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MTN-027 Phase 1 Safety and Pharmacokinetics Study of MK MTN-027 Phase 1 Safety and Pharmacokinetics Study of MK-2048/Vicriviroc (MK-4176)/MK-2048A Intravaginal Rings 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 #: 12014 IND Sponsor: DAIDS Pharmaceutical Collaborator: Merck & Co. PIND# 123,134 Protocol Chair: Craig Hoesley, MD Version 1.0 December 20, 2014 MTN-027 Phase 1 Safety and Pharmacokinetics Study of MK-2048/Vicriviroc (MK-4176)/MK-2048A Intravaginal Rings TABLE OF CONTENTS LIST OF ABBREVIATIONS AND ACRONYMS ............................................................... 6 PROTOCOL TEAM ROSTER ......................................................................................... 9 INVESTIGATOR SIGNATURE FORM .......................................................................... 18 PROTOCOL SUMMARY ............................................................................................... 19 1 KEY ROLES .................................................................................................... 23 1.1 Protocol Identification ...................................................................................... 23 1.2 Funders, Sponsor and Monitor Identification................................................... 23 1.3 Medical Officer ................................................................................................ 24 1.4 Clinical Laboratories ....................................................................................... 24 1.5 Data Center ..................................................................................................... 24 1.6 Study Implementation ..................................................................................... 24 2 INTRODUCTION ............................................................................................ 25 2.1 Human Immunodeficiency Virus (HIV) Prevention and Intravaginal Rings ..... 25 2.2 Rationale ......................................................................................................... 25 2.3 Vicriviroc (MK-4176) IVR................................................................................. 27 2.4 MK-2048 IVR .................................................................................................. 27 2.5 MK-2048A IVR (VCV [MK-4176] + MK-2048) ................................................. 28 2.6 Placebo IVR .................................................................................................... 28 2.7 In vitro and Ex Vivo Studies ............................................................................ 29 2.8 Nonclinical Studies .......................................................................................... 36 2.9 Clinical Studies ............................................................................................... 41 2.10 Study Hypothesis and Rationale for Study Design .......................................... 46 3 OBJECTIVES .................................................................................................. 47 3.1 Primary Objectives .......................................................................................... 47 3.2 Secondary Objectives ..................................................................................... 47 3.3 Exploratory Objectives .................................................................................... 47 4 STUDY DESIGN ............................................................................................. 48 4.1 Identification of Study Design .......................................................................... 48 4.2 Summary of Major Endpoints .......................................................................... 48 4.3 Description of Study Population ...................................................................... 49 4.4 Time to Complete Accrual ............................................................................... 49 4.5 Study Groups .................................................................................................. 49 4.6 Expected Duration of Participation .................................................................. 49 4.7 Sites ................................................................................................................ 49 5 STUDY POPULATION .................................................................................... 50 5.1 Selection of the Study Population ................................................................... 50 5.2 Inclusion Criteria ............................................................................................. 50 5.3 Exclusion Criteria ............................................................................................ 52 5.4 Co-enrollment Guidelines ............................................................................... 54 MTN-027, Version 1.0 2 December 20, 2014 6 STUDY PRODUCT ......................................................................................... 54 6.1 Regimen.......................................................................................................... 54 6.2 Administration ................................................................................................. 55 6.3 Study Product Formulation.............................................................................. 55 6.4 Supply and Accountability ............................................................................... 55 6.5 Concomitant Medications ................................................................................ 57 6.6 Prohibited Medications and Practices ............................................................. 57 7 STUDY PROCEDURES ................................................................................. 58 7.1 Pre-screening .................................................................................................. 58 7.2 Visit 1- Screening ............................................................................................ 58 7.3 Visit 2- Enrollment (Day 0) .............................................................................. 60 7.4 Follow-up Visits ............................................................................................... 61 7.5 Follow-up Procedures for Participants Who Permanently Discontinue Study Product ........................................................................................................... 65 7.6 Follow-up Procedures for Participants Who are on a Temporary Clinical Study Product Hold ................................................................................................... 66 7.7 Pharmacokinetics ............................................................................................ 67 7.8 Behavioral Measures ...................................................................................... 67 7.9 Adherence Counseling and Assessment ........................................................ 69 7.10 Clinical Evaluations and Procedures ............................................................... 70 7.11 Laboratory Evaluations ................................................................................... 70 7.12 Specimen Collection and Processing .............................................................. 72 7.13 Specimen Handling ......................................................................................... 72 7.14 Biohazard Containment .................................................................................. 72 8 ASSESSMENT OF SAFETY ........................................................................... 73 8.1 Safety Monitoring ............................................................................................ 73 8.2 Clinical Data and Safety Review ..................................................................... 73 8.3 Adverse Events Definitions and Reporting Requirements .............................. 74 8.4 Expedited Adverse Event Reporting Requirements ........................................ 75 8.5 Pregnancy and Pregnancy Outcomes ............................................................ 76 8.6 Regulatory Requirements ............................................................................... 76 8.7 Social Harms Reporting .................................................................................. 77 9 CLINICAL MANAGEMENT ............................................................................. 77 9.1 Grading System .............................................................................................. 77 9.2 Dose Modification Instructions ........................................................................ 77 9.3 General Criteria for Temporary Hold and Permanent Discontinuation of Study Product ........................................................................................................... 77 9.4 Temporary Product Hold/Permanent Discontinuation in Response to Adverse Events ............................................................................................................. 78 9.5 Other Clinical Events ...................................................................................... 79 9.6 HIV-1 Infection ...............................................................................................
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