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MTN-028Phase 1 Pharmacokinetic Trial of Two Intravaginal Rings (IVRs) ContainingDifferent Dose Strengths of Vicriviroc (MK-4176) and MK-2048Microbicide Trials NetworkFunding Agencies:Division of AIDS, US National Institute of Allergy and Infectious DiseasesUS Eunice Kennedy Shriver National Institute ofChild Health and Human DevelopmentUS National Institute of Mental HealthUS National Institutes of HealthGrant Numbers:UM1AI068633, UM1AI068615, UM1AI106707DAIDS Protocol #: 12022IND Sponsor:DAIDSPharmaceutical Collaborator:Merck & Co.IND# 123,134Protocol Chair:Albert Liu, MD, MPHVersion 1.0February 12, 2015
MTN-028Phase 1 Pharmacokinetic Trial of Two Intravaginal Rings (IVRs) ContainingDifferent Dose Strengths of Vicriviroc (MK-4176) and MK-2048TABLE OF CONTENTSLIST OF ABBREVIATIONS AND ACRONYMS . 5PROTOCOL TEAM ROSTER . 8INVESTIGATOR SIGNATURE FORM . 16PROTOCOL SUMMARY . 171KEY ROLES. 201.1Protocol Identification . 201.2Funders, Sponsor and Monitor Identification. 201.3Medical Officer . 211.4Clinical Laboratories . 211.5Data Center. 211.6Study Implementation . 212INTRODUCTION . 222.1Human Immunodeficiency Virus (HIV) Prevention and Intravaginal Rings . 222.2Rationale . 222.3MK-2048A IVR . 242.4In vitro and Ex Vivo Studies . 252.5Nonclinical Studies . 322.6Clinical Studies . 382.7Study Hypothesis and Rationale for Study Design. 423OBJECTIVES. 433.1Primary Objectives . 433.2Secondary Objective . 434STUDY DESIGN . 434.1Identification of Study Design. 434.2Summary of Major Endpoints . 434.3Description of Study Population . 444.4Time to Complete Accrual . 444.5Study Groups . 444.6Expected Duration of Participation . 444.7Site . 445STUDY POPULATION . 455.1Selection of the Study Population . 455.2Inclusion Criteria . 455.3Exclusion Criteria . 475.4Co-enrollment Guidelines. 496STUDY PRODUCT . 496.1Regimen. 496.2Administration . 506.3Study Product Formulation. 506.4Supply and Accountability . 50MTN-028, Version 1.01February 12, 2015
0.110.210.310.410.510.610.711Concomitant Medications . 51Prohibited Medications and Practices . 52STUDY PROCEDURES. 53Pre-screening. 53Visit 1- Screening . 53Visit 2- Enrollment (Day 0) . 55Follow-up Visits . 56Follow-up Procedures for Participants Who Permanently Discontinue StudyProduct . 60Follow-up Procedures for Participants Who are on a Temporary Clinical StudyProduct Hold . 61Pharmacokinetics . 61Product Use/Adherence Counseling . 62Clinical Evaluations and Procedures . 62Laboratory Evaluations . 63Specimen Collection and Processing . 64Specimen Handling . 65Biohazard Containment . 65ASSESSMENT OF SAFETY. 65Safety Monitoring . 65Clinical Data and Safety Review . 65Adverse Events Definitions and Reporting Requirements . 66Expedited Adverse Event Reporting Requirements . 68Pregnancy and Pregnancy Outcomes . 69Regulatory Requirements . 69Social Harms Reporting . 69CLINICAL MANAGEMENT . 70Grading System . 70Dose Modification Instructions . 70General Criteria for Temporary Hold and Permanent Discontinuation of StudyProduct . 70Temporary Product Hold/Permanent Discontinuation in Response to AdverseEvents . 71Other Clinical Events . 71HIV-1 Infection . 73Pregnancy . 73Criteria for Early Termination of Study Participation . 74STATISTICAL CONSIDERATIONS . 74Overview and Summary of Design. 74Study Endpoints . 74Sample Size and Power Calculations . 75Participant Accrual, Follow-up and Retention . 76Randomization . 77Blinding . 77Data and Safety Monitoring and Analysis . 77DATA HANDLING AND RECORDKEEPING . 78MTN-028, Version 1.02February 12, 2015
