at each clinical laboratory assessment time point as listed in Section 2: sodium, potassium, chloride, bicarbonate, glucose, ALT, AST and bilirubin (total, direct, and indirect) and uric acid. The following tests will be performed on Day 1, and at Weeks 4, 8, 12, 24, 36, 48, 72 and at the safety follow-up visit: calcium, phosphorus, creatinine, urea nitrogen, gamma-glutamyl transferase, lactate dehydrogenase, alkaline phosphatase, total protein, albumin, creatine phosphokinase, total cholesterol, low-density lipoprotein, high-density lipoprotein, and TSH; prothrombin time (PT)/INR and partial thromboplastin time (PTT). The following tests will be performed at Day 1 and at the time of the SVR assessment (Week 48 or Week 72): haptoglobin, alpha2-macroglobulin, and apolipoprotein A1. These tests, along with other serum chemistry tests included above, will allow for Fibrotest® analysis (serum markers of liver fibrosis). The following tests will be performed during screening to assess eligibility: HCV RNA, HBsAg, HIV 1 and 2 Ab, and ANA titers; HCV genotype and subtype; AFP; HbA1C (only for subjects with a history of diabetes), and urinalysis. Paxgene DNA: On Day 1 (predose), 1 blood sample (tube) will be collected for the evaluation of drug metabolizing enzymes (CYP isoforms), and cellular immune receptors (HLA typing), for the continuing investigation of factors that may be associated with an increased risk of the development of rash. These samples may not be processed for all subjects, but may be processed only for subjects with rash and appropriate controls. No other testing will be performed on these samples. Immune Response Markers: On Day 1 (predose), 1 plasma sample will be collected for the evaluation of immune response markers. The specific biomarkers that will be evaluated will be based on the results of ongoing research on samples from the Phase 2 clinical studies.

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Pregnancy surveillance for women of childbearing potential (see “Note” in Section 11.7): Pregnancy surveillance will be performed as listed in Section 2 and according to the following schedule: •

For female subjects: o at screening with a serum β-hCG (beta-human chorionic gonadotropin) test; o every 4 weeks starting at Day 1 and continuing through the Safety Follow-up visit with a urine β-hCG test, and when there are no scheduled study visits, with a urine home pregnancy test kits provided by the site; and o on 1 occasion each month for 6 months following the last dose of RBV (in accordance with the RBV package insert provided in the Pharmacy Manual) with a urine home pregnancy test kit provided by the site



For female partners of male subjects, pregnancy testing cannot be mandated because the partners are not study participants. However, monthly pregnancy testing until 7 months after the male’s last dose of RBV is strongly recommended, in accordance with the product labeling for RBV.

If a urine pregnancy test is positive, all study drug dosing should stop and the pregnancy should be confirmed with a serum β-hCG test. If confirmed, the pregnancy must be reported and the subject will be permanently withdrawn from study treatment as discussed in Section 11.7.1.2. Additional laboratory testing will be performed in the event of rash. See Section 13.1.2. 11.4.3 Physical Examinations and Vital Signs A full physical examination (review of all body systems) and vital signs will be performed at select study visits, as listed in Section 2. For all other scheduled visits, a symptom-directed physical examination and symptom-directed vital signs will be performed as appropriate. A full physical examination includes a review of the following systems: head/neck/thyroid; eyes/ears/nose/throat; lungs; heart; lymph nodes; abdomen; skin; musculoskeletal; and neurological. Breast, anorectal, and genital examinations will be performed when medically indicated. The physical examination at screening will also include an eye examination as per the package insert for Peg-IFN-alfa-2a provided in the Pharmacy Manual. For the conduct of the eye examination, the site’s standard procedures should be followed. Per the Exclusion Criteria, potential subjects with a history of hypertension or diabetes must have written clearance from an opthamologist to begin interferon therapy. Vital signs include blood pressure (systolic and diastolic), temperature, heart rate, and respiratory rate. These will be assessed following a 5-minute rest in the supine position. Additional vital sign assessments may be performed if clinically indicated, in the opinion of the investigator.

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11.4.4 Electrocardiograms Standard 12-lead ECGs will be performed using an analog machine with print-out and manually read at the site. ECGs should be performed at screening, at the safety follow-up visit, and at any other time if clinically indicated. Print-outs will be maintained with the source documentation. All clinically relevant abnormalities will be reported as adverse events. The performance of all ECGs must adhere to the following guidelines: •

The subject will be instructed to rest in the supine position for 5 minutes before having an ECG performed;



The ECG will be performed prior to the performance of any other procedures that may affect heart rate (e.g., blood draws).

11.5 Pharmacokinetics For the evaluation of plasma concentrations of telaprevir, VRT-127394 (epimer of telaprevir), Peg-IFN-alfa-2a, and RBV, blood samples will be collected from all subjects at sites that have the technical capability to process the samples (see the Laboratory Manual). On Day 1, pharmacokinetic samples will be collected predose. At study visits on Weeks 1, 2, 4, 8, and 12, random pharmacokinetic samples will be collected. At a subset of sites selected to perform pharmacokinetic sampling, additional pharmacokinetic samples for telaprevir and VRT-127394 analysis will be obtained from approximately 45 subjects who provide informed consent for these additional procedures. This additional pharmacokinetic sampling will involve sampling in order to assess the full pharmacokinetic curve at the Week 2 or Week 4 visit, with time points including: predose, 0.5, 1, 2.5, 4, 6, and 8 hours post-morning dose. Subjects will be compensated for this additional stay at the clinic. Lastly, at the sites that have the technical capability to process the samples, an additional sample will be collected if a subject develops a Grade 3 rash. These samples should be collected as close to the time of onset of rash as possible, and if possible, prior to the discontinuation of study drugs. 11.6 Viral Sequencing Samples will be collected for sequence analysis of the HCV NS3 protease region at the times listed in Table 2-1, Table 2-2, Table 2-3, Table 2-4, and Section 8.2.3. 11.6.1 Sequencing Method HCV will be isolated from the plasma and amplified by reverse transcription-polymerase chain reaction (RT-PCR) and analyzed using a population sequencing method in samples with HCV RNA > 1000 IU/mL. 11.6.2 Samples Analyzed Baseline and all post-baseline viral sequencing samples will be analyzed for the following subjects with virologic failure:

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subjects in any treatment group who meet any of the treatment modification criteria listed in Table 8-2;



subjects in the T8/PR and T12/PR groups (including subjects who discontinue early) who have a detectable HCV RNA result during the follow-up period.

11.7 Contraception and Pregnancy 11.7.1.1 Contraception The effects of telaprevir on conception, pregnancy, and lactation are not known. In a 13-week rat toxicology study, effects of telaprevir on spermatogenesis were noted. No similar findings were observed in a 13-week toxicology study in dogs. Telaprevir reproductive toxicology studies are in progress at this time. RBV is a known teratogen and has effects on spermatogenesis and RBV can be detected in seminal fluid. Female subjects of childbearing potential must use a combination of 2 effective birth control methods when having heterosexual intercourse, during dosing with RBV and for 6 months after the last dose of RBV. Non-vasectomized male subjects who have a female partner of childbearing potential must use a combination of 2 effective birth control methods when having heterosexual intercourse, during RBV dosing and for 7 months after the last dose of RBV. (Note: current RBV guidance on the duration of contraception and pregnancy surveillance is region-dependent. To facilitate the conduct of the study, the most conservative requirements have been stipulated in the protocol.) In addition, the pharmacokinetic effects of co-administration of telaprevir with an ethinyl estradiol (EE)-containing oral contraceptive (OC) have been evaluated in Clinical Study VX06-950-007.22 Based on these findings, the administration of telaprevir to subjects taking hormonal contraceptives (e.g., norethindrone [NE]/EE containing OC) may result in reduced efficacy of the OC. Therefore, subjects may choose to continue taking a hormonal contraceptive if they were already using it at the time that dosing with RBV was initiated. In these cases, subjects must add 2 non-hormonal methods of contraception, including 1 barrier method (e.g., male condom OR female condom [not both simultaneously], diaphragm with spermicidal jelly, cervical cap) for the duration of telaprevir/placebo dosing and for 2 additional months following telaprevir/placebo dosing, at which point the hormonal contraception may constitute as 1 of the 2 required, effective methods. Note: The use of birth control methods does not apply if the male partner has undergone a vasectomy or if the female partner has a bilateral oophrectomy, hysterectomy, tubal ligation, or if she is postmenopausal for at least 2 years. 11.7.1.2 Pregnancy If a subject becomes pregnant while participating in the study, study drug dosing must be permanently discontinued immediately. If the female partner of a male subject becomes pregnant, the male subject must permanently discontinue study treatment, as required by the RBV Package Insert. The Investigator must immediately report the pregnancy to the Study Medical Monitor listed in Section 10.11.2 and to the territory-specific safety contacts listed

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in Section 13.1.4.2 within 1 working day of the site’s knowledge of the subject’s (or partner’s) pregnancy. Vertex will report the pregnancy to Roche Pharmaceuticals. Subjects or their partners who become pregnant while participating in the trial and have received telaprevir will be followed until delivery, or the end of pregnancy, and with consent, the mother and baby will be followed for 1 year after the birth. A separate informed consent form will be provided to explain these activities. If conception occurs in a partner of a male study participant, the pregnancy will be reported and followed in the same manner, if the woman agrees to be followed. The pregnancy must be followed through outcome for SAEs. 11.8 Patient-Reported Outcomes and Health Economics •

Total Fatigue Score from the FSS19



EQ-5D20



Work productivity survey21



Recording of any visits to physicians (i.e., for treatment of an adverse events) in addition to scheduled study visits (type of physician, indication for visit, and number of visits)

12 STATISTICAL AND ANALYTICAL PLANS 12.1 Determination of Sample Size The primary efficacy variable is the proportion of subjects achieving SVR, defined as undetectable HCV RNA 24 weeks after the last planned study drug dosing (Week 48 for subjects in the T8/PR and T12/PR groups who achieve eRVR, and Week 72 for subjects in the T8/PR and T12/PR groups who do not achieve eRVR and all subjects in the Pbo12/PR group), regardless of whether the subject completed all study drug dosing. Assuming a 50% response rate in the control group, a 64% response rate in a telaprevir group, a 2-sided continuity corrected Chi-squared test, with an overall significance level of 5% (adjusted for multiple comparisons), a sample size of 350 subjects in each treatment group will provide a power of 92% to demonstrate a statistically significant treatment difference. 12.2 Analytical Plans 12.2.1 Efficacy and Safety Analyses 12.2.1.1

Statistical Considerations

For all efficacy analyses, subjects will be analyzed in the treatment regimen to which they were randomized. That is, telaprevir-treated subjects who achieve eRVR as well as those who do not achieve eRVR will be analyzed in the telaprevir treatment regimen (T8/PR or T12/PR) to which they were randomized.

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Interim Analyses

While the study is in progress, an Independent Data Monitoring Committee (IDMC) will conduct regular, planned reviews of the safety data to evaluate safety and tolerability of the study drug dosing regimens in order to safeguard subjects’ safety. The analysis and preparation of the safety data for each IDMC review will be performed by statistical group independent from the sponsor. An IDMC Charter defining the objectives and operational details of the IDMC will be finalized prior to the first IDMC data review meeting. No interim efficacy analysis is planned for this study. 12.2.1.3

Final Analysis

The final analysis will be performed after all subjects have completed the visit 24 weeks after the last planned dose of study drug (Week 48 for the T8/PR and T12/PR subjects who achieve eRVR, and Week 72 for T8/PR and T12/PR subjects who do not achieve eRVR and for all Pbo12/PR subjects), and the database has been locked. A more detailed description of the planned final statistical analysis will be presented in the Statistical Analysis Plan (SAP). The SAP will be generated and finalized before HCV RNA unblinding. 12.2.1.3.1 Final Analysis Sets Two efficacy analysis data sets will be used for the final statistical analyses: the Full Analysis (FA) and the Per Protocol Analysis (PPA) datasets. FA Dataset Includes all subjects randomized and exposed to at least one dose of study drug. PPA Dataset Includes all FA subjects without any major protocol violations (i.e., have not been determined to violate the protocol requirements) that may have a severe impact on efficacy. The criteria to be used for excluding subjects from the PPA dataset will be documented before final lock of the database. The FA dataset will be used for evaluations of efficacy and safety. The PPA dataset will be used to provide supportive efficacy analysis of the primary efficacy and key secondary efficacy endpoints. 12.2.1.3.2 Final Efficacy Analysis Primary Endpoint The primary efficacy endpoint is the proportion of subjects achieving SVR, i.e. undetectable HCV RNA 24 weeks after the last planned dose of study treatment. The SVR assessment time point for the primary efficacy endpoint will be •

the Week 48 viral assessment for subjects with a planned treatment duration of 24 weeks (i.e., subjects in the T8/PR and T12/PR groups who achieve eRVR), and

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the Week 72 viral assessment for subjects with a planned treatment duration of 48 weeks (i.e., subjects in the T8/PR and T12/PR groups who do not achieve eRVR, and all subjects in the Pbo12/PR group).

The following treatment success and treatment failure definitions will be applied to the analysis of the primary efficacy endpoint: Treatment Success The following subjects will be considered treatment successes: •

Subjects who complete the assigned treatment regimens and achieve SVR



Subjects who prematurely discontinue their assigned treatment regimen for reasons other than virologic failure (as specified in Table 8-2) and who achieve SVR

Treatment Failure The following subjects will be considered treatment failures: •

Subjects who complete treatment as assigned and have detectable HCV RNA at EOT or relapse during antiviral follow-up



Subjects with a missing SVR assessment



Subjects who prematurely discontinue their assigned treatment regimen for virologic failure (as specified in Table 8-2) whether or not they complete the 24-week post-treatment follow-up period and achieve SVR

The final analysis of the primary efficacy endpoint will include a comparison of odds ratios using a logistic regression model with SVR rate as the dependent variable and treatment, genotype 1 subtype, and baseline HCV RNA plasma level as factors. The results will be presented in terms of P values and confidence intervals for the odds ratios between the control group (Pbo12/PR) and each of the telaprevir groups (T8/PR and T12/PR). A supportive analysis will be provided using Cochran-Mantel-Hanszel method. Furthermore, the following additional analyses of the viral response rate will be performed to examine telaprevir’s effect: (1) comparative subgroup analysis of telaprevir-treated subjects who achieve eRVR and therefore receive treatment with Peg-IFN-alfa-2a and RBV for no more than 24 weeks versus Pbo12/PR (that is, only telaprevir-treated subjects who achieve eRVR will be considered in this subgroup analysis), and (2) descriptive statistics of telaprevir-treated subjects who do not achieve eRVR and are treated for 48 weeks with PegIFN-alfa-2a and RBV. A sensitivity analysis of the primary endpoint will be performed also using the logistic model described above, with the interaction terms for the main effects included in the model. For telaprevir subjects who discontinue telaprevir treatment at Week 4 and Week 12 because of virologic failure (HCV RNA >1000 IU/mL), HCV RNA data following the Week 4 and Week 12 visits, respectively, will be collected, and summarized separately and descriptively. Adjustment of significance level for multiple comparisons will be carried out using the Hochberg procedure.

