Protocol

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Apr 21, 2010 - 2) is made of surgical grade 316LVM stainless steel, laser cut into pre-specified geometric pattern with flexible longitudinal struts and no.

Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Verheye S, Jolicœur EM, Behan MW, et al. Efficacy of a device to narrow the coronary sinus in refractory angina. N Engl J Med 2015;372:519-27. DOI: 10.1056/NEJMoa1402556

Re: 14-02556 - Efficacy of the Coronary Sinus Reducer in Patients with Refractory Angina - COSIRA Trial As requested attached please find a PDF file which contains the following items: 1. Original protocol, final protocol, summary of the amendments to each of the protocols (3 in total). 2. Original statistical (and only) analysis plan.

COronary SInus Reducer for Treatment of Refractory Angina

Clinical Protocol for the COSIRA Study (#REDCLN-178)

Neovasc Reducer™ System DCO#: REDCLN-006 Rev. A

Revision history: Revision Description A Initial revision

Date 2010-04-21

This document and the information expressed therein is confidential and privileged information of Neovasc, Inc. Any unauthorized dissemination or copying is strictly prohibited. Confidential and privileged information is not open to the public and requires special precautions to protect it from unauthorized use, disclosure, modification or destruction. Neither receipt, nor possession of this document transfers any right to reproduce or disclose this document or any part thereof, including any information contained therein, or to practice any method or process described there in, except by written permission from or written agreement with Neovasc, Inc.

COSIRA Clinical Study (#REDCLN-178) Clinical protocol

Neovasc Reducer™ System

PROTOCOL APPROVAL

Protocol #REDCLN-178: Coronary Sinus Reducer for Treatment of Refractory Angina (COSIRA) Protocol Date: 2010-04-21 Revision: A Neovasc Inc. has approved this protocol. The following signatures document this approval.

2010-04-21

Marc Schwartz Director Clinical & Regulatory Affairs

Date

2010-04-21

Shmuel Banai, M.D. Medical Director

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Date

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

Neovasc Reducer™ System

INVESTIGATOR'S STATEMENT AND SIGNATURE Prior to enrolling patients in the COSIRA Study, the Principal Investigator must obtain written approval from his/her Ethics Committee (EC). This approval must be in the Principal Investigator’s name and a copy sent to Neovasc Inc., along with the EC approved Informed Consent and the signed Clinical Trial Agreement. Additionally, the Principal Investigator must sign the declaration below: I have read this protocol and agree to adhere to the requirements. I will provide copies of this protocol and all pertinent information to the study personnel under my supervision. I will discuss this material with them and ensure they are fully informed regarding the investigational device and the conduct of the study.

Principal Investigator’s Signature

Date

Principal Investigator’s Printed Name

Site Name

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Site #

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

Neovasc Reducer™ System

TABLE OF CONTENTS Acronyms ............................................................................................................................ 7 1

Protocol Summary ...................................................................................................... 9

2

Background and Study Justification ....................................................................... 13 2.1 Scientific justification ........................................................................................... 13 2.2 Prior pre-clinical and clinical data........................................................................ 16

3

Investigational Device ............................................................................................... 18 3.1 Neovasc Reducer™ System ................................................................................. 18 3.2 Indication for use................................................................................................... 19

4

Risk/Benefit ............................................................................................................... 20 4.1 Anticipated clinical benefits ................................................................................. 20 4.2 Risk analysis and residual risks........................................................................... 21 4.3 Risks and adverse effects..................................................................................... 21 4.4 Measures to mitigate risks.................................................................................... 22 4.5 Risk/benefit rationale ............................................................................................ 22

5

Objectives and Hypothesis ....................................................................................... 23 5.1 Study objectives .................................................................................................... 23 5.2 Hypothesis ............................................................................................................. 23

6

Study Design ............................................................................................................. 24 6.1 Measures to minimize/avoid bias ......................................................................... 24 6.2 Study endpoints .................................................................................................... 25 6.3 Tools to assess endpoints and observational measures ................................... 26 6.4 Justification for study design ............................................................................... 27

7

Study Population ....................................................................................................... 28 7.1 Eligibility criteria ................................................................................................... 28 7.2 Patient enrollment and screening ........................................................................ 30 7.3 Number of subjects and investigational sites ..................................................... 31 7.4 Study duration ....................................................................................................... 31 7.5 Early discontinuation of patients ......................................................................... 31 7.6 Patients lost to follow-up ...................................................................................... 31

8

Study Procedures...................................................................................................... 33

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

Neovasc Reducer™ System

8.1 Activities performed by sponsor representative ................................................. 34 8.2 Screening ............................................................................................................... 34 8.3 Completion of screening and procedure ............................................................. 34 8.4 Post-procedure through hospital discharge ....................................................... 35 8.5 Thirty-day (± 7 days) follow-up visit ..................................................................... 35 8.6 Three-month (± 2 weeks) follow-up evaluation.................................................... 37 8.7 Six-month (± 1 month) follow-up visit .................................................................. 37 9

Materials .................................................................................................................... 38 9.1 Investigational device ........................................................................................... 38 9.2 Comparator ............................................................................................................ 38 9.3 Supply, storage, traceability, and accountability ................................................ 38 9.4 Labeling ................................................................................................................. 39 9.5 Concomitant Medications ..................................................................................... 39

10

Statistics .................................................................................................................... 40

10.1 Software ................................................................................................................. 40 10.2 Sample size ............................................................................................................ 40 10.3 Analysis population .............................................................................................. 40 10.4 Missing data........................................................................................................... 41 10.5 Primary analysis .................................................................................................... 41 10.6 Secondary efficacy outcomes .............................................................................. 41 10.7 Baseline demographics and subject characteristics .......................................... 42 10.8 Subgroup analysis ................................................................................................ 42 10.9 Safety outcome...................................................................................................... 42 10.10

Interim analyses............................................................................................. 43

10.11

Analysis modification .................................................................................... 43

11

Adverse Event Handling and Reporting .................................................................. 44

11.1 Definitions.............................................................................................................. 44 11.2 Recording and reporting requirements for all AEs ............................................. 44 11.3 Reporting procedures for all AEs......................................................................... 45 11.4 Reporting procedures for serious adverse events ............................................. 46 11.5 Device deficiencies ............................................................................................... 47 11.6 Safety monitoring and adjudication of adverse events ...................................... 47 11.7 Clinical Events Committee.................................................................................... 48 Copyright © 2010 All rights reserved Company Confidential

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

Neovasc Reducer™ System

11.8 Data Safety Monitoring Board .............................................................................. 48 12

Data Management...................................................................................................... 49

13

Quality Control and Quality Assurance ................................................................... 50

13.1 Pre-study assessment .......................................................................................... 50 13.2 Monitoring .............................................................................................................. 50 13.3 Protocol deviations ............................................................................................... 51 13.4 Audits and inspections ......................................................................................... 52 13.5 Direct access to source documents..................................................................... 52 13.6 Training .................................................................................................................. 53 14

Ethics and Regulatory............................................................................................... 54

14.1 Informed consent .................................................................................................. 54 14.2 Independent ethics committee ............................................................................. 55 14.3 Patient confidentiality ........................................................................................... 55 15

Administrative and Legal Obligations ..................................................................... 56

15.1 Protocol amendments ........................................................................................... 56 15.2 Study documentation and archive ....................................................................... 56 15.3 Steering Committee............................................................................................... 56 15.4 Publication policy .................................................................................................. 57 15.5 Liability................................................................................................................... 57 15.6 Study termination .................................................................................................. 57 Appendix A: Study Definitions ........................................................................................ 58 Appendix B: Study Flow Chart ........................................................................................ 60 Appendix C: Sample Instructions for Use ...................................................................... 62 Appendix D: Declaration of Helsinki ................................................................................ 63

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

Neovasc Reducer™ System

Acronyms ACT ADE AE BUN CCS COPD CEC CTA CBC CT CHF CABG CAD CS DSMB DHF Dobutamine ECHO; DSE eCRFs EC ETT EECP FIM ICSO LAO LBBB MRI MI PTT PCI PMR PT RA RHC SAQ SADE SAE SPECT SDV SCS SC Copyright © 2010 All rights reserved Company Confidential

Activated Clotting Time Adverse Device Effect Adverse Event Blood Urea Nitrogen Canadian Cardiovascular Society Chronic Obstructive Pulmonary Disease Clinical Events Committee Clinical Trial Agreement Complete Blood Count Computed Tomography Congestive Heart Failure Coronary Artery Bypass Graft Coronary Artery Disease Coronary Sinus Data Safety Monitoring Board Design History File Dobutamine Stress Echocardiography Electronic Case Report Forms Ethics Committee Exercise Tolerance Test External Balloon Counter Pulsation First-In-Man Intermittent Coronary Sinus Occlusion Left Anterior Oblique Left-Bundle Branch Block Magnetic Resonance Imaging Myocardial Infarction Partial Thromboplastin Time Percutaneous Coronary Intervention Percutaneous Myocardial Revascularization Prothrombin Time Right Atrium Right Heart Catheterization Seattle Angina Questionnaire Serious Adverse Device Effect Serious Adverse Event Single Photon Emission Computed Tomography Source Data Verification Spinal Cord Stimulation Steering Committee Effective Date: 2010 04 21 DOC-006 Rev A. Page 7 of 67

COSIRA Clinical Study (#REDCLN-178) Clinical protocol

SOC TMR USADE VF VT WMSI

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Neovasc Reducer™ System

System Organ Class Transcutaneous Myocardial Laser Revascularization Unanticipated Serious Adverse Device Effect Ventricular Fibrillation Ventricular Tachycardia Wall Motion Score Index

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

1

Neovasc Reducer™ System

Protocol Summary

Title COSIRA – COronary SInus Reducer™ for Treatment of Refractory Angina Study / protocol number #REDCLN-178 Device name Neovasc Reducer™ System (Reducer) Indication for use The Reducer is indicated as an aid in the management of chronic refractory angina pectoris. Methodology Prospective, multicenter, randomized, double-blind, sham-controlled (1:1 randomization ratio), confirmatory clinical study of the safety and effectiveness of the Reducer. The following groups will be studied: •

Reducer Group: right heart catheterization as the last screening test, followed by Reducer implantation, and completion of the catheterization procedure



Control Group: right heart catheterization as the last screening test, followed by completion of the catheterization procedure

Study centers The study will be conducted at a maximum of six medical centers, in Europe and Canada. Number of patients A maximum of 124 patients will be randomized (1:1 Reducer vs. Control) in order to generate an evaluable cohort of 112 patients at six months post-procedure. The study will contain a subset study at one site. This subset study population, in addition to all specified imaging assessments, will undergo perfusion Cardiac MRI at baseline and at six-month evaluation. The sub-study will be conducted at a single site and will include a maximum of 20 patients. Objective The objective of this study is to confirm the safety and effectiveness of the Reducer when used in patients with refractory angina who demonstrate evidence of reversible ischemia.

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

Neovasc Reducer™ System

Diagnosis and key eligibility criteria Patients with refractory angina pectoris who demonstrate objective evidence of reversible myocardial ischemia, who have limited treatment options and are thus referred to as ‘no-option’ patients, will undergo screening for the COSIRA study. Key eligibility criteria include: • • • • •

>18 years old Symptomatic CAD with chronic refractory angina pectoris classified as Canadian Cardiovascular Society (CCS) grade III or IV despite attempted optimal medical therapy for thirty days prior to screening Non-candidate for surgical or percutaneous coronary intervention, as determined by the investigator Reversible ischemia of the left ventricular wall demonstrated by Dobutamine Stress Echocardiography (Dobutamine ECHO; DSE) ≥1 mm ST-segment depression at baseline exercise testing

Primary endpoint CCS Classification: a decrease in two or more CCS grades from baseline to six-month post-procedural evaluation in Reducer and Control groups Secondary endpoints 1. Technical success: in the Reducer group, defined as successful delivery and deployment of the Reducer to the intended site as assessed by the investigator 2. Procedural success: in the Reducer group, defined as technical success and the absence of acute need for clinically-driven intervention to address an Adverse or Serious Adverse Device Effect prior to hospital discharge, as adjudicated by the Clinical Events Committee (CEC) 3. Periprocedural Serious Adverse Event (SAE): in the Reducer group, defined as a composite of death, myocardial infarction (MI), cardiac tamponade, clinically-driven re-dilation of a failed Reducer, life-threatening arrhythmias (ventricular tachycardia [VT] or ventricular fibrillation [VF]), and respiratory failure through 30 days postprocedure, as adjudicated by the CEC 4. Periprocedural SAE: in the Control group, defined as a composite of death, MI, cardiac tamponade, life-threatening arrhythmias (VT or VF), and respiratory failure through 30 days post-procedure, as adjudicated by the CEC 5. Major Adverse Events: a composite of cardiac death, major stroke, and MI in the Reducer and Control groups through hospital discharge, and at 30-day, three-month, and six-month post-procedural evaluations 6. CCS Classification: a decrease one or more CCS grades from baseline to six-month post-procedural evaluation in Reducer and Control groups 7. Dobutamine ECHO Wall Motion Score Index (WMSI): in the Reducer and Control groups at baseline and six-month post-procedural evaluation Copyright © 2010 All rights reserved Company Confidential

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

Neovasc Reducer™ System

8. Seattle Angina Questionnaire (SAQ) Score: in the Reducer and Control groups at baseline and six-month post-procedural evaluation 9. Total Exercise Duration (min), Time to ST-Segment Depression (min), and Maximal ST-Segment Depression (mm) by Exercise Stress Test: in the Reducer and Control groups at baseline and six-month post-procedural evaluation Observational measures 1. Thallium Single Photon Emission Computed Tomography (SPECT) Segmental Analysis: in the Reducer and Control groups at baseline and six-month postprocedural evaluation 2. Cardiac Magnetic Resonance Imaging (MRI) Endocardial / Epicardial Blood Flow Distribution and Wall Motion Analysis: in the subset group undergoing perfusion Cardiac MRI at baseline and six-month post-procedural evaluation Duration of study (per subject) Excluding the screening period, the duration of participation for each patient will be approximately six months. Randomized patients will be hospitalized as per local protocol. Patients will be evaluated at hospital discharge, and post-procedurally at 30 days, three months, and six months. See Appendix B for study flowchart. Statistical methodology The sample size calculation is based on the following assumptions: •

H 0 : Proportion of patients in the Reducer group with a decrease of two or more CCS grades at six months = Proportion of patients in the Control group with a decrease two or more CCS grades at six months



H 1 : Proportion of patients in the Reducer group with a decrease of two or more CCS grades at six months ≠ Proportion of patients in the Control group with a decrease two or more CCS grades at six months



Based on a literature review, the proportion of patients expected to exhibit a decline of two or more CCS grades at six months is 0.40 (Reducer) and 0.15 (Control)



Type I error rate of 5% (2-sided)



Power of 80%



Calculation based on the Pearson chi-square test with continuity correction

Based on these assumptions, the sample size is 56 patients per group (a total of 112 patients). It is further assumed that up to 10% of the randomized cohort may not complete the six-month evaluations. The sample size is therefore increased to a maximum of 62 per group, for a total trial size of 124.

