Safety and Pharmacokinetics of Oral Islatravir (MK-8591) Once Monthly in Participants at Low Risk of Human Immunodeficiency Virus 1 (HIV-1) Infection (MK-8591-016)

A Phase 2a, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Oral MK-8591 Once-Monthly in Participants at Low- Risk for HIV-1 Infection

This study will evaluate the safety, tolerability and pharmacokinetics (PK) of 6 once-monthly doses of oral islatravir (60 mg and 120 mg) compared with placebo in adults at low risk of HIV-1 infection

Study Overview

• Status: Completed
• Conditions: HIV-1 Infection
• Intervention / Treatment: Drug: Islatravir; Drug: Placebo

Detailed Description

This study is ongoing for collection of safety follow-up of infants born to mothers participating in the study. The present results are based on the Week 68 interim analysis.

• Study Type: Interventional
• Enrollment (Actual): 242
• Phase: Phase 2

Contacts and Locations

Study Locations

• Israel
  • Haifa, Israel, 3109601
    • Rambam Medical Center ( Site 0017)
  • Yerushalayim
    • Jerusalem, Yerushalayim, Israel, 9112001
      • Hadassah Ein Karem Jerusalem ( Site 0016)
• South Africa
  • Free State
    • Bloemfontein, Free State, South Africa, 9301
      • JOSHA Research ( Site 0015)
  • Gauteng
    • Johannesburg, Gauteng, South Africa, 2092
      • Clinical HIV Research Unit CHRU ( Site 0014)
  • Western Cape
    • Cape Town, Western Cape, South Africa, 7750
      • Emavundleni Vaccine Centre ( Site 0011)
• United States
  • Florida
    • Hollywood, Florida, United States, 33024
      • Research Centers of America, LLC ( Site 0007)
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins School of Medicine - Drug Development Unit ( Site 0002)
  • Nebraska
    • Lincoln, Nebraska, United States, 68502
      • Celerion, Inc. ( Site 0006)
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Magee Womens Research Institute ( Site 0001)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Is in general good health with acceptable laboratory values at screening
• Is confirmed HIV-uninfected based on negative HIV-1/HIV-2 test result before randomization
• Has low risk of HIV infection, within 12 months prior to screening visit or the rescreening visit (if applicable)
• Use contraceptives consistent with local regulations
• Female is not pregnant or breastfeeding, and is not a woman of childbearing potential (WOCBP)
• A WOCBP is using an acceptable contraceptive method, or is abstinent from heterosexual intercourse as their preferred and usual lifestyle; or has a negative pregnancy test.

Exclusion Criteria:

• Has hypersensitivity or other contraindication to any of the components of the study interventions as determined by the investigator
• Has an active diagnosis of hepatitis due to any cause
• Has a history of malignancy ≤5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.

• Is taking or is anticipated to require systemic immunosuppressive therapy, immune modulators, or any prohibited therapies from 30 days prior to Day

  1 through the duration of the study.