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Secondary Efficacy Endpoints •

An analysis of the key secondary efficacy endpoint, proportions of subjects with undetectable HCV RNA at Week 72, will be provided to assess the sustainability of the SVR response observed in the T8/PR and T12/PR groups at Week 48. This analysis will be done using the model described above for the analysis of the primary efficacy endpoint.



For all other binary secondary endpoints (i.e., the analyses of the proportions of subjects who achieve RVR, eRVR, undetectable HCV RNA at Week 12, EOT, 12 weeks after the last planned dose of treatment, and 24 weeks after the last actual dose of treatment) will be evaluated in the same way as the primary endpoint described above.



Descriptive statistics will be provided for the subgroup of subjects who relapse, defined as those who complete treatment as assigned, have undetectable HCV RNA at the EOT, and subsequently become HCV RNA detectable during antiviral follow-up.



Descriptive statistics will be provided for the subgroup of subjects who relapse, defined as those who have undetectable HCV RNA at the EOT, and become HCV RNA detectable during antiviral follow-up.



Analyses of biochemical response including the transaminases and noninvasive markers of liver fibrosis will be defined in the SAP.

Handling of Missing Data For a secondary sensitivity analysis of the primary endpoint, if a subject (with SVR12) has a missing SVR24 result, the SVR24 value will be imputed using the SVR12 result for that subject. Subjects with missing SVR12 and SVR24 will be treated as failures in this analysis. Furthermore, a linear interpolation regression method using adjacent values before (including baseline value) and after missing values will be used to impute missing values. A time–to-withdrawal analysis, along with Kaplan-Meier curves and log-rank test, will be provided to compare withdrawal patterns among treatment groups. If a significant difference in withdrawal pattern is observed among treatment groups, additional sensitivity analyses will be conducted to understand the impact of the differences in withdrawal patterns on the primary efficacy results. 12.2.1.3.3 Final Safety Analysis No hypothesis testing will be performed. Standard safety data summaries will be provided for adverse events, laboratory data, physical examination findings, vital signs, and ECGs. Adverse Events Adverse events will be summarized by group by tabulating the number of subjects with at least 1 treatment-emergent adverse event (i.e., any adverse event that occurs from the first dose of study drug until 4 weeks after the last actual dose of study drug). The number and percentage of subjects who have at least 1 treatment-emergent adverse event within each MedDRA system organ class and preferred term will be reported. Subject frequency counts and percentages within MedDRA system organ class and preferred term will also be Vertex Pharmaceuticals Incorporated

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presented by severity and relationship. If a subject has more than 1 occurrence of the same event, then the highest severity observed will be reported in the severity summary, and the highest relationship will be used in the relationship tabulation. For events of rash and anemia, a time to onset analysis and additional analyses will be conducted. Further details will be provided in the SAP. Laboratory Results Summary statistics (n, mean, standard deviation, median, minimum, and maximum) will be presented by treatment group at each assessment time point for each continuous chemistry and hematology laboratory measurement. Changes from baseline will also be summarized by visit and treatment group. The number and percentage of subjects with shift changes from baseline based on the laboratory normal ranges and prespecified toxicity grades will be tabulated for select continuous laboratory assessment. Clinically relevant abnormal findings in the laboratory results will be reported as adverse events. Physical Examinations Physical examination findings will be presented in data listings. Clinically significant abnormal findings will be reported as adverse events. Vital Signs Standard safety data summaries will be provided for vital signs. Clinically significant abnormal findings in the vital signs results will be reported as adverse events. Electrocardiograms The number and percentage of subjects with clinically significant, on-treatment shifts from baseline will be presented. Clinically significant abnormal findings will be reported as adverse events. All ECG data will be presented in data listings. 12.2.1.3.4 Patient-Reported Outcomes and Health Economic Analyses A detailed description of the planned analyses of the patient-reported outcome, work productivity, and healthcare utilization data will be presented in a separate analysis plan to be finalized before unblinding. 12.2.2 Pharmacokinetic and Pharmacodynamic Analyses Pharmacokinetic assessments of telaprevir, VRT-127394, Peg-IFN-alfa-2a, and RBV will be performed during the study. An attempt will be made to use these assessments in combination with the efficacy assessments to further develop a model for the prediction of achieving undetectable HCV RNA and clinical efficacy based on pharmacokinetic parameters. If indicated, the relationships of pharmacokinetic parameters will also be compared to safety data collected including both clinical (adverse events) and laboratory results for the purpose of enhancing the understanding of the safety profile of the study drug combination.

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12.2.2.1 Pharmacokinetic and Pharmacodynamic Sampling Design Population pharmacokinetic analysis will be used with the pharmacokinetic sampling scheme to estimate pharmacokinetic parameters of telaprevir, if the data allows. For efficacy, the HCV RNA levels will be measured at scheduled visits (as described in Section 2, Section 8.2.2, and Section 8.2.3) to allow modeling of the decline in HCV RNA, if data warrants. If the data warrant, safety data including clinical (adverse events) and laboratory values will be correlated with dose and/or drug exposure parameters. 12.2.2.2 Pharmacokinetic and Pharmacodynamic Analysis Population All subjects who provide pharmacokinetic samples will be included in the PK-PD analysis. 12.2.2.3 Analytical Plan A clinical pharmacology analysis plan (CPAP) will be developed before database hardlock. The methods of analysis are summarized briefly below; the CPAP will describe the analysis in detail. 12.2.2.3.1 Pharmacokinetic Analysis For telaprevir, a structured approach for the analysis of population pharmacokinetic data will be used. This involves the use of a combination of exploratory data analysis and nonlinear mixed effects modeling techniques described by Ette and Ludden.23 Briefly, raw concentrations and covariates will first be examined graphically for patterns. Demographic variables (e.g., weight, age), selected laboratory parameters (e.g., AST, ALT, serum creatinine), and stage of liver disease will be explored. Thereafter, a nonlinear mixed-effects modeling approach implemented in the NONMEM software will be used to determine the pharmacokinetic model that best describes the data for telaprevir, if applicable. The posthoc individual Bayesian parameter estimates will be obtained with the final pharmacokinetic model. The pharmacokinetics of Peg-IFN-alfa-2a and RBV will be described using summary statistics only. 12.2.2.3.2 Pharmacokinetic and Pharmacodynamic Analysis PK-PD analyses may include examinations of the relationships between telaprevir concentrations and markers of efficacy or safety. These analyses will be data-driven and only conducted if warranted by the data. 12.2.3 Viral Sequencing Analyses Amino acid changes from baseline sequence in the HCV NS3 protease domain will be determined for subjects with treatment failure (subjects who stop treatment due to virologic failure and subjects who complete the treatment regimen but have detectable HCV RNA at EOT or relapse during antiviral follow-up). Potential amino acid substitutions conferring telaprevir resistance will be initially defined using a Poisson analysis. Sequencing results

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will be evaluated with HCV RNA responses to determine whether changes in viral sequence were correlated with treatment failure.

13 PROCEDURAL, ETHICAL, REGULATORY, AND ADMI NISTRATIVE CONSIDERATIONS 13.1 Adverse Event and Serious Adverse Event Documentation, Grading, and Reporting 13.1.1 Adverse Events For the purposes of this study, an adverse event is defined as any untoward medical occurrence in a subject during the study; the event does not necessarily have a causal relationship with the treatment. An adverse event can be any unfavorable and unintended sign (e.g., including an abnormal laboratory finding), symptom, or disease that occurs during the study, whether or not it is considered to be study drug related. This includes any newly occurring event or previous condition that has increased in severity or frequency after the informed consent form is signed. Any abnormal findings in clinical laboratory assessments, ECGs, physical examinations, or vital signs that are judged by the investigator to be clinically significant should also be reported on the adverse events eCRF and source document. Planned hospital admissions or surgical procedures for an illness or disease which existed before the subject was enrolled in the study are not to be considered adverse events unless the condition deteriorated in an unexpected manner during the study (e.g., surgery was performed earlier than planned). SAEs are defined in Section 13.1.4.1. 13.1.1.1

Events of Special Interest

All skin reactions involving rash or rash-like events that occur during the study and which meet any of the following 3 criteria will be considered an ‘Event of Special Interest’ (ESI): •

Permanent discontinuation of any or all study drugs due to rash



A Grade 3 (severe) rash



Rash which meets the criteria to be an SAE (serious adverse event)

An ESI is a clinical event for which the sponsor has implemented special reporting procedures for surveillance, monitoring and management purposes. All ESIs require: 1) Submission of an ESI report form to the territory-specific safety contacts listed in Section 13.1.4.2. 2) Assessment, treatment, and management as per the guidelines outlined in Section 13.1.2.

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Collection Period for Adverse Events

All adverse events, serious and non-serious, will be collected beginning after the informed consent form is signed through the safety follow-up assessment. In addition, all adverse events reported spontaneously during the course of the study, through the safety follow-up assessment, will be collected. Adverse events will be recorded regardless of the suspected cause of the event. Following the Safety Follow-up assessment (see Table 2-4), only SAEs considered related to the study drug regimen may be reported, and these may be reported indefinitely. 13.1.1.3

Documentation of Adverse Events

All adverse events will be recorded in the eCRF and source document (the subject’s permanent medical record). Adverse events should be reported and documented in accordance with the procedures outlined below. All adverse events occurring during the study must be documented on the relevant eCRF pages. The following data should be documented for each adverse event: •

Description of the event



Classification of “serious” or “not serious” (see Section 13.1.4)



Date of first occurrence and date of resolution (if applicable)



Severity (see Section 13.1.1.4)



Causal relationship to study drug (see Section 13.1.1.5)



Action taken (see Section 13.1.1.6)



Outcome (see Section 13.1.1.7)



Concomitant or other treatment given (see Section 13.1.1.8)

When possible, a constellation of signs and/or symptoms should be identified as 1 overall event or diagnosis. Laboratory results as adverse events are described in Section 13.1.1.9. 13.1.1.4

Adverse Event Severity

The investigator must determine the severity of all serious and non-serious adverse events. A scale for grading the intensity of adverse events that are frequently associated with hepatitis C is included in Table 15-1. The severity of an adverse event that does not appear in the scale in Table 15-1 should be determined according to the definitions in Table 13-1.

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Table 13-1 Grading of Adverse Event Severity Mild (Grade 1)

Awareness of the event; may cause minimal interference with the subject’s daily life.

Moderate (Grade 2)

Discomfort enough to cause a noticeable impact on the subject’s daily life.

Severe (Grade 3)

Incapacitation or significant impact on the subject’s daily life.

13.1.1.5

Adverse Event Causality

Every effort should be made by the investigator to assess the relationship of the adverse event, if any, to the study drug(s). Causality should be classified using the categories presented in Table 13-2. Table 13-2 Classifications for Adverse Event Causality Related

Experience follows a reasonable temporal association from administration of study drug without significant alternative etiology. May be supported by improvement upon study drug discontinuation and/or a positive rechallenge.

Possibly Related

Experience follows a reasonable temporal association from administration of study drug, but may have been produced by the subject’s clinical state or other factors. Information on drug withdrawal (dechallenge) may be lacking or unclear.

Unlikely Related

Experience does not follow a clear temporal association with study drug administration, is probably produced by the subject's clinical state or other factors. Also included are clinical events for which there is insufficient information or contradictory information which prohibits a proper assessment.

Not Related

No relationship between the experience and administration of the study drug.

13.1.1.6

Study Drug Action Taken

The action taken for each study drug should be classified according to the categories shown in Table 13-3.

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Table 13-3 Classifications for Study Drug Action Taken with Regard to an Adverse Event Drug Interrupted

Study drug administration interrupted in response to an adverse event.

Drug Withdrawn

Study drug administration permanently discontinued in response to an adverse event.

Dose Not Changed

Study drug dose not changed in response to the adverse event.

Dose Reduced

Study drug dose reduced in response to an adverse event.

Not Applicable

Action taken regarding study drug administration does not apply. “Not applicable” should be used in circumstances such as when the investigational treatment had been completed before the adverse event began and no opportunity to decide whether to continue, interrupt or withdraw treatment is possible.

Unknown

13.1.1.7

Action taken is unknown (e.g., a subject hospitalized at a hospital not under the case of the investigator and the investigator has no knowledge whether study drugs were continued or not).

Adverse Event Outcome

An adverse event should be followed until the investigator has determined and provided the final outcome. The outcome should be classified according to the categories shown in Table 13-4. Table 13-4 Classifications for Outcome of an Adverse Event Recovered/Resolved

Resolution of an adverse event with no residual signs or symptoms.

Recovered/ Resolved With Sequelae

Resolution of an adverse event with residual signs or symptoms.

Not Recovered/ Not Resolved (Continuing)

Either incomplete improvement or no improvement of an adverse event, such that it remains ongoing.

Fatal

Outcome of an adverse event is death. “Fatal” should be used when death is at least possibly related to the adverse event.

Unknown

Outcome of an adverse event is not known. e.g. a subject lost to followup.

13.1.1.8

Treatment Given

The investigator ensures adequate medical care is provided to subjects for any adverse events, including clinically significant laboratory values related to study drug. In addition, the investigator will describe whether any treatment was given for the adverse event. 13.1.1.9

Laboratory Test Results as Adverse Events

The determination of whether laboratory test results are clinically significant should be made by a physician or by a clinical study staff member who is experienced in reviewing and Vertex Pharmaceuticals Incorporated

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assessing laboratory tests. This determination is important, as a clinically significant laboratory abnormality must be associated with an adverse event, either directly or indirectly as explained below. The criteria for determining whether an abnormal laboratory test finding should be clinically significant are as follows: •

Test result is associated with clinical signs or symptoms. If the signs or symptoms are related to a diagnosis that has already been documented as an adverse event, the lab abnormality itself generally does not have to be reported as an additional adverse event (e.g., hyperglycemia with an adverse event of new-onset diabetes; if diabetes is documented as an adverse event, hyperglycemia does not need to be documented separately as it is a common finding as part of the diabetes diagnosis)



Test result requires additional diagnostic testing or medical/surgical intervention



Test result leads to a change in study drug dosing or to discontinuation from the study



Test result is considered by the investigator to be an adverse event (i.e., any new unfavorable sign/symptom, or previous condition that has increased in severity or frequency during the study).