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

Neovasc Reducer™ System

A Data Safety Monitoring Board (DSMB) will review summaries of safety periodically. Two interim analyses will be performed. The first interim analysis will occur after approximately 30 randomized patients have thirty-day data available. The second interim analysis will include six-month safety and effectiveness data of approximately 50% of the randomized population. Tentative time course EC Submission: First Patient In: Last Patient In: First Interim Analysis:

Q2-2010 Q3-2010 Q3-2011 Q1-2011

Second Interim Analysis: Last Patient Follow-up: Final Report:

Q3-2011 Q1-2012 Q2-2012

Coordinating investigator Stefan Verheye, MD Antwerp Cardiovascular Institute Antwerp, Belgium Email: [email protected] Monitoring genae associates nv Antwerp, Belgium Contact: Aly Talen, RN Email: [email protected] Data management genae associates nv, Antwerp, Belgium Dobutamine echo core lab Cardiovascular Research Institute Washington, District of Columbia, United States Contact: Neil J. Weissman, MD Email: [email protected] ETT core lab Duke Clinical Research Institute Durham, North Carolina, United States Contact: Mitchell W. Krucoff, MD Email: [email protected] Sponsor Neovasc Inc. 13700 Mayfield Place Unit # 2135 Richmond, British Columbia V6V 2E4 Canada Phone: +1 (604) 270-4344 Contact: Marc Schwartz Email: [email protected]

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

2

Background and Study Justification

2.1

Scientific justification

Neovasc Reducer™ System

Refractory angina pectoris Over the last few decades, increasing numbers of coronary revascularization procedures along with improved drug and device therapies have greatly increased the life expectancy of patients with coronary artery disease (CAD). Despite such advances in medicine, there are still a considerable number of patients who remain severely disabled by chronic refractory angina pectoris. This group of patients is rapidly growing as available improvements in cardiovascular care have continued to extend life expectancy without the ability to treat symptoms. This group of patients, referred to as ‘no-option’ patients, includes those who have significant disability with limiting symptoms resulting from myocardial ischemia, multiple medications, and frequent hospital admissions, despite optimal medical therapy. These ‘no option’ patients have severe diffuse CAD, and are thus not amenable to further revascularization by coronary artery bypass surgery (CABG) or by percutaneous coronary intervention (PCI). Refractory angina pectoris in spite of optimal medical therapy is a relatively common clinical problem. It is estimated that there are as many as 525,000 angina patients in the EU and US classified each year as having no revascularization options. Additionally, there are well over 500,000 other patients who have undergone either PCI or CABG for revascularization but continue to suffer from angina, which brings the total number of patients that could potentially benefit from new angina therapies to over 1 million annually. 1,2 A considerable number of therapeutic strategies have been investigated to treat severe chronic angina, such as transcutaneous electric nerve stimulation, spinal cord stimulation (SCS), left stellate ganglion blockade, endoscopic thoracoscopic sympathectomy, thoracic epidural anesthesia, external balloon counter pulsation (EECP), stem cell therapy, and, finally, myocardial laser revascularization by surgical (TMR) or percutaneous (PMR) technique. 3,4 Each existing therapy has a limited degree of efficacy, and none of these approaches have become widely-utilized therapies.

1 Mannheimer C, et al. The Problem of Chronic Refractory Angina. Eur. Heart J. 2002;23: 355-370.

2 Mukherjee D. et. al. Clinical Outcome of a Cohort of Patients Eligible for Therapeutic Angiogenesis or Transmyocardil Revascularization. Am. Heart Journal 2001;84: 598-600. 3 Rouleau JR, White M: Effects of coronary sinus pressure elevation on coronary blood flow distribution in dogs with normal preload. Can J Physiol Pharmacol. 1985;63(7):787-97. 4 Sato M, Saito T, Mitsugi M, Saitoh S, Niitsuma T, Maehara K, Maruyama Y: Effects of cardiac contraction and coronary sinus pressure elevation on collateral flow. Am J Physiol 1996; 271:H1433H1440. Copyright © 2010 All rights reserved Company Confidential

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

Neovasc Reducer™ System

Narrowing the coronary sinus – the Beck 1 procedure Fifty years ago, Claude Beck performed a surgical narrowing of the coronary sinus (CS) to achieve redistribution of myocardial blood flow into ischemic territories of the myocardium with remarkable success. Using open chest surgery in patients with severe, disabling angina, he created a 60-70% narrowing of the CS to achieve a 3 mm residual lumen diameter. The therapeutic results included significant relief of angina symptoms, improved functional class, and a reduced five-year mortality rate. A comparative study of 185 patients at the Cleveland Clinic showed that long-term mortality in the group of patients treated as per Beck’s procedure to be significantly lower, at 13%, than the 30% mortality rate observed in the control group. Furthermore, in the surgical group, 90% of patients reported complete or significant relief of their symptoms as measured by reduction of pain and need for medication. The portion of patients fit for work also doubled in the treatment group from 45%, prior to the intervention, to 90% as determined by patient self-report at follow-up. Beck’s pre-clinical and clinical work demonstrated that the success of the ‘Beck 1’ procedure was likely driven by elevated CS pressure, which triggered protective mechanisms that improved perfusion of ischemic territories. Beck’s studies have been duplicated by numerous other surgeons with equally positive results – the procedure led to considerable relief of angina symptoms, allowing the patients to return to work and activities, and possibly increasing life expectancy. The Beck 1 procedure was so successful that it became a standard of care for treating patients with angina pectoris in the 1950’s and 1960’s before CABG became mainstream. The open-chest Beck 1 procedure is, however, considered to be too high-risk in patients for whom further revascularization is not an option, and thus is not suitable for the group of no-option patients who continue to suffer from chronic refractory angina pectoris despite optimal medical treatment. 5,6,7,8 Intermittent coronary sinus occlusion (ICSO) Intermittent coronary sinus occlusion (ICSO) is a recently proposed non-surgical method to elevate coronary sinus pressure. This procedure uses a closed loop CS balloon system that automatically occludes and releases the CS while continuously monitoring CS pressure.

5 Wising PJ . The Beck-I Operation for Angina Pectoris. Acta Medica Scandinavica 1963; 174Fasc1: 9397. 6 Sandler G, et al. The Beck Operation in the Treatment of Angina Pectoris. Thorax 1967;22: 34-37. 7 Beck CS, et al. Operation for Coronary Artery Disease. J.A.M.A. Nov. 27, 1954;156(13): 1226-1233. 8 Zoll PM, et al. Inter-arterial Coronary Anastomosis in the Human Heart with Particular Reference to Anemia and Relative Cardia Anoxia. Circulation Dec. 1951;4: 797–815.

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

Neovasc Reducer™ System

ICSO has been demonstrated to reduce myocardial ischemia. Mohl and colleagues showed in their experimental and clinical work that the redistribution of flow and the salvage potential of ICSO are related to the acute collateralization of the ischemic territory. 9 They demonstrated a 29-39% decrease in ischemic damage to the myocardium during coronary occlusion when ICSO was applied concomitantly. A number of experiments have utilized ICSO in combination with retroperfusion of arterial blood into the coronary sinus to try and salvage ischemic myocardium. The results show that the addition of retro-perfusion of arterial blood exhibits no additional benefit in salvaging the ischemic myocardium in comparison with that provided by ICSO alone. 10 Mohl and colleagues propose that the success of the technique is related to initiation of a number of angiogenic pathways in the cardiac endothelium, rather than any direct effect on myocardial reperfusion. 11 While the results of ICSO and variations on this technique are quite compelling, the technique has not been adopted for routine clinical use due to the requirement of having a balloon catheter indwelling in the CS for a prolonged period of time. The Neovasc Reducer™ System (Reducer) The Reducer is designed to be implanted in the CS to establish a narrowing, which alters blood flow and venous pressure. The CS is the ‘final pathway’ of the cardiac venous drainage left coronary circulation. In the setting of obstructive CAD, increased CS pressure can lead to redistribution of collateral blood flow from non-ischemic to ischemic territories of the myocardium. Such redistribution of arterial blood can significantly reduce myocardial ischemic damage, as historically established by the Beck 1 procedure.5, 6, 7, 8, 12, 13, 14, 15

9 Mohl W. et al. Intermittent Pressure Elevation of the Coronary Venous System as a Method to Protect Ischemic Myocardium. Interactive CardioVascular and Thoracic Surgery 2005;4: 66-69. 10 Syeda B. et al. The salvage potential of coronary sinus interventions: Meta-analysis and pathophysiologic consequences. The Journal of Thoracic and Cardiovascular Surgery 2004;127: 17031712. 11 Mohl W. et al. Is activation of coronary venous cells the key to cardiac regeneration? Nature Reviews Cardiology 2008;5: 528–530. 12 Syeda B, Schukro C, Heinze G, Modaressi K, Glogar D, Maurer G, Mohl W: The salvage potential of coronary sinus intervention: Meta-analysis and pathophysiologic consequences. The Journal of Thoracic and Cardiovascular Surgery 2004; 127:1703-1712. 13 Wising PJ.: The BECK-I operation for angina pectoris: medical aspects. Acta Med Scand. 1963;174:93-8. 14 Yang EH, Barness GW, Gersh BJ, Chandrasekaran K, Lerman A: Current and future treatment strategies for refractory angina. Mayo Clin Proc. 2004; 79:1284-1292. 15 Zalewski, Maroko et. al, Myocardial protection via coronary sinus interventions: superior effects of arterialization compared with intermittent occlusion. Circulation 1985; 71:1215-1223. Copyright © 2010 All rights reserved Company Confidential

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

Neovasc Reducer™ System

If shown to be safe, the Reducer may provide an alternative treatment strategy that to improve symptoms of refractory angina in patients with coronary artery disease presenting with reversible myocardial ischemia.

2.2

Prior pre-clinical and clinical data

The Neovasc Reducer™ System was designed in accordance with the Neovasc Quality Management System that is reflective of this Class III medical device. The Reducer has gone through two design iterations, with the main difference between GEN I and GEN II being the delivery system and the technique used to implant the device. The Reducer has undergone careful pre-clinical and clinical testing, as outlined below. Summary information of these bench, biocompatibility, animal, and clinical studies is provided in the Reducer Investigator’s Brochure (DCO #: REDCLN-004). 2.2.1 Bench testing Neovasc Inc. (Neovasc) has conducted extensive verification and validation testing of the Reducer. Bench and design verification testing was carried out to verify the product requirements and functional specifications, as well as to provide evidence of the safety and effectiveness of the device in achieving its intended use. All of the different components of Reducer have been stress tested to ensure that the system as a whole provides all the capabilities necessary to operate safely and effectively. These include: • • •

Mechanical and engineering performance specifications for the Reducer design and material; Functional specifications to ensure that the Reducer performs as designed for its intended use; and Compatibility of the Reducer with its delivery system and with the intended delivery method.

2.2.2 Biocompatibility The biological safety of the Reducer was evaluated in accordance with the requirements of ISO 10993-1:2003 (“Biological evaluation of medical devices - Evaluation and testing”) and the FDA guidance document, “Required Biocompatibility Training and Toxicology Profiles for Evaluation of Medical Devices” (G95-1). The findings of the biocompatibility evaluation support the use of the Reducer in the proposed clinical study.

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

Neovasc Reducer™ System

2.2.3 Animal studies Neovasc has conducted animal studies on a total of 47 mini-swine under two separate protocols. Conclusions based upon the animal studies were that the Reducer was a feasible device that demonstrated safety and efficacy consistent with its intended use. 2.2.4 Prior clinical studies Neovasc has also conducted a First-In-Man (FIM) clinical study with the Neovasc Reducer™ System, including a long term surveillance study of the FIM patients. The FIM study was initiated using the GEN1 device in November 2004 and completed in March 2006. Fifteen patients at three different medical centers underwent Reducer implantation. 16 This study was designed to provide initial indication of safety and feasibility of the device. The FIM study concluded that implantation of the Reducer in patients with chronic refractory angina is safe and feasible. At the six-month follow-up, improvement in angina scores, a reduction in ST-segment depression, and reduced dobutamine-induced myocardial ischemia was observed in the majority of these patients. These findings, along with the clinical improvement observed, support further evaluation of the clinical efficacy of the Reducer as an alternative tool to treat patients with chronic refractory ischemia who are not candidates, or are at high risk, for revascularization. The surveillance follow-up, 17 conducted between April and May 2009, was a three-year follow-up study of the original 15 FIM patients, and was designed to provide evidence of the long-term safety and efficacy of the device. At the three-year follow-up, there were no deaths, MI, or adverse events attributable to the device. Computed tomography (CT) angiography revealed that all Reducers were patent and located at the exact site of deployment with no evidence of migration or occlusion. The improvement in angina score and in ischemic severity as demonstrated by the dobutamine echo, thallium SPECT, and stress test results that were observed at six months post-procedure in the original FIM study were maintained through the three-year follow-up.