11.1 Data Management Responsibilities . 7811.2 Source Documents and Access to Source Data/Documents . 7811.3 Quality Control and Quality Assurance . 7912CLINICAL SITE MONITORING. 7913HUMAN SUBJECTS PROTECTIONS . 8013.1 Institutional Review Boards . 8013.2 Protocol Registration . 8013.3 Study Coordination . 8113.4 Risk Benefit Statement . 8113.5 Informed Consent Process. 8313.6 Participant Confidentiality. 8413.7 Special Populations . 8513.8 Compensation . 8513.9 Communicable Disease Reporting. 8613.10 Access to HIV-related Care. 8613.11 Study Discontinuation . 8614PUBLICATION POLICY . 8615APPENDICES . 87APPENDIX I: SCHEDULE OF STUDY VISITS AND PROCEDURES. 88APPENDIX II: ALGORITHM FOR HIV ANTIBODY TESTING . 90APPENDIX III: SAMPLE INFORMED CONSENT FORM (SCREENING,ENROLLMENT, LONG-TERM STORAGE AND FUTURE TESTING) . 91Reference List . 106Table of FiguresFigure 1: MTN-028 Study Visit Schedule . 19Figure 2: In vitro release of VCV (MK-4176) and MK-2048 from MK-2048A combinationIVR . 32Figure 3: Plasma and vaginal fluid concentrations for MK-2048 (A) and VCV (MK-4176)(B) following insertion of IVRs containing MK-2048 (30 mg) and/ VCV (MK-4176) (182mg) to virginal Dorset sheep .35Table 1: PK Specimen Collection Schedule . 19Table 2: In vitro/Ex vivo studies of VCV (MK-4176)/VCV (MK-7690) . 26Table 3: Summary of Cross-Resistance Profiles for VCV-Resistant Mutants. 28Table 4: In vitro/Ex vivo studies of MK-2048 supporting a microbicide indication . 29Table 5: Antiviral Activity of free drug VCV (MK-4176) and MK-2048 Alone or inCombination . 30Table 6: Ex vivo studies of IVRs containing MK-2048 and/or VCV or placebo . 31Table 7: Non-clinical safety/toxicity studies of VCV (MK-4176), MK-2048 and thecombination of VCV (MK-4176) MK-2048 via topical administration . 36Table 8: Study Regimen . 49Table 9: Retrieval of Study Product . 51Table 10: Visit 1- Screening Visit . 54Table 11: Enrollment Visit- Visit 2 (Day 0) . 55MTN-028, Version 1.03February 12, 2015
Table 12: Visits 3-8 (Days 1, 2, 3, 7, 14, 21) . 56Table 13: Visit 9 (Day 28) Ring Removal Visit. 57Table 14: Visits 10-12 (Days 29, 30, 31) . 58Table 15: Visit 13 (Day 35) Final Clinic/Early Termination Visit . 59Table 16: PK Specimen Collection Schedule . 62Table 17. Standard errors and 95% confidence interval of the pharmacokinetic endpointAUC in each arm based on the standard deviations estimated from the preliminarystudy. .75Table 18 The probability of observing a number of participants of having a safety eventgven the true event rate and the sample size in the group . 76MTN-028, Version 1.04February 12, 2015
MTN-028Phase 1 Pharmacokinetic Trial of Two Intravaginal Rings (IVRs) ContainingDifferent Dose Strengths of Vicriviroc (MK-4176) and MK-2048LIST OF ABBREVIATIONS AND CFRCHCAcquired Immunodeficiency Syndromealanine transaminaseActive pharmaceutical agentantiretroviral therapyantiretroviralAmerican Society for Microbiologyaspartate aminotransferaseAmerican Society for Testing and Materialsarea under the curvebis in die, twice a dayBehavioral Research Working Groupcomplete blood countCenters for Disease Control and PreventionCode of Federal Regulationscombination hormonal aximum concentrationClinical Microbicide Research BranchCentral nerve systemCiprofloxacincase report formClinical Trial Agreementcervical vaginal fluidCommunity Working GroupDAIDS Adverse Event Reporting SystemDivision of AIDSdeoxyribonucleic acidexpedited adverse eventElectroencephalographyEnrollmentethylene vinyl acetate(US) Food and Drug AdministrationFred Hutchinson Cancer Research CenterFederal Rules of Civil ProcedureGood Clinical Practicesgeneralized estimating equationsGood laboratory practiceGood Manufacturing PracticesHepatitis B virusHepatitis C virusHead, Eye, Ear, Nose and ThroatMTN-028, Version 1.05February 12, 2015
