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Study Protocol NCT02417064 Janssen Research & Development* Clinical Protocol A Randomized, Double-blind, Multicenter, Active-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Fixed Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Subjects with Treatment-resistant Depression Trial of Rapid-acting Intranasal Esketamine for Treatment-resistant Major Depressive Disorder (TRANSFORM-1) Protocol ESKETINTRD3001; Phase 3 AMENDMENT 2 JNJ-54135419 (esketamine) *Janssen Research & Development is a global organization that operates through different legal entities in various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen Biologics, BV; Janssen-Cilag International NV; Janssen, Inc.; Janssen Sciences Ireland UC; or Janssen Research & Development, LLC. The term “sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is identified on the Contact Information page that accompanies the protocol. This compound is being investigated in Phase 3 clinical studies. This study will be conducted under US Food & Drug Administration IND regulations (21 CFR Part 312). EudraCT NUMBER: 2014-004584-20 Status: Approved Date: 31 May 2016 Prepared by: Janssen Research & Development, LLC EDMS number and version: EDMS-ERI-93094731, 3.0 GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory requirements. Confidentiality Statement The information in this document contains trade secrets and commercial information that are privileged or confidential and may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or confidential. Status: Approved, Date: 31 May 2016 1 NCT02417064 JNJ-54135419 (esketamine) Clinical Protocol ESKETINTRD3001 Amendment 2 TABLE OF CONTENTS TABLE OF CONTENTS ............................................................................................................................... 2 LIST OF ATTACHMENTS............................................................................................................................ 5 LIST OF IN-TEXT TABLES AND FIGURES ................................................................................................ 5 PROTOCOL AMENDMENTS....................................................................................................................... 6 SYNOPSIS.................................................................................................................................................. 29 TIME AND EVENTS SCHEDULE (Screening/Prospective Observational Phase and Double- blind Induction Phase).............................................................................................................................. 41 TIME AND EVENTS SCHEDULE (Follow-up Phase) .............................................................................. 48 ABBREVIATIONS ...................................................................................................................................... 51 1. INTRODUCTION................................................................................................................................ 53 1.1. Background .................................................................................................................................... 54 1.1.1. Summary of Nonclinical Findings ............................................................................................... 54 1.1.2. Clinical Studies ........................................................................................................................... 57 1.1.2.1. Pharmacokinetics and Product Metabolism ............................................................................ 57 1.1.2.2. Pharmacodynamics and Efficacy ............................................................................................ 59 1.1.2.3. Safety and Tolerability............................................................................................................. 61 1.1.3. Marketing Experience ................................................................................................................. 65 1.2. Active Comparators in Double-blind Induction Phase ................................................................... 65 1.2.1. Selective Serotonin Reuptake Inhibitors..................................................................................... 65 1.2.1.1. Escitalopram ............................................................................................................................ 65 1.2.1.2. Sertraline ................................................................................................................................. 66 1.2.2. Serotonin and Norepinephrine Reuptake Inhibitors ................................................................... 67 1.2.2.1. Duloxetine................................................................................................................................ 67 1.2.2.2. Venlafaxine Extended-release................................................................................................. 67 1.3. Overall Rationale for the Study ...................................................................................................... 68 2. OBJECTIVES AND HYPOTHESIS ................................................................................................... 68 2.1. Objectives ...................................................................................................................................... 68 2.2. Hypothesis ..................................................................................................................................... 70 3. STUDY DESIGN AND RATIONALE ................................................................................................. 70 3.1. Overview of Study Design.............................................................................................................. 70 3.2. Study Design Rationale.................................................................................................................. 73 3.2.1. Study Population......................................................................................................................... 73 3.2.2. Study Phases.............................................................................................................................. 74 3.2.3. Blinding and Randomization....................................................................................................... 75 3.2.4. Treatment Groups and Dose Selection ...................................................................................... 75 3.2.5. Efficacy Measures ...................................................................................................................... 77 3.2.6. Safety Evaluations ...................................................................................................................... 78 3.2.7. Medical Resource Utilization ...................................................................................................... 79 3.2.8. Other Assessments .................................................................................................................... 79 3.2.9. Pharmacokinetic Assessments................................................................................................... 79 3.2.10. Biomarker, Pharmacogenomic (DNA), and Expression (RNA) Evaluations .............................. 80 4. STUDY POPULATION ...................................................................................................................... 80 4.1. Inclusion Criteria ............................................................................................................................ 80 4.2. Exclusion Criteria ........................................................................................................................... 84 4.3. Prohibitions and Restrictions ......................................................................................................... 89 Status: Approved, Date: 31 May 2016 2 NCT02417064 JNJ-54135419 (esketamine) Clinical Protocol ESKETINTRD3001 Amendment 2 5. TREATMENT ALLOCATION AND BLINDING................................................................................. 89 6. DOSAGE AND ADMINISTRATION .................................................................................................. 91 6.1. Screening/Prospective Observational Phase ................................................................................ 91 6.2. Double-Blind Induction Phase........................................................................................................ 92 6.2.1. Guidance on Blood Pressure Monitoring on Intranasal Treatment Session Days ..................... 94 6.3. Follow-up Phase ............................................................................................................................ 95 7. TREATMENT COMPLIANCE...........................................................................................................
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