16 Banai, S., et al. JACC. 2007;49:1783-1789 17 Banai, S., et al. Long Term Follow-up to Evaluate the Safety of the Neovasc Reducer A Device-Based

Therapy for Chronic Refractory Angina. Accepted for Oral Presentation American College of Cardiology Annual Conference March 2010 Copyright © 2010 All rights reserved Company Confidential

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

3

Neovasc Reducer™ System

Investigational Device

The Neovasc Reducer™ System is designed to be implanted in the CS and establish a narrowing, which alters blood flow and venous pressure. In the setting of obstructive CAD, increased CS pressure can lead to redistribution of collateral blood flow from nonischemic to ischemic territories of the myocardium. Such redistribution of arterial blood can significantly reduce myocardial ischemic damage. The Reducer is an alternative treatment strategy that may improve symptoms of refractory angina in patients with coronary artery disease presenting with reversible myocardial ischemia.

3.1

Neovasc Reducer™ System

The Neovasc Reducer™ System (GEN2, Fig 1) is comprised of the Neovasc Reducer™ pre-mounted on the Neovasc Reducer™ Balloon Catheter.

Fig. 1: The Neovasc Reducer™ System

The Neovasc Reducer™ (Fig. 2) is made of surgical grade 316LVM stainless steel, laser cut into pre-specified geometric pattern with flexible longitudinal struts and no welding points.

Fig. 2: The Neovasc Reducer™

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

Neovasc Reducer™ System

The Reducer is typically introduced into the CS via right heart catheterization through the right internal jugular vein and is available in one single model designed to fit the range of anatomies encountered in most patients. Its final expanded diameters are dependent on the inflation pressure of the semi-compliant Neovasc Reducer™ Balloon Catheter. The Neovasc Reducer™ Balloon Catheter (Fig. 3) is an over the wire catheter with a unique hour glass shape balloon. The proximal and distal portions of the balloon have differing diameters to conform to the taper typically encountered in the CS. Two radiopaque markers, located on the catheter shaft, mark the location of the crimped Reducer on the deployment balloon. A third marker located just proximally to the balloon is used to assist the operator to visualize when the balloon section of the catheter is completely outside of the tip of the guide catheter.

Fig. 3: The Neovasc Reducer™ Balloon Catheter

3.2

Indication for use

The Reducer is indicated as an aid in the management of chronic refractory angina pectoris.

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4

Risk/Benefit

4.1

Anticipated clinical benefits

Neovasc Reducer™ System

It is possible that the patient will not receive any benefits from implantation of the Reducer in the CS. Potential benefits that may be realized by the patients assigned to the Reducer group include reduction or relief of the symptoms associated with refractory angina, including a reduction in the frequency of chest pain, less fatigue, reduced need for medications, and improved quality of life. The following benefits of the Reducer implantation in the CS have been observed in prior preclinical and clinical studies: •





In a pre-clinical study using a mini-swine model of myocardial ischemia, four of eight animals were treated with the Reducer and the remaining four were left untreated as a control. Through 180 days, all four Reducer animals showed a significant reduction of ischemia severity as evident by dobutamine echocardiography, and all four survived. The four control animals showed no improvement in ischemia severity, and three of the four animals died. In an open-label FIM study involving 15 patients with chronic refractory angina, implantation of the Reducer in the CS resulted in an improved angina scores and a reduction in ST segment depression as evaluated at 6 months post-procedure. Additionally, dobutamine-induced myocardial ischemia was reduced in the majority of these patients. A three-year surveillance follow-up study of the 15 FIM patients demonstrated sustained safety, sustained improvement in angina score, and reduction ischemic severity as demonstrated by DSE, thallium SPECT, and stress test results.

Another known benefit to patients participating in the study is the ability to learn more about their angina through the assessments that will be performed throughout the course of the study. Additionally, patients will be closely observed by the study staff throughout their participation in the study. Last, Neovasc, the study sponsor, will pay all medical costs over the usual costs of treatment that are associated with study participation.

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4.2

Neovasc Reducer™ System

Risk analysis and residual risks

The Reducer has undergone a thorough risk analysis process, in accordance with applicable standards, including ISO 14971. The risk analysis commenced during the design input stage of developing the system, and continued throughout the design and post-design processes. The risk analysis review team encompassed members of multiple disciplines, including medicine, product design, quality assurance, regulatory systems, clinical research, and marketing. The risk analysis report (DCO #: REDRSK002) is maintained on file and is available upon request. During the risk analysis process, risks were divided into three categories: Acceptable, As Low as Reasonably Possible (ALARP) and Unacceptable. Already prior to risk mitigation, the majority of risks identified were categorized as Acceptable, a small number were categorized as ALARP, and none were categorized as Unacceptable. Pursuant to risk mitigation, all risks identified were categorized as Acceptable.

4.3

Risks and adverse effects

The potential risks associated with this study include the known risks of right heart catheterization and percutaneous coronary intervention, as well as risks associated with the standard routine clinical evaluations (e.g., exercise tolerance test [ETT], dobutamine ECHO, thallium SPECT, perfusion MRI). Risks and adverse effects that may be associated with or result from participating in the COSIRA study, the procedure, or use of the Reducer include, but are not limited to: • • • • • • • • • • • • • • • •

Allergic reaction to required mediations or contrast medium; Arrhythmias, including VT or VF; Cardiac tamponade; Death; Dissection; Emboli (air, tissue, or thrombotic); Emergent surgery / PCI; Heart block; Hypotension / hypertension; Infection and / or pain at access site; Ischemic event; Major bleeding event, including hemorrhage; Major vascular event, including pseudoaneurysm; Myocardial infarction; Perforation / rupture; Pulmonary edema;

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

• • • • • • •

Neovasc Reducer™ System

Pulmonary embolism; Reducer and/or coronary sinus occlusion; Reducer embolization; Reducer migration; Respiratory failure; Spasm; and Stroke / cerebrovascular accident / transient ischemic attack.

There may be additional risks that are unknown at this time.

4.4

Measures to mitigate risks

The following efforts will minimize risks to patients during the COSIRA study: • • • • •

Conduct of the study following successful completion of extensive non-clinical testing, initial clinical testing, and careful risk analysis; Selection of investigators who are experienced and skilled in management of refractory angina pectoris and coronary catheterization procedures; Establishment of a training program for study staff members (investigators, coordinators, and clinical monitors); Clearly defining the inclusion and exclusion criteria such that only appropriate patients are enrolled in the study; and Ensuring that the treatment of the patient is consistent with current medical practices.

4.5

Risk/benefit rationale

Assessing the above-listed risks against the potential benefits of the Reducer to improve symptoms and decrease the severity of myocardial ischemia, Neovasc and the study investigators have determined that there is a high likelihood that the expected benefit may outweigh the risk in patients fulfilling the study eligibility criteria.

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

5

Objectives and Hypothesis

5.1

Study objectives

Neovasc Reducer™ System

The objective of this study is to confirm the safety and effectiveness of the Reducer when used in patients with refractory angina who demonstrate evidence of reversible ischemia.

5.2

Hypothesis

H 0 : Proportion of patients in the Reducer group with a decrease of two or more CCS grades at six months = Proportion of patients in the Control group with a decrease two or more CCS grades at six months H 1 : Proportion of patients in the Reducer group with a decrease of two or more CCS grades at six months ≠ Proportion of patients in the Control group with a decrease two or more CCS grades at six months

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

6

Neovasc Reducer™ System

Study Design

The COSIRA is a prospective, multicenter, randomized, double-blind, sham-controlled (1:1 randomization ratio), confirmatory clinical study of the safety and effectiveness of the Reducer. It consists of baseline assessments, implantation of the Reducer in the study group, and assessments of both Reducer and Control groups at hospital discharge and at 30-day, three-month, and six-month post-procedural evaluations. The study will contain a subset study at one site. This subset study population, in addition to all specified imaging assessments, will undergo perfusion Cardiac MRI at baseline and at six-month evaluation. The sub-study will be conducted at a single site and will include a maximum of 20 patients.

6.1

Measures to minimize/avoid bias

6.1.1 Randomization A total of approximately 124 patients will be randomized in a 1:1 ratio using a computergenerated permuted block randomization scheme, with investigational sites as strata. 6.1.2 Sham control Following enrollment, all prospective study patients will undergo screening tests (Section 8.1) to determine eligibility. Right heart catheterization is the final screening test, following which eligible patients will be randomized to either the Control or Reducer group. In patients who are randomized to the Control group, the procedure will be complete following the right heart catheterization. Patients randomized to the Reducer group will have a Reducer implanted immediately following the coronary sinus angiography. All patients will remain blinded throughout the study period (e.g., six months) In order to maintain patient blinding, a sham procedure will be performed in the Control group patients. The implanting physicians will be instructed to behave in the exact same manner with both Control and Reducer group patients, thus maintain blinding of the patient as to study group assignment. Independent, blinded, physicians will perform the post-procedural CCS assessments for patients in both groups. These physicians will be provided the necessary criteria for assessing CCS in this trial, as well as specific instructions as to how the assessment should be performed. Questions to the patients about their condition, with regards to CCS scoring, will be scripted to ensure that every physician asks the same questions in Copyright © 2010 All rights reserved Company Confidential

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

Neovasc Reducer™ System

an identical manner to each patient. These measures will be imposed to ensure the elimination or minimization of any bias. Core laboratories will also be blinded to group assignments. They will analyze each test data from each clinical site in order to ensure that standardized measurements are employed. Any deviations will be reported to the sponsor.

6.2

Study endpoints

6.2.1 Primary endpoint CCS Classification: a decrease in two or more CCS grades from baseline to six-month post-procedural evaluation in Reducer and Control groups 6.2.2 Secondary endpoints Technical success: in the Reducer group, defined as successful delivery and deployment of the Reducer to the intended site as assessed by the investigator Procedural success: in the Reducer group, defined as technical success and the absence of acute need for clinically-driven intervention to address an Adverse or Serious Adverse Device Effect prior to hospital discharge, as adjudicated by the CEC Periprocedural SAE: in the Reducer group, defined as a composite of death, MI, cardiac tamponade, clinically-driven re-dilation of a failed Reducer, life-threatening arrhythmias (VT or VF), and respiratory failure through 30 days post-procedure, as adjudicated by the CEC Periprocedural SAE: in the Control group, defined as a composite of death, MI, cardiac tamponade, life-threatening arrhythmias (VT or VF), and respiratory failure through 30 days post-procedure, as adjudicated by the CEC Major Adverse Events: a composite of cardiac death, major stroke, and MI in the Reducer and Control groups through hospital discharge, and at 30-day, three-month, and six-month post-procedural evaluations CCS Classification: a decrease one or more CCS grades from baseline to six-month post-procedural evaluation in Reducer and Control groups Dobutamine ECHO Wall Motion Score Index: in the Reducer and Control groups at baseline and six-month post-procedural evaluation

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

Neovasc Reducer™ System

Seattle Angina Questionnaire Score: in the Reducer and Control groups at baseline and six-month post-procedural evaluation Total Exercise Duration (min), Time to ST-Segment Depression (min), and Maximal STSegment Depression (mm) by Exercise Stress Test: in the Reducer and Control groups at baseline and six-month post-procedural evaluation 6.2.3 Observational measures Thallium SPECT Segmental Analysis: in the Reducer and Control groups at baseline and six-month post-procedural evaluation Cardiac MRI Endocardial / Epicardial Blood Flow Distribution and Wall Motion Analysis: in the subset group undergoing perfusion Cardiac MRI at baseline and six-month postprocedural evaluation

6.3

Tools to assess endpoints and observational measures

Endpoints and observational measures will be evaluated using the assessment tools listed below: • • • • • •

• •

All data will be collected using an Electronic Data Collection (EDC) System. See Section 12 for details. CCS grade will be recorded by the blinded assessing physician or designee using a pre-specified questionnaire. A copy of the questionnaire and completion instructions will be provided in the study Manual of Operations. Technical success will be determined by the investigators. All Adverse Events will be classified by the investigator as device and/or procedure related. Association with Procedural success, Periprocedural SAE, and Major Adverse Events will be adjudicated and determined by the CEC. Dobutamine ECHO parameters will be evaluated by a core laboratory. A copy of the core lab guidelines will be provided in the study Manual of Operations. The self-administered SAQ to be completed by study patients will be analyzed with the statistical software provided by Cardiovascular Outcomes, Inc. A copy of the questionnaire and completion instructions will be provided in the study Manual of Operations. Exercise stress test will be evaluated by a core laboratory. A copy of the core lab guidelines will be provided in the study Manual of Operations. Guidelines for thallium SPECT and cardiac MRI will also be provided in the study Manual of Operations.