CSMCSSPSTIMTN-028, Version 1.0Health and Human ServicesHuman Immunodeficiency VirusHerpes simplex virushuman peripheral blood lymphocytesInternational Air Transport Associationinformed consent formsInternational Committee of the Red CrossInvestigational New DrugInternational normalized ratioInstitutional Review Boardintrauterine deviceIntravaginal Ringpotassium hydroxideLaboratory Data Management Systemlower limit of quantificationLeadership and Coordinating Centermaximum calculated percent inhibitionMerck Sharp & DohmeMicrobicide Trials Networknucleic acid amplification testnext generation ringsNational Institute of Allergy and Infectious DiseasesEunice Kennedy Shriver National Institute of Child Health and HumanDevelopmentNational Institutes of HealthNational Institute of Mental Healthno-observed-adverse-effect-levelOptimized Background TherapyOffice for Human Research ProtectionsOverall susceptibility scorePeripheral blood mononuclear cellspost-exposure prophylaxispharmacokineticsPharmaceutical Product DevelopmentPre-Exposure ProphylaxisProtocol Registration OfficeProtocol Safety Review Teamparticipant identificationRegulatory EntityRibonucleic acidRegulatory Support Centerreproductive tract infectionserious adverse eventScreeningStatistical Data Management CenterStudy Monitoring Committeestudy specific proceduressexually transmitted infection6February 12, 2015
UPMCUSAUTIVCVWHOMTN-028, Version 1.0University of Pittsburgh Medical CenterUnited States of Americaurinary tract infectionVicrivirocWorld Health Organization7February 12, 2015
MTN-028Phase 1 Pharmacokinetic Trial of Two Intravaginal Rings (IVRs) ContainingDifferent Dose Strengths of Vicriviroc (MK-4176) and MK-2048PROTOCOL TEAM ROSTERProtocol ChairAlbert Liu, MD, MPHProtocol Chair/Site InvestigatorDirector, HIV Prevention Intervention StudiesBridge HIV CRSSan Francisco Department of Public Health25 Van Ness Avenue, Suite 100San Francisco, CA 94102 USAPhone: 415-437-7408Fax: 415-431-7029Email: albert.liu@sfdph.orgMTN-028, Version 1.08February 12, 2015
Site InvestigatorAlbert Liu, MD, MPHProtocol Chair/Site InvestigatorDirector, HIV Prevention Intervention StudiesBridge HIV CRSSan Francisco Department of Public Health25 Van Ness Avenue, Suite 100San Francisco, CA 94102 USAPhone: 415-437-7408Fax: 415-431-7029Email: albert.liu@sfdph.orgMTN-028, Version 1.09February 12, 2015
US National Institutes of Health (NIH)Roberta Black, PhDChief, Clinical Microbicide Research BranchDivision of AIDS (DAIDS), National Institute of Allergy and Infectious Diseases (NIAID),National Institutes of Health (NIH) - U.S. Department of Health and Human Services (HHS)5601 Fishers Lane, Room 8B62, MSC 9831Rockville, MD 20852 USAPhone: 301-496-8199Email: rblack@niaid.nih.govNaana Cleland, MHCAHealth Specialist, Clinical Microbicide Resear
Phase 1 Pharmacokinetic Trial of Two Intravaginal Rings (IVRs) Containing Different Dose Strengths of Vicriviroc (MK-4176) and MK-2048 Microbicide Trials Network Funding Agencies: Division of AIDS, US National Institute of Allergy and Infectious Diseases US Eunice Kennedy Shriver
