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)

Study Overview
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Brief Summary
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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
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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. 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. Screening and randomization of new participants have stopped, with no new participants being enrolled in Part 2 or Part 3.

Official Title
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A Phase 3, Randomized, Active-Controlled, Double-Blind Clinical Study to Evaluate the Efficacy and Safety of Oral Islatravir Once-Monthly as Preexposure Prophylaxis in Cisgender Men and Transgender Women Who Have Sex With Men, and Are at High Risk for HIV-1 Infection

Conditions
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HIV Preexposure Prophylaxis

Intervention / Treatment
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* Drug: ISL
* Drug: FTC/TDF
* Drug: FTC/TAF
* Drug: Placebo to ISL
* Drug: Placebo to FTC/TDF
* Drug: Placebo to FTC/TAF


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Islatravir (ISL) Once Monthly (QM) Group<br>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. | Drug: ISL<br>* ISL 60 mg tablet, QM, orally for up to 24 months<br>* Other names: MK-8591;Drug: Placebo to FTC/TDF<br>* Placebo FTC/TDF 0 mg tablets QD, orally for up to 24 months<br>Drug: Placebo to FTC/TAF<br>* Placebo FTC/TAF 0 mg tablets QD, orally for up to 24 months<br>|
| Active Comparator: FTC/TDF or FTC/TAF QD Group<br>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. | Drug: FTC/TDF<br>* Participants receive 200/245 mg of FTC/TDF combination tablet, QD, orally for up to 24 months<br>* Other names: Emtricitabine/Tenofovir Disoproxil Fumarate;Drug: FTC/TAF<br>* Participants receive 200/25 mg of FTC/TAF combination tablet, QD, orally for up to 24 months<br>* Other names: Emtricitabine/Tenofovir Alafenamide;Drug: Placebo to ISL<br>* Placebo ISL 0 mg tablets QM, orally for up to 24 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Experienced an Adverse Event (AE) | 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 percentage of participants who experienced an AE will be reported for each treatment arm. | Up to approximately 26 months | 
| Percentage of Participants Who Discontinued Study Treatment Due to an AE | 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 percentage of participants who experienced an AE will be reported for each treatment arm. | Up to approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence Rate Per Year of Confirmed HIV-1 infection Among Participants | Incidence rate per year of confirmed HIV-1 infections is the number of participants with confirmed HIV-1 infections divided by the amount of person-years of follow-up time to HIV-1 infection status. The secondary incidence analysis to compare the incidence rate per year of confirmed HIV-1 Infections between the ISL QM arm and the FTC/TDF or FTC/TAF QD arm participants. HIV serology tests and PCR tests will be done at pre-specified timepoints to confirm HIV-1 infection. | Up to approximately 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Preexposure prophylaxis (PrEP), Prevention