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

6.4

Neovasc Reducer™ System

Justification for study design

The COSIRA trial has been designed to demonstrate safety and effectiveness of the Reducer and the associated implant procedure. In order for Neovasc to provide unbiased results, the use of a sham procedure will equalize the placebo effect across groups and provide a direct comparator by which to assess device effectiveness, while also demonstrating safety. One of the screening tests to determine eligibility is the measurement of right atrial (RA) pressures and CS selective angiography. These are performed using the same procedure and techniques as one would use to perform a right heart catheterization (RHC). The RHC is a common and safe procedure with a low complication rate, 18 and is routinely performed on cardiac patients by interventional cardiologists. The implant procedure for the Reducer is initiated using the same techniques and some of the initial equipment that was used to perform the RA pressure measurements and CS angiography. Patients that have been randomized into the Control arm will undergo essentially the same procedure as those randomized to the Reducer arm, with the exception of Reducer implantation following angiography. Thus, angiography serves as the sham procedure. Patients will be provided informed consent and a written description outlining all of the possible risks associated with the procedure, as well as potential benefits of participating in the study, including those specific to the Reducer arm, should they be randomized to that group. All RHC screening failures will be followed for 30 days post-procedure for safety. Patients in both Control and Reducer arms will be evaluated at 30 days, three months, and six months post-procedure to evaluate safety and efficacy.

18 Hoper, M., et al. Complications of Right Heart Catheterization Procedures in Patients With

Pulmonary Hypertension in Experienced Centers. Journal of American College of Cardiology. December 19, 2006:2546–52. Copyright © 2010 All rights reserved Company Confidential

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

7

Study Population

7.1

Eligibility criteria

Neovasc Reducer™ System

Patients with refractory angina pectoris who demonstrate objective evidence of reversible myocardial ischemia, but who have limited treatment options, are referred to as ‘no-option’ patients In order to be randomized in this study, patients must fulfill all of the inclusion and none of the exclusion criteria. 7.1.1 Inclusion criteria 1. Patient is older than 18 years of age 2. Symptomatic CAD with chronic refractory angina pectoris classified as Canadian Cardiovascular Society grade III or IV despite attempted optimal medical therapy for three months prior to screening 3. Patient has limited treatment options for revascularization by coronary artery bypass grafting or by percutaneous coronary intervention 4. Evidence of reversible ischemia that is attributable to the left coronary arterial system 5. At least 1 mm ST-segment depression at baseline exercise testing 6. Left ventricular ejection fraction greater than 25% 7. Male or non-pregnant female (NB: Females of child bearing potential must have a negative pregnancy test) 8. Patient understands the nature of the procedure and provides written informed consent prior to enrollment 9. Patient is willing to comply with specified follow-up evaluation and can be contacted by telephone

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

Neovasc Reducer™ System

7.1.2 Exclusion criteria Clinical & General 1. Recent (within three months) acute coronary syndrome 2. Recent (within six months) PCI or CABG 3. Unstable angina (recent onset angina, crescendo angina, or rest angina with ECG changes) during the thirty days prior to screening 4. De-compensated congestive heart failure (CHF) or hospitalization due to CHF during the three months prior to screening 5. Life threatening rhythm disorders or any rhythm disorders that would require placement of an internal defibrillator and or pacemaker 6. Severe chronic obstructive pulmonary disease (COPD) as indicated by a forced expiratory volume in one second that is less than 55% of the predicted value 7. Patient cannot undergo exercise stress test (treadmill) for reasons other than refractory angina 8. Severe valvular heart disease 9. Patient with pacemaker or defibrillator electrode in the right atrium, right ventricle, or coronary sinus 10. Patient having undergone tricuspid valve replacement or repair 11. Chronic renal failure (serum creatinine >2 mg/dL), including patients on chronic hemodyalisis 12. Moribund patients, or patients with comorbidities limiting life expectancy to less than one year 13. Contraindication to required study medications that cannot be adequately controlled with pre-medication 14. Known allergy to stainless steel or nickel 15. Contraindication to having an MRI performed (NB: Cardiac MRI subset patients only) 16. Currently enrolled in another investigational device or drug trial that has not completed the primary endpoint or that clinically interferes with the current study endpoints Copyright © 2010 All rights reserved Company Confidential

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

Neovasc Reducer™ System

Angiographic 17. Mean right atrial pressure higher than or equal to 15 mmHg 18. Patient with anomalous or abnormal CS as demonstrated by angiogram. Abnormality defined as: •

Abnormal CS anatomy (e.g., tortuosity, aberrant branch, persistent left SVC) and/or;



CS diameter at the site of planned reducer implantation less than 9.5 mm or greater than 13 mm

7.2

Patient enrollment and screening

Prior to participating in this study, the investigator will inform the patient about the scope, purpose, rights, duties, and possible risks of the study. The patient must confirm consent in writing. Written informed consent must be obtained from every study patient prior to initiating baseline testing. A signed copy of the consent must be given to the patient and must be kept on file by the investigator. The point of enrollment is the time at which a patient signs and dates the informed consent form. Following enrollment, the patient will undergo screening tests (Section 8.1) to determine eligibility. Screening failures will be identified in a screening log. Patients who meet all inclusion criteria and none of the general exclusion criteria will be scheduled for right heart catheterization and angiography. The right heart catheterization is utilized to assess right atrial pressure. At the time that the right heart catheterization is performed, contrast angiography in the LAO projection will be used to assess the coronary sinus to determine size and tortuosity. If the patient meets all of the inclusion and none of the exclusion criteria, including the angiographic criteria, the patient will remain enrolled in the study. If a patient is enrolled, but found to be ineligible for the study based upon right heart catheterization data and/or angiographic eligibility criteria, the subject will be marked as “Screening Failure” in the screening log and will not take part in the study. Screening failure subjects will not be included in the intent to treat analysis, nor will they be counted as part of the target patient sample number. Patients that remain enrolled in this study will be randomized into the Control or Reducer group of the study. In patients that are randomized into to the Control arm, the procedure will be complete following the right heart catheterization. Patients that are randomized into the Reducer group will have a Reducer implanted immediately

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

Neovasc Reducer™ System

following the coronary sinus angiography. All patients will remain blinded through the six-month post-procedural evaluation.

7.3

Number of subjects and investigational sites

A maximum of 124 patients will be randomized (1:1 Reducer to Control ratio) in order to generate an evaluable cohort of 112 patients at six months post-procedure. The patients will be recruited from a maximum of six sites located in Europe and Canada. A current list of sites will be maintained in the study files.

7.4

Study duration

The anticipated overall study duration is 18-21 months from the first patient screening through last patient six-month follow-up. Screening will be carefully monitored to identify potential changes in this estimate as per actual availability of eligible patient populations at the investigational sites. Excluding the screening period, the duration of participation for each patient will be approximately six months. Randomized patients will be hospitalized per local protocol. Patients will be evaluated at hospital discharge, and at 30-day, three-month, and sixmonth post-procedural evaluations

7.5

Early discontinuation of patients

The investigator may prematurely discontinue the participation any patient in the study if the investigator feels that the patient can no longer fully comply with the requirements of the study or if any of the study procedures are deemed potentially harmful to the patient. Once a patient has been enrolled in the study, he/she may withdraw his/her consent to participate in the study at any time without prejudice. Participation in this clinical investigation is entirely voluntary. As much as possible, attempts will be made to conduct an exit/final visit prior to a patient terminating participation in the study. The reason for early discontinuation will be documented in the source documents and case report forms.

7.6

Patients lost to follow-up

If a patient does not show for a follow-up visit and cannot be contacted to collect followup information, he/she will be counted as a “missed visit” for that specific schedule. Attempts shall be made to contact the patient for the next scheduled follow-up. A Copyright © 2010 All rights reserved Company Confidential

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

Neovasc Reducer™ System

patient will be considered “lost to follow-up” only after the last scheduled follow-up visit for that patient. If a patient is lost to follow-up, the methods used to attempt to contact the patient should be noted. At least three attempts should be made to contact the patient via all available routes, and a certified letter should be sent to the permanent address on file.

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

8

Neovasc Reducer™ System

Study Procedures

Screening

Procedure

Hospital Discharge

Thirty Days

Three Months (visit or phone)

Six Months

Informed consent

X

Medical history

X

Physical exam

X

X

X

Listing of current medications

X

X

X

Pregnancy test (♀ only)

X1

Blood work

X1

Cardiac enzymes

X2

X4

ECG

X2

X

CCS assessment

X

Exercise tolerance test (ETT)

X

X

Dobutamine ECHO

X

X

Thallium SPECT

X

X

SAQ

X

Perfusion MRI (subgroup only)

X

X X

X X

X

X

X X

X

X

X X

Right heart catheterization

X

Coronary sinus angiography

X

Randomization

X

Reducer implantation

X3

Adverse events (AE)

X

X

X

X

X

1) Within seven days prior to procedure 2) Within 24 hours prior to procedure 3) In Reducer group only 4) Cardiac enzymes (CK, CK-MB, Troponin) within 8-12 hours post procedure

Table 1: Summary of study requirements from screening through follow-up

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

8.1

Neovasc Reducer™ System

Activities performed by sponsor representative

During the catheterization procedure and implantation of the Reducer, a sponsor representative associated with the study may attend. The involvement of such representative may include: • Presence at the catheterization laboratory for supporting the site personnel • Presence at the catheterization laboratory for watching the use of the device and gathering information and feedback from the doctors performing the procedure The representatives’ activities will occur in such a way that they do not influence the conduct of the procedure, nor do they interfere with any medical decisions or bias the data integrity. Additionally they will be described in the informed consent.

8.2

Screening

Signed, written, informed consent must be obtained for all patients who are potential study candidates prior to enrollment. The screening and baseline evaluations will include the following: • • • • • • • • • • •

Full medical history and physical examination; Full listing of current medications and dosages; Complete blood cell count (CBC), blood urea nitrogen (BUN), creatinine, electrolytes, prothrombin time (PT), partial thromboplastin time (PTT), and pregnancy test (if applicable) – within seven days prior to procedure; Cardiac Enzymes (CK, CK-MB, troponin) – within 24 hours prior to procedure; ECG – within 24 hours prior to procedure; CCS assessment; Seattle Angina Questionnaire; Exercise tolerance test; Dobutamine ECHO; Thallium SPECT; and Perfusion MRI (in the subset study population only).

8.3

Completion of screening and procedure

The completion of screening will include the following: • •

Patient preparation for right heart catheterization as per the instructions provided in the Reducer Instructions for Use (IFU; see Appendix C) or as per standard of care; Right heart catheterization and pressure measurements of the right atrium, right ventricle, pulmonary artery, and wedge pressure; and

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol



Neovasc Reducer™ System

Coronary sinus angiography.

The procedure will include the following: • • • • • • • • •

Randomization (start of procedure); For patients randomized to Control group, complete assessment as per standard of care to ensure that the patient remains blinded; For patients randomized to Reducer group, preparation of the investigational device as per the instructions provided in the Reducer IFU; Adherence to administration of pre-, intra-, and post-procedure medications as outlined in Section 9.5; Adherence to the Reducer IFU for implant instructions, warnings, and precautions; Measurement of activated clotting time (ACT) at intervals throughout the procedure; Culmination of the procedure defined as the time the venous sheath is removed; Procedure-related information recorded in the case report form (CRF); and Recording of all adverse events occurring during the procedure in the CRF.

8.4 • • • • •

Post-procedure through hospital discharge

Physical exam; ECG; Cardiac enzymes (CK, CK-MB, Troponin, within 8-12 hours post procedure); Full listing of current medications and dosages; and Adverse events, which will be recorded in the CRF in accordance with the specific categories defined in Section 11 of this protocol.

The research coordinator will review the follow-up requirements with the patient to help ensure compliance with the follow-up schedule. Telephone numbers must be obtained from the patient to ensure the ability to contact him/her. These phone numbers should include all home numbers, work numbers and primary physician numbers. A phone number of a relative or friend should also be requested.

8.5

Thirty-day (± 7 days) follow-up visit

The thirty-day follow-up visit will consist of: • • • • •

Physical examination; ECG; CCS assessment; Seattle Angina Questionnaire; Adverse events, which will be recorded in the CRF in accordance with the specific categories defined in Section 11 of this protocol; and

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol



Neovasc Reducer™ System

Full listing of current medications and dosages.

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

8.6

Neovasc Reducer™ System

Three-month (± 2 weeks) follow-up evaluation

The three-month follow-up evaluation can be conducted in person or via telephone interview between the investigator and patient. The follow-up will consist of: • • • •

CCS assessment Seattle Angina Questionnaire Adverse events, which will be recorded in the CRF in accordance with the specific categories defined in Section 11 of this protocol Full listing of current medications and dosages

8.7

Six-month (± 1 month) follow-up visit

The six-month follow-up evaluation will consist of: • • • • • • • • • •

Physical exam; ECG; CCS assessment; Seattle Angina Questionnaire; Exercise tolerance test; Dobutamine ECHO; Thallium SPECT; Perfusion MRI (in the subset study population); Adverse events, which will be recorded in the CRF in accordance with the specific categories defined in Section 11 of this protocol; and Full listing of current medications and dosages.

Following completion of the six-month assessment, patients will be exited from the study and the blind broken. No further medical care or evaluations will be performed as part of the COSIRA study.

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

9

Materials

9.1

Investigational device

Neovasc Reducer™ System

The investigational device is the Neovasc Reducer™ System. Each patient in the Reducer group will be implanted with a single Reducer.

9.2

Comparator

The Control group will undergo right heart catheterization only. No device will be implanted.

