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A Phase 3 Multicenter Study of the Long-Term Safety and Tolerability Of A Phase 3 Multicenter Study of the Long-term Safety and Tolerability of ALKS 5461 for the Adjunctive Treatment of Major Depressive Disorder in Adults who Have an Inadequate Response to Antidepressant Therapy (the FORWARD-2 Study) Unique Protocol ID: ALK5461-208 NCT Number: NCT02141399 EudraCT Number: 2014-000380-41 Date of Statistical Analysis 15 September 2017 Plan: STATISTICAL ANALYSIS PLAN PHASE III ALK5461-208 A Phase 3 Multicenter Study of the Long-term Safety and Study Title: Tolerability of ALKS 5461 for the Adjunctive Treatment of Major Depressive Disorder in Adults who Have an Inadequate Response to Antidepressant Therapy (the FORWARD-2 Study) Document Status: Final Document Date: 15 September 2017 Based on: Study protocol amendment 3 (dated 03 March 2016) Study protocol amendment 2 (dated 12 May 2015) Study protocol amendment 1 (dated 17 April 2014) Original study protocol (dated 16 December 2013) Sponsor: Alkermes, Inc. 852 Winter Street Waltham, MA 02451 USA CONFIDENTIAL Information and data in this document contain trade secrets and privileged or confidential information, which is the property of Alkermes, Inc. No person is authorized to make it public without the written permission of Alkermes, Inc. These restrictions or disclosures will apply equally to all future information supplied to you that is indicated as privileged or confidential. This study is being conducted in compliance with good clinical practice, including the archiving of essential documents. Alkermes, Inc. ALKS 5461 CONFIDENTIAL SAP-ALK5461-208 TABLE OF CONTENTS LIST OF ABBREVIATIONS ..........................................................................................................5 1. INTRODUCTION ........................................................................................................7 1.1. Study Objectives ...........................................................................................................7 1.2. Summary of the Study Design and Schedule of Assessments ......................................7 1.3. Criteria for Evaluation ..................................................................................................9 2. SAMPLE SIZE AND STATISTICAL POWER CONSIDERATION .......................10 3. DATA ANALYSIS ....................................................................................................10 3.1. General Statistical Methodology ................................................................................10 3.2. Study Population .........................................................................................................10 3.2.1. Definitions of Analysis Populations (Analysis Sets) ..................................................10 3.2.2. Disposition ..................................................................................................................13 3.2.3. Protocol Deviations ....................................................................................................13 3.3. Demographics and Baseline Characteristics ...............................................................14 3.4. Prior and Concomitant Medications ...........................................................................14 3.5. Treatment Adherence Rate and Extent of Exposure ...................................................15 3.6. Efficacy Analysis ........................................................................................................16 3.6.1. General Considerations ...............................................................................................16 3.6.1.1. Pooling of Centers ......................................................................................................16 3.6.1.2. Multiple Comparisons/Multiplicity ............................................................................16 3.6.1.3. Examination of Subgroups .........................................................................................16 3.6.2. Efficacy Analysis ........................................................................................................16 3.6.2.1. Montgomery-Asberg Depression Rating Scale (MADRS) ........................................16 3.6.2.2. Hamilton Rating Scale for Anxiety (HAM-A) ...........................................................17 3.6.2.3. Clinical Global Impression – Severity (CGI-S) ..........................................................17 3.7. Safety Analysis ...........................................................................................................18 3.7.1. General Considerations ...............................................................................................18 3.7.2. Adverse Events ...........................................................................................................18 3.7.3. Adverse Events of Special Interest .............................................................................20 3.7.4. Clinical Laboratory Parameters ..................................................................................21 3.7.4.1. Descriptive Analysis of Laboratory Parameters .........................................................21 3.7.4.2. Outlier Analyses of Laboratory Parameters ...............................................................22 Page 2 of 57 Alkermes, Inc. ALKS 5461 CONFIDENTIAL SAP-ALK5461-208 3.7.4.3. Hepatic Effects ............................................................................................................25 3.7.5. Vital Signs ..................................................................................................................26 3.7.6. Electrocardiograms .....................................................................................................27 3.7.7. Columbia Suicide Severity Rating Scale (C-SSRS) ...................................................28 3.7.8. Clinical Opiate Withdrawal Scale (COWS) Scores ....................................................31 4. INTERIM ANALYSES ..............................................................................................32 5. CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE PROTOCOL ...............................................................................................................32 6. DEFINITIONS AND CONVENTIONS FOR HANDLING OF THE DATA ..........32 6.1. Analysis Visit Windows .............................................................................................32 6.2. Efficacy Data Handling ..............................................................................................32 6.3. Handling of Partial Dates of Prior and Concomitant Medications .............................33 7. GENERAL STATISTICAL METHODOLOGY .......................................................33 7.1. Statistical Conventions ...............................................................................................33 7.2. Reporting Precision ....................................................................................................33 8. PROGRAMMING SPECIFICATIONS .....................................................................34 9. MOCK TABLES, LISTINGS AND FIGURES (TLFS) ............................................34 10. REFERENCES ...........................................................................................................34 APPENDIX 1. AESI – ABUSE POTENTIAL ...........................................................................35 APPENDIX 2. AESI – DEPENDENCE .....................................................................................37 APPENDIX 3. AESI – WITHDRAWAL ...................................................................................38 APPENDIX 4. AESI – SUICIDAL IDEATION AND BEHAVIOR .........................................40 APPENDIX 5. AESI – HYPOMANIA/MANIA ........................................................................41 APPENDIX 6. AESI – CNS DEPRESSION AND SEDATION................................................42 APPENDIX 7. AESI – RESPIRATORY DEPRESSION ...........................................................43 APPENDIX 8. AESI – ORTHOSTASIS HYPOTENSION .......................................................44 APPENDIX 9. AESI – HYPERSENSITIVITY ..........................................................................45 APPENDIX 10. AESI – SLOWING OF VENTRICULAR REPOLARIZATION ....................53 APPENDIX 11. AESI – HEPATIC EFFECTS ...........................................................................54 APPENDIX 12. AESI – SEXUAL DYSFUNCTION ................................................................57 Page 3 of 57 Alkermes, Inc. ALKS 5461 CONFIDENTIAL SAP-ALK5461-208 LIST OF TABLES Table 1: Schedule of Safety Assessments ...................................................................................9 Table 2: Baseline and Study Period for Safety Endpoints ........................................................12 Table 3: Definitions to Define Study Drug Cumulative Exposure ...........................................15 Table 4: Potentially Clinically Significant Abnormal Laboratory Values ................................23 Table 5: Shift Criteria and Denominator for Alanine Aminotransferase (ALT) ......................25 Table 6: Shift Criteria and Denominator for Aspartate Aminotransferase (AST) ....................26 Table 7: Shift Criteria and Denominator for Total Bilirubin (TBILI) ......................................26 Table 8: Potentially Clinically Significant Abnormal Vital Sign Values .................................27 Table
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