Laboratory abnormalities that are associated with a chronic, stable medical condition (e.g., slightly elevated ALT in subject with hepatitis C that is unchanged or decreased from baseline) do not have to be considered clinically significant, but this judgment is left to the investigator. Note that repeating a test to confirm an abnormal result, in the absence of any of the above, does not mean that a lab must be clinically significant. An abnormal result that is found to be in error is not clinically significant and should not be reported as an adverse event. 13.1.2 Assessment, Treatment and Management of Rash Management of rash should always follow generally accepted medical standards. In addition, the following procedures for the assessment, treatment and management of rash should be followed. All Grade 3 skin rashes (regardless of seriousness), any skin rash events resulting in permanent discontinuation of any or all study drugs, or any skin rashes which are serious adverse events will be considered an Event of Special Interest (ESI) and should be reported within 24 hours to the territory-specific safety contacts described in Section 13.1.4.2.

13.1.2.1

Rash Assessment: Severity Grading

The grade and severity rating of rash events should be assigned using the following criteria: Grade 1, mild: rash is defined as a localized skin eruption and/or a skin eruption with a limited distribution (e.g., up to several isolated sites on the body), with or without associated

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pruritus. A mild rash will have no target lesions, no signs of systemic involvement, and no involvement of mucous membranes or signs of epidermal detachment. Grade 2, moderate: rash is defined as a diffuse skin eruption involving up to approximately 50% of the body surface; with or without superficial skin peeling, pruritus, or mucous membranes involvement with no ulceration. A moderate rash will have no signs of target lesions or epidermal detachment. A moderate rash may have systemic symptoms which are mild and/or limited. Grade 3, severe: rash is defined as a generalized rash involving over 50% of the body surface; or rash presenting with any of the following characteristics: •

rash with vesicles or bullae



superficial ulceration of mucous membranes



epidermal detachment (full thickness epidermal necrosis and separation of epidermis from underlying dermis)



atypical or typical target lesions



palpable purpura/non-blanching erythema

Rash with appearance of significant systemic signs or symptoms that are new and are considered related to the onset and/or progression of rash should be considered to be Grade 3. In addition to events meeting the criteria above, any events of Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), Drug-Related Eosinophilia with Systemic Symptoms (DRESS), or Erythema Multiforme (EM) should always be categorized as Grade 3. Determination of seriousness of skin rash events will follow the standard ICH criteria for serious adverse events as described in 13.1.4.1. 13.1.2.2

Rash Treatment

Antihistamines and corticosteroids may provide symptomatic relief to subjects who develop rash and experience associated symptoms such as pruritus. Permitted topical and systemic antihistaminic drugs allowed for use for all grades of rash include diphenhydramine (Benadryl), hydroxyzine, levocetirizine (Xyzal), and desloratadine (Clarinex). As described in Section 10.12 (Guidance on Prior and Concomitant Medications and Other Substances) the following antihistamines are prohibited: astemizole, terfenadine, and fexofenadine. Because immunosuppression due to systemic corticosteroids can cause significant elevations in HCV RNA levels, systemic corticosteroids should be used only when clinically necessary and after sufficient efforts using other treatments and measures have been employed, when possible, including consultation with a dermatologist. All study drugs must be discontinued immediately if a subject receives treatment with systemic corticosteroids. Topical corticosteroid use is permitted, but should be limited to brief periods, e.g., up to 2 weeks of continuous/regular use, and limited to use on up to 50% of the body surface. Use of topical corticosteroids for longer than 2 weeks or over more than 50% of the body surface Vertex Pharmaceuticals Incorporated

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should be discussed with the study Medical Monitor. If topical corticosteroids are needed, cream or lotion preparations are recommended, due to a lower absorption potential. Use of gel or ointment preparations of topical corticosteroids is discouraged due to a relative higher absorption potential. Treatment of skin eruptions with investigational agents or use of approved medications in an off-label manner is also discouraged. 13.1.2.3

Rash Management

13.1.2.3.1 Management of Grade 1 or 2 Rash General recommendations: For subjects experiencing a Grade 1 or 2 rash, medical management will be at the discretion of the investigator, and should follow generally accepted medical standards. Medications to help alleviate symptoms as described above may be employed. In addition, subjects experiencing skin rash or pruritus should be advised of other strategies to minimize the intensity or progression of their signs and symptoms (e.g., limiting sun exposure and heat; baking soda or oatmeal baths; loose-fitting clothes). Rash associated with RBV may complicate the assessment of rash in subjects receiving telaprevir; in all cases, the investigator should follow subjects carefully if there are any skin adverse events. Study drug discontinuation: For subjects experiencing a Grade 1 rash, discontinuation of telaprevir, Peg-IFN-alfa-2a, and RBV is generally not necessary. However, for subjects experiencing a progressive Grade 2 rash, discontinuation of study drug dosing should be considered. If discontinuation of study drug due to rash is necessary, it is recommended that telaprevir be discontinued first. If the rash does not improve, symptomatically or objectively, within 7 days following telaprevir discontinuation, RBV use should be interrupted. Interruption of RBV dosing may be done sooner if the rash worsens despite discontinuation of telaprevir. Peg-IFN-alfa-2a may be continued unless interruption is also medically indicated. Resumption of study drug dosing: Telaprevir dosing cannot be restarted after it is discontinued. Peg-IFN-alfa-2a and/or RBV may be restarted, if interrupted due to rash, if there is subsequent improvement in the rash within 14 days following their respective discontinuation. Resumed administration of either Peg-IFN-alfa-2a and RBV is not permitted following 14 days after their interruption for rash, respectively. RBV monotherapy is not permitted, so if Peg-IFN-alfa-2a and RBV dosing are interrupted and RBV is restarted, Peg-IFN must also be restarted. Management: Subjects should be closely monitored for any progression or worsening of signs or symptoms of systemic involvement. For subjects with a Grade 1 or 2 rash that results in permanent discontinuation of any study drug the event meets the criteria to be an ESI and the procedures described in Section 13.1.2.3.2, including reporting of the event to the sponsor or Parexel within 24 hours, dermatology consultation, photographs and laboratory tests should be followed. For subjects with a rash that does not result in changes to study drug dosing, additional diagnostic work-up will be at the investigator’s discretion, as clinically indicated. In all cases, subjects should be followed until the rash has resolved completely. Vertex Pharmaceuticals Incorporated

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13.1.2.3.2 Management of Grade 3 Rash General recommendations: For subjects experiencing a Grade 3 rash, the same general recommendations for subjects experiencing Grade 1 and Grade 2 rashes apply. Study drug discontinuation: For subjects experiencing a Grade 3 rash, telaprevir should be discontinued immediately. If the rash does not improve, symptomatically or objectively, within 7 days following telaprevir discontinuation, RBV use should also be interrupted. Interruption of RBV dosing may be done sooner if the subject’s rash worsens despite discontinuation of telaprevir. Peg-IFN-alfa-2a may be continued unless interruption is also medically indicated. The investigator may discontinue all study drugs simultaneously and immediately, if clinically indicated. However, any subjects diagnosed with or suspected to have SJS, TEN, DRESS, EM, or a skin rash considered life-threatening must have all study drugs permanently discontinued immediately. Resumption of study drug dosing: Telaprevir administration is not permitted after it is discontinued. Peg-IFN-alfa-2a and/or RBV may be restarted, if interrupted due to rash, if there is subsequent improvement in the rash within 14 days following their respective discontinuation. Resumed administration of either Peg-IFN-alfa-2a and RBV is not permitted following 14 days after their interruption for rash, respectively. RBV monotherapy is not permitted, so if Peg-IFN-alfa-2a and RBV dosing are interrupted and RBV is restarted, Peg-IFN must also be restarted. Any subjects who discontinue from the study due to SJS, TEN, DRESS, EM, or a skin rash considered life-threatening should not resume study drugs. Management: Close clinical follow-up and appropriate medical intervention should be instituted. Daily follow-up, in person or by telephone, to monitor for progression of the event may be necessary from the onset of the event until improvement is observed. Additional visits should be performed (e.g., each week or more often, as clinically appropriate). All subjects should be followed until rash has resolved completely. All Grade 3 skin rash events (whether or not they meet the criteria for an SAE), all skin reactions resulting in discontinuation of any or all study drugs, and all skin rash events meeting the criteria for a serious adverse event will be considered ESIs and should be reported within 24 hours to the sponsor. For all ESIs, the following evaluations and procedures should be performed: •

Reporting of the event as an ESI within 24 hours (see Section 13.1.4.2)



Photographs of the skin reaction



A consultation with a dermatologist for further characterization of the rash and skin biopsy



Laboratory tests: WBC w/differential, ALT/AST, serum creatinine, CPK (creatine phosphokinase), and LDH (lactate dehydrogenase)



a blood sample for pharmacokinetic analysis (only at the sites that have the technical capability to process the samples, as close to the time of onset of rash as possible, and if possible, prior to the discontinuation of study drugs).

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Any additional or subsequent laboratory testing should be performed as needed, e.g., rash is worsening or if significant laboratory abnormalities that are identified requiring monitoring. 13.1.2.4

Advisory Panel Review of ESIs

In addition to the sponsor’s review of the ESIs, the sponsor will have the information (e.g., any biopsy, photos, consults) collected on the ESIs reviewed by an external panel of experts. This panel, acting in an advisory capacity to the sponsor, will perform reviews on a periodic and ad hoc reviews, as deemed necessary by the sponsor. 13.1.3 Management of Study Drug in Cases of Anemia For the management of anemia, dose reductions will be made in accordance with the product labeling for RBV. If RBV is discontinued for the management of anemia, telaprevir/placebo must also be discontinued. Telaprevir/placebo dose reductions are prohibited and once telaprevir/placebo treatment is discontinued, it may not be reinitiated. All interventions for anemia should be recorded in the source document and eCRF. Subjects must not receive any erythropoiesis-stimulating agents (ESAs) during the course of the study.

13.1.4 Reporting of Serious Adverse Events and Rash Events of Special Interest 13.1.4.1

Serious Adverse Event Definition

A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless of causality that •

results in death.



is life-threatening. Life-threatening means that the subject was at immediate risk of death from the reaction as it occurred.



requires inpatient hospitalization or prolongation of existing hospitalization.



results in persistent or significant disability/incapacity. Disability is defined as a substantial disruption of a persons’ ability to conduct normal life functions.



is a congenital anomaly or birth defect.



is an important medical event, based upon appropriate medical judgment, and may jeopardize the subject or may require medical or surgical intervention to prevent one of the outcomes listed above (e.g., death, life-threatening, hospitalization, etc).

13.1.4.2

Procedures for Recording and Reporting Serious Adverse Events and Rash Events of Special Interest

All SAEs and ESIs that occur during the course of the study regardless of causality must be reported by the investigator to the territory-specific safety contact (Sponsor or Parexel as listed below) by fax within 24 hours from the point in time when the investigator becomes aware of the SAE or ESI.

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All SAEs and ESIs, regardless of causality, as well as serious events deemed by the investigator to be related to study conduct, should be collected and reported beginning with signing of the informed consent form through the safety follow-up visit. Any SAEs or ESIs that occur after the safety follow-up assessment has concluded, including after the study has concluded, and that are considered related to the study drug regimen are considered reportable, and must be also be reported to the Sponsor within 24 hours. The SAE/ ESI form will be provided to each clinical study site. The information collected by the site will include a minimum of the following: subject number; a thorough description (narrative) of the event, including its onset, relevant signs/symptoms, progression, treatment and outcome; and an assessment by the investigator as to the severity of the event and relatedness to any/all study drug(s). The information reported on the SAE/ ESI report form should match the data provided by the site on the eCRF. The investigator is also responsible for spontaneously reporting any subsequent follow-up information, including clinically relevant additional information, such as change in outcome. Follow-up information on SAEs and ESIs should also be reported within 24 hours to the territory-specific safety contacts (Sponsor or Parexel). The sponsor and/or Parexel will conduct follow-up on SAE and ESI cases by contact with the site. 13.1.4.3

Expedited Reporting and Investigator Safety Letters

Vertex, or designee, will be responsible for unblinding and submitting suspected, unexpected, serious adverse reactions (SUSARs) involving the study drug(s) to the applicable regulatory authorities according to ICH guidelines. In addition, Vertex, or designee, will be responsible for the submission of safety letters to the central IRB/EC and to participating investigators of all SUSARs involving telaprevir according to applicable regulations. For clinical sites that use a local IRB/EC, it is the responsibility of the investigator to promptly notify the local IRB/EC of all unexpected serious adverse drug reactions involving risk to human subjects. 13.2 Administrative Requirements 13.2.1 Ethical Considerations The study will be conducted in accordance with ethical principles founded in the Declaration of Helsinki. The IRB/IEC will review all appropriate study documentation in order to safeguard the rights, safety and well-being of the subjects. The study will only be conducted at sites where IRB/IEC approval has been obtained. The protocol, Investigator Brochure, informed consent form, advertisements (if applicable), written information given to the subjects (including diary cards), safety updates, annual progress reports, and any revisions to these documents will be provided to the IRB/IEC by the investigator or the sponsor, as allowable by local regulations. A Data Safety Monitoring Plan (DSMP) has been instituted in this study. The components are addressed in various sections of this protocol and include guidelines for adverse event

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collection and analysis, IDMC conduct and communication, time points for data collection and safety event monitoring as outlined in Section 2, and on-site data monitoring. 13.2.2 Subject Information and Informed Consent After the study has been fully explained, written informed consent will be obtained from the subject prior to study participation. The method of obtaining and documenting the informed consent and the contents of the consent will comply with ICH-GCP and all applicable regulatory requirement(s) and will be subject to approval by Vertex or its designee. 13.2.3 Investigator Compliance No modifications to the protocol should be made without the approval of both the investigator and Vertex. Changes that significantly affect the safety of the subjects, the scope of the investigation, or the scientific quality of the study (i.e., efficacy assessments) will require IRB/IEC notification prior to implementation, except where the modification is necessary to eliminate an apparent immediate hazard to human subjects. Vertex will submit all protocol modifications to the required regulatory authorities. When circumstances require an immediate departure from procedures set forth in the protocol, the investigator will contact Vertex to discuss the planned course of action. If possible, contact should be made prior to the implementation of any changes. Any departures from protocol must be fully documented in the source documentation and in a protocol deviation log. 13.2.4 Access to Records The investigator must make the office and/or hospital records of subjects enrolled in this study available for inspection by Vertex or its representative at the time of each monitoring visit. The records must also be available for inspection, verification and copying, as required by regulations, by officials of the regulatory health authorities (FDA and others). The investigator must comply with applicable privacy and security laws for use and disclosure of information related to this research set forth in this protocol. 13.2.5 Subject Privacy To maintain subject confidentiality, all eCRFs, study reports, and communications relating to the study will identify subjects by assigned subject numbers. As required by federal regulations, the investigator will allow Vertex Pharmaceuticals Incorporated and/or its representatives access to all pertinent medical records in order to allow for the verification of data gathered in the eCRFs and for the review of the data collection process. The FDA (or other regulatory authority) may also request access to all study records, including source documentation for inspection. As applicable, in accordance with the Health Insurance Portability and Accountability Act of 1996 (HIPAA) and associated privacy regulations, a subject authorization to use personally identifiable health information may be required from each subject prior to research activities. This authorization document must clearly specify what parties will have access to a subject’s personal health information, for what purpose and for how long.

