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MTN-026 a Randomized, Double Blind, Placebo-Controlled, Phase 1 MTN-026 A Randomized, Double Blind, Placebo-Controlled, Phase 1 Safety and Pharmacokinetic Study of Dapivirine Gel (0.05%) Administered Rectally to HIV-1 Seronegative Adults Microbicide Trials Network Funding Agencies: Division of AIDS, US National Institute of Allergy and Infectious Diseases US Eunice Kennedy Shriver National Institute of Child Health and Human Development US National Institute of Mental Health US National Institutes of Health Grant Numbers: UM1AI068633, UM1AI068615, UM1AI106707 DAIDS Protocol ID: 12021 IND Sponsor: DAIDS IND#: [XXXXX] Protocol Chair: Ross D. Cranston, MD, FRCP Version 2.0 July 21, 2017 MTN-026 A Randomized, Double Blind, Placebo-Controlled, Phase 1 Safety and Pharmacokinetic Study of Dapivirine Gel (0.05%) Administered Rectally to HIV-1 Seronegative Adults TABLE OF CONTENTS PROTOCOL SUMMARY ........................................................................................................... 19 1 KEY ROLES ........................................................................................................................ 22 1.1 Protocol Identification .................................................................................................. 22 1.2 Funding Agencies, Sponsor and Monitor Identification ............................................... 22 1.3 Medical Officer ............................................................................................................ 23 1.4 Clinical Laboratories ................................................................................................... 23 1.5 Data Center ................................................................................................................. 23 1.6 Study Implementation ................................................................................................. 23 2 INTRODUCTION ................................................................................................................. 24 2.1 Dapivirine Gel ............................................................................................................. 24 2.2 Universal Placebo gel ................................................................................................. 25 2.3 Non-Clinical Studies .................................................................................................... 26 2.4 Clinical Studies ........................................................................................................... 30 2.5 Other Clinical Studies of Dapivirine ............................................................................. 38 2.6 Study Hypotheses and Rationale for Study Design .................................................... 40 3 OBJECTIVES....................................................................................................................... 41 3.1 Primary Objectives ...................................................................................................... 41 3.2 Secondary Objectives ................................................................................................. 41 3.3 Exploratory Objectives ................................................................................................ 41 4 STUDY DESIGN .................................................................................................................. 42 4.1 Identification of Study Design ...................................................................................... 42 4.2 Summary of Major Endpoints ...................................................................................... 42 4.3 Description of Study Population .................................................................................. 43 4.4 Time to Complete Accrual ........................................................................................... 43 4.5 Study Groups .............................................................................................................. 43 4.6 Expected Duration of Participation .............................................................................. 43 4.7 Sites ............................................................................................................................ 43 5 STUDY POPULATION ......................................................................................................... 44 5.1 Selection of the Study Population ............................................................................... 44 5.2 Inclusion Criteria ......................................................................................................... 44 5.3 Exclusion Criteria ........................................................................................................ 45 5.4 Co-enrollment Guidelines ........................................................................................... 48 6 STUDY PRODUCT .............................................................................................................. 48 6.1 Regimen...................................................................................................................... 48 6.2 Administration ............................................................................................................. 49 6.3 Study Product Formulation.......................................................................................... 49 6.4 Study Applicator .......................................................................................................... 49 6.5 Study Product Supply and Accountability ................................................................... 50 6.6 Study Product Dispensing ........................................................................................... 50 MTN-026, Version 2.0 2 July 21, 2017 6.7 Retrieval of Unused Study Products ........................................................................... 50 6.8 Ancillary Study Supplies ............................................................................................. 51 6.9 Concomitant Medications ............................................................................................ 51 6.10 Prohibited Medications and Practices ......................................................................... 51 7 STUDY PROCEDURES ...................................................................................................... 52 7.1 Pre-screening .............................................................................................................. 52 7.2 Visit 1: Screening ........................................................................................................ 53 7.3 Visit 2: Enrollment (Day 0) .......................................................................................... 54 7.4 Visit 3: Single Dose Administration Visit ..................................................................... 55 7.5 Visits 4-6 (~24, 48, 72 Hours After Application of Study Product) ............................... 56 7.6 Visits 7-12: Study Product Administration Visits .......................................................... 57 7.7 Visit 13: Last Study Product Administration Visit/Early Termination Visit .................... 58 7.8 Visits 14-16: PK Visits (~24, 48, 72 Hours After Last Application of Study Product) ...................................................................................................................... 59 7.9 Visit 17: Follow-Up Safety Contact and Termination Visit .......................................... 60 7.10 Follow-up Procedures for Participants Who Permanently Discontinue Study Product ....................................................................................................................... 60 7.11 Interim Visits ............................................................................................................... 61 7.12 Study Product Use / Adherence Counseling ............................................................... 61 7.13 Clinical Evaluations and Procedures ........................................................................... 61 7.14 Behavioral Assessments ............................................................................................. 62 7.15 Pharmacokinetics, Pharmacodynamics and Mucosal Safety ...................................... 63 7.16 Laboratory Evaluations ............................................................................................... 64 7.17 Specimen Collection and Processing .......................................................................... 65 7.18 Specimen Handling ..................................................................................................... 66 7.19 Biohazard Containment .............................................................................................. 66 8 ASSESSMENT OF SAFETY ............................................................................................... 66 8.1 Safety Monitoring ........................................................................................................ 66 8.2 Clinical Data and Safety Review ................................................................................. 66 8.3 Adverse Events Definitions and Reporting Requirements .......................................... 67 8.4 Adverse Event Reporting Requirements ..................................................................... 70 8.5 Pregnancy and Pregnancy Outcomes ........................................................................ 71 8.6 Regulatory Requirements
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