A5343 A Trial of the Safety, Tolerability, and Pharmacokinetics of Bedaquiline and Delamanid, Alone and in Combination, among Participants Taking Multidrug Treatment for Drug-Resistant Pulmonary Tuberculosis A Limited-Center Trial of the AIDS Clinical Trials Group (ACTG) Sponsored by: National Institute of Allergy and Infectious Diseases Industry Support Provided by: Janssen Pharmaceuticals, Inc. Otsuka Pharmaceutical Company, Ltd. ViiV Healthcare, Ltd. IND# 127,382 The ACTG Tuberculosis Transformative Science Group Gavin Churchyard, MBBCh, MMED, FCP, PhD, Chair Protocol Co-Chairs: Kelly Dooley, MD, PhD Gary Maartens, MBChB, MMed Protocol Vice Chair: Francesca Conradie, MD, DTM&H DAIDS Clinical Representatives: Richard Hafner, MD Roxana Rustomjee MbChB, MMed, FCPhM, FRCP, PhD Clinical Trials Specialists: Laura E. Moran, MPH Chanelle Houston, BS FINAL Version 4.0 June 26, 2018 A5343 FINAL Version 4.0 06/26/18 A Trial of the Safety, Tolerability, and Pharmacokinetics of Bedaquiline and Delamanid, Alone and in Combination, among Participants Taking Multidrug Treatment for Drug-Resistant Pulmonary Tuberculosis SIGNATURE PAGE I will conduct the study in accordance with the provisions of this protocol and all applicable protocol-related documents. I agree to conduct this study in compliance with United States (US) Health and Human Service regulations (45 CFR 46); applicable U.S. Food and Drug Administration regulations; standards of the International Conference on Harmonization Guideline for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee determinations; all applicable in-country, state, and local laws and regulations; and other applicable requirements (eg, US National Institutes of Health, Division of AIDS) and institutional policies. Principal Investigator: _______________________________________________ Print/Type Signed: ___________________________________ Date: _____________ Name/Title A5343 FINAL Version 4.0 06/26/18 TABLE OF CONTENTS Page SIGNATURE PAGE .................................................................................................................... 2 SITES PARTICIPATING IN THE STUDY .................................................................................... 5 PROTOCOL TEAM ROSTER ..................................................................................................... 6 STUDY MANAGEMENT ........................................................................................................... 10 GLOSSARY OF PROTOCOL-SPECIFIC TERMS ..................................................................... 12 SCHEMA .................................................................................................................................. 14 1.0 HYPOTHESES AND STUDY OBJECTIVES.................................................................. 15 1.1 Hypotheses ........................................................................................................ 15 1.2 Primary Objectives ............................................................................................. 15 1.3 Secondary Objectives ........................................................................................ 16 1.4 Exploratory Objectives ....................................................................................... 16 2.0 INTRODUCTION ........................................................................................................... 17 2.1 Background........................................................................................................ 17 2.2 Rationale ........................................................................................................... 29 3.0 STUDY DESIGN ........................................................................................................... 31 4.0 SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................ 33 4.1 Inclusion Criteria ................................................................................................ 33 4.2 Exclusion Criteria ............................................................................................... 35 4.3 Study Enrollment Procedures............................................................................. 37 4.4 Co-enrollment Guidelines ................................................................................... 38 5.0 STUDY TREATMENT ................................................................................................... 38 5.1 Regimens, Administration, and Duration ............................................................ 38 5.2 Study Product Formulation and Preparation ....................................................... 39 5.3 Pharmacy: Product Supply, Distribution, and Accountability .............................. 40 5.4 Concomitant Medications ................................................................................... 40 6.0 CLINICAL AND LABORATORY EVALUATIONS ........................................................... 43 6.1a Schedule of Evaluations (SOE): Screening through Treatment ........................ 43 6.1b SOE: Follow-up and Premature Discontinuation ................................................ 45 6.2 Timing of Evaluations ......................................................................................... 46 6.3 Instructions for Evaluations ................................................................................ 47 7.0 CLINICAL MANAGEMENT ISSUES .............................................................................. 56 7.1 Specific Management of Toxicities Related to Study-Provided Drugs or MBT .... 57 7.2 Toxicity Management – Other ............................................................................ 65 7.3 Pregnancy.......................................................................................................... 66 7.4 Expected Toxicities of MBT Drugs ..................................................................... 66 8.0 CRITERIA FOR DISCONTINUATION ........................................................................... 67 8.1 Permanent and Premature Treatment Discontinuation ....................................... 67 A5343 FINAL Version 4.0 06/26/18 CONTENTS (Cont’d) Page 8.2 Premature Study Discontinuation ....................................................................... 68 9.0 STATISTICAL CONSIDERATIONS ............................................................................... 68 9.1 General Design Issues ....................................................................................... 68 9.2 Outcome Measures ............................................................................................ 70 9.3 Randomization and Stratification ........................................................................ 73 9.4 Sample Size and Accrual ................................................................................... 73 9.5 Monitoring .......................................................................................................... 76 9.6 Analyses ............................................................................................................ 80 10.0 PHARMACOLOGY PLAN.............................................................................................. 83 10.1 Pharmacology Objectives .................................................................................. 83 10.2 Pharmacology Study Design .............................................................................. 83 10.3 Primary and Secondary Data, Modeling, and Data Analysis............................... 85 10.4 Anticipated Outcomes ........................................................................................ 86 11.0 DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING ........ 86 11.1 Records to Be Kept ............................................................................................ 86 11.2 Role of Data Management ................................................................................. 86 11.3 Clinical Site Monitoring and Record Availability .................................................. 86 11.4 Expedited Adverse Event (EAE) Reporting to DAIDS ........................................ 87 12.0 HUMAN PARTICIPANTS .............................................................................................. 88 12.1 Institutional Review Board (IRB) Review and Informed Consent ........................ 88 12.2 Participant Confidentiality ................................................................................... 89 12.3 Study Discontinuation ........................................................................................ 89 13.0 PUBLICATION OF RESEARCH FINDINGS .................................................................. 89 14.0 BIOHAZARD CONTAINMENT....................................................................................... 89 15.0 REFERENCES .............................................................................................................. 90 APPENDIX I: ASSESSMENT OF CEREBROSPINAL FLUID (CSF) CONCENTRATIONS OF DELAMANID AND BEDAQUILINE AMONG PARTICIPANTS WITH MDR-TB ................................................................................... 96 APPENDIX II: SAMPLE INFORMED CONSENT .................................................................... 102 APPENDIX II-A: A5343 STUDY VISITS .................................................................................. 113 APPENDIX III: CONSENT FOR OPTIONAL