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13.2.6 Record Retention The investigator will maintain all study records according to ICH-GCP and/or applicable local regulatory requirement(s), whichever is longest. If the investigator withdraws from the responsibility of keeping the study records, custody must be transferred to a person willing to accept the responsibility and Vertex must be notified. 13.2.7 Study Termination For reasonable cause, either the investigator, IRB/IEC, or Vertex may terminate the study at a given center or all centers. Conditions that may warrant termination include, but are not limited to: •

Subject or investigator noncompliance.



Unsatisfactory subject enrollment.



Lack of adherence to protocol procedures.



Lack of evaluable and/or complete data.



Potentially unacceptable risk to study subjects.



Decision to modify drug development plan.



Decision by FDA or other regulatory authority.

Written notification that includes the reason for the protocol termination is required. 13.3 Data Quality Assurance Vertex or its designated representative will conduct a study site visit to verify the qualifications of each investigator, inspect trial site facilities, and inform the investigator of responsibilities and procedures for ensuring adequate and correct study documentation. The investigator is required to prepare and maintain adequate and accurate case histories designed to record all observations and other data pertinent to the study for each study participant. Study data will be entered into an eCRF by site personnel using a secure, validated web-based EDC application. Any data not entered by the site (e.g., patientreported outcome data) will be entered into an eCRF by trained data entry staff using a secure, validated, web-based EDC application. Vertex will have access to all data upon entry in the EDC application. Study monitors will discuss instances of missing or uninterpretable data with the investigator for resolution. Any changes to study data will be made to the eCRF and documented via an electronic audit trail associated with the affected eCRF. 13.4 Monitoring Monitoring and auditing procedures developed or approved by Vertex will be followed, in order to comply with GCP guidelines. On-site checking of the eCRFs for completeness and clarity, cross-checking with source documents, and clarification of administrative matters will be performed.

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The study will be monitored by Vertex or its designee. Monitoring will be done by personal visits from a representative of the sponsor (site monitor) who will review the eCRFs and source documents. The site monitor will ensure that the investigation is conducted according to protocol design and regulatory requirements. 13.5 Electronic Data Capture Vertex will provide the study sites with secure access to and training on the EDC application, sufficient to permit site personnel to enter or correct information in the eCRFs for the subjects for which they are responsible. eCRFs will be completed for each study subject. It is the investigator’s responsibility to ensure the accuracy, completeness, clarity, and timeliness of the data reported in the subject’s eCRF. Source documentation supporting the eCRF data should indicate the subject’s participation in the study and should document the dates and details of study procedures, adverse events, other observations, and subject status. The investigator, or designated representative, should complete the eCRF as soon as possible after information is collected. An explanation should be provided for all missing data. The audit trail entry will show the user’s identification information, and the date and time of the correction. The investigator must provide through the EDC application formal approval of all the information in the eCRFs and changes to the eCRFs to endorse the final submitted data for the subjects for which he is responsible. Vertex will retain the eCRF data and corresponding audit trails. A copy of the final archival eCRF in the form of a CD or other electronic media will be placed in the investigator’s study file. 13.6 Report and Publications 13.6.1 Publication of Study Results Any and all scientific, commercial, and technical information disclosed by Vertex in this protocol or elsewhere should be considered the confidential and proprietary property of Vertex. The investigator shall hold such information in confidence and shall not disclose the information to any third party except to such of the investigator’s employees and staff as have been made aware that the information is confidential and who are bound to treat it as such and to whom disclosure is necessary in order to evaluate that information. The investigator shall not use such information for any purpose other than for determining mutual interest in performing the study and, if the parties decide to proceed with the study, for the purpose of conducting the study. The investigator understands that the information developed from this clinical study will be used by Vertex in connection with the development of the study drug and therefore may be disclosed as required to other clinical investigators, the US FDA, and to other government agencies. The investigator also understands that, in order to allow for the use of the information derived from the clinical study, the investigator has the obligation to provide Vertex with complete test results and all data developed in the study.

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No publication or disclosure of study results will be permitted except under the terms and conditions of a separate written agreement between Vertex and the investigator and/or the investigator’s institution. 13.6.2 Clinical Study Report A clinical study report, written in accordance with ICH Guideline E3, will be submitted in accordance with local regulations.

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14 REFERENCES 1

Afdhal NH, Dieterich DT, Pockros PJ, et al. Epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, doubleblind, randomized controlled study. Gastroenterology, 2004; 126(5):1302-1311.

2

Douglas T. Dieterich, Ronald Wasserman, Norbert Bräu, et al. Once-weekly epoetin alfa improves anemia and facilitates maintenance of ribavirin dosing in hepatitis C virus–infected patients receiving ribavirin plus interferon alfa. The American Journal of Gastroenterology, 2003; 98(11): 2491-2499.

3

Paul J. Pockros, Mitchell L. Shiffman, Eugene R. Schiff, et al. Epoetin alfa improves quality of life in anemic HCV infected patients receiving combination therapy. Hepatology, 2004; 40(6): 1450-1458.

4

Mark Sulkowski, Mitchell L. Shiffman, Nezam H. Afdhal, et al. Treatment-related anemia is associated with higher SVR rates among persons treated with peginterferon (PEG)/ribavirin (RBV): Results From the IDEAL Study. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), Oct 31-Nov 1 2008, San Francisco, CA.

5

Pascal Lebray, Bertrand Nalpas, Anaïs Vallet-Pichard, et al. The impact of haematopoietic growth factors on the management and efficacy of antiviral treatment in patients with hepatitis C virus. Antiviral Therapy, 2005; 10:769–776.

6

Shiffman ML, Salvatore J, Hubbard S, et al. Treatment of Chronic Hepatitis C Virus Genotype 1 with Peginterferon, Ribavirin, and Epoetin alpha. Hepatology 2007; 46:371 379.

7

http://www.hepcscotland.co.uk/health-care-professionals/the-sign-guideline/treatment/treatment-of-chronic-hepatitis-c/managementof-adverse-effects.html#952, Accessed on 14 April 2009.

8

http://www.hepatitis.va.gov/pdf/va01-pr/prtop-04/erythropoietin_criteria.pdf, Accessed on 10 April 2009.

9

http://www.lakemedelsverket.se/upload/Hälso-%20och%20sjukvård/behandlingsrek/Hepatit%20C- rek_webb.pdf; Accessed on 10 April 2009.

10

http://afssaps.sante.fr/htm/3/t2a/data/neorecormon-acceptable.pdf, Accessed on 9 January 2009.

11

Wasley A, Alter MJ. Epidemiology of hepatitis C: geographic differences and temporal trends. Semin Liver Dis 2000;20:1-16.

12

Alter HJ, Seeff LB. Recovery, persistence, and sequelae in hepatitis C virus infection: a perspective on long-term outcome. Semin Liver Dis 2000;20:17-35.

13

Hoffman-La Roche Inc. Advisory committee briefing document for PEGASYS® in combination with COPEGUSTM treatment of chronic hepatitis C. 14 November 2002.

14

Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001;358(9286):958-65.

15

Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL, Jr., et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347(13):975-82.

16

Vertex Pharmaceuticals Incorporated. Telaprevir Investigator’s Brochure.

17

IND 71,832. Sequence 0162 Telaprevir (VX-950) for Hepatitis C

18

IND 71,832. Sequence 0134 Telaprevir (VX-950) for Hepatitis C

19

Kleinman L, Zodet MW, Hakim Z, Aledort J, Barker C, Chan K, et al. Psychometric evaluation of the fatigue severity scale for use in chronic hepatitis C. Quality of Life Research. 2000;499-508.

20

EuroQol Group. Details of EQ-5D development and current status. Available at http://www.euroqol.org.

21

McHutchison JG, Ware Jr JE, Bayliss MS, Pianko S, Albrecht JK, et al. The effects of interferon alpha-2b in combination with ribavirin on health related quality of life and work productivity. Journal of Hepatology. 2001;140-147.

22

Vertex Pharmaceuticals Incorporated. Study VX06-950-007: An Open-label Phase 1 Study of VX 950 in Healthy Adult Female Subjects to Examine the Drug-Drug Interaction Between VX 950 and Oral Contraceptives; Report Number C210. Date: 28 September 2007.

23

Ette EI, Ludden TM. Population pharmacokinetic modeling: importance of informative graphics. Pharmaceutical Research. 1995;1845–1855.

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15 APPENDIX 1: GRADING SCALE FOR THE SEVERITY OF ADVERSE EVENTS IN HEPATITIS C CLINICAL TRIALS Table 15-1 Grading Scale For the Sev erity Of Adverse Events In Hepatitis C Clinical Trials Grade 1 (Mild)

Grade 2 (Moderate)

Grade 3 (Severe)

Absolute Neutrophil Count (per mm3)

1,500 - < 2,000

1,000 - 20,000

Lymphocyte (per mm3)

1,000 – 750

749 – 500

2.33 x ULN

PT

1.01 – 1.25 x ULN

1.26 – 1.50 x ULN

> 1.50 x ULN

Albumin (g/dL)

3.1 - 2.8

2.7 – 2.5

1.0 - 1.5 x ULN

Low: 7.7 – 7.0 High: 11.6 – 12.5 >1.5 – 2.0 × ULN

Low: < 7.0 High: > 12.5 >2.0 × ULN

Creatinine

1.1 – 1.5 x ULN

1.6 – 3.0 x ULN

> 3.0 x ULN

Glucose (fasting) (mg/dL) Magnesium (mEq/L)

Low: < LLN - 60 High: > 116 - 160 1.4 – 1.2

Low: 50 – 59 High: 161 - 250 1.1 – 0.9

Low: < 50 High: > 250 < 0.9

Phosphorus (mg/dL)

2.4 – 2.0

1.9 – 1.5

< 1.5

Potassium (mEq/L)

Total Protein (g/dL)

Low: 3.0 – 3.4 High: 5.6 – 6.0 Low: 130 - 135 High: 146 - 150 6.0 – 5.5

Low: 2.5 – 2.9 High: 6.1 – 6.5 Low: 123 - 129 High: 151 - 157 5.4 – 5.0

Low: High: Low: High: 750

Uric Acid (mg/dL)

7.5 - 10

10.1 – 12.0

> 12.0

Alkaline Phosphatase

1.25 – 2.5 x ULN

2.6 – 5.0 x ULN

> 5.0 x ULN

ALT (SGPT) (SGOT/SGPT)

1.25 – 2.5 x ULN

2.6 – 5.0 x ULN

> 5.0 x ULN

Amylase

1.10 – 1.5 x ULN

1.6 – 2.0 x ULN

> 2.0 x ULN

AST (SGOT)

1.25 – 2.5 x ULN

2.6 – 5.0 x ULN

> 5.0 x ULN

CPK (mg/dL)

1.25 – 2.0 x ULN

2.1 – 5.0 x ULN

> 5.0 x ULN

GGT

1.25 – 2.5 x ULN

2.6 – 5.0 x ULN

> 5.0 x ULN

Lipase

1.10 – 1.5 x ULN

1.6 – 2.0 x ULN

> 2.0 x ULN

1+

2 –3 +

4+

Sodium (mEq/L)

< 2.5 > 6.5 < 123 > 157

ENZYMES

URINALYSIS Proteinuria

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Table 15-1 Grading Scale For the Sev erity Of Adverse Events In Hepatitis C Clinical Trials Grade 1 (Mild)

Grade 2 (Moderate)

Grade 3 (Severe)

microscopic, 10 rbc/hpf 2+

gross blood, with or without clots

Cardiac Rhythm

palpitation; fluterring; otherwise asymptomatic

transient symptoms, no Rx required

recurrent/persistent; unstable dysrhythmia; symptomatic Rx or hospitalization required;

Hypertension

transient increase > 20 mm/Hg; no treatment

recurrent, chronic increase > 20mm/Hg. /treatment required

acute treatment - outpatient treatment or hospitalization required; end organ damage may occur

Hypotension

transient orthostatic hypotension with heart rate increased by 7 loose stools/day or bloody diarrhea; or orthostatic hypotension or electrolyte imbalance or >2L IV fluids required; hypotensive shock or physiological consequences; requiring hospitalization

Abdominal pain

mild, transient

persistent or recurrent, no or minimal treatment required

severe or intractable, requiring analgesic

Headache

mild, relieved by NSAIDs or acetaminophen

moderate ,persistent or recurrent,; treatment required

severe or intractable; requires repeated narcotic therapy

Muscle strength

subjective weakness no objective symptoms/ signs

objective signs/symptoms; no decrease in function

objective weakness or function limited; paralysis

Paresthesia (burning, tingling, etc.)

mild discomfort; no treatment required

moderate discomfort; nonnarcotic analgesia required

severe discomfort or incapacitating; narcotic analgesia required with symptomatic improvement; may not respond to narcotic analgesia

NEUROLOGICAL

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Table 15-1 Grading Scale For the Sev erity Of Adverse Events In Hepatitis C Clinical Trials Grade 1 (Mild)

Grade 2 (Moderate)

Grade 3 (Severe)

Arthralgia (joint pain)

mild pain not interfering with function

moderate pain, analgesics and/or pain interfering with function but not with activities of daily living

severe or disabling pain and/or analgesics interfering with activities of daily living

Arthritis

mild pain with inflammation, erythema or joint swelling – but not interfering with function

moderate pain with inflammation, erythema or joint swelling – interfering with function, but not with activities of daily living (ADL)

severe pain with inflammation, erythema or joint swelling interfering with activities of daily living (ADL); or permanent and/or disabling joint destruction - inability to perform ADL.

