Oral ISL QM as PrEP in Cisgender Women at High Risk for HIV-1 Infection (MK-8591-022)

Study Overview
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Brief Summary
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This study will evaluate whether oral islatravir (ISL) is effective in preventing Human Immunodeficiency Virus Type 1 (HIV-1) infection in women at high-risk for HIV-1 infection. The study will compare oral ISL taken once a month with standard-of-care medication for prevention of HIV-1 infection, emtricitabine/tenofovir disoproxil (FTC/TDF), taken once per day. The primary hypothesis is that oral ISL is more effective than FTC/TDF at reducing the incidence rate per year of confirmed HIV-1 infections.

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 and screening and randomization of new participants was ended. Blinded assessments conducted prior to this date are designated as Study Part 1. During Study Part 2, participants from Part 1 have the option to receive daily FTC/TDF while continuing in the study. Study Part 3 was added to unblind each participant's Part 1 study intervention assignment, continue participants on FTC/TDF, and monitor safety.

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 Women at High Risk for HIV-1 Infection

Conditions
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HIV-I, Human Immunodeficiency Virus Type 1, Prophylaxis

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed HIV-uninfected based on negative HIV-1/HIV-2 test results before randomization. Sexually active (vaginal and/or anal sex) with a male sexual partner in the 30 days prior to screening. High risk for HIV-1 infection. Not pregnant or breastfeeding, and one of the following conditions applies: Not a woman of childbearing potential (WOCBP) or is a WOCBP and is using an acceptable contraceptive method during the intervention period and for at least 42 days after the last dose. A WOCBP must have a negative pregnancy test within 24 hours prior to the first dose of study intervention. Exclusion Criteria: Hypersensitivity or other contraindication to any of the components of the study interventions as determined by the investigator. Findings of chronic hepatitis B virus (HBV) infection or past HBV. Current or chronic history of liver disease. History of malignancy within 5 years of screening except for adequately-treated basal cell or squamous cell skin cancer, or in situ cervical cancer. Past or current use of cabotegravir, lenacapavir, or any other long-acting HIV prevention product. Currently participating in or has participated in an interventional clinical study with an investigational compound or device, within 30 days prior to Day 1. Expecting to conceive or donate eggs at any time during the study.

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ISL QM<br>ISL (islatravir) once monthly AND placebo to FTC/TDF (emtricitabine/tenofovir disoproxil) once daily during Part 1. | Drug: Islatravir<br>* Oral 60 mg tablet administered once monthly during Part 1.<br>* Other names: MK-8591;Drug: Placebo to FTC/TDF<br>* 0 mg tablet administered once daily during Part 1.<br>|
| Active Comparator: FTC/TDF QD<br>FTC/TDF (TRUVADA™ or generic product emtricitabine/tenofovir disoproxil) administered once daily in Parts 1, 2, and 3. Placebo to ISL (islatravir) also administered once monthly during Part 1. | Drug: FTC/TDF<br>* Each tablet contains 200 mg emtricitabine and 245 mg of tenofovir disoproxil (equivalent to 300 mg tenofovir disoproxil fumarate or 201.22 mg tenofovir disproxil phosphate), administered orally once daily in Parts 1, 2, and 3.<br>* Other names: Emtricitabine/Tenofovir disoproxil fumarate;Drug: Placebo to ISL<br>* 0 mg tablet administered orally once monthly in Part 1.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence Rate Per Year of Confirmed HIV-1 Infections | Incidence rate per year of confirmed HIV-1 infections is the number of participants with confirmed HIV-1 infections divided by the total person-years of follow-up time to HIV-1 infection status. The primary analysis will compare the incidence rate per year of confirmed HIV-1 Infections between the ISL QM arm participants and incidence rate per year of confirmed HIV-1 Infections in the FTC/TDF QD arm participants. HIV serology tests and polymerase chain reaction (PCR) tests will be done at pre-specified timepoints to confirm HIV-1 infection. | Up to approximately 36 months | 
| Percentage of Participants Who Experienced One or More Adverse Events | An adverse event (AE) is any untoward medical occurrence in a study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign, symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. | Up to approximately 37 months | 
| Percentage of Participants Who Discontinued Treatment Due to an Adverse Event | An adverse event (AE) is any untoward medical occurrence in a study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign, symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. | Up to approximately 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence Rate per Year of Confirmed HIV-1 Infections Among Participants | Incidence rate per year of confirmed HIV-1 infections is the number of participants with confirmed HIV-1 infections divided by the total person-years of follow-up time to HIV-1 infection status. The secondary analysis will compare the incidence rate per year of confirmed HIV-1 Infections between the ISL QM arm participants and the background incidence rate calculated from screened participants. The background incidence rate will be estimated using tests based on biomarkers that can differentiate recent from nonrecent infections in the population screened for this study. | Up to approximately 36 months | 

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