Oral Islatravir (MK-8591) Once-Monthly as Preexposure Prophylaxis (PrEP) in Men and Transgender Women Who Are at High Risk for HIV-1 Infection (MK-8591-024)

Phase 3

Terminated

Conditions: HIV Preexposure Prophylaxis

Interventions: Drug: ISL
Drug: FTC/TDF
Drug: Placebo to FTC/TDF
Drug: FTC/TAF
Drug: Placebo to FTC/TAF
Drug: Placebo to ISL

Registration Number: NCT04652700

Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary: The main purpose of the study is to evaluate the safety and tolerability of oral Islatravir (ISL) once monthly (QM) as Preexposure Prophylaxis (PrEP) in cisgender men who have sex with men (MSM) and transgender women (TGW) who have sex with men and who are at high risk of HIV-1 infection with 48 or 96 weeks of treatment and a minimum follow-up of 42 days.

Detailed Description: Based on laboratory findings of decreased lymphocyte and CD4+ T-cell counts across the islatravir program, dosing of blinded study intervention was halted on 13-Dec-2021. Blinded assessments conducted prior to then are designated as Study Part 1. During Study Part 2, participants from Part 1 were switched to PrEP therapy with emtricitabine/tenofovir disoproxil (FTC/TDF) or emtricitabine/tenofovir alafenamide (FTC/TAF) while continuing in the study, but participants, investigators, and Sponsor personnel remained blinded to the Part 1 treatment. In Part 3, participants, investigators, and all Sponsor personnel are unblinded to participant's original randomized intervention group, and participants may continue to receive unblinded FTC/TDF or FTC/TAF.

Recruitment & Eligibility

Status: TERMINATED

Sex: Male

Target Recruitment: 494

Inclusion Criteria

Has confirmed Human Immunodeficiency Virus (HIV) uninfected based on negative HIV-1/HIV-2 test result before randomization
Is sexually active with male or transgender women (TGW) partners defined as having anal sexual intercourse with a man or TGW at least once in the past month
Is at high risk for sexually acquiring HIV-1 infection based on self-report of at least 1 of the following: a) Condomless receptive anal intercourse in the 6 months prior to screening occurring outside a mutually monogamous HIV seronegative concordant relationship b) More than 5 partners (anal intercourse) in the 6 months prior to screening c) Any unprescribed stimulant drug use in the 6 months prior to screening d) Rectal or urethral gonorrhea or chlamydia or incident syphilis in the 6 months prior to screening
Participants 16 or 17 years of age must weigh ≥35 kg. Enrollment for 16- to 17-year-old participants will begin only after completion of the Sentinel Cohort IA and review of IA results by the external data monitoring committee (eDMC)
Has no plans to relocate or travel away from the site for ≥4 consecutive weeks during study participation

Exclusion Criteria

Has hypersensitivity or other contraindication to any component of the study interventions as determined by the investigator
Has chronic HBV infection or past HBV infection which could indicate risk for Hepatitis B reactivation
Has known current or chronic history of liver disease or known hepatic or biliary abnormalities, unless the participant has stable liver function tests and no evidence of hepatic synthetic dysfunction
Has a history of malignancy within 5 years of screening except for adequately treated basal cell or squamous cell skin cancer or in situ anal cancers
Has a history or current evidence of any condition, therapy, laboratory abnormality or other circumstance that might, in the opinion of the investigator, confound the results of the study or interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to enroll
Has taken cabotegravir, lenacapavir, or any other long-acting HIV prevention product at any time
Is currently receiving or is anticipated to require any prohibited therapies outlined in the study from 30 days prior to Day 1 through the duration of the study
Is currently participating in or has participated in an interventional or prevention clinical study with an investigational compound or device, within 30 days prior to Day 1 through the duration of the study
Has exclusionary laboratory values within 45 days prior to Day 1