9.3

Supply, storage, traceability, and accountability

The Reducer is supplied as a kit including the following components: 1 - Neovasc Reducer™ premounted on a Neovasc Reducer™ Balloon Catheter 1 - 9F Straight Guiding Catheter (Cordis Vista Brite Tip 55cm Ref# 598-943p) 1 - Rotating Hemostasis Valve (MEDEX Inc. MX336LB) The investigational device must be kept in a secure, limited-access location. The Reducer will be identified with lot numbers. Complete traceability records will be kept of all devices and accessory equipment used during this clinical study. Upon receipt of the investigational device, an inventory must be performed. A device receipt log must be filled out and signed by the person accepting the shipment. It is important that the designated study staff count and verify that the shipment contains all the items noted in the shipment documentation. Any damaged or unusable study device in a given shipment will be documented in the study files. The investigator must notify Neovasc of any damaged or unusable study devices that were provided to the site. The study device will only be used for treating patients enrolled in the study, in accordance with the protocol. The designated study staff member will maintain the study device inventory using the accountability form(s) provided by Neovasc or designee. The study device inventory must be available for periodic inspection/verification. At the completion of the study, there will be a final reconciliation of devices shipped, used, and remaining. This reconciliation will be logged on the device reconciliation form, Copyright © 2010 All rights reserved Company Confidential

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

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signed and dated. Any discrepancies noted will be investigated, resolved, and documented prior to return of unused study devices under the direction of the sponsor. Detailed instructions and forms for device inventory handling will be provided separately.

9.4

Labeling

A sample of the Instructions for Use (IFU) for the Reducer is included in Appendix C. All investigational devices will be labeled with the statement "Exclusively for Clinical Investigation."

9.5

Concomitant Medications Pre-procedure

Aspirin

Clopidogrel

OR1

Prasugrel

≥80 mg q.d. aspirin for at least 72 hours prior to the procedure 75mg q.d. for at least 7 days prior to the procedure OR Loading dose of 300600mg within 24 hours prior to the procedure

---

75mg q.d. for at least 6 months post procedure, or longer as per physician’s discretion --10 mg for at least 6 months post procedure, or longer as per physician’s discretion 2

---

Bivalirudin

Post-procedure ≥80 mg q.d. aspirin until study completion (recommended indefinitely for stent patients)

Loading dose of 60mg within 24 hours prior to the procedure

Heparin OR

Procedure

Initial bolus IV with additional boluses to 3 maintain ACT ≥250 sec

---

4

IV Bolus and drip

1) The option between Clopidogrel and Prasugrel should be at the physician’s discretion. Patients may be placed on Ticlid if they are contraindicated to Clopidogrel or Prasugrel. Regimen should follow local standard of care. NOTE: Prasugrel can only be used in countries where it is approved for market 2) Heparin initial bolus 70 U/Kg, or per local protocol 3) ACT should be maintained ≥200 seconds if GPIIb/IIIa needs to be used. 4) Bivalirudin initial bolus 0.75 mg/Kg and drip 1.75 mg/Kg/hr, or per local protocol

Table 2: Pre-, intra-, and post-procedure medications

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

10

Neovasc Reducer™ System

Statistics

10.1 Software All analyses will be performed using SAS version 9 or greater or other validated statistical software.

10.2 Sample size The sample size calculation for the proposed trial is based on the following assumptions: • • • • • •

H 0 : Proportion of patients in the Reducer group with a decrease of two or more CCS grades at six months = Proportion of patients in the Control group with a decrease two or more CCS grades at six months H 1 : Proportion of patients in the Reducer group with a decrease of two or more CCS grades at six months ≠ Proportion of patients in the Control group with a decrease two or more CCS grades at six months Based on a literature review, the proportion of patients expected to exhibit a decline of two or more CCS grades at six months is 0.40 (Reducer) and 0.15 (Control). Type I error rate of 5% (2-sided) Power of 80% Calculation based on the Pearson chi-square test with continuity correction

Based on these assumptions, the sample size is 56 patients per group (a total of 112 patients). It is further assumed that up to 10% of the randomized cohort may not complete the six-month evaluation. The sample size is therefore increased to a maximum of 62 per group, for a total trial size of 124.

10.3 Analysis population The intent-to-treat (ITT) population will include all randomized patients. For this study, the ITT population will consist of all subjects who sign the written informed consent, meet the study entry criteria, and are randomized to a study arm. The ITT population will be used for the primary analysis. Each subject will be analyzed according to his or her original randomized treatment group. Analysis will also be performed on the per-protocol population set, defined as all randomized patients who completed the procedure and have a six month CCS.

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The safety population will include all randomized patients. All safety analyses will evaluate patients according to the actual treatment received, and will be performed using the safety population.

10.4 Missing data The statistical analysis of the primary endpoint will use the ITT population. Patients who die prior to the six-month post-procedural evaluation will be counted as failures unless adjudicated by the CEC that the cause of death was non-cardiovascular and could not have been attributed to the device or procedures. A sensitivity analysis will be conducted to assess the impact of patients who do not have a six-month CCS evaluation, other than for deaths. Details of the sensitivity analysis will be outlined in the statistical analysis plan. Missing data will not be imputed for the analyses of the secondary endpoints.

10.5 Primary analysis A success is defined as a patient who has a reduction of at least two grades in CCS classification from the baseline screening to the six-month post-procedural evaluation. The proportion of successes will be calculated from the Reducer and Control groups. The difference between the group proportions will be calculated and compared with the Pearson chi-square test with continuity correction. If the resulting p-value is 18 years old • Symptomatic CAD with chronic refractory angina pectoris classified as Canadian Cardiovascular Society (CCS) grade III or IV despite attempted optimal medical therapy for thirty days prior to screening • Non-candidate for surgical or percutaneous coronary intervention, as determined by the investigator • Reversible ischemia of the left ventricular wall demonstrated by Dobutamine Stress Echocardiography (Dobutamine ECHO; DSE) Primary endpoint CCS Classification: a decrease in two or more CCS grades from baseline to six-month post-procedural evaluation in Reducer and Control groups Secondary endpoints 1. Technical success: in the Reducer group, defined as successful delivery and deployment of the Reducer to the intended site as assessed by the investigator 2. Procedural success: in the Reducer group, defined as technical success and the absence of acute need for clinically-driven intervention to address an Adverse or Serious Adverse Device Effect prior to hospital discharge, as adjudicated by the Clinical Events Committee (CEC) 3. Periprocedural Serious Adverse Event (SAE): in the Reducer group, defined as a composite of death, myocardial infarction (MI), cardiac tamponade, clinically-driven re-dilation of a failed Reducer, life-threatening arrhythmias (ventricular tachycardia [VT] or ventricular fibrillation [VF]), and respiratory failure through 30 days postprocedure, as adjudicated by the CEC 4. Periprocedural SAE: in the Control group, defined as a composite of death, MI, cardiac tamponade, life-threatening arrhythmias (VT or VF), and respiratory failure through 30 days post-procedure, as adjudicated by the CEC 5. Major Adverse Events: a composite of cardiac death, major stroke, and MI in the Reducer and Control groups through hospital discharge, and at 30-day, three-month, and six-month post-procedural evaluations 6. CCS Classification: a decrease of one or more CCS grades from baseline to sixmonth post-procedural evaluation in Reducer and Control groups 7. Dobutamine ECHO Wall Motion Score Index (WMSI): in the Reducer and Control groups at baseline and six-month post-procedural evaluation

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8. Seattle Angina Questionnaire (SAQ) Score: in the Reducer and Control groups at baseline and six-month post-procedural evaluation 9. Total Exercise Duration (min), Metabolic Equivalents of Task, Double Product and for patients that exhibit ST- Segment Depression, Time to ST-Segment Depression (min), and Maximal ST-Segment Depression (mm) by Exercise Tolerance Test: in the Reducer and Control groups at baseline and six-month post-procedural evaluation Observational measures 1. Thallium/MIBI Single Photon Emission Computed Tomography (SPECT) Segmental Analysis: in the Reducer and Control groups at baseline and six-month postprocedural evaluation 2. CT Angio Analysis: in the Reducer Patients only, at six-month post-procedural evaluation 3. Cardiac Magnetic Resonance Imaging (MRI) Endocardial / Epicardial Blood Flow Distribution and Wall Motion Analysis: in the subset group undergoing perfusion Cardiac MRI at baseline and six-month post-procedural evaluation Duration of study (per subject) Excluding the screening period, the duration of participation for each patient will be approximately six months. Randomized patients will be hospitalized as per local protocol. Patients will be evaluated at hospital discharge, and post-procedurally at 30 days, three months, and six months. See Appendix B for study flowchart. Statistical methodology The sample size calculation is based on the following assumptions: • H 0 : Proportion of patients in the Reducer group with a decrease of two or more CCS grades at six months = Proportion of patients in the Control group with a decrease two or more CCS grades at six months • H 1 : Proportion of patients in the Reducer group with a decrease of two or more CCS grades at six months ≠ Proportion of patients in the Control group with a decrease two or more CCS grades at six months • Based on a literature review, the proportion of patients expected to exhibit a decline of two or more CCS grades at six months is 0.40 (Reducer) and 0.15 (Control) • Type I error rate of 5% (2-sided) • Power of 80% • Calculation based on the Pearson chi-square test with continuity correction Based on these assumptions, the sample size is 56 patients per group (a total of 112 patients). It is further assumed that up to 10% of the randomized cohort may not complete the six-month evaluations. The sample size is therefore increased to a maximum of 62 per group, for a total trial size of 124. A Data Safety Monitoring Board (DSMB) will periodically review interim summaries of study data. The first interim analysis will review only safety summaries and will occur after Copyright © 2010 All rights reserved Company Confidential

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approximately 30 randomized patients have thirty-day data available. Another interim analysis will include six-month safety and effectiveness data of approximately 50% of the randomized population. Additional DSMB reviews will occur as requested by the DSMB or Neovasc.

Tentative time course EC Submission: First Patient In: Last Patient In: First Interim Analysis:

Q2-2010 Q3-2010 Q3-2011 Q1-2011

Second Interim Analysis: Last Patient Follow-up: Final Report:

Q3-2011 Q1-2012 Q2-2012

Coordinating investigator Stefan Verheye, MD Antwerp Cardiovascular Institute Antwerp, Belgium Email: [email protected] Monitoring genae associates nv Antwerp, Belgium Contact: Aly Talen, RN Email: [email protected] Data management genae associates nv, Antwerp, Belgium Dobutamine echo core lab Cardiovascular Research Institute Washington, District of Columbia, United States Contact: Neil J. Weissman, MD Email: [email protected] ETT core lab Institut De Cardiologie De Montreal Montreal, Quebec, Canada Contact: Martin Juneau, MD Email: [email protected] Contact: Anil Nigam, MD Email: [email protected] CT Angio core lab Cardiovascular Research Institute Washington, District of Columbia, United States Contact: Allen Taylor, MD Email: [email protected]

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Sponsor Neovasc Inc. 13700 Mayfield Place Unit # 2135 Richmond, British Columbia V6V 2E4 Canada Phone: +1 (604) 270-4344 Contact: Marc Schwartz Email: [email protected]

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2

Background and Study Justification

2.1

Scientific justification

Neovasc Reducer™ System

Refractory angina pectoris Over the last few decades, increasing numbers of coronary revascularization procedures along with improved drug and device therapies have greatly increased the life expectancy of patients with coronary artery disease (CAD). Despite such advances in medicine, there are still a considerable number of patients who remain severely disabled by chronic refractory angina pectoris. This group of patients is rapidly growing as available improvements in cardiovascular care have continued to extend life expectancy without the ability to treat symptoms. This group of patients, referred to as ‘no-option’ patients, includes those who have significant disability with limiting symptoms resulting from myocardial ischemia, multiple medications, and frequent hospital admissions, despite optimal medical therapy. These ‘no option’ patients have severe diffuse CAD, and are thus not amenable to further revascularization by coronary artery bypass surgery (CABG) or by percutaneous coronary intervention (PCI). Refractory angina pectoris in spite of optimal medical therapy is a relatively common clinical problem. It is estimated that there are as many as 525,000 angina patients in the EU and US classified each year as having no revascularization options. Additionally, there are well over 500,000 other patients who have undergone either PCI or CABG for revascularization but continue to suffer from angina, which brings the total number of patients that could potentially benefit from new angina therapies to over 1 million annually. 1,2 A considerable number of therapeutic strategies have been investigated to treat severe chronic angina, such as transcutaneous electric nerve stimulation, spinal cord stimulation (SCS), left stellate ganglion blockade, endoscopic thoracoscopic sympathectomy, thoracic epidural anesthesia, external balloon counter pulsation (EECP), stem cell therapy, and, finally, myocardial laser revascularization by surgical (TMR) or percutaneous (PMR) technique. 3,4 Each existing therapy has a limited degree of efficacy, and none of these approaches have become widely-utilized therapies.

