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)

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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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

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: Islatravir
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

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 60 mg<br>60 mg islatravir + placebo for islatravir administered once monthly, orally in capsule form for 24 weeks | Drug: Islatravir<br>* Islatravir 30 mg capsules taken by mouth.<br>* Other names: MK-8591;Drug: Placebo<br>* Placebo capsules taken by mouth.<br>|
| Experimental: Islatravir 120 mg<br>120 mg islatravir administered once monthly, orally in capsule form for 24 weeks | Drug: Islatravir<br>* Islatravir 30 mg capsules taken by mouth.<br>* Other names: MK-8591;|
| Placebo Comparator: Placebo<br>Placebo for islatravir administered once monthly, orally in capsule form for 24 weeks | Drug: Placebo<br>* Placebo capsules taken by mouth.<br>|

What is the study measuring?
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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 |