Myalgia

myalgia with no limitation of activity

muscle tenderness (at other than injection site) or with moderate impairment of activity

severe muscle tenderness with marked impairment of activity; or frank myonecrosis

---

---

---

< 15mm

15-30 mm

>30mm

not requiring symptomatic treatment 37.7 - 38.5 C or 100.0 - 101.5 F

prolonged or requiring symptomatic treatment 38.6 - 39.5 C or 101.6 - 102.9 F

not responsive to symptomatic treatment >39.50 or >103.00 F

normal activity reduced < 48 hours

normal activity decreased 2550% > 48 hours

normal activity decreased by > 50%; can’t work ; inability to care for self

MUSCULOSKELETAL

SKIN Rash For rash event grading, please see Section 13.1.2, Assessment, Treatment and Management of Rash Injection Site Reaction Induration Erythema Edema SYSTEMIC Chills and Rigors Fever: oral Fatigue

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Table 15-1 Grading Scale For the Sev erity Of Adverse Events In Hepatitis C Clinical Trials Grade 1 (Mild)

Grade 2 (Moderate)

Grade 3 (Severe)

awareness of the event; may cause minimal interference with the subject's daily life.

discomfort enough to cause a noticeable impact on the subject's daily life.

incapacitation or significant impact on the subject's daily life.

OTHER Other clinical symptoms not listed in the table

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16 APPENDIX 2: SUMMARY OF CHANG ES TO THE PROTOCOL (VERSION 2.0) Major changes are described below. In addition, editorial corrections and clarifications were made throughout the document. 1.

2.

Several changes were made to the Treatment and Procedural Modification Criteria. They are as follows: •

Week 4 RVR Criterion. The criterion that allowed T8/PR and T12/PR subjects to have a shorter duration of treatment (24 weeks as opposed to 48 weeks) was modified. In Version 2.0, T8/PR and T12/PR subjects will be allowed a shorter treatment duration if they have undetectable HCV RNA at Week 4 (RVR) and at Week 12. The criterion is now called “extended RVR” (eRVR). This change further safeguards against the potential for relapse.



Week 4 Breakthrough Criterion. This criterion was revised, and renamed “virologic failure.” In Version 2.0, T8/PR and T12/PR subjects who have HCV RNA >1000 IU/mL at Week 4 will discontinue telaprevir and continue with peginterferon alfa-2a (Peg-IFN-alfa-2a) and ribavirin (RBV) dosing for a planned total duration of 48 weeks. Telaprevir will not be replaced by placebo as indicated in Version 1.0. T8/PR and T12/PR subjects who have virologic failure will be considered to have met the study endpoint and will be considered treatment failures in the SVR determination. However, they will continue on treatment (unblinded) and Peg-IFN-alfa-2a and RBV will be provided to them to give them the best chance at re-responding to treatment.



Week 8 Breakthrough Criterion and Week 12 EVR Criterion. The timing for the Week 8 criterion was changed to Week 12 and renamed “virologic failure.” In Version 2.0, T8/PR and T12/PR subjects are assessed for virologic failure at Week 4 and Week 12, which conforms to standard clinical practice. In addition to the Week 12 virologic failure criterion that applies to the T8/PR and T12/PR subjects, the Week 12 EVR criterion will still be applied to all groups as in Version 1.0. T8/PR and T12/PR subjects who have virologic failure will be considered to have met the study endpoint and will be considered treatment failures in the SVR determination. However, they will continue on treatment (unblinded) and Peg-IFN-alfa-2a and RBV will be provided to them to give them the best chance at re-responding to treatment, if they also meet the EVR assessment for response.

These changes are reflected in the Protocol Synopsis and Sections 2, 7.1, 7.2.1, 7.2.2, 8.1, 8.2.2, 8.2.3, 8.3.1.3, 8.3.2, 12.1, 12.2.1.1, 12.2.1.3, and 12.2.1.3.2. The list of secondary endpoints was revised. “Proportion of subjects with EVR” has been replaced with the “proportion of subjects who are undetectable at Week 12”. The “proportion of subjects with eRVR” was added. “Noninvasive markers of fibrosis” was separated from the biochemical response endpoints. These changes are reflected in the Protocol Synopsis, Section 7.2.2, and

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Section 12.2.1.3.2. 3.

4.

5. 6.

The Inclusion and Exclusion criteria were revised. In general, the study population is similar to that described in Version 1.0. Revisions were made to provide additional clarification regarding exclusionary comorbidities and contraindications. Other changes were made to delete redundancy between the inclusion and exclusion criteria. Major changes were as follows: o To define the study population, subjects who were HCV RNA positive with a history of a remote risk factor were previously eligible. Rather than using a history of a remote risk factor to categorize the disease as chronic, subjects must now have a diagnosis of HCV for >6 months prior to screening. o Hemoglobin levels require for entry were changed from “within normal limits” to ≥12 g/dL for females and ≥13 g/dL for males. o The allowance of +3 months for the liver biopsy was deleted. (This change was also made in Table 2-1.) o The pregnancy- and contraception-related criteria were region-specific in Version 1.0. In this version, a single set of criteria have been specified (see Contraception/Pregnancy changes below). o Contraindications for Peg-IFN-alfa-2a and RBV were modified in accordance with the Peg-IFN-alfa-2a and RBV product labeling. o Poorly-controlled diabetes is now specified in the list of illnesses or conditions that might confound the results of the study or pose an additional risk. o The history of acute or chronic pancreatitis has restricted to just subjects with a history of acute pancreatitis with 5 years prior to screening. These and other minor changes to the inclusion criteria are reflected in Section 9.1. These and other minor changes to the exclusion criteria are reflected in Section 9.2 HCV RNA results will be unblinded to the study investigator at Week 28, rather than at Week 24. In addition, the investigator may share results after Week 28 with the subject. This change is reflected in the Protocol Synopsis, Section 8, and Section 10.11. Starting at Week 28, the investigator may choose to confirm HCV RNA levels with a repeat test if a subject has detectable HCV RNA that is < 1000 IU/mL. The laboratory assessment schedule was modified as follows: o The number of laboratory assessments performed at each study visit was reduced, and assessments at Week 14 were removed. o Insulin was removed. o HbA1C will be performed at screening for subjects with a history of diabetes to assess eligibility. o A Paxgene DNA sample will be collected on Day 1 (predose) for evaluation of drug metabolizing enzymes (CYP isoforms), and cellular immune receptors (HLA typing), for the continuing investigation of factors that may be associated with an increased risk of the development of rash. o A plasma sample will be collected on Day 1 (predose) for the evaluation of immune response markers. The specific biomarkers that will be evaluated will be based on the results of ongoing research on samples from the Phase 2

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9.

10.

11.

12.

13. 14. 15. 16. 17. 18. 19. 20.

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clinical studies. These changes are reflected in Section 2 and Section 11.4.2. Electrocardiograms will not be performed on Day 1 (3 to 5 hours postdose) or at Week 2. This change is reflected in Section 2. The assessment schedules for FSS, EQ-5D, and the work productivity questions were modified such that all questionnaires will administered according to the same schedule. In addition, data on healthcare utilization will also be collected at the same time points. These changes are reflected in Protocol Synopsis, Section 7.3, and Section 11.8. The contraception and pregnancy surveillance guidelines have been modified. Current RBV guidance on the duration of contraception and pregnancy surveillance is region-dependent. To facilitate the conduct of the study, the most conservative requirements have been stipulated in the protocol. These changes are reflected in Section 9.2, Section 11.4.2, and Section 11.7. The schedule for pharmacokinetic sampling has been reduced. Samples will not be collected on Day 1 (3 to 5 hours postdose) or at Week 3, 6, and 10. The scope of the sample collection has increased, however. Samples will be collected from all subjects at sites that have the technical capability to process the samples. These changes are reflected in Section 2 and Section 11.5. The definition of relapse was revised. Relapsed subjects are defined as those who complete treatment as assigned, have undetectable HCV RNA at the end of treatment, and become HCV RNA detectable during antiviral follow-up. This change is reflected in the Protocol Synopsis, Section 7.2.2, and Section 12.2.1.3.2. The definition of “treatment failure” was revised to include subjects who do complete treatment as assigned and have detectable HCV RNA at EOT or relapse during antiviral follow-up. This change is reflected in Section 12.2.1.3.2. The rationale for the sample size was modified. The overall sample size, 350 subjects per group, remained the same. This change is reflected in Section 12.1. Rules for the “Handling of Missing Data” were revised. These changes appear in Section 12.2.1.3.2. The planned analyses of the vital sign and ECG data were revised. These data will be presented in data listings. For the ECG analysis, only a shift analysis will be performed. These changes appear in Section 12.2.1.3.3. A subsection titled “HCV RNA Reporting” was removed. Details will be handled in other study-related documents. Minor modifications to the guidelines for the assessment, treatment, and management of rash were made. These changes are reflected in Section 13.1.2. Granulocyte-colony stimulating factor was deleted from Table 10-2. Progesterone and testosterone were deleted from Table 10-3. Etravirine was added to Table 10-2. Buprenorphine was added to Table 10-1. Information regarding the DSMP was added in Section 13.2.1. Subjects must provide written informed consent to participate in the study. The allowance for legal guardians to provide consent on behalf of a study subject was

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removed. This is reflected in Section 13.2.2. Information previously contained in Sections 13.2 and 13.3 was consolidated under Section 13.2. Requirements for record retention were modified. Changes are reflected in Section 13.2.6.

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17 APPENDIX 3: SUMMARY OF CHANG ES TO THE PROTOCOL (VERSION 3.0)

Section Revised General

Revision Detail

Section 1, Synopsis, Study Centers

Was:

Minor typographical and editorial errors were corrected throughout the protocol.

This multicenter study will be conducted at approximately 100 sites globally. With revision in bold, changed to: This multicenter study will be conducted at 125 sites globally.

Section 1, Synopsis, Study Design and Study Endpoints

Two secondary endpoints added:

Section 1, Synopsis, Study Design and Study Endpoints

The language regarding blinding was revised.

• •

Proportion of subjects who have undetectable HCV RNA 24 weeks after last actual dose of study treatment Proportion of subjects who relapse, defined as those who have undetectable HCV RNA at the EOT, and become HCV RNA detectable during antiviral follow-up.

Was: Treatment assignments will be double-blinded until Week 72. HCV RNA results will be double-blinded up to, but not including, Week 28. With revision in bold, changed to: Treatment assignments will be double-blinded until database lock. HCV RNA results will be double-blinded up to, but not including, Week 28. From Week 28 onward, the HCV RNA results will be available to the investigator. Note: HCV RNA results from tests prior to Week 28 will not be available to the investigator until database lock.

Section 2, Study Assessment Flow Charts, Table 2-3

Table 2-3 was modified to add a Week 40 visit for all subjects. At this visit, only a urine pregnancy test, and HCV RNA and viral sequencing samples will be collected. Footnotes “a” and “c” were revised combined into a single footnote “a”. These footnotes were: Footnote “a”: The subject will remain on study through Week 48, regardless of HCV RNA status. If HCV RNA is undetectable at Week 48, the subject will continue study visits through Week 72. If HCV RNA becomes detectable, additional samples must be drawn for viral sequencing which may result in additional study visits, possibly to Week 96. See Follow-up Schedule in Section 8.2.3 (Table 8-3). Footnote “c”: If subject becomes HCV RNA detectable, the subject will remain on study through Week 72, and possibly out to Week 96 to allow for the collection of viral sequencing samples. See Follow-up Schedule in Section 8.2.3 (Table 8-3). The new combined footnote “a” reads: Footnote “a”: All subjects will remain on study through Week 72, regardless of treatment duration and HCV RNA status. If HCV RNA becomes detectable, HCV RNA and viral sequencing samples must be collected 4 and 24 weeks after the subject

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becomes detectable, which may result in additional study visits unless these visits fall within ±1 week of a scheduled study visit, and possibly out to Week 96 if the detectable result occurs at Week 72. After HCV RNA results are unblinded at Week 28, and only for the last dosing visit, the safety follow-up, and antiviral follow up visits, a confirmatory HCV RNA and viral sequencing sample must be drawn if the result is “< 25 IU/mL, detectable”. This confirmatory HCV RNA and viral sequencing sample must be drawn within 2 weeks of the visit when the “< 25 IU/mL, detectable” sample was drawn. See Section 8.2.2 and 8.2.3. Section 2, Study Assessment Flow Charts, Table 2-4

Title was: Table 2-4

Safety Follow-up Assessment

Title changed to: Table 2-4 Follow-up Assessments 4 and 24 Weeks After the Last Actual Dose of Study Drug Column headers were added to read “Safety Follow-up” and “Antiviral Follow-up”. Column and footnotes were added to the Table 2-4: A column added to show assessments that are required 24 weeks after the last actual dose of study drug (HCV RNA and viral sequencing sample collection). Footnote “a” was added, stating that if this visit falls within ±1 week of a scheduled study visit in which HCV RNA and viral sequencing samples are collected (as shown in Table 2-1, Table 2-2, or Table 2-3), it does not need to be performed. Footnote “b” was added, stating that after HCV RNA results are unblinded at Week 28, a confirmatory HCV RNA and viral sequencing sample must be drawn if the result is “< 25 IU/mL, detectable”. This confirmatory HCV RNA and viral sequencing sample must be drawn within 2 weeks of the visit when the “< 25 IU/mL, detectable” sample was drawn.

Section 2, Study Assessment Flow Charts

Table added to show visits when study drug is dispensed. The table number and title is as follows:

Section 7.2.2, Other Secondary Endpoints

Two secondary endpoints added:

Section 8.2.2, On-Treatment Period, 3rd paragraph

Table 2- 5 Accountability

Schedule of Visits for Study Drug Dispensing and Drug



Proportion of subjects who have undetectable HCV RNA 24 weeks after last actual dose of study treatment



Proportion of subjects who relapse, defined as those who have undetectable HCV RNA at the EOT, and become HCV RNA detectable during antiviral follow-up.

Was: For the first 24 weeks, study visits will occur at Weeks 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24. Viral response assessments will be conducted at Weeks 4 and 12, and treatment and procedural modifications will be made in accordance with Table 8-2. Regardless of treatment modifications, all subjects are expected to attend all study visits through the SVR assessment time point (Week 48 or Week 72) for their planned treatment assignment, which will be communicated to the investigator at Week 24.