1 Mannheimer C, et al. The Problem of Chronic Refractory Angina. Eur. Heart J. 2002;23: 355-370. 2 Mukherjee D. et. al. Clinical Outcome of a Cohort of Patients Eligible for Therapeutic Angiogenesis or Transmyocardil Revascularization. Am. Heart Journal 2001;84: 598-600. 3 Rouleau JR, White M: Effects of coronary sinus pressure elevation on coronary blood flow distribution in dogs with normal preload. Can J Physiol Pharmacol. 1985;63(7):787-97. 4 Sato M, Saito T, Mitsugi M, Saitoh S, Niitsuma T, Maehara K, Maruyama Y: Effects of cardiac contraction and coronary sinus pressure elevation on collateral flow. Am J Physiol 1996; 271:H1433H1440. Copyright © 2010 All rights reserved Company Confidential

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Narrowing the coronary sinus – the Beck 1 procedure Fifty years ago, Claude Beck performed a surgical narrowing of the coronary sinus (CS) to achieve redistribution of myocardial blood flow into ischemic territories of the myocardium with remarkable success. Using open chest surgery in patients with severe, disabling angina, he created a 60-70% narrowing of the CS to achieve a 3 mm residual lumen diameter. The therapeutic results included significant relief of angina symptoms, improved functional class, and a reduced five-year mortality rate. A comparative study of 185 patients at the Cleveland Clinic showed that long-term mortality in the group of patients treated as per Beck’s procedure to be significantly lower, at 13%, than the 30% mortality rate observed in the control group. Furthermore, in the surgical group, 90% of patients reported complete or significant relief of their symptoms as measured by reduction of pain and need for medication. The portion of patients fit for work also doubled in the treatment group from 45%, prior to the intervention, to 90% as determined by patient self-report at follow-up. Beck’s pre-clinical and clinical work demonstrated that the success of the ‘Beck 1’ procedure was likely driven by elevated CS pressure, which triggered protective mechanisms that improved perfusion of ischemic territories. Beck’s studies have been duplicated by numerous other surgeons with equally positive results – the procedure led to considerable relief of angina symptoms, allowing the patients to return to work and activities, and possibly increasing life expectancy. The Beck 1 procedure was so successful that it became a standard of care for treating patients with angina pectoris in the 1950’s and 1960’s before CABG became mainstream. The open-chest Beck 1 procedure is, however, considered to be too high-risk in patients for whom further revascularization is not an option, and thus is not suitable for the group of no-option patients who continue to suffer from chronic refractory angina pectoris despite optimal medical treatment. 5,6,7,8 Intermittent coronary sinus occlusion (ICSO) Intermittent coronary sinus occlusion (ICSO) is a recently proposed non-surgical method to elevate coronary sinus pressure. This procedure uses a closed loop CS balloon system that automatically occludes and releases the CS while continuously monitoring CS pressure.

5 Wising PJ . The Beck-I Operation for Angina Pectoris. Acta Medica Scandinavica 1963; 174Fasc1: 9397. 6 Sandler G, et al. The Beck Operation in the Treatment of Angina Pectoris. Thorax 1967;22: 34-37. 7 Beck CS, et al. Operation for Coronary Artery Disease. J.A.M.A. Nov. 27, 1954;156(13): 1226-1233. 8 Zoll PM, et al. Inter-arterial Coronary Anastomosis in the Human Heart with Particular Reference to Anemia and Relative Cardia Anoxia. Circulation Dec. 1951;4: 797–815. Copyright © 2010 All rights reserved Company Confidential

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ICSO has been demonstrated to reduce myocardial ischemia. Mohl and colleagues showed in their experimental and clinical work that the redistribution of flow and the salvage potential of ICSO are related to the acute collateralization of the ischemic territory. 9 They demonstrated a 29-39% decrease in ischemic damage to the myocardium during coronary occlusion when ICSO was applied concomitantly. A number of experiments have utilized ICSO in combination with retroperfusion of arterial blood into the coronary sinus to try and salvage ischemic myocardium. The results show that the addition of retroperfusion of arterial blood exhibits no additional benefit in salvaging the ischemic myocardium in comparison with that provided by ICSO alone. 10 Mohl and colleagues propose that the success of the technique is related to initiation of a number of angiogenic pathways in the cardiac endothelium, rather than any direct effect on myocardial reperfusion. 11 While the results of ICSO and variations on this technique are quite compelling, the technique has not been adopted for routine clinical use due to the requirement of having a balloon catheter indwelling in the CS for a prolonged period of time. The Neovasc Reducer™ System (Reducer) The Reducer is designed to be implanted in the CS to establish a narrowing, which alters blood flow and venous pressure. The CS is the ‘final pathway’ of the cardiac venous drainage left coronary circulation. In the setting of obstructive CAD, increased CS pressure can lead to redistribution of collateral blood flow from non-ischemic to ischemic territories of the myocardium. Such redistribution of arterial blood can significantly reduce myocardial ischemic damage, as historically established by the Beck 1 procedure.5, 6, 7, 8, 10, 12, 13 If shown to be safe, the Reducer may provide an alternative treatment strategy to improve symptoms of refractory angina in patients with coronary artery disease presenting with reversible myocardial ischemia.

9 Mohl W. et al. Intermittent Pressure Elevation of the Coronary Venous System as a Method to Protect Ischemic Myocardium. Interactive CardioVascular and Thoracic Surgery 2005;4: 66-69. 10 Syeda B. et al. The salvage potential of coronary sinus interventions: Meta-analysis and pathophysiologic consequences. The Journal of Thoracic and Cardiovascular Surgery 2004;127: 17031712. 11 Mohl W. et al. Is activation of coronary venous cells the key to cardiac regeneration? Nature Reviews Cardiology 2008;5: 528–530. 12 Yang EH, Barness GW, Gersh BJ, Chandrasekaran K, Lerman A: Current and future treatment strategies for refractory angina. Mayo Clin Proc. 2004; 79:1284-1292. 13 Zalewski, Maroko et. al, Myocardial protection via coronary sinus interventions: superior effects of arterialization compared with intermittent occlusion. Circulation 1985; 71:1215-1223. Copyright © 2010 All rights reserved Company Confidential

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2.2

Neovasc Reducer™ System

Prior pre-clinical and clinical data

The Neovasc Reducer™ System was designed in accordance with the Neovasc Quality Management System that is reflective of this Class III medical device. The Reducer has gone through two design iterations, with the main difference between GEN I and GEN II being the delivery system and the technique used to implant the device. The Reducer has undergone careful pre-clinical and clinical testing, as outlined below. Summary information of these bench, biocompatibility, animal, and clinical studies is provided in the Reducer Investigator’s Brochure (Document #: REDCLN-004). 2.2.1 Bench testing Neovasc Inc. (Neovasc) has conducted extensive verification and validation testing of the Reducer. Bench and design verification testing was carried out to verify the product requirements and functional specifications, as well as to provide evidence of the safety and effectiveness of the device in achieving its intended use. All of the different components of the Reducer have been stress tested to ensure that the system as a whole provides all the capabilities necessary to operate safely and effectively. These include: • • •

Mechanical and engineering performance specifications for the Reducer design and material; Functional specifications to ensure that the Reducer performs as designed for its intended use; and Compatibility of the Reducer with its delivery system and with the intended delivery method.

2.2.2 Biocompatibility The biological safety of the Reducer was evaluated in accordance with the requirements of ISO 10993-1:2003 (“Biological evaluation of medical devices - Evaluation and testing”) and the FDA guidance document, “Required Biocompatibility Training and Toxicology Profiles for Evaluation of Medical Devices” (G95-1). The findings of the biocompatibility evaluation support the use of the Reducer in the proposed clinical study.

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2.2.3 Animal studies Neovasc has conducted animal studies on a total of 47 mini-swine under two separate protocols. Conclusions based upon the animal studies were that the Reducer was a feasible device that demonstrated safety and efficacy consistent with its intended use. 2.2.4 Prior clinical studies Neovasc has also conducted a first-in-man (FIM) clinical study with the Neovasc Reducer™ System, including a long-term surveillance study of the FIM patients. The FIM study was initiated using the GEN 1 device in November 2004 and completed in March 2006. Fifteen patients at three different medical centers underwent Reducer implantation. 14 This study was designed to provide initial indication of safety and feasibility of the device. The FIM study concluded that implantation of the Reducer in patients with chronic refractory angina is safe and feasible. At the six-month follow-up, improvement in angina scores, a reduction in ST-segment depression, and reduced dobutamine-induced myocardial ischemia was observed in the majority of these patients. These findings, along with the clinical improvement observed, support further evaluation of the clinical efficacy of the Reducer as an alternative tool to treat patients with chronic refractory ischemia who are not candidates, or are at high risk, for revascularization. The surveillance follow-up, 15 conducted between April and May 2009, was a three-year follow-up study of the original 15 FIM patients, and was designed to provide evidence of the long-term safety and efficacy of the device. At the three-year follow-up, there were no deaths, MI, or adverse events attributable to the device. Computed tomography (CT) angiography revealed that all Reducers were patent and located at the exact site of deployment with no evidence of migration or occlusion. The improvement in angina score and in ischemic severity as demonstrated by the dobutamine echo, thallium SPECT, and stress test results that were observed at six months post-procedure in the original FIM study were maintained through the three-year follow-up.

14 Banai, S., et al. JACC. 2007;49:1783-1789 15 Banai, S., et al. Long Term Follow-up to Evaluate the Safety of the Neovasc Reducer A Device-Based Therapy for Chronic Refractory Angina. Accepted for Oral Presentation American College of Cardiology Annual Conference March 2010 Copyright © 2010 All rights reserved Company Confidential

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3

Neovasc Reducer™ System

Investigational Device

The Neovasc Reducer™ System is designed to be implanted in the CS and establish a narrowing, which alters blood flow and venous pressure. In the setting of obstructive CAD, increased CS pressure can lead to redistribution of collateral blood flow from nonischemic to ischemic territories of the myocardium. Such redistribution of arterial blood can significantly reduce myocardial ischemia. The Reducer is an alternative treatment strategy that may improve symptoms of refractory angina in patients with coronary artery disease presenting with reversible myocardial ischemia.

3.1

Neovasc Reducer™ System

The Neovasc Reducer™ System – Reference # RED-001 was CE Marked November 14, 2011

The Neovasc Reducer™ System (Fig 1) is comprised of the Neovasc Reducer™ premounted on the Neovasc Reducer™ Balloon Catheter.

Fig. 1: The Neovasc Reducer™ System

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The Neovasc Reducer™ (Fig. 2) is made of surgical grade 316LVM stainless steel, laser cut into pre-specified geometric pattern with flexible longitudinal struts and no welding points.

Fig. 2: The Neovasc Reducer™ The Reducer is typically introduced into the CS via right heart catheterization through the right internal jugular vein and is available in one single model designed to fit the range of anatomies encountered in most patients. Its final expanded diameters are dependent on the inflation pressure of the semi-compliant Neovasc Reducer™ Balloon Catheter. The Neovasc Reducer™ Balloon Catheter (Fig. 3) is an over the wire catheter with a unique hour glass shape balloon. The proximal and distal portions of the balloon have differing diameters to conform to the taper typically encountered in the CS. Two radiopaque markers, located on the catheter shaft, mark the location of the crimped Reducer on the deployment balloon. A third marker located just proximally to the balloon is used to assist the operator to visualize when the balloon section of the catheter is completely outside of the tip of the guide catheter.

Fig. 3: The Neovasc Reducer™ Balloon Catheter

3.2

Indication for use

The Reducer is indicated as an aid in the management of chronic refractory angina pectoris.

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4

Risk/Benefit

4.1

Anticipated clinical benefits

Neovasc Reducer™ System

It is possible that the patient will not receive any benefits from implantation of the Reducer in the CS. Potential benefits that may be realized by the patients assigned to the Reducer group include reduction or relief of the symptoms associated with refractory angina, including a reduction in the frequency of chest pain, less fatigue, reduced need for medications, and improved quality of life. The following benefits of the Reducer implantation in the CS have been observed in prior pre-clinical and clinical studies: •





In a pre-clinical study using a mini-swine model of myocardial ischemia, four of eight animals were treated with the Reducer and the remaining four were left untreated as a control. Through 180 days, all four Reducer animals showed a significant reduction of ischemia severity as evident by dobutamine echocardiography, and all four survived. The four control animals showed no improvement in ischemia severity, and three of the four animals died. In an open-label FIM study involving 15 patients with chronic refractory angina, implantation of the Reducer in the CS resulted in improved angina scores and a reduction in ST segment depression as evaluated at six months post-procedure. Additionally, dobutamine-induced myocardial ischemia was reduced in the majority of these patients. A three-year surveillance follow-up study of the 15 FIM patients demonstrated sustained safety, sustained improvement in angina score, and reduction ischemic severity as demonstrated by DSE, thallium SPECT, and stress test results.

Another known benefit to patients participating in the study is the ability to learn more about their angina through the assessments that will be performed throughout the course of the study. Additionally, patients will be closely observed by the study staff throughout their participation in the study. Last, Neovasc, the study sponsor, will pay all medical costs over the usual costs of treatment that are associated with study participation.

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4.2

Neovasc Reducer™ System

Risk analysis and residual risks

The Reducer has undergone a thorough risk analysis process, in accordance with applicable standards, including ISO 14971. The risk analysis commenced during the design input stage of developing the system, and continued throughout the design and post-design processes. The risk analysis review team encompassed members of multiple disciplines, including medicine, product design, quality assurance, regulatory systems, clinical research, and marketing. The risk analysis report (Document #: REDRSK-002) is maintained on file and is available upon request. During the risk analysis process, risks were divided into three categories: Acceptable, As Low as Reasonably Possible (ALARP) and Unacceptable. Already prior to risk mitigation, the majority of risks identified were categorized as Acceptable, a small number were categorized as ALARP, and none were categorized as Unacceptable. Pursuant to risk mitigation, all risks identified were categorized as Acceptable.

4.3

Risks and adverse effects

The potential risks associated with this study include the known risks of right heart catheterization and percutaneous coronary intervention, as well as risks associated with the standard routine clinical evaluations (e.g., exercise tolerance test [ETT], dobutamine ECHO, thallium/MIBI SPECT, CT Angio, perfusion MRI). Risks and adverse effects that may be associated with or result from participating in the COSIRA study, the procedure, or use of the Reducer include, but are not limited to: • • • • • • • • • • • • • • • •

Allergic reaction to required mediations or contrast medium; Arrhythmias, including VT or VF; Cardiac tamponade; Death; Dissection; Emboli (air, tissue, or thrombotic); Emergent surgery / PCI; Heart block; Hypotension / hypertension; Infection and / or pain at access site; Ischemic event; Major bleeding event, including hemorrhage; Major vascular event, including pseudoaneurysm; Myocardial infarction; Perforation / rupture; Pulmonary edema;

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• • • • • • •

Neovasc Reducer™ System

Pulmonary embolism; Reducer and/or coronary sinus occlusion; Reducer embolization; Reducer migration; Respiratory failure; Spasm; and Stroke / cerebrovascular accident / transient ischemic attack.