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Islatravir (ISL) Once Monthly (QM) Group	ISL	Participants receive 60 mg tablet of ISL QM, orally plus Placebo to Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) tablet once daily (QD) or Placebo to Emtricitabine/Tenofovir Alafenamide (FTC/TAF) tablet QD, orally for up to 24 months of treatment duration.
Islatravir (ISL) Once Monthly (QM) Group	Placebo to FTC/TDF	Participants receive 60 mg tablet of ISL QM, orally plus Placebo to Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) tablet once daily (QD) or Placebo to Emtricitabine/Tenofovir Alafenamide (FTC/TAF) tablet QD, orally for up to 24 months of treatment duration.
Islatravir (ISL) Once Monthly (QM) Group	Placebo to FTC/TAF	Participants receive 60 mg tablet of ISL QM, orally plus Placebo to Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) tablet once daily (QD) or Placebo to Emtricitabine/Tenofovir Alafenamide (FTC/TAF) tablet QD, orally for up to 24 months of treatment duration.
FTC/TDF or FTC/TAF QD Group	FTC/TDF	Participants receive 200/245 mg or 200/300 mg of FTC/TDF combination tablet, QD, orally or 200/25 mg of FTC/TAF combination tablet, QD, orally at investigator's discretion plus Placebo to ISL tablet QM, orally for up to 24 months of treatment duration.
FTC/TDF or FTC/TAF QD Group	FTC/TAF	Participants receive 200/245 mg or 200/300 mg of FTC/TDF combination tablet, QD, orally or 200/25 mg of FTC/TAF combination tablet, QD, orally at investigator's discretion plus Placebo to ISL tablet QM, orally for up to 24 months of treatment duration.
FTC/TDF or FTC/TAF QD Group	Placebo to ISL	Participants receive 200/245 mg or 200/300 mg of FTC/TDF combination tablet, QD, orally or 200/25 mg of FTC/TAF combination tablet, QD, orally at investigator's discretion plus Placebo to ISL tablet QM, orally for up to 24 months of treatment duration.

Primary Outcome Measures

Name	Time	Method
Number of Participants Who Experienced an Adverse Event (AE) During Blinded Treatment	Up to approximately 10.5 months	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who experienced an AE will be reported for each treatment arm.
Number of Participants Who Discontinued From Blinded Study Treatment Due to an AE	Up to approximately 9 months	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who experienced an AE will be reported for each treatment arm.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Confirmed HIV-1 Infection	Up to approximately 10.5 months	The number of participants with confirmed HIV-1 infections during the blinded treatment period is presented.

Trial Locations

Locations (25): Howard Brown Health Center ( Site 0004)
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Chicago, Illinois, United States
Desmond Tutu HIV Foundation ( Site 0202)
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Cape Town, Western Cape, South Africa
Bridge HIV - San Francisco Department of Public Health ( Site 0003)
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San Francisco, California, United States
The Crofoot Research Center ( Site 0025)
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Houston, Texas, United States
University of Alabama at Birmingham-UAB 1917 Research Clinic ( Site 0007)
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Birmingham, Alabama, United States
Global Research Institute ( Site 0031)
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Los Angeles, California, United States
UCLA Center for Clinical AIDS Research and Education ( Site 0011)
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Los Angeles, California, United States
Midway Immunology and Research Center ( Site 0014)
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Fort Pierce, Florida, United States
Rutgers New Jersey Medical School-Clinical Research Center ( Site 0017)
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Newark, New Jersey, United States
The GW Medical Faculty Associates-Medicine ( Site 0033)
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Washington, District of Columbia, United States
The University of Mississippi Medical Center ( Site 0012)
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Jackson, Mississippi, United States
Centro de Referência e Treinamento DST/AIDS ( Site 0351)
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Sao Paulo, Brazil
University of Miami Miller School of Medicine-Infectious Disease ( Site 0029)
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Miami, Florida, United States
Ponce De Leon Center Grady Health ( Site 0032)
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Atlanta, Georgia, United States
Central Texas Clinical Research ( Site 0002)
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Austin, Texas, United States
Hôpital Saint-Louis-Infectious Diseases and tropical diseases ( Site 0151)
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Paris, Ile-de-France, France
Center Hospital of the National Center for Global Health and Medicine ( Site 0101)
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Shinjyuku-ku, Tokyo, Japan
Perinatal HIV Research Unit (PHRU)-HIV Prevention CRS ( Site 0203)
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Johannesburg, Gauteng, South Africa
Research Institute for Health Sciences-Research Institute for Health Sciences Building 1 ( Site 0052
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Chiang Mai, Thailand
Via Libre ( Site 0404)
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Lima, Peru
Wits Reproductive Health and HIV Institute (WRHI)-Research Center ( Site 0201)
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Johannesburg, Gauteng, South Africa
HIV Netherlands Australia Thailand Research Collaboration ( Site 0056)
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Bangkok, Krung Thep Maha Nakhon, Thailand
Chulalongkorn University-Pediatrics ( Site 0051)
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Bangkok, Krung Thep Maha Nakhon, Thailand
The University of North Carolina at Chapel Hill ( Site 0019)
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Chapel Hill, North Carolina, United States
Orlando Immunology Center ( Site 0010)
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Orlando, Florida, United States