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With revisions in bold, changed to: For the first 24 weeks, study visits will occur at Weeks 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, and 24. Viral response assessments will be conducted at Weeks 4 and 12, and treatment and procedural modifications will be made in accordance with Table 8-2. Regardless of whether treatment is modified or discontinued, all subjects are expected to attend all study visits through Week 72. Planned treatment duration will be communicated to the investigator between Weeks 23 and 26.

Section 8.2.2, On-Treatment Period, 6th paragraph

A Week 40 HCV RNA test was added. Was: Subjects with a planned treatment duration of 48 weeks (SVR assessment time point at Week 72) will continue to attend all study visits through Week 48. Additionally, if these subjects are still receiving Peg-IFN-alfa-2a and RBV treatment past Week 24 (i.e., they have not met a criterion requiring study drug dosing discontinuation as noted in Table 8-2), they will continue dosing pending the viral response assessments from HCV RNA testing at Weeks 24, 28, and 36 (see Table 8-2). Following Week 48, they will enter antiviral follow-up (see Section 8.2.3). With revisions in bold, changed to: Subjects with a planned treatment duration of 48 weeks (SVR assessment time point at Week 72) will continue to attend all study visits through Week 48. Additionally, if these subjects are still receiving Peg-IFN-alfa-2a and RBV treatment past Week 24 (i.e., they have not met a criterion requiring study drug dosing discontinuation as noted in Table 8-2), they will continue dosing pending the viral response assessments from HCV RNA testing at Weeks 24, 28, 36, and 40 (see Table 8-2). Following Week 48, they will enter antiviral follow-up (see Section 8.2.3).

Section 8.2.2, On-Treatment Period, before the last paragraph

A paragraph was added to require confirmatory HCV RNA testing and viral sequencing sample collection under the following circumstances:

Section 8.2.2, On-Treatment Period, Table 8-2, Week 4, “Treatment and Procedural Modifications” Column, “> 1000 IU/mL (Virologic Failure)” row

Was:

After Week 28 HCV RNA unblinding, a confirmatory HCV RNA and viral sequencing sample must be drawn if a subject’s result is “< 25 IU/mL, detectable” at the last dosing visit. The confirmatory HCV RNA and viral sequencing sample must be drawn within 2 weeks of the visit when the “< 25 IU/mL, detectable” sample was drawn.

At Week 6, investigator will be instructed to: • discontinue telaprevir and continue Peg-IFN-alfa-2a and RBV dosing, and • continue subject on study until their SVR assessment time point (Week 72). With revision in bold, changed to: At Week 6, investigator will be instructed to: • discontinue telaprevir and continue Peg-IFN-alfa-2a and RBV dosing, and • continue subject on study until Week 72.

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Was:

Section 8.2.2, On-Treatment Period, Table 8-2, Week 24, “Treatment and Procedural Modifications” Column, “Subset of T8/PR and T12/PR who achieve eRVR” row

Was:

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At Week 14, investigator will be instructed to: • discontinue all study drug dosing, • continue subject on study until their SVR assessment time point (Week 72), • perform Safety Follow-up Visit (including HCV RNA and viral sequencing samples) 4 weeks after last dose of study drug, and • test HCV RNA and collect viral sequencing samples 24 weeks after Week 12 visit (i.e., Week 36). With revision in bold, changed to: At Week 14, investigator will be instructed to: • discontinue all study drug dosing, • continue subject on study until Week 72, • perform Safety Follow-up Visit (including HCV RNA and viral sequencing samples) 4 weeks after last actual dose of study drug, and • test HCV RNA and collect viral sequencing samples at 4 and 24 weeks after becoming detectable.

At Week 24, investigator will be informed that planned treatment duration is 24 weeks and that the SVR assessment time point is Week 48. Investigator will be instructed to: • discontinue all study drug dosing, • continue subject on study until their SVR assessment time point (Week 48), and • perform Safety Follow-up Visit (including HCV RNA and viral sequencing samples) 4 weeks after last dose of study drug (i.e., Week 28). With revisions in bold, changed to: Between Weeks 23 and 26, investigator will be informed that planned treatment duration is 24 weeks. Investigator will be instructed to: • discontinue all study drug dosing, • continue subject on study until Week72, and • perform a Safety Follow-up Visit (as detailed in Table 2-4).

Section 8.2.2, On-Treatment Period, Table 8-2, Week 24, “Treatment and Procedural Modifications” Column, “All other subjects” row

Was: At Week 24, investigator will be informed that planned treatment duration is 48 weeks and that the SVR assessment time point is Week 72. Study drug dosing will continue pending the results of Week 24 HCV RNA (available at Week 26). With revision in bold, changed to: After Week 24 (by Week 26), investigator will be informed that planned treatment duration is 48 weeks. Study drug dosing will continue pending the results of Week 24 HCV RNA (available at Week 26). For those with undetectable HCV RNA Was: At Week 26, subject continues study drug dosing as planned.

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Changed to: After Week 24 (by Week 26), the investigator will be instructed to continue the subject on study treatment. For those with detectable (HCV RNA >10 IU/mL, Virologic Failure) Was: At Week 26, investigator will be instructed to: • discontinue all study drug dosing, • continue subject on study until their SVR assessment time point (Week 72), • perform Safety Follow-up Visit (including HCV RNA and viral sequencing samples) 4 weeks after last dose of study drug, and • test HCV RNA and collect viral sequencing samples 24 weeks after Week 24 visit (i.e., Week 48). With revisions in bold, changed to: After Week 24 (by Week 26), investigator will be instructed to: • • • •

Section 8.2.2, On-Treatment Period, Table 8-2, Week 28, “Treatment and Procedural Modifications” Column, “Detectable” row

discontinue all study drug dosing, continue subject on study until Week 72, perform Safety Follow-up Visit (as detailed in Table 2-4), and test HCV RNA and collect viral sequencing samples at 4 and 24 weeks after becoming detectable.

Was: As soon as HCV RNA results are available, investigator will: • discontinue all study drug dosing, • continue subject on study until their SVR assessment time point (Week 72), • perform Safety Follow-up Visit (including HCV RNA and viral sequencing samples) 4 weeks after last dose of study drug, and • test HCV RNA and collect viral sequencing samples 24 weeks after Week 28 visit (i.e., Week 52). Note: If HCV RNA is detectable, but < 1000 IU/mL, the investigator may repeat the HCV RNA assessment to confirm the value before making changes to treatment. With revisions in bold, changed to: As soon as HCV RNA results are available, investigator will: • discontinue all study drug dosing, • continue subject on study until Week 72, • perform Safety Follow-up Visit (as detailed in Table 2-4) 4 weeks after last actual dose of study drug, and • test HCV RNA and collect viral sequencing samples at 4 and 24 weeks after becoming detectable. Note: If HCV RNA is detectable, but < 1000 IU/mL, the investigator may repeat the HCV RNA assessment to confirm the value before making changes to treatment.

Section 8.2.2, On-Treatment

Was:

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As soon as HCV RNA results are available, investigator will: • discontinue all study drug dosing, • continue subject on study until their SVR assessment time point (Week 72), • perform Safety Follow-up Visit (including HCV RNA and viral sequencing samples) 4 weeks after last dose of study drug, and • test HCV RNA and collect viral sequencing samples 24 weeks after Week 36 visit (i.e., Week 60). Note: If HCV RNA is detectable, but < 1000 IU/mL, the investigator may repeat the HCV RNA assessment to confirm the value before making changes to treatment. With revisions in bold, changed to: As soon as HCV RNA results are available, investigator will: • discontinue all study drug dosing, • continue subject on study until Week 72, • perform Safety Follow-up Visit (as detailed in Table 2-4) 4 weeks after last actual dose of study drug, and • test HCV RNA and collect viral sequencing samples at 4 and 24 weeks after becoming detectable. Note: If HCV RNA is detectable, but < 1000 IU/mL, the investigator may repeat the HCV RNA assessment to confirm the value before making changes to treatment.

Section 8.2.2, On-Treatment Period, Table 8-2

A stopping rule was added for the new Week 40 HCV RNA assessment. This stopping rule is identical to the revised stopping rule at Week 36.

Section 8.2.3, Follow-up Period

Was: All subjects will have a Safety Follow-up visit 4 weeks after receiving their last dose of study drug. This may be an additional visit, unless it falls within 1 week of a scheduled study visit. The assessments are shown in Table 2-4. Regardless of HCV RNA status, all subjects must attend all study visits and be followed for antiviral response through their SVR assessment time point (Week 48 or Week 72, see Section 8.2.2). The antiviral follow-up schedules are described in Table 8-3. Section was completely revised. The new text appears below with major changes described in parenthesis in italic: 8.2.3.1 Safety Follow-up All subjects will have a Safety Follow-up visit 4 weeks after receiving their last actual dose of study drug. This may be an additional visit, unless it falls within ±1 week of a scheduled study visit. The assessments are shown in Table 2-4. 8.2.3.2 Antiviral Follow-up Antiviral Follow-up Visits (Clarification was made that ALL subjects must attend study visits through Week 72, regardless of treatment duration or HCV RNA status.) Regardless of treatment duration and HCV RNA status, all subjects must attend all study visits and be followed for antiviral response through Week 72, as shown in Table

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2-1, Table 2-2, Table 2-3, and Table 2-4. • For subjects who complete their assigned treatment at Week 24, antiviral follow-up will occur at Weeks 28, 36, 40, 48, 60 and 72. • For subjects who complete their assigned treatment at Week 48, antiviral follow-up will occur at Weeks 60 and 72. • For subjects who discontinue study treatment early, antiviral follow-up will begin at the next scheduled visit that falls after the safety follow-up visit. From that point onward, the subject will follow the same visit schedule as shown in Table 2-1, Table 2-2, Table 2-3, and Table 2-4. Antiviral Follow-up Visits with Subject-dependent Timing •

Follow-up 24 Weeks After the Last Actual Dose of Study Drug (This was added.) For all subjects, HCV RNA testing and viral sequencing sampling will be performed 24 weeks after the last actual dose of study drug is received. This may result in an additional study visit unless it falls within ±1 week of a scheduled visit. See Table 2-4.



Follow-up for Subjects who Become HCV RNA Detectable For any subject who becomes HCV RNA detectable, HCV RNA and viral sequencing samples must be collected at 4 and 24 weeks after becoming detectable. These may be additional visits unless they fall within ± 1 week of a scheduled study visit.

Confirmatory HCV RNA Testing and Viral Sequence Sampling After Week 28 (Confirmatory RNA testing and viral sequence sampling has been added.) After Week 28 HCV RNA unblinding, a confirmatory HCV RNA and viral sequence sample must be drawn if a subject’s result is “< 25 IU/mL, detectable” at the last dosing visit, the safety follow-up visit, or at any antiviral follow-up visit. The confirmatory HCV RNA and viral sequencing sample must be drawn within 2 weeks of the visit when the “< 25 IU/mL, detectable” sample was drawn. Long-term Follow-up (This was changed to clarify that only T8/PR and T12/PR subjects would be followed long-term.) Any T8/PR or T12/PR subject who has undetectable HCV RNA at Week 72 may be asked to participate in a separate clinical protocol to collect long-term follow-up data. Any T8/PR or T12/PR subject who has virologic failure will be asked to participate in a separate protocol to collect long-term follow-up data. Section 8.2.3, Follow-up Period, Table 8-3,

Table was deleted.

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Was: Although a subject may discontinue study treatment, every effort must be made to continue the subject on the study, returning for a Safety Follow-up Visit 4 weeks after the last dose of study drug as outlined in Table 2-4, and attending all scheduled visits as described in Section 8.2.2 and Section 8.2.3. In addition, subjects who discontinue treatment must follow the contraception and pregnancy surveillance procedures outlined in Section 11.7. With additions in bold, changed to: Although a subject may discontinue study treatment, every effort must be made to continue the subject on the study, returning for a Safety Follow-up Visit 4 weeks after the last actual dose of study drug and an antiviral follow-up visit 24 weeks after the last actual dose of study drug as outlined in Table 2-4, and attending all scheduled visits through Week 72. In addition, subjects who discontinue treatment must follow the contraception and pregnancy surveillance procedures outlined in Section 11.7.

Section 10.4.1.2, Discontinuation of All 3 Study Drugs in the Treatment Regimen

Was:

Section 10.7, Study Drug Supply, Storage, and Handling, 1st paragraph

Was:

If a subject prematurely discontinues dosing with all 3 study drugs, the subject will remain on study regardless of HCV RNA status, attending all scheduled visits as described in Section 8.2.2, Section 8.2.3, and Section 9.3. With revision in bold, changed to: If a subject prematurely discontinues dosing with all 3 study drugs, the subject will remain on study, attending all scheduled visits through Week 72 regardless of HCV RNA status.

Telaprevir will be supplied as tablets containing 375 mg telaprevir. Before being opened, each dosing card of telaprevir must be stored refrigerated at 2 to 8°C and should not be exposed to freezing temperatures or prolonged light exposure during storage at the clinical site. Once the weekly dosing card has been started, it can be kept at room temperature and does not need to be refrigerated. Instructions regarding the storage and handling of telaprevir after dispensation to subjects will be provided to sites. All study drug must be stored in a secure area of limited access. With revision in bold, changed to: Telaprevir will be supplied as tablets containing 375 mg telaprevir. Before being opened, each dosing card of telaprevir must be stored according to current specifications. Once the weekly dosing card has been started, it can be kept at room temperature and does not need to be refrigerated. Instructions regarding the storage and handling of telaprevir after dispensation to subjects will be provided to sites. All study drug must be stored in a secure area of limited access.

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Section was revised extensively. See strikethrough text for deletion and bold text for additions. Treatment assignments will be double-blinded until Week 72 database lock. HCV RNA results will be double-blinded up to, but not including, Week 28. From Week 28 onward, the HCV RNA results will be available to the investigator. Note: HCV RNA results from tests prior to Week 28 will not be available to the investigator until Week 72 database lock. The sponsor’s study team will receive HCV RNA data after all subjects complete the Week 52 visit (post-treatment for all subjects). This team will remain blinded to treatment group. In addition, unblinded virologists, who are not part of the study team, will be aware of treatment group and will receive HCV RNA results throughout the study to conduct the viral sequencing analyses for subjects with treatment failure (Section 11.6). Sequencing results will not be revealed until after database lock. Lastly, select members of the sponsor’s quality assurance team, who are not part of the study team, may be unblinded to study data to allow for the performance of quality assurance activities. To maintain double-blinding during the first 12 weeks, Pbo12/PR subjects will receive telaprevir-matching placebo (placebo) from Day 1 through Week 12, T8/PR subjects will receive placebo from Week 9 through Week 12.

