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)

• ClinicalTrials.gov Identifier: NCT04003103
• Recruitment Status: Completed
• First Posted: July 1, 2019
• Results First Posted: March 21, 2023
• Last Update Posted: April 12, 2023
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Study Description

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

Condition or disease	Intervention/treatment	Phase
HIV-1 Infection	Drug: Islatravir; Drug: Placebo	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 242 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• Official Title: 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
• Actual Study Start Date: September 19, 2019
• Actual Primary Completion Date: March 18, 2022
• Actual Study Completion Date: November 24, 2022

Arms and Interventions

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 Name: 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 Name: 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.

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With ≥1 Adverse Event (AE) Through Week 36 [ Time Frame: Up to 36 weeks ]
   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.
2. Number of Participants Discontinuing From Study Therapy Due to AE [ Time Frame: Up to 20 weeks ]
   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.
3. Number of Participants Discontinuing From Study Therapy Due to ≥1 Drug-related AE [ Time Frame: Up to 20 weeks ]
   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.
4. Number of Participants With ≥1 Drug-related AE Through Week 36 [ Time Frame: Up to 36 weeks ]
   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.
5. Number of Participants With ≥1 Serious Adverse Event (SAE) Through Week 36 [ Time Frame: Up to 36 weeks ]
   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.
6. Number of Participants With a ≥1 Grade 3 to Grade 5 AE up to Week 36 [ Time Frame: Up to 36 weeks ]
   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').
7. Number of Participants With ≥1 Drug-related SAE Through Week 36 [ Time Frame: Up to 36 weeks ]
   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.
8. Number of Participants With ≥1 Drug-related Grade 3 to 5 AE Through Week 36 [ Time Frame: Up to 36 weeks ]
   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).
9. Number of Participants With an AE Resulting in Death Through Week 36 [ Time Frame: Up to 36 weeks ]
   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.

Secondary Outcome Measures :

1. Area Under the Plasma Concentration-time Curve From Dosing to 672 Hours Postdose (AUC0-672) of Plasma ISL [ Time Frame: 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. ]
   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.
2. Maximum Plasma Concentration (Cmax) of ISL [ Time Frame: 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. ]
   The Cmax of ISL after dosing on Day 1 and Day 140 is reported. Only ISL-treated participants are included in the PK analysis.
3. Trough Plasma Concentration (Ctrough) of ISL [ Time Frame: 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. ]
   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.
4. Apparent Plasma Terminal Half-life (t1/2) of ISL [ Time Frame: 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. ]
   The plasma t1/2 of ISL after dosing on Day 140 is reported. Only ISL-treated participants are included in the PK analysis.
5. Number of Participants With ≥1 AE Through Week 24 [ Time Frame: Up to 24 weeks ]
   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.
6. Number of Participants With ≥1 Drug-related AE Through Week 24 [ Time Frame: Up to 24 weeks ]
   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.
7. Number of Participants With ≥1 SAE Through Week 24 [ Time Frame: Up to 24 weeks ]
   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.
8. Number of Participants With a ≥1 Grade 3 to Grade 5 AE up to Week 24 [ Time Frame: Up to 24 weeks ]
   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').
9. Number of Participants With ≥1 Drug-related SAE Through Week 24 [ Time Frame: Up to 24 weeks ]
   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.
10. Number of Participants With ≥1 Drug-related Grade 3 to 5 AE Through Week 24 [ Time Frame: Up to 24 weeks ]
    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).
11. Number of Participants With an AE Resulting in Death Through Week 24 [ Time Frame: Up to 24 weeks ]
    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.

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, Florida

Research Centers of America, LLC ( Site 0007)

Hollywood, Florida, United States, 33024

United States, Maryland

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

Baltimore, Maryland, United States, 21287

United States, Nebraska

Celerion, Inc. ( Site 0006)

Lincoln, Nebraska, United States, 68502

United States, Pennsylvania

Magee Womens Research Institute ( Site 0001)

Pittsburgh, Pennsylvania, United States, 15213

Israel

Hadassah Ein Karem Jerusalem ( Site 0016)

Jerusalem, Yerushalayim, Israel, 9112001

Rambam Medical Center ( Site 0017)

Haifa, Israel, 3109601

South Africa

JOSHA Research ( Site 0015)

Bloemfontein, Free State, South Africa, 9301

Clinical HIV Research Unit CHRU ( Site 0014)

Johannesburg, Gauteng, South Africa, 2092

Emavundleni Vaccine Centre ( Site 0011)

Cape Town, Western Cape, South Africa, 7750

Sponsors and Collaborators

Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

  Study Documents (Full-Text)

Documents provided by Merck Sharp & Dohme LLC:

Study Protocol  [PDF] December 8, 2021

Statistical Analysis Plan  [PDF] December 8, 2021

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT04003103
• Other Study ID Numbers: 8591-016; Merck Protocol Number ( Other Identifier: MK-8591-016 ); 2019-001704-38 ( EudraCT Number )
• First Posted: July 1, 2019
• Results First Posted: March 21, 2023
• Last Update Posted: April 12, 2023
• Last Verified: April 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Infections; Communicable Diseases; Disease Attributes; Pathologic Processes; Islatravir; Antiviral Agents; Anti-Infective Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Anti-Retroviral Agents