There may be additional risks that are unknown at this time.

4.4

Measures to mitigate risks

The following efforts will minimize risks to patients during the COSIRA study: • • • • •

Conduct of the study following successful completion of extensive non-clinical testing, initial clinical testing, and careful risk analysis; Selection of investigators who are experienced and skilled in management of refractory angina pectoris and coronary catheterization procedures; Establishment of a training program for study staff members (investigators, coordinators, and clinical monitors); Clearly defining the inclusion and exclusion criteria such that only appropriate patients are enrolled in the study; and Ensuring that the treatment of the patient is consistent with current medical practices.

4.5

Risk/benefit rationale

Assessing the above-listed risks against the potential benefits of the Reducer to improve symptoms and decrease the severity of myocardial ischemia, Neovasc and the study investigators have determined that there is a high likelihood that the expected benefit may outweigh the risk in patients fulfilling the study eligibility criteria.

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5

Objectives and Hypothesis

5.1

Study objectives

Neovasc Reducer™ System

The objective of this study is to confirm the safety and effectiveness of the Reducer when used in patients with refractory angina who demonstrate evidence of reversible ischemia.

5.2

Hypothesis

H 0 : Proportion of patients in the Reducer group with a decrease of two or more CCS grades at six months = Proportion of patients in the Control group with a decrease of two or more CCS grades at six months H 1 : Proportion of patients in the Reducer group with a decrease of two or more CCS grades at six months ≠ Proportion of patients in the Control group with a decrease of two or more CCS grades at six months

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6

Neovasc Reducer™ System

Study Design

The COSIRA is a prospective, multicenter, randomized, double-blind, sham-controlled (1:1 randomization ratio), confirmatory clinical study of the safety and effectiveness of the Reducer. It consists of baseline assessments, implantation of the Reducer in the study group, and assessments of both Reducer and Control groups at hospital discharge and at 30-day, three-month, and six-month post-procedural evaluations. The study will contain a subset study at one site. This subset study population, in addition to all specified imaging assessments, will undergo perfusion Cardiac MRI at baseline and at six-month evaluation. The sub-study will be conducted at a single site and will include a maximum of 20 patients.

6.1

Measures to minimize/avoid bias

6.1.1 Randomization A total of approximately 124 patients will be randomized in a 1:1 ratio using a computergenerated permuted block randomization scheme, with investigational sites as strata. 6.1.2 Sham control Following enrollment, all prospective study patients will undergo screening tests (Section 8.2) to determine eligibility. Right heart catheterization is the final screening test, following which eligible patients will be randomized to either the Control or Reducer group. In patients who are randomized to the Control group, the procedure will be complete following the right heart catheterization. Patients randomized to the Reducer group will have a Reducer implanted immediately following the coronary sinus angiography. All patients will remain blinded throughout the study period (e.g., six months). In order to maintain patient blinding, a sham procedure will be performed in the Control group patients. The implanting physicians will be instructed to behave in the exact same manner with both Control and Reducer group patients, thus maintain blinding of the patient as to study group assignment. Independent, blinded, physicians will perform the pre- and post-procedural CCS assessments for patients in both groups. These physicians will be provided the necessary criteria for assessing CCS in this trial, as well as specific instructions as to how the assessment should be performed. Questions to the patients about their condition, with regards to CCS scoring, will be scripted to ensure that every physician Copyright © 2010 All rights reserved Company Confidential

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asks the same questions in an identical manner to each patient. These measures will be imposed to ensure the elimination or minimization of any bias. Dobutamine ECHO and ETT core laboratories will also be blinded to group assignments. They will analyze each test data from each clinical site in order to ensure that standardized measurements are employed. Any deviations will be reported to the sponsor.

6.2

Study endpoints

6.2.1 Primary endpoint CCS Classification: a decrease in two or more CCS grades from baseline to six-month post-procedural evaluation in Reducer and Control groups 6.2.2 Secondary endpoints Technical success: in the Reducer group, defined as successful delivery and deployment of the Reducer to the intended site as assessed by the investigator Procedural success: in the Reducer group, defined as technical success and the absence of acute need for clinically-driven intervention to address an Adverse or Serious Adverse Device Effect prior to hospital discharge, as adjudicated by the CEC Periprocedural SAE: in the Reducer group, defined as a composite of death, MI, cardiac tamponade, clinically-driven re-dilation of a failed Reducer, life-threatening arrhythmias (VT or VF), and respiratory failure through 30 days post-procedure, as adjudicated by the CEC Periprocedural SAE: in the Control group, defined as a composite of death, MI, cardiac tamponade, life-threatening arrhythmias (VT or VF), and respiratory failure through 30 days post-procedure, as adjudicated by the CEC Major Adverse Events: a composite of cardiac death, major stroke, and MI in the Reducer and Control groups through hospital discharge, and at 30-day, three-month, and six-month post-procedural evaluations CCS Classification: a decrease of one or more CCS grades from baseline to six-month post-procedural evaluation in Reducer and Control groups Dobutamine ECHO Wall Motion Score Index: in the Reducer and Control groups at baseline and six-month post-procedural evaluation Copyright © 2010 All rights reserved Company Confidential

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Seattle Angina Questionnaire Score: in the Reducer and Control groups at baseline and six-month post-procedural evaluation Total Exercise Duration (min), Metabolic Equivalents of Task (METs), and Double Product by Exercise Tolerance Test: in the Reducer and Control groups at baseline and six-month post-procedural evaluation Total Exercise Duration (min), Time to ST-Segment Depression (min), and Maximal STSegment Depression (mm) by Exercise Tolerance Test: in the Reducer and Control groups (in only those patients that demonstrate ST-Segment depression) at baseline and six-month post-procedural evaluation

6.2.3 Observational measures Thallium/MIBI SPECT Segmental Analysis: in the Reducer and Control groups at baseline and six-month post-procedural evaluation CT Angio Analysis: in the Reducer Patients only, at six-month post-procedural evaluation Cardiac MRI Endocardial / Epicardial Blood Flow Distribution and Wall Motion Analysis: in the subset group undergoing perfusion Cardiac MRI at baseline and six-month postprocedural evaluation

6.3

Tools to assess endpoints and observational measures

Endpoints and observational measures will be evaluated using the assessment tools listed below: • • • • • •

All data will be collected using an Electronic Data Collection (EDC) System. See Section 12 for details. CCS grade will be recorded by the blinded assessing physician or designee using a standard list of questions and assessing criteria that have been set forth by the coordinating investigator. Technical success will be determined by the investigators. All Adverse Events will be classified by the investigator as device and/or procedure related. Association with Procedural success, Periprocedural SAE, and Major Adverse Events will be adjudicated and determined by the CEC. Dobutamine ECHO parameters will be evaluated by a core laboratory. A copy of the core lab guidelines will be provided in the study Manual of Operations. The SAQ will be completed by the blinded assessing physician or designee along with the study patients. Answers will be analyzed with the statistical software

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

• • •

Neovasc Reducer™ System

provided by Cardiovascular Outcomes, Inc. A copy of the questionnaire and completion instructions will be provided in the study Manual of Operations. Exercise tolerance test will be evaluated by a core laboratory. A copy of the core lab guidelines will be provided in the study Manual of Operations. Guidelines for thallium/MIBI SPECT and cardiac MRI will also be provided in the study Manual of Operations. CT Angio parameters will be evaluated by a core laboratory. A copy of the core lab guidelines will be provided in the study Manual of Operations.

6.4

Justification for study design

The COSIRA trial has been designed to demonstrate safety and effectiveness of the Reducer and the associated implant procedure. In order for Neovasc to provide unbiased results, the use of a sham procedure will equalize the placebo effect across groups and provide a direct comparator by which to assess device effectiveness, while also demonstrating safety. One of the screening tests to determine eligibility is the measurement of right atrial (RA) pressures and CS selective angiography. These are performed using the same procedure and techniques as one would use to perform a right heart catheterization (RHC). The RHC is a common and safe procedure with a low complication rate, 16 and is routinely performed on cardiac patients by interventional cardiologists. The implant procedure for the Reducer is initiated using the same techniques and some of the initial equipment that was used to perform the RA pressure measurements and CS angiography. Patients that have been randomized into the Control arm will undergo essentially the same procedure as those randomized to the Reducer arm, with the exception of Reducer implantation following angiography. Thus, angiography serves as the sham procedure. Patients will be provided informed consent and a written description outlining all of the possible risks associated with the procedure, as well as potential benefits of participating in the study, including those specific to the Reducer arm, should they be randomized to that group.

16 Hoper, M., et al. Complications of Right Heart Catheterization Procedures in Patients With Pulmonary Hypertension in Experienced Centers. Journal of American College of Cardiology. December 19, 2006:2546–52. Copyright © 2010 All rights reserved Company Confidential

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7

Study Population

7.1

Eligibility criteria

Neovasc Reducer™ System

Patients with refractory angina pectoris who demonstrate objective evidence of reversible myocardial ischemia, but who have limited treatment options, are referred to as ‘no-option’ patients In order to be randomized in this study, patients must fulfill all of the inclusion and none of the exclusion criteria. 7.1.1 Inclusion criteria 1. Patient is older than 18 years of age 2. Symptomatic CAD with chronic refractory angina pectoris classified as Canadian Cardiovascular Society grade III or IV despite attempted optimal medical therapy for 30 days prior to screening 3. Patient has limited treatment options for revascularization by coronary artery bypass grafting or by percutaneous coronary intervention 4. Evidence of reversible ischemia that is attributable to the left coronary arterial system by Dobutamine Echo 5. Left ventricular ejection fraction greater than 25% 6. Male or non-pregnant female (NB: Females of child bearing potential must have a negative pregnancy test) 7. Patient understands the nature of the procedure and provides written informed consent prior to enrollment 8. Patient is willing to comply with specified follow-up evaluation and can be contacted by telephone

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7.1.2 Exclusion criteria Clinical & General 1. Recent (within three months) acute coronary syndrome 2. Recent (within six months) successful PCI or CABG 3. Unstable angina (recent onset angina, crescendo angina, or rest angina with ECG changes) during the 30 days prior to screening 4. De-compensated congestive heart failure (CHF) or hospitalization due to CHF during the three months prior to screening 5. Life threatening rhythm disorders or any rhythm disorders that would require placement of an internal defibrillator and or pacemaker 6. Severe chronic obstructive pulmonary disease (COPD) as indicated by a forced expiratory volume in one second that is less than 55% of the predicted value 7. Patient cannot undergo exercise tolerance test (bicycle) for reasons other than refractory angina 8. Severe valvular heart disease 9. Patient with pacemaker or defibrillator electrode in the right atrium, right ventricle, or coronary sinus 10. Patient having undergone tricuspid valve replacement or repair 11. Chronic renal failure (serum creatinine >2 mg/dL), including patients on chronic hemodyalisis 12. Moribund patients, or patients with comorbidities limiting life expectancy to less than one year 13. Contraindication to required study medications that cannot be adequately controlled with pre-medication 14. Known allergy to stainless steel or nickel 15. Contraindication to having an MRI performed (NB: Cardiac MRI subset patients only) 16. Currently enrolled in another investigational device or drug trial that has not completed the primary endpoint or that clinically interferes with the current study endpoints Copyright © 2010 All rights reserved Company Confidential

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Angiographic 17. Mean right atrial pressure higher than or equal to 15 mmHg 18. Patient with anomalous or abnormal CS as demonstrated by angiogram Abnormality defined as: • •

7.2

Abnormal CS anatomy (e.g., tortuosity, aberrant branch, persistent left SVC) and/or; CS diameter at the site of planned reducer implantation less than 9.5 mm or greater than 13 mm

Patient enrollment and screening

Prior to participating in this study, the investigator will inform the patient about the scope, purpose, rights, duties, and possible risks of the study. The patient must confirm consent in writing. Written informed consent must be obtained from every study patient prior to initiating baseline testing. A signed copy of the consent must be given to the patient and must be kept on file by the investigator. The point of enrollment is the time at which a patient signs and dates the informed consent form. Following enrollment, the patient will undergo screening tests (Section 8.2) to determine eligibility. Screening failures will be identified in a screening log. Patients who meet all inclusion criteria and none of the general exclusion criteria will be scheduled for right heart catheterization and angiography. The right heart catheterization is utilized to assess right atrial pressure. At the time that the right heart catheterization is performed, contrast angiography in the LAO projection will be used to assess the coronary sinus to determine size and tortuosity. If the patient meets all of the inclusion and none of the exclusion criteria, including the angiographic criteria, the patient will remain enrolled in the study (i.e., be randomized). If a patient is enrolled, but found to be ineligible for the study based upon right heart catheterization data and/or angiographic eligibility criteria, the subject will be marked as “Screening Failure” in the screening log and will not take part in the study. Screening failure subjects will not be included in the intent to treat analysis, nor will they be counted as part of the target patient sample number. Patients that remain enrolled in this study will be randomized into the Control or Reducer group of the study. In patients that are randomized into to the Control arm, the procedure will be complete following the right heart catheterization. Patients that are randomized into the Reducer group will have a Reducer implanted immediately following the coronary sinus angiography. All patients will remain blinded through the six-month post-procedural evaluation. Copyright © 2010 All rights reserved Company Confidential

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7.3

Neovasc Reducer™ System

Number of subjects and investigational sites

A maximum of 124 patients will be randomized (1:1 Reducer to Control ratio) in order to generate an evaluable cohort of 112 patients at six months post-procedure. The patients will be recruited from a maximum of 14 sites located in Europe and Canada. A current list of sites will be maintained in the study files.