Section 10.12, Guidance on Prior and Concomitant Medications and Other Substances

Section was extensively revised to cross-reference the Investigator’s Brochure which contains the most up-to-date information. Use of ESAs (erythropoiesis-stimulating agents) was also prohibited during the course of the study. Section was: 10.12 Guidance on Prior and Concomitant Medications and Other Substances In vitro studies suggest that telaprevir is metabolized in the liver primarily by cytochrome P450 (CYP) 3A4. Additional in vivo studies indicated telaprevir was a CYP3A4/5 inhibitor when midazolam was the substrate, and this indicates the potential for telaprevir to cause drug-drug interactions when it is co-administered with drugs that are substrates of CYP3A4. In vitro studies indicated telaprevir was a mild inducer of CYP1A activity. To date, human drug-drug interaction studies with ketoconazole, ritonavir, midazolam, and oral contraceptives containing ethinyl estradiol and norethindrone have been completed. Drug-drug interaction data for telaprevir with an ethinyl estradiol (EE)-containing oral contraceptive (OC) are provided in Section 11.7, along with contraception guidance for investigators. Other drug-drug interaction studies are being conducted to characterize the interaction potential for telaprevir with other drugs. Because the interaction of telaprevir with other medications is not yet known, caution should be used when co-administering medications that are substrates, inhibitors, or inducers of CYP3A4. The information provided in this clinical study protocol will be updated as data from these ongoing studies become available. The tables below, Table 10-1, Table 10-2, and Table 10-3, provide a listing of medications that may interact with these enzymes. Note: the listing provided is not intended to be a complete list. Other medications that would be used in the study population infrequently (such as antipsychotic medications, or medications usually given in the inpatient setting), or for illnesses which are contraindications for enrollment in the study (such as rifampin for the treatment of tuberculosis), are not included in this list. Drug-drug interaction potential has not been evaluated with antidepressant drugs.

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Some antidepressants with a potential to interact with telaprevir are sertraline and venlafaxine, and should be used with caution (Table 10-3). Other antidepressants that are commonly used such as citalopram, escitalopram, and fluoxetine have low potential for interaction with telaprevir. Use of any of the medications listed in Table 10-1 is prohibited during telaprevir treatment. In addition, the following medications are also prohibited from Day -14 until the EOT: •

All antiviral medications, with the exception of topical antiviral medications and oral antiviral medications specifically indicated for the treatment of herpetic outbreaks. Note: In these cases, the subject should be monitored closely for adverse events.



Ursodiol (ursodeoxycholic acid), which is sometimes used to lower ALT and aspartate aminotransferase (AST) levels in patients with hepatitis



Systemic corticosteroids



Immunosuppressants



Granulocyte-colony stimulating factor

Subjects should also be advised against the consumption of grapefruit juice since it is a known inhibitor of CYP3A. Some herbal medications may result in unknown interactions and thus, all herbal medications should be taken with caution. Intermittent or inadvertent use of a prohibited medication listed in Table 10-1 and Table 10-2 will be considered as a protocol deviation (e.g., if a subject used a single dose). A subject who requires repeated treatment with any medication listed in Table 10-1 and Table 10-2 should be withdrawn from study treatment. Subjects may use the medications listed in Table 10-3, although the subject should be monitored by the investigator for adverse events, and the use of these medications will not be considered protocol deviations. If questions arise regarding potential interactions with any medication, the Study Medical Monitor should be contacted. If telaprevir treatment is stopped, but Peg-IFN-alfa-2a and RBV treatment is continued, the investigator should refer to the package inserts for Pegasys and Copegus for guidance on prohibited medications. [Table 10-1, Table10-2, and Table 10-3 were deleted.] With revisions, changed to: 10.12 Guidance on Prior and Concomitant Medications and Other Substances 10.12.1 General Guidance In vitro studies suggest that telaprevir is metabolized in the liver primarily by cytochrome P450 (CYP) 3A4. Additional in vivo studies indicated telaprevir was a CYP3A4/5 inhibitor when midazolam was the substrate, and this indicates the potential for telaprevir to cause drug-drug interactions when it is co-administered with drugs that are substrates of CYP3A4. In vitro studies indicated telaprevir was a mild inducer of CYP1A activity. Data from human drug-drug interaction studies for telaprevir completed to date are provided in the Investigator’s Brochure.16 Contraception guidance for investigators is provided in the Investigator’s Brochure and Section 11.7.1.1 of this protocol. Other drug-drug interaction studies are being conducted to characterize the interaction potential for telaprevir with other drugs. The information provided in the telaprevir Investigator’s Brochure will be updated as data from these ongoing studies become

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available. Because the interaction of telaprevir with other medications is not yet known, caution should be used when coadministering medications that are substrates, inhibitors, or inducers of CYP3A4. The Investigator’s Brochure provides a listing of medications that may interact with these enzymes.16 Note: the listing provided is not intended to be a complete list. Other medications that would be used in the study population infrequently (such as antipsychotic medications, or medications usually given in the inpatient setting), or for illnesses which are contraindications for enrollment in the study (such as rifampin for the treatment of tuberculosis), are not included in this list. A list of other prohibited medications and medications to be used with caution while receiving treatment with telaprevir are located in the Investigator’s Brochure.16 Intermittent or inadvertent use of a prohibited medication listed in the Investigator’s Brochure will be considered as a protocol deviation (e.g., if a subject used a single dose). A subject who requires repeated treatment with any of the prohibited medications listed in the telaprevir Investigator’s Brochure should be withdrawn from study treatment. Subjects requiring the use of medications that are noted to be used with caution should be monitored by the investigator for adverse events, and the use of these medications will not be considered protocol deviations. If questions arise regarding potential interactions with any medication, the Study Medical Monitor should be contacted. Subjects should also be advised against the consumption of grapefruit juice since it is a known inhibitor of CYP3A. Some herbal medications may result in unknown interactions and thus, all herbal medications should be taken with caution. In addition, subjects must not receive any erythropoiesis-stimulating agents (ESAs) during the course of the study. If telaprevir treatment is stopped, but Peg-IFN-alfa-2a and RBV treatment is continued, the investigator should refer to the package inserts for Pegasys and Copegus for guidance on prohibited medications. During the subjects’ participation in this study, all antiviral treatments for hepatitis C or other RNA viruses with the exception of those administered under this protocol are prohibited. 10.12.2 Timing of Prior and Concomitant Medication Data Collection Prior and concomitant medications will be collected beginning at the time of Screening or 14 days before signing informed consent, whichever is earlier, through the safety follow-up assessment. Section 11.4.2, Clinical Laboratory Assessments

Text was added:

Section 11.7.1.1, Contraception

The following paragraph, a duplicate of the preceding paragraph in the original text, was deleted:

For subjects who are off-treatment, in the follow-up period, and who would otherwise be lost-to-follow-up, a mobile blood sample collection may be used. In these cases, only HCV RNA and viral sequencing samples will be drawn.

The potential effect of telaprevir on the efficacy of hormonal contraceptives is difficult to quantify or exclude. Therefore, subjects may choose to continue taking a hormonal contraceptive if they were already using it at the time that dosing with telaprevir/placebo and RBV was initiated. In these cases, subjects must add 2 non-hormonal methods of contraception, including 1 barrier method for the duration of telaprevir/placebo dosing and for 2 additional months following telaprevir/placebo dosing, at which point the hormonal contraceptive may constitute as 1 of the 2 required

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effective methods. Section 12.2.1.3.1, Final Analysis Sets

In the descriptions of the analysis datasets, Intent-to-Treat (ITT) was replaced by Full Analysis (FA) in all places.

Section 12.2.1.3.2, Final Efficacy Analysis, Primary Efficacy Endpoint

As shown in strikethrough text, “country” was removed from the model.

Section 12.2.1.3.2, Final Efficacy Analysis, Secondary Efficacy Endpoints

The first bullet point was revised. As shown in strikethrough text, the last 2 sentences were deleted from the text:

The final analysis of the primary efficacy endpoint will include a comparison of odds ratios using a logistic regression model with SVR rate as the dependent variable and treatment, genotype 1 subtype, country, and baseline HCV RNA plasma level as factors. The results will be presented in terms of P values and confidence intervals for the odds ratios between the control group (Pbo12/PR) and each of the telaprevir groups (T8/PR and T12/PR). A supportive analysis will be provided using Cochran-MantelHanszel method.

• An analysis of the key secondary efficacy endpoint, proportions of subjects with undetectable HCV RNA at Week 72, will be provided to assess the sustainability of the SVR response observed in the T8/PR and T12/PR groups at Week 48. This analysis will be done using the model described above for the analysis of the primary efficacy endpoint. For this analysis, subjects who achieve SVR at Week 48 during antiviral follow-up, but become detectable thereafter, will be treated as treatment failures while those who achieve SVR at Week 48 but are lost to followup thereafter will be treated as treatment successes. An additional analysis that treats subjects as failures if they are lost to follow-up for the Week 72 assessment (i.e., with no SVR assessment) will be conducted. Second bullet point was: For all other binary secondary endpoints (i.e., the analyses of the proportions of subjects who achieve RVR, eRVR, undetectable HCV RNA at Week 12, EOT, and undetectable HCV RNA 12 weeks after the last planned dose of treatment) will be evaluated in the same way as the primary endpoint described above. With revisions in bold, changed to: For all other binary secondary endpoints (i.e., the analyses of the proportions of subjects who achieve RVR, eRVR, undetectable HCV RNA at Week 12, EOT, 12 weeks after the last planned dose of treatment, and 24 weeks after the last actual dose of treatment) will be evaluated in the same way as the primary endpoint described above. To describe the analysis for the new relapse-related secondary endpoint, an additional bullet point was added: • Descriptive statistics will be provided for the subgroup of subjects who relapse, defined as those who have undetectable HCV RNA at the EOT, and become HCV RNA detectable during antiviral follow-up.

Section 12.2.1.3.3, Final Safety Analysis, Vital Signs

The description of the analyses related to vital signs was modified. With deletions in strikethrough and additions in bold, text changed to: Vital signs data will be presented in data listings. Standard safety data summaries will be provided for vital signs. Clinically significant abnormal findings in the vital signs results will be reported as adverse events.

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Was: Following the Safety Follow-up assessment, only SAEs considered related to the study drug regimen may be reported, and these may be reported indefinitely. With revision in bold, changed to: Following the Safety Follow-up assessment (see Table 2-4), only SAEs considered related to the study drug regimen may be reported, and these may be reported indefinitely.

Section 13.13, Management of Study Drug in Cases of Anemia

Text in bold was added to prohibit the use of ESAs during the course of the study.

Section 13.3, Data Quality Assurance, 2nd paragraph

Was:

For the management of anemia, dose reductions will be made in accordance with the product labeling for RBV. If RBV is discontinued for the management of anemia, telaprevir/placebo must also be discontinued. Telaprevir/placebo dose reductions are prohibited and once telaprevir/placebo treatment is discontinued, it may not be reinitiated. All interventions for anemia should be recorded in the source document and eCRF. Subjects must not receive any erythropoiesis-stimulating agents (ESAs) during the course of the study.

The investigator is required to prepare and maintain adequate and accurate case histories designed to record all observations and other data pertinent to the study for each study participant. Study data will be entered into an eCRF by site personnel using a secure, validated web-based EDC application. Diaries and patient-reported outcomes will be entered into an eCRF by trained data entry staff using a secure, validated, web-based EDC application. Vertex will have access to all data upon entry in the EDC application. With revision in bold, changed to: The investigator is required to prepare and maintain adequate and accurate case histories designed to record all observations and other data pertinent to the study for each study participant. Study data will be entered into an eCRF by site personnel using a secure, validated web-based EDC application. Any data not entered by the site (e.g., patient-reported outcome data) will be entered into an eCRF by trained data entry staff using a secure, validated, web-based EDC application. Vertex will have access to all data upon entry in the EDC application.

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Statistical Analysis Plan Vertex Study VX07-950-108

VERTEX PHARMACEUTICALS INCORPORATED

TIBOTEC BVBA

Statistical Analysis Plan Protocol Number VX07-950-108 A Phase 3 Study of 2 Dose Regimens of Telaprevir in Combination With Peginterferon Alfa-2a (Pegasys®) and Ribavirin (Copegus®) in Treatment-Naïve Subjects with Genotype 1 Chronic Hepatitis C Author of SAP: Hugh Xiao Version: 3.0 Version Date of SAP: 07 May 2010 Vertex Pharmaceuticals Incorporated 130 Waverly Street Cambridge, Massachusetts 02139-4242 Tibotec BVBA Gen De Wittelaan L 11B 3 B-2800 Mechelen, Belgium

CONFIDENTIAL

This document contains confidential information. Any use, distribution, or disclosure without the prior written consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under applicable laws or regulations. Persons to whom the information is disclosed must be informed that the information is confidential and may not be further disclosed by them.

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1 1 2 3 4 5

6

7 8

TABLE OF CONTENTS Table of Contents ............................................................................ 2 List of Abbreviations and Definitions ............................................... 4 Introduction ................................................................................... 7 Study Objectives ............................................................................. 7 4.1 Primary Objective................................................................................................... 7 4.2 Secondary Objective ............................................................................................... 7 Endpoints ....................................................................................... 7 5.1 Primary Efficacy Endpoint...................................................................................... 7 5.2 Secondary Efficacy Endpoints ................................................................................ 7 5.3 Tertiary Endpoints .................................................................................................. 8 Study Design and procedures ........................................................... 8 6.1 Overall Study Design.............................................................................................. 8 6.2 Sample Size and Power........................................................................................... 9 6.3 Study Population................................................................................................... 10 6.4 Subject Replacement............................................................................................. 10 6.5 Randomization...................................................................................................... 10 6.6 Blinding Procedures.............................................................................................. 10 6.7 Modifications/Clarifications from the Statistical Section of the CSP ..................... 10 6.8 Modifications From the Approved Statistical Analysis Plan.................................. 13 Analysis Sets ................................................................................. 13 7.1 Full Analysis Set................................................................................................... 13 7.2 Per Protocol Analysis Set...................................................................................... 13 Statistical Methods of Analysis ...................................................... 13 8.1 Statistical Considerations ...................................................................................... 13 8.1.1 Definition of Baseline Values........................................................................ 14 8.1.2 Derived Variables ......................................................................................... 14 8.1.3 Incomplete/Missing Data............................................................................... 16 8.1.4 Windows for Time Points.............................................................................. 18 8.1.5 Measurements Collected at Local Laboratories.............................................. 18 8.1.6 HCV RNA Confirmatory Values................................................................... 18 8.1.7 Replicated Observations................................................................................ 18 8.1.8 Multicenter Considerations............................................................................ 19 8.1.9 Subgroup Analysis ........................................................................................ 19 8.1.10 Multiplicity ................................................................................................... 20 8.2 Computer Software............................................................................................... 21 8.3 Subject Disposition............................................................................................... 21 8.4 Baseline Characteristics and Baseline Comparisons .............................................. 22 8.5 Medical History .................................................................................................... 22 8.6 Concomitant Medication....................................................................................... 22

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8.7 Study Drug Compliance........................................................................................ 22 8.8 Exposure to Study Drug........................................................................................ 23 9 Interim Analyses ........................................................................... 23 9.1 Interim Analysis Considerations ........................................................................... 23 10 Final Analyses .............................................................................. 23 10.1 Final Efficacy Analyses ........................................................................................ 23 10.1.1 Efficacy Variables......................................................................................... 23 10.1.2 Analyses of Efficacy Variables...................................................................... 27 10.2 Final Safety Analyses ........................................................................................... 32 10.2.1 Adverse Events ............................................................................................. 32 10.2.2 Laboratory Data ............................................................................................ 35 10.2.3 Physical Examination and Vital Signs ........................................................... 35 10.2.4 ECG.............................................................................................................. 35 10.2.5 Virology........................................................................................................ 36 10.3 Other Analyses ..................................................................................................... 37 10.3.1 Other Variables ............................................................................................. 37 10.3.2 Analyses of Other Variables.......................................................................... 37 11 List of Tables, Figures and listings ................................................ 38 11.1 Tables and Figures for Section 14 of the Clinical Study Report............................. 38 11.2 Data Displays for Section 16 of the Clinical Study Report .................................... 50 11.3 Literature Citations/References............................................................................. 51 11.4 Data Not Covered by This Plan............................................................................. 51 12 List of Appendices ........................................................................ 51 12.1 Schedule of Events ............................................................................................... 51 12.2 On-treatment Virologic Failure Criteria a............................................................... 57 12.3 DAIDS Scale ........................................................................................................ 58 12.4 MedDRA Terms Used for Identifying Rash SSC .................................................. 61 12.5 MedDRA Terms Used for Identifying Pruritus SSC.............................................. 62 12.6 MedDRA Terms Used for Identifying Anemia SSC.............................................. 62 12.7 MedDRA Terms Used for Identifying Anorectal Disorder SSC............................. 63 12.8 MedDRA Terms Used for Identifying Injection Site Reaction SSC....................... 63 12.9 Criteria for Excluding Subjects from the Per Protocol Analysis............................. 64 12.10 Table and Figure Shells......................................................................................... 65

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2

LIST OF ABBREVIATIONS AND DEFINITIONS

Abbreviation

Term

AE CDM CSP CSR DCRI DMP ECG eCRF FA FSS HCV HCV RNA IDMC IWRS LiPA LLOQ NPV pbo Peg IFN-alfa-2a PPA PPV PR PRO PT q8h RBV SAE SAP SSC

adverse event clinical data management clinical study protocol clinical study report Duke Clinical Research Institute data management plan electrocardiogram electronic case report form full analysis Fatigue Severity Scale hepatitis C virus hepatitis C virus ribonucleic acid independent data monitoring committee Interactive web-based response system Inno-lipa line probe assay lower limit of quantitation negative predictive value placebo peginterferon alfa-2a (Pegasys®) per protocol analysis positive predictive value peginterferon alfa-2a (Pegasys®) and ribavirin (Copegus®) patient-reported outcomes preferred term every 8 hours ribavirin (Copegus®) serious adverse event statistical analysis plan special search category

Abbreviation/Term

Term/Definition

EOT

end of treatment, a time point when a subject takes the last dose of any study drug (regardless of whether or not this coincides with last planned dose for the subject)

EOT visit

first visit occuring on or after EOT

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Abbreviation/Term

Term/Definition

eRVR

extended rapid viral response, defined as undetectable HCV RNA at Week 4 and at Week 12

EVR

early viral response, defined as ≥ 2-log10 decrease in HCV RNA at Week 12 compared to baseline

Overall Treatment Phase

from first date of exposure to any study drug to 30 days after last exposure to any study drug

Relapse Actual

undetectable HCV RNA at EOT visit, and confirmed detectable HCV RNA between EOT visit and 24 weeks after last actual dose

Relapse Late (Actual)

an SVR24Actual with a confirmed detectable HCV RNA thereafter

Relapse Late (Planned)

an SVR24Planned with a confirmed detectable HCV RNA thereafter (Note: This endpoint is only analyzed for subjects in the T8/PR and T12/PR groups who achieve eRVR and have a planned treatment duration of 24 weeks.)

Relapse Planned

undetectable HCV RNA at EOT visit, and confirmed detectable HCV RNA between EOT visit and up to and including the SVR24Planned assessment time point

RVR

rapid viral response, defined as undetectable HCV RNA at Week 4

SVR12Actual

undetectable HCV RNA at EOT visit and at 12 weeks after the last actual dose of study treatment without any confirmed detectable in between

SVR12Planned

undetectable HCV RNA at EOT visit and at 12 weeks after the last planned dose of study treatment without any confirmed detectable in between

SVR24Actual

undetectable HCV RNA at EOT visit and at 24 weeks after the last actual dose of study treatment without any confirmed detectable in between

SVR24Planned

undetectable HCV RNA at EOT visit and at 24 weeks after the last planned dose of study treatment without any confirmed detectable in between

SVR at Week 72 Treatment Completion

achieve SVR24Planned and undetectable HCV RNA at Week 72 without any confirmed detectable in between any subject who completes 24 or 48 weeks of treatment with at least one study drug

Treatment Discontinuation

any subject who does not meet definition for Treatment Completion

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Abbreviation/Term

Term/Definition

VBT

viral breakthrough, defined as as (1) an increase in on-treatment HCV RNA of >1-log10 compared to the lowest recorded ontreatment value (confirmed by values obtained at 2 consecutive visits) or (2) an on-treatment HCV RNA level of >100 IU/mL (confirmed by values obtained at 2 consecutive visits) in a subject who had undetectable HCV RNA at a prior time point.

Virologic Failure

Criteria listed in Appendix 12.2, these are based on Table 8-2 in the clinical study protocol

Telaprevir/Placebo Treatment Phase

from first date of exposure to any study drug to 1 days after last telaprevir/placebo dose

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3

INTRODUCTION

This Statistical Analysis Plan (SAP) has been written based on the information contained in the Clinical Study Protocol (CSP) Version 3.0 dated 05 May 2009. The purpose of this SAP is to provide a detailed description of the planned statistical analyses of efficacy and safety data that have been outlined in the CSP, and to prospectively document any modifications/clarifications or additions to the CSP specified analyses before final database lock This SAP was finalized before the final lock of the database and treatment unblinding. 4

STUDY OBJECTIVES

4.1

Primary Objective

To demonstrate the efficacy of telaprevir in combination with Peg-IFN-alfa-2a and RBV in treatment-naïve subjects with genotype 1 chronic hepatitis C 4.2

Secondary Objective

To evaluate the safety of telaprevir in combination with Peg-IFN-alfa-2a and RBV in treatment-naïve subjects with genotype 1 chronic hepatitis C 5

ENDPOINTS

5.1

Primary Efficacy Endpoint

Proportion of subjects achieving sustained viral response (SVR), demonstrated by achieving undetectable HCV RNA 24 weeks after last planned dose of study treatment. 5.2

Secondary Efficacy Endpoints

Key Secondary Efficacy Endpoint: Proportion of subjects who have SVR at Week 72 (i.e., 24 weeks after last planned dose for subjects with a planned treatment duration of 48 weeks, and 48 weeks after last planned dose for subjects with a planned treatment duration of 24 weeks) Other Secondary Efficacy Endpoints: •

Proportion of subjects achieving a rapid viral response (RVR), demonstrated by achieving undetectable HCV RNA 4 weeks after starting study treatment.



Proportion of subjects achieving extended rapid viral response (eRVR), demonstrated by achieving undetectable HCV RNA at Week 4 and at Week 12



Proportion of subjects who have undetectable HCV RNA at Week 12



Proportion of subjects who have undetectable HCV RNA at the end of treatment (EOT)

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Proportion of subjects who have undetectable HCV RNA 12 weeks after last planned dose of study treatment





Proportion of subjects who have undetectable HCV RNA 24 weeks after last actual dose of study treatment Proportion of subjects who relapse, defined as those who complete treatment as assigned, have undetectable HCV RNA at EOT, and become HCV RNA detectable during antiviral follow-up



Proportion of subjects who relapse, defined as those who have undetectable HCV RNA at the EOT, and become HCV RNA detectable during antiviral follow-up



Biochemical response including transaminase levels



Noninvasive markers of fibrosis



Total Fatigue Score from the Fatigue Severity Scale (FSS)



Adverse events, physical examination findings, and clinical laboratory, vital sign, and electrocardiogram (ECG) assessments

5.3

Tertiary Endpoints



Amino acid sequence of the HCV NS3 protease domain



Pharmacokinetics and pharmacokinetic-pharmacodynamic relationships of telaprevir, VRT-127394, Peg-IFN-alfa-2a, and RBV



Patient-reported outcomes including EQ-5D, assessments of work productivity, and assessments of healthcare utilization

6

STUDY DESIGN AND PROCEDURES

6.1

Overall Study Design

This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study to be conducted in treatment-naïve subjects with genotype 1, chronic hepatitis C infection. The study is designed to compare each of 2 dose regimens of telaprevir dosed with Peg-IFN-alfa2a and RBV against standard of care, Peg-IFN-alfa-2a and RBV. As described in Table 6.1-1 subjects will be randomized to 1 of 3 treatment groups. Two of the groups will receive a regimen of telaprevir, Peg-IFN-alfa-2a, and RBV. The third group (the control) will receive a regimen of telaprevir-matching placebo, Peg-IFN-alfa-2a, and RBV. Subjects will be randomized to these treatment groups in a 1:1:1 ratio stratified by genotype 1 subtype and baseline viral load.

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Table 6.1-1 Treatment Groups Treatment Group T8/PR

Planned Telaprevir Dosing Period Day 1 through Week 8

Treatments Planned Telaprevir-matching Planned Peg-IFN-alfa-2a and RBV Placebo Dosing Period Dosing Period Weeks 9 through 12

Day 1 through Week 24–with eRVR Day 1 through Week 48–without eRVR

T12/PR

Day 1 through Week 12 ---

Day 1 through Week 24–with eRVR Day 1 through Week 48–without eRVR

Pbo/PR48 --Weeks 1 through 12 Day 1 through Week 48 T = telaprevir, PR = Peg-IFN-alfa-2a and RBV, Pbo=placebo, eRVR=extended rapid viral response (undetectable HCV RNA at Week 4 and Week 12)

The telaprevir regimens have a planned total treatment duration of 24 or 48 weeks, with telaprevir given in combination with Peg-IFN-alfa-2a and RBV for either the first 8 weeks (T8/PR group) or the first 12 weeks (T12/PR group). For subjects who achieve an extended rapid viral response (eRVR, defined as undetectable HCV RNA at Week 4 and at Week 12), Peg-IFN-alfa-2a and RBV dosing is planned for 24 weeks. For subjects who do not achieve eRVR, Peg-IFN-alfa-2a and RBV dosing is planned for 48 weeks. The control group has a planned total treatment duration of 48 weeks, with telaprevirmatching placebo given for the first 12 weeks and Peg-IFN-alfa-2a and RBV dosing planned for the entire 48 weeks (Pbo/PR48 group). All subjects will remain on study through Week 72, regardless of treatment duration and HCV RNA status. A more detailed description of the study design is presented in Sections 8.1, 8.2, and 8.3 of the CSP. 6.2

Sample Size and Power

The primary efficacy variable is the proportion of subjects achieving SVR, defined as undetectable HCV RNA 24 weeks after the last planned study drug dosing (Week 48 for subjects in the T8/PR and T12/PR groups who achieve eRVR, and Week 72 for subjects in the T8/PR and T12/PR groups who do not achieve eRVR and all subjects in the Pbo/PR48 group), regardless of whether the subject completed all study drug dosing. Assuming a 50% response rate in the control group, a 64% response rate in a telaprevir group, a 2-sided continuity corrected Chi-squared test, with an overall significance level of 5% (adjusted for multiple comparisons), a sample size of 350 subjects in each treatment group will provide a power of 92% to demonstrate a statistically significant treatment difference.

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6.3

Study Population

Male and female subjects with treatment-naïve, genotype 1, chronic hepatitis C who are between 18 and 70 years of age (inclusive), who meet all of the entry criteria (as detailed in Sections 9.1 and 9.2 of the CSP) are eligible to participate in the study. 6.4

Subject Replacement

No subjects will be replaced. Randomization will continue until the number of subjects exposed to study drug is equal to the pre-specified sample size. 6.5

Randomization

Subjects will be randomized to 1 of 3 treatment groups. Two of the groups will receive a regimen of telaprevir, Peg-IFN-alfa-2a, and RBV. The third group (the control) will receive a regimen of telaprevir-matching placebo, Peg-IFN-alfa-2a, and RBV. Subjects will be randomized to these treatment groups in a 1:1:1 ratio stratified by genotype 1 subtype and baseline viral load. 6.6

Blinding Procedures

Treatment assignments will be double-blinded until database lock. HCV RNA results will be double-blinded up to, but not including, Week 28. From Week 28 onward, the HCV RNA results will be available to the investigator. HCV RNA results from tests prior to Week 28 will not be available to the investigator until database lock. The sponsor’s study team will receive HCV RNA data after all subjects complete the Week 52 visit (post-treatment for all subjects). This team will remain blinded to treatment group. In addition, unblinded virologists, who are not part of the study team, will be aware of treatment group and will receive HCV RNA results throughout the study to conduct the viral sequencing analyses for subjects with treatment failure (Section 11.6 of CSP). Sequencing results will not be revealed until after database lock. Lastly, select members of the sponsor’s quality assurance team, who are not part of the study team, may be unblinded to study data to allow for the performance of quality assurance activities. To maintain double-blinding during the first 12 weeks, Pbo/PR48 subjects will receive telaprevir-matching placebo (placebo) from Day 1 through Week 12, T8/PR subjects will receive placebo from Week 9 through Week 12. 6.7

Modifications/Clarifications from the Statistical Section of the CSP

The criteria for being considered undetectable (section 8.1.3.1) have been extended to also include: •

one HCV RNA value ‘