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)

NCT04003103 | Completed Phase 2 Results FDA Drug

• 3 other identifiers: 8591-016Merck Protocol Number2019-001704-38
• Study Type: interventional
• Target: 242
• Locations: 3 countries
• Sites: 9

Brief Summary

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

Conditions

HIV-1 Infection

Outcome Measures

Primary Outcomes (9)

• 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 Outcomes (11)

• Area Under the Plasma Concentration-time Curve From Dosing to 672 Hours Postdose (AUC0-672) of Plasma ISL

  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

  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

  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

  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

  Up to 24 weeks

Study Arms (3)

Islatravir 60 mg

EXPERIMENTAL

60 mg islatravir + placebo for islatravir administered once monthly, orally in capsule form for 24 weeks

Drug: Islatravir; Drug: Placebo

Islatravir 120 mg

EXPERIMENTAL

120 mg islatravir administered once monthly, orally in capsule form for 24 weeks

Drug: Islatravir

Placebo

PLACEBO COMPARATOR

Placebo for islatravir administered once monthly, orally in capsule form for 24 weeks

Drug: Placebo

Interventions

Islatravir DRUG

Islatravir 30 mg capsules taken by mouth.

Also known as: MK-8591

Islatravir 120 mg; Islatravir 60 mg

Placebo DRUG

Placebo capsules taken by mouth.

Islatravir 60 mg; Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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
• 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.

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Study Sites (9)

Research Centers of America, LLC ( Site 0007)

Hollywood, Florida, 33024, United States

Location

Johns Hopkins School of Medicine - Drug Development Unit ( Site 0002)

Baltimore, Maryland, 21287, United States

Location

Celerion, Inc. ( Site 0006)

Lincoln, Nebraska, 68502, United States

Location

Magee Womens Research Institute ( Site 0001)

Pittsburgh, Pennsylvania, 15213, United States

Location

Hadassah Ein Karem Jerusalem ( Site 0016)

Jerusalem, Jerusalem, 9112001, Israel

Location

Rambam Medical Center ( Site 0017)

Haifa, 3109601, Israel

Location

JOSHA Research ( Site 0015)

Bloemfontein, Free State, 9301, South Africa

Location

Clinical HIV Research Unit CHRU ( Site 0014)

Johannesburg, Gauteng, 2092, South Africa

Location

Emavundleni Vaccine Centre ( Site 0011)

Cape Town, Western Cape, 7750, South Africa

Location

Related Publications (3)

• 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 Human Immunodeficiency Virus Type 1. J Infect Dis. 2025 Nov 14;232(5):1050-1060. doi: 10.1093/infdis/jiaf222.

  PMID: 40327547 RESULT

• Pham M, Wickremasingha P, Vargo R, Patel M, Nedrow K, Homony B, Robertson MN, Plank RM. Brief Report: Exploratory Substudy of a Phase 2 Trial to Evaluate the Pharmacokinetic Effect of Once-Monthly Islatravir on Long-Acting Reversible Contraceptives. J Acquir Immune Defic Syndr. 2025 Aug 1;99(4):374-378. doi: 10.1097/QAI.0000000000003678.

  PMID: 40260892 DERIVED

• 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.

  PMID: 33540481 DERIVED

Related Links

• Merck Clinical Trials Information

MeSH Terms

Interventions

islatravir

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme LLC

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 27, 2019
• First Posted: July 1, 2019
• Study Start: September 19, 2019
• Primary Completion: March 18, 2022
• Study Completion: November 24, 2022
• Last Updated: July 18, 2025
• Results First Posted: March 21, 2023

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will share

Locations

IL (2); ZA (3); US (4)