• Is currently participating in or has participated in an interventional clinical study with an investigational compound or device within 30 days prior to Day1 through the duration of the study.
• Has previously been randomized in a study and received islatravir (MK-8591).
• Female is expecting to conceive or donate eggs at any time during the study
• Has QTc interval (using Fridericia correction) >450 msec (for males) or >460 msec (for females) or deemed clinically abnormal by the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Islatravir 60 mg; 60 mg islatravir + placebo for islatravir administered once monthly, orally in capsule form for 24 weeks	Drug: Islatravir; Islatravir 30 mg capsules taken by mouth.; Other Names: MK-8591; Drug: Placebo; Placebo capsules taken by mouth.
Experimental: Islatravir 120 mg; 120 mg islatravir administered once monthly, orally in capsule form for 24 weeks	Drug: Islatravir; Islatravir 30 mg capsules taken by mouth.; Other Names: MK-8591
Placebo Comparator: Placebo; Placebo for islatravir administered once monthly, orally in capsule form for 24 weeks	Drug: Placebo; Placebo capsules taken by mouth.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With ≥1 Adverse Event (AE) Through Week 36	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.	Up to 36 weeks
Number of Participants Discontinuing From Study Therapy Due to 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.	Up to 20 weeks
Number of Participants Discontinuing From Study Therapy Due to ≥1 Drug-related AE	A drug-related AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, that is considered related to the study therapy.	Up to 20 weeks
Number of Participants With ≥1 Drug-related AE Through Week 36	A drug-related AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, that is considered related to the study intervention.	Up to 36 weeks
Number of Participants With ≥1 Serious Adverse Event (SAE) Through Week 36	An SAE is defined as any untoward medical occurrence that, at any dose, results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or is an other important medical event.	Up to 36 weeks
Number of Participants With a ≥1 Grade 3 to Grade 5 AE up to Week 36	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study therapy, whether or not considered related to the study intervention. Toxicity grading was according to the National Institutes of Health Division of AIDS (NIH DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events version 2.1 (Grade 3 is 'severe'; Grade 4 is 'potentially life-threatening'; and Grade 5 'results in death').	Up to 36 weeks
Number of Participants With ≥1 Drug-related SAE Through Week 36	An drug-related SAE is defined as any untoward medical occurrence that, at any dose, results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or is an other important medical event, that is considered related to study therapy.	Up to 36 weeks
Number of Participants With ≥1 Drug-related Grade 3 to 5 AE Through Week 36	A drug-related Grade 3 to Grade 5 AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention; has a toxicity Grade 3 (severe), 4 (potentially life-threatening), or 5 (results in death); and is considered related to study therapy. Toxicity grading was according to the NIH DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (v. 2.1).	Up to 36 weeks
Number of Participants With an AE Resulting in Death Through Week 36	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.	Up to 36 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Plasma Concentration-time Curve From Dosing to 672 Hours Postdose (AUC0-672) of Plasma ISL	The AUC0-672 of ISL after dosing on Day 1 and Day 140 is reported. Only ISL-treated participants are included in the PK analysis.	Day 1 and Day 140: predose and 30-min postdose. On Day 2 collect ~24 hours after Day 1 dose. On Weeks 4, 8, 12 and 16, collect predose. Weeks 1, 2, 3, 21, 22, 23 and 24: collect at any time during the study visit.
Maximum Plasma Concentration (Cmax) of ISL	The Cmax of ISL after dosing on Day 1 and Day 140 is reported. Only ISL-treated participants are included in the PK analysis.	Day 1 and Week 20, collect predose and 30-min postdose. On Day 2 collect ~24 hours after Day 1 dose. On Weeks 4, 8, 12 and 16, collect predose. Weeks 1, 2, 3, 21, 22, 23 and 24: collect at any time during the study visit.
Trough Plasma Concentration (Ctrough) of ISL	The plasma Ctrough of ISL after dosing on Day 1 and Day 140 is reported. Only ISL-treated participants are included in the PK analysis.	Day 1 and Week 20: predose and 30-min postdose. Day 2: 24 hours post Day 1 dose. Weeks 1, 2, 3, 21, 22, 23 and 24: any time during the study visit. Weeks 4, 8, 12 and 16: predose.
Apparent Plasma Terminal Half-life (t1/2) of ISL	The plasma t1/2 of ISL after dosing on Day 140 is reported. Only ISL-treated participants are included in the PK analysis.	Day 1 and Week 20, collect predose and 30-min postdose. On Day 2 collect ~24 hours after Day 1 dose. On Weeks 4, 8, 12 and 16, collect predose. Weeks 1, 2, 3, 21, 22, 23 and 24: collect at any time during the study visit.
Number of Participants With ≥1 AE Through Week 24	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.	Up to 24 weeks
Number of Participants With ≥1 Drug-related AE Through Week 24	A drug-related AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, that is considered related to the study intervention.	Up to 24 weeks
Number of Participants With ≥1 SAE Through Week 24	An SAE is defined as any untoward medical occurrence that, at any dose, results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or is an other important medical event.	Up to 24 weeks
Number of Participants With a ≥1 Grade 3 to Grade 5 AE up to Week 24	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study therapy, whether or not considered related to the study intervention. Toxicity grading was according to the National Institutes of Health Division of AIDS (NIH DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events version 2.1 (Grade 3 is 'severe'; Grade 4 is 'potentially life-threatening'; and Grade 5 'results in death').	Up to 24 weeks
Number of Participants With ≥1 Drug-related SAE Through Week 24	An drug-related SAE is defined as any untoward medical occurrence that, at any dose, results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or is an other important medical event, that is considered related to study therapy.	Up to 24 weeks
Number of Participants With ≥1 Drug-related Grade 3 to 5 AE Through Week 24	A drug-related Grade 3 to Grade 5 AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention; has a toxicity Grade 3 (severe), 4 (potentially life-threatening), or 5 (results in death); and is considered related to study therapy. Toxicity grading was according to the NIH DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (v. 2.1).	Up to 24 weeks
Number of Participants With an AE Resulting in Death Through Week 24	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.	Up to 24 weeks

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Devanathan AS, Cottrell ML. Pharmacology of HIV Cure: Site of Action. Clin Pharmacol Ther. 2021 Apr;109(4):841-855. doi: 10.1002/cpt.2187. Epub 2021 Mar 5.
• Hillier SL, Bekker LG, Riddler SA, Hendrix CW, Badal-Faesen S, Macdonald P, Nair G, Lombaard J, Caraco Y, Peer A, Patel M, Vargo R, Homony B, Nedrow K, Evans B, Wickremasingha P, Zhou YP, Teal V, Hwang P, McMullan C, Kaufman KD, Robertson MN, Plank RM. Safety, Tolerability, and Pharmacokinetics of Once-Monthly Oral Islatravir: a Phase 2a Study in Participants at Low Risk for Acquiring HIV-1. J Infect Dis. 2025 May 6:jiaf222. doi: 10.1093/infdis/jiaf222. Online ahead of print.

Helpful Links

• Merck Clinical Trials Information

Study record dates

Study Major Dates

• Study Start (Actual): September 19, 2019
• Primary Completion (Actual): March 18, 2022
• Study Completion (Actual): November 24, 2022

Study Registration Dates

• First Submitted: June 27, 2019
• First Submitted That Met QC Criteria: June 27, 2019
• First Posted (Actual): July 1, 2019

Study Record Updates

• Last Update Posted (Actual): July 18, 2025
• Last Update Submitted That Met QC Criteria: July 8, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Infections; Communicable Diseases; Anti-Infective Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Nucleic Acid Synthesis Inhibitors; Antiviral Agents; Reverse Transcriptase Inhibitors; Anti-Retroviral Agents; Islatravir
• Other Study ID Numbers: 8591-016; Merck Protocol Number (Other Identifier: MK-8189-011); 2019-001704-38 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: https://trialstransparency.msdclinicaltrials.com/pdf/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No