7.4

Study duration

The anticipated overall study duration is 18-21 months from the first patient screening through last patient six-month follow-up. Screening will be carefully monitored to identify potential changes in this estimate as per actual availability of eligible patient populations at the investigational sites. Excluding the screening period, the duration of participation for each patient will be approximately six months. Randomized patients will be hospitalized per local protocol. Patients will be evaluated at hospital discharge, and at 30-day, three-month, and sixmonth post-procedural evaluations. All RHC screening failures will be followed for 30 days post-procedure for safety. Patients in both Control and Reducer arms will be evaluated at 30 days, three months, and six months post-procedure to evaluate safety and efficacy.

7.5

Early discontinuation of patients

The investigator may prematurely discontinue the participation any patient in the study if the investigator feels that the patient can no longer fully comply with the requirements of the study or if any of the study procedures are deemed potentially harmful to the patient. Once a patient has been enrolled in the study, he/she may withdraw his/her consent to participate in the study at any time without prejudice. Participation in this clinical investigation is entirely voluntary. As much as possible, attempts will be made to conduct an exit/final visit, or at a minimum obtain CCS score, prior to a patient terminating participation in the study. The reason for early discontinuation will be documented in the source documents and case report forms.

7.6

Patients lost to follow-up

If a patient does not show up for a follow-up visit and cannot be contacted to collect follow-up information, he/she will be counted as a “missed visit” for that specific Copyright © 2010 All rights reserved Company Confidential

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schedule. Attempts shall be made to contact the patient for the next scheduled followup. A patient will be considered “lost to follow-up” only after the last scheduled followup visit for that patient. If a patient is lost to follow-up, the methods used to attempt to contact the patient should be noted. At least three attempts should be made to contact the patient via all available routes, and a certified letter should be sent to the permanent address on file.

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

8

Neovasc Reducer™ System

Study Procedures

Screening

Procedure

Hospital Discharge

30 Days

Three Months (visit or phone)

Six Months

Informed consent

X

Medical history

X

Physical exam

X

X

X

Listing of current medications

X

X

X

Pregnancy test (♀ only)

X1

Blood work

X1

Cardiac enzymes

X2

X4

ECG

X2

X

CCS assessment

X

Exercise tolerance test (ETT)

X

X

Dobutamine ECHO

X

X

Thallium/MIBI SPECT

X

X

SAQ

X

Perfusion MRI (subgroup only)

X

X X

X X

X

X

X X

X

X

X X X3

CT Angio Right heart catheterization

X

Coronary sinus angiography

X

Randomization

X

Reducer implantation

X3

Adverse events (AE)

X

X

X

X

X

1) Within seven days prior to procedure 2) Within 24 hours prior to procedure 3) In Reducer group only; to be performed only AFTER CCS and SAQ assessments 4) Cardiac enzymes (CK, CK-MB, Troponin) within 8-12 hours post procedure

Table 1: Summary of study requirements from screening through follow-up Copyright © 2010 All rights reserved Company Confidential

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

8.1

Neovasc Reducer™ System

Activities performed by sponsor representative

During the catheterization procedure and implantation of the Reducer, a sponsor representative associated with the study may attend. The involvement of such representative may include: • •

Presence at the catheterization laboratory for supporting the site personnel Presence at the catheterization laboratory for watching the use of the device and gathering information and feedback from the doctors performing the procedure

The representatives’ activities will occur in such a way that they do not influence the conduct of the procedure, nor do they interfere with any medical decisions or bias the data integrity. Additionally they will be described in the informed consent.

8.2

Screening

Signed, written, informed consent must be obtained for all patients who are potential study candidates prior to enrollment. The screening and baseline evaluations will include the following: • • • • • • • • • • •

Full medical history and physical examination; Full listing of current medications and dosages; Complete blood cell count (CBC), blood urea nitrogen (BUN), creatinine, electrolytes, prothrombin time (PT), partial thromboplastin time (PTT), and pregnancy test (if applicable) – within seven days prior to procedure; Cardiac Enzymes (CK, CK-MB, troponin) – within 24 hours prior to procedure; ECG – within 24 hours prior to procedure; CCS assessment; Seattle Angina Questionnaire; Exercise tolerance test (bicycle); Dobutamine ECHO; Thallium/MIBI SPECT; and Perfusion MRI (in the subset study population only).

8.3

Completion of screening and procedure

The completion of screening will include the following: •

Patient preparation for right heart catheterization as per the instructions provided in the Reducer Instructions for Use (IFU; see Appendix C) or as per standard of care;

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

• •

Neovasc Reducer™ System

Right heart catheterization and pressure measurements of the right atrium, right ventricle, pulmonary artery, and wedge pressure; and Coronary sinus angiography.

The procedure will include the following: • • • • • • • • •

Randomization (start of procedure); For patients randomized to Control group, complete assessment as per standard of care to ensure that the patient remains blinded; For patients randomized to Reducer group, preparation of the investigational device as per the instructions provided in the Reducer IFU; Adherence to administration of pre-, intra-, and post-procedure medications as outlined in Section 9.5; Adherence to the Reducer IFU for implant instructions, warnings, and precautions; Measurement of activated clotting time (ACT) at intervals throughout the procedure (at facilities where this is not standard practice, ACT may be omitted); Culmination of the procedure defined as the time the venous sheath is removed; Procedure-related information recorded in the case report form (CRF); and Recording of all adverse events occurring during the procedure in the CRF.

8.4 • • • • •

Post-procedure through hospital discharge

Physical exam; ECG; Cardiac enzymes (CK, CK-MB, Troponin, within 8-12 hours post procedure); Full listing of current medications and dosages; and Adverse events, which will be recorded in the CRF in accordance with the specific categories defined in Section 11 of this protocol.

The research coordinator will review the follow-up requirements with the patient to help ensure compliance with the follow-up schedule. Telephone numbers must be obtained from the patient to ensure the ability to contact him/her. These phone numbers should include all home numbers, work numbers and primary physician numbers. A phone number of a relative or friend should also be requested.

8.5

Thirty-day (± 7 days) follow-up visit

The 30-day follow-up visit will consist of: • • •

Physical examination; ECG; CCS assessment;

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• • •

Neovasc Reducer™ System

Seattle Angina Questionnaire; Adverse events, which will be recorded in the CRF in accordance with the specific categories defined in Section 11 of this protocol; and Full listing of current medications and dosages.

8.6

Three-month (± 2 weeks) follow-up evaluation

The three-month follow-up evaluation can be conducted in person or via telephone interview between the investigator and patient. The follow-up will consist of: • • • •

CCS assessment Seattle Angina Questionnaire Adverse events, which will be recorded in the CRF in accordance with the specific categories defined in Section 11 of this protocol Full listing of current medications and dosages

8.7

Six-month (± 1 month) follow-up visit

The six-month follow-up evaluation will be conducted in person and will consist of: • • • • • • • • • • •

Physical exam; ECG; CCS assessment; Seattle Angina Questionnaire; Exercise tolerance test (bicycle); Dobutamine ECHO; Thallium/MIBI SPECT; CT Angio (Reducer implanted patients only) Note - to be performed only after CCS and Seattle Angina Questionnaire have been completed; Perfusion MRI (in the subset study population); Adverse events, which will be recorded in the CRF in accordance with the specific categories defined in Section 11 of this protocol; and Full listing of current medications and dosages.

Following completion of the six-month assessment, patients will be exited from the study and the blind broken. No further medical care or evaluations will be performed as part of the COSIRA study.

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COSIRA Clinical Study (#REDCLN-178) Clinical protocol

9

Materials

9.1

Investigational device

Neovasc Reducer™ System

The investigational device is the Neovasc Reducer™ System. Each patient in the Reducer group will be implanted with a single Reducer.

9.2

Comparator

The Control group will undergo right heart catheterization only. No device will be implanted.

9.3

Supply, storage, traceability, and accountability

The Reducer is supplied as a kit including the following components: 1 - Neovasc Reducer™ premounted on a Neovasc Reducer™ Balloon Catheter 1 - 9F Straight Guiding Catheter (Cordis Vista Brite Tip 55cm Ref# 598-943p) 1 - Rotating Hemostasis Valve (MEDEX Inc. MX336LB) The investigational device must be kept in a secure, limited-access location. The Reducer will be identified with lot numbers. Complete traceability records will be kept of all devices and accessory equipment used during this clinical study. Upon receipt of the investigational device, an inventory must be performed. A device receipt log must be filled out and signed by the person accepting the shipment. It is important that the designated study staff count and verify that the shipment contains all the items noted in the shipment documentation. Any damaged or unusable study device in a given shipment will be documented in the study files. The investigator must notify Neovasc of any damaged or unusable study devices that were provided to the site. The study device will only be used for treating patients enrolled in the study, in accordance with the protocol. The designated study staff member will maintain the study device inventory using the accountability form(s) provided by Neovasc or designee. The study device inventory must be available for periodic inspection/verification. At the completion of the study, there will be a final reconciliation of devices shipped, used, and remaining. This reconciliation will be logged on the device reconciliation form, Copyright © 2010 All rights reserved Company Confidential

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Neovasc Reducer™ System

signed and dated. Any discrepancies noted will be investigated, resolved, and documented prior to return of unused study devices under the direction of the sponsor. Detailed instructions and forms for device inventory handling will be provided separately.

9.4

Labeling

A sample of the Instructions for Use (IFU) for the Reducer is included in Appendix C. All investigational devices will be labeled with the statement "Exclusively for Clinical Investigation."

9.5

Concomitant medications Pre-procedure

Aspirin

Clopidogrel

OR2

Prasugrel

≥80 mg q.d . aspirin for at least 72 hours prior to the procedure 1

75mg q.d. for at least 7 days prior to the procedure OR Loading dose of 300600mg within 24 hours prior to the procedure

≥80 mg q.d . aspirin until study completion (recommended indefinitely for stent patients)

---

75mg q.d. for at least 6 months post procedure, or longer as per physician’s discretion --10 mg for at least 6 months post procedure, or longer as per physician’s discretion 3

---

Bivalirudin

Post-procedure 1

Loading dose of 60mg within 24 hours prior to the procedure

Heparin OR

Procedure

Initial bolus IV with additional boluses to 4 maintain ACT ≥250 sec

---

IV Bolus and drip5

1) Or standard dosing based on hospital and physician practice 2) The option between Clopidogrel and Prasugrel should be at the physician’s discretion. Patients may be placed on Ticlid if they are contraindicated to Clopidogrel or Prasugrel. Regimen should follow local standard of care. NOTE: Prasugrel can only be used in countries where it is approved for market 3) Heparin initial bolus 70 U/Kg, or per local protocol 4) ACT should be maintained ≥200 seconds if GPIIb/IIIa needs to be used 5) Bivalirudin initial bolus 0.75 mg/Kg and drip 1.75 mg/Kg/hr, or per local protocol

Table 2: Pre-, intra-, and post-procedure medications

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10

Neovasc Reducer™ System

Statistics

10.1 Software All analyses will be performed using SAS version 9 or greater or other validated statistical software.

10.2 Sample size The sample size calculation for the proposed trial is based on the following assumptions: • • • • • •

H 0 : Proportion of patients in the Reducer group with a decrease of two or more CCS grades at six months = Proportion of patients in the Control group with a decrease of two or more CCS grades at six months H 1 : Proportion of patients in the Reducer group with a decrease of two or more CCS grades at six months ≠ Proportion of patients in the Control group with a decrease of two or more CCS grades at six months Based on a literature review, the proportion of patients expected to exhibit a decline of two or more CCS grades at six months is 0.40 (Reducer) and 0.15 (Control). Type I error rate of 5% (2-sided) Power of 80% Calculation based on the Pearson chi-square test with continuity correction

Based on these assumptions, the sample size is 56 patients per group (a total of 112 patients). It is further assumed that up to 10% of the randomized cohort may not complete the six-month evaluation. The sample size is therefore increased to a maximum of 62 per group, for a total trial size of 124.

10.3 Analysis population The intent-to-treat (ITT) population will include all randomized patients. For this study, the ITT population will consist of all subjects who sign the written informed consent, meet the study entry criteria, and are randomized to a study arm. The ITT population will be used for the primary analysis. Each subject will be analyzed according to his or her original randomized treatment group. Analysis will also be performed on the per-protocol population set, defined as all randomized patients who completed the procedure and have a six-month CCS.

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The safety population will include all randomized patients. All safety analyses will evaluate patients according to the actual treatment received, and will be performed using the safety population.

10.4 Missing data The statistical analysis of the primary endpoint will use the ITT population. Patients who die prior to the six-month post-procedural evaluation will be counted as failures unless adjudicated by the CEC that the cause of death was non-cardiovascular and could not have been attributed to the device or procedures. A sensitivity analysis will be conducted to assess the impact of patients who do not have a six-month CCS evaluation, other than for deaths. Details of the sensitivity analysis will be outlined in the statistical analysis plan. Missing data will not be imputed for the analyses of the secondary endpoints.

10.5 Primary analysis A success is defined as a patient who has a reduction of at least two grades in CCS classification from the baseline screening to the six-month post-procedural evaluation. The proportion of successes will be calculated and presented for the Reducer and Control groups. The difference between the group proportions will be calculated and compared with the Pearson chi-square test with continuity correction. If the resulting pvalue is