A Study of Islatravir (MK-8591) in Anti-Retroviral Therapy-Naive, Human Immunodeficiency Virus-1 Infected Participants (MK-8591-003)

Study Overview
=================
Brief Summary
-----------------
This study will evaluate the safety, tolerability, pharmacokinetics, and anti-retroviral therapy (ART) activity of islatravir (MK-8591) monotherapy in ART-naive, human immunodeficiency virus-1 (HIV-1) infected participants. The primary hypothesis is that at a safe and tolerable dose of islatravir, the true mean difference in the plasma HIV-1 ribonucleic acid (RNA) reduction from baseline between islatravir and placebo is at least 0.5 log (base10) copies/mL.

Official Title
-----------------
A Single-Dose Clinical Trial to Study the Safety, Tolerability, Pharmacokinetics, and Anti-Retroviral Activity of MK-8591 Monotherapy in Anti-Retroviral Therapy (ART)-Naive, HIV-1 Infected Patients

Conditions
-----------------
HIV-1

Intervention / Treatment
-----------------
* Drug: 1 mg islatravir
* Drug: 2 mg islatravir
* Drug: 10 mg islatravir
* Drug: 30 mg islatravir
* Drug: 0.5 mg islatravir
* Drug: 0.25 mg islatravir


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Non-pregnant, non-breast feeding, postmenopausal or surgically sterile female Female with reproductive potential agrees to use (or have male partner use) two acceptable methods of birth control Male agrees to use acceptable method of contraception during study and for 90 days after last dose of trial drug Has stable baseline health, other than HIV infection Has no significantly abnormal electrocardiogram Is HIV-1 positive Have a screening plasma HIV-1 RNA ≥ 10,000 copies/mL within 30 days prior to the treatment phase of this study. For inclusion in Panel Islatravir Extended Observation, participants must also have a screening plasma HIV-1 RNA ≤ 25,000 copies/mL within 30 days prior to the treatment phase. Is ART naive Has not received any investigational agent or marketed ART within 30 days of trial drug administration Is diagnosed with HIV-1 infection >= 3 months prior to screening Is willing to receive no other ART during treatment phase of study Has no evidence of mutations conferring resistance to nucleoside reverse transcriptase inhibitors (NRTIs) Exclusion Criteria: Is mentally or legally institutionalized/incapacitated, or has significant emotional problems, or has a history of clinically significant psychiatric disorder of the last 5 years Has a history of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological (outside of HIV-1 infection), renal, respiratory, genitourinary, major neurological abnormalities or diseases Has a history of cancer (malignancy) Has a history of significant multiple and/or severe allergies, or had an anaphylactic reaction to drugs or food Is positive for hepatitis B surface antigen Has a history of chronic Hepatitis C Had major surgery or lost 500 mL of blood with 4 weeks prior to screening visit Has participated in another investigational trial within 4 weeks prior to dosing visit Will use any medications, prescribed drugs, or herbal remedies 4 weeks prior to dosing of trial drug, up to the post-trial visit Consumes excessive amounts of alcohol, caffeinated beverages, or tobacco products Uses illicit drugs or has a history of drug abuse within the prior 2 years

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Islatravir 1 mg<br>Single oral dose of islatravir 1 mg | Drug: 1 mg islatravir<br>* Single oral dose of 1 mg islatravir administered following ≥8 hour fast<br>* Other names: MK-8591;|
| Experimental: Islatravir 2 mg<br>Single oral dose of islatravir 2 mg | Drug: 2 mg islatravir<br>* Single oral dose of 2 mg islatravir administered following ≥8 hour fast<br>* Other names: MK-8591;|
| Experimental: Islatravir 10 mg<br>Single oral dose of islatravir 10 mg | Drug: 10 mg islatravir<br>* Single oral dose of 10 mg islatravir administered following ≥8 hour fast<br>* Other names: MK-8591;|
| Experimental: Islatravir 30 mg<br>Single oral dose of islatravir 30 mg | Drug: 30 mg islatravir<br>* Single oral dose of 30 mg islatravir administered following ≥8 hour fast<br>* Other names: MK-8591;|
| Experimental: Islatravir 0.5 mg<br>Single oral dose of islatravir 0.5 mg | Drug: 0.5 mg islatravir<br>* Single oral dose of 0.5 mg islatravir administered following ≥8 hour fast<br>* Other names: MK-8591;|
| Experimental: Islatravir 0.25 mg<br>Single oral dose of islatravir 0.25 mg | Drug: 0.25 mg islatravir<br>* Single oral dose of 0.25 mg islatravir administered following ≥8 hour fast<br>* Other names: MK-8591;|
| Experimental: Islatravir 30 mg Extended Observation<br>Single oral dose of 30 mg islatravir administered following >8 hour fast. Participants will be closely monitored for viral load for up to approximately 21 days prior to starting standard of care ART. | Drug: 30 mg islatravir<br>* Single oral dose of 30 mg islatravir administered following ≥8 hour fast<br>* Other names: MK-8591;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Plasma HIV-1 RNA at 168 Hours Post-Dose | Plasma HIV-1 RNA was measured using the Roche COBAS Ampliprep/COBAS TaqMan HIV-1 test v.2.0, which has a linear range from 20 to 10,000,000 copies/mL. The lower limit of detection has 100% specificity at 20 copies/mL. Additionally, the test increases the probability of detection and expands coverage by targeting two highly conserved regions of the HIV-1 genome to compensate for the possibility of mutations or mismatches. | Baseline and 168 hours (7 days) post-dose | 
| Number of Participants With One or More Adverse Events | An adverse event (AE) is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. | Up to 21 days post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-Time Curve of Islatravir Triphosphate in Peripheral Blood Mononuclear Cells From Time 0 to 168 Hours (AUC0-168hr) | Blood was collected to measure intracellular islatravir triphosphate concentration in peripheral blood mononuclear cells and determine AUC0-168hr. | 4, 12, 24, 96, 120, 144, and 168 hours after islatravir administration. Value at predose was inferred from plasma predose sample. | 
| Maximum Concentration (Cmax) of Islatravir Triphosphate in Peripheral Blood Mononuclear Cells | Blood was collected to measure intracellular islatravir triphosphate concentration in peripheral blood mononuclear cells and determine Cmax. | 4, 12, 24, 96, 120, 144, and 168 hours after islatravir administration. Value at predose was inferred from plasma predose sample. | 
| Concentration of Islatravir Triphosphate in Peripheral Blood Mononuclear Cells at 168 Hours Post-Dose (C168hr) | Blood was collected to measure intracellular islatravir triphosphate concentration in peripheral blood mononuclