The COAPT Trial CLINICAL INVESTIGATIONAL PLAN 11-512 Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (The COAPT Trial) A Clinical Evaluation of the Safety and Effectiveness of the MitraClip® System for the Treatment of Functional Mitral Regurgitation in Symptomatic Heart Failure Subjects IDE Number G120024 Version Number 8.0 Date October 12, 2016 National Principal Investigator Michael J. Mack, MD (CT Surgeon) National Principal Investigator Gregg W. Stone, MD (Interventional Cardiologist) National Heart Failure Specialist William T. Abraham, MD Co-Principal Investigators JoAnn Lindenfeld, MD Trial Type Prospective, randomized, parallel-controlled, multicenter clinical evaluation of the MitraClip device for the treatment of clinically significant functional mitral regurgitation in symptomatic heart failure subjects who are treated per standard of care and who have been determined by the site’s local heart team as not appropriate for mitral valve surgery. Eligible subjects will be randomized in a 1:1 ratio to the MitraClip device (Device group) or to no MitraClip device (Control group). Sponsor Evalve, Inc. A subsidiary of Abbott Vascular Inc. 4045 Campbell Avenue Menlo Park, CA 94025 USA Enrollment/Randomization Service Medidata RAVE Data Management and Analysis Abbott Vascular Inc. 3200 Lakeside Drive Santa Clara, CA 95054 USA Electronic Data Capture Software Medidata RAVE Clinical Investigational Plan 11-512: Version 8.0 October 12, 2016 Confidential and Proprietary Page 1 Do not distribute or reproduce without the prior written permission of Abbott Vascular Inc. The COAPT Trial Data Monitoring Committee Ionna Kosmidou, MD, PhD Management Director of Events Adjudication and Reporting Cardiovascular Research Foundation 1700 Broadway, 9th Floor New York, NY 10019 Clinical Events Committee Ionna Kosmidou, MD, PhD Management Director of Events Adjudication and Reporting Cardiovascular Research Foundation 1700 Broadway, 9th Floor New York, NY 10019 Echocardiography Core Laboratory MedStar Health Research Institute Neil Weissman, MD 6495 New Hampshire Avenue, Suite 201 Hyattsville, MD 20783 USA Steering Committee Chairpersons Michael J. Mack, MD Gregg W. Stone, MD Heart Failure Specialists William Abraham, MD JoAnn Lindenfeld, MD Cardio-Thoracic Surgeons Steven F. Bolling, MD Michael J. Mack, MD Patrick M. McCarthy, MD Interventional Cardiologists Ted E. Feldman, MD Samir Kapadia, MD Gregg W. Stone, MD Echocardiographer/Cardiologist Paul A. Grayburn, MD Sponsor Representative Gary Johnson Clinical Investigational Plan Author Jeffrey T. Ellis, PhD Clinical Investigational Plan 11-512: Version 8.0 October 12, 2016 Confidential and Proprietary Page 2 Do not distribute or reproduce without the prior written permission of Abbott Vascular Inc. The COAPT Trial Table of Contents TABLE OF CONTENTS ....................................................................................................... 3 TABLE OF FIGURES ............................................................................................................ 8 TABLE OF TABLES .............................................................................................................. 9 CLINICAL TRIAL SUMMARY......................................................................................... 11 1 INTRODUCTION ............................................................................................................ 20 2 BACKGROUND INFORMATION ................................................................................ 20 2.1 MITRACLIP CLINICAL PROGRAM ............................................................................................................ 20 2.2 RESULTS ................................................................................................................................................. 22 2.2.1 EVEREST I Trial .......................................................................................................................... 22 2.2.2 EVEREST II RCT .......................................................................................................................... 22 2.2.3 EVEREST II High Risk Registry (HRR) Study .............................................................................. 24 2.2.4 EVEREST II REALISM Continued Access Study .......................................................................... 25 2.2.5 ACCESS-EU Study ....................................................................................................................... 25 2.2.6 Results in High Surgical Risk Patients ......................................................................................... 26 2.3 RATIONALE TO CONDUCT THE COAPT TRIAL ........................................................................................ 29 2.3.1 Intended Indication ....................................................................................................................... 30 2.4 SUMMARY OF INVESTIGATIONAL DEVICE AND CONTROL THERAPY ....................................................... 30 2.4.1 Name of the Investigational Device .............................................................................................. 30 2.4.2 Description of the Investigational Device (MitraClip System) ..................................................... 30 2.4.3 Description of the Control Group Therapy .................................................................................. 31 2.4.4 Procedures Involved in the Use of the Device .............................................................................. 32 2.4.5 Training Required for the Use of the Device ................................................................................ 32 2.4.6 Investigational Device Accountability .......................................................................................... 32 3 TRIAL OBJECTIVES ..................................................................................................... 32 3.1 PRIMARY OBJECTIVES ............................................................................................................................. 33 3.2 SECONDARY OBJECTIVES ........................................................................................................................ 33 4 TRIAL ENDPOINTS ....................................................................................................... 34 4.1 PRIMARY SAFETY ENDPOINT .................................................................................................................. 34 4.2 PRIMARY EFFECTIVENESS ENDPOINT ...................................................................................................... 34 4.3 SECONDARY SAFETY ENDPOINTS............................................................................................................ 34 4.4 SECONDARY EFFECTIVENESS ENDPOINTS ............................................................................................... 34 4.5 ADDITIONAL ENDPOINTS ........................................................................................................................ 35 4.5.1 Device or Procedure-Related Adverse Events .............................................................................. 35 4.5.2 Device and Procedure-Related Endpoints .................................................................................... 35 4.5.3 Echocardiographic Endpoints ...................................................................................................... 36 4.5.4 Clinical Endpoints ........................................................................................................................ 37 4.5.5 CPX Sub-Study Endpoint .............................................................................................................. 39 4.5.6 Health Economic Data ................................................................................................................. 40 5 TRIAL DESIGN, SCOPE AND DURATION ............................................................... 40 5.1 TRIAL DESIGN ......................................................................................................................................... 40 5.2 NUMBER OF SUBJECTS TO BE REGISTERED.............................................................................................. 40 5.3 TRIAL DURATION .................................................................................................................................... 41 Clinical Investigational Plan 11-512: Version 8.0 October 12, 2016 Confidential and Proprietary Page 3 Do not distribute or reproduce without the prior written permission of Abbott Vascular Inc. The COAPT Trial 5.4 PARTICIPATION OF WOMEN IN COAPT .................................................................................................. 41 5.4.1 Sex-Specific Prevalence of Valvular Heart Disease, Diagnosis and Treatment Patterns ............ 41 5.4.2 Proportion of Women Included in Past Studies for Target Indication ......................................... 42 5.4.3 Safety and Effectiveness Outcomes by Sex .................................................................................... 42 5.4.4 Representation of Women in the COAPT Trial ............................................................................. 42 5.4.5 Subgroup Analysis for Sex ...........................................................................................................