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Efficacy and Safety of Intranasal Esketamine When Tapered from Twice-Weekly Dosing to Once Per Week Dosing and Then Dosing Once Every Other Week

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Janssen Research & Development * Clinical Protocol A Double-Blind, Doubly-Randomized, Placebo-Controlled Study of Intranasal Esketamine in an Adaptive Treatment Protocol to Assess Safety and Efficacy in Treatment-Resistant Depression (SYNAPSE) Protocol ESKETINTRD2003; Phase 2a AMENDMENT INT-3 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 Infectious Diseases BVBA; Janssen R&D Ireland; 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 study will be conducted under US Food & Drug Administration IND regulations (21 CFR Part 312). EudraCT NUMBER: 2013-004005-11 Status: Approved Date: 28 April 2014 Prepared by: Janssen Research & Development, LLC EDMS No & Version: EDMS-ERI-71950055:5.0 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. 1 Status: Approved, Date: 28 April 2014 Downloaded From: https://jamanetwork.com/ on 10/01/2021 JNJ-54135419 (esketamine) Clinical Protocol ESKETINTRD2003 – Amendment INT-3 TABLE OF CONTENTS TABLE OF CONTENTS ............................................................................................................................... 2 LIST OF ATTACHMENTS............................................................................................................................ 4 LIST OF IN-TEXT TABLES AND FIGURES ................................................................................................ 5 PROTOCOL AMENDMENTS....................................................................................................................... 6 SYNOPSIS.................................................................................................................................................. 22 TIME AND EVENTS SCHEDULE 1 (OF 2): SCREENING AND DOUBLE-BLIND TREATMENT PHASES FOR PANEL A AND PANEL B ......................................................................................... 38 TIME AND EVENTS SCHEDULE 2 (OF 2): OPTIONAL OPEN-LABEL TREATMENT AND POSTTREATMENT PHASES FOR PANEL A AND PANEL B........................................................ 41 ABBREVIATIONS ...................................................................................................................................... 44 1. INTRODUCTION................................................................................................................................ 46 1.1. Background .................................................................................................................................... 47 1.1.1. Nonclinical Studies ..................................................................................................................... 47 1.1.2. Clinical Studies ........................................................................................................................... 50 1.1.2.1. Summary of Ketamine/Esketamine Efficacy ........................................................................... 50 1.1.2.2. Summary of Ketamine/Esketamine Safety Profile................................................................... 51 1.1.2.3. Human Pharmacokinetics of Intravenous Ketamine/Esketamine ........................................... 56 1.2. Overall Rationale for the Study ...................................................................................................... 60 2. OBJECTIVES AND HYPOTHESIS ................................................................................................... 60 2.1. Objectives ...................................................................................................................................... 60 2.2. Hypothesis ..................................................................................................................................... 61 3. STUDY DESIGN AND RATIONALE ................................................................................................. 61 3.1. Overview of Study Design.............................................................................................................. 61 3.2. Study Design Rationale.................................................................................................................. 68 4. SUBJECT POPULATION.................................................................................................................. 75 4.1. Inclusion Criteria ............................................................................................................................ 76 4.2. Exclusion Criteria ........................................................................................................................... 78 4.3. Prohibitions and Restrictions ......................................................................................................... 81 5. TREATMENT ALLOCATION AND BLINDING................................................................................. 82 6. DOSAGE AND ADMINISTRATION .................................................................................................. 84 7. TREATMENT COMPLIANCE............................................................................................................ 87 8. PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 87 9. STUDY EVALUATIONS .................................................................................................................... 89 9.1. Study Procedures........................................................................................................................... 89 9.1.1. Overview..................................................................................................................................... 89 9.1.2. Screening Phase ........................................................................................................................ 92 9.1.3. Double-Blind Treatment Phase .................................................................................................. 93 9.1.4. Optional Open-Label Treatment Phase...................................................................................... 94 9.1.5. Posttreatment Phase (Follow-Up) .............................................................................................. 95 9.2. Efficacy........................................................................................................................................... 95 9.2.1. Evaluations ................................................................................................................................. 95 2 Approved, Date: 28 April 2014 Downloaded From: https://jamanetwork.com/ on 10/01/2021 JNJ-54135419 (esketamine) Clinical Protocol ESKETINTRD2003 – Amendment INT-3 9.2.1.1. Primary .................................................................................................................................... 96 9.2.1.2. Secondary................................................................................................................................ 96 9.2.1.3. Exploratory............................................................................................................................... 97 9.2.2. Endpoints.................................................................................................................................... 98 9.2.2.1. Primary Endpoint ..................................................................................................................... 98 9.2.2.2. Secondary Endpoints .............................................................................................................. 98 9.3. Pharmacokinetics........................................................................................................................... 99 9.3.1. Evaluations ................................................................................................................................. 99 9.3.2. Analytical Procedures ................................................................................................................. 99 9.3.3. Pharmacokinetic Parameters ..................................................................................................... 99 9.4. Pharmacokinetic/Pharmacodynamic Evaluations.......................................................................... 99 9.5. Biomarkers ..................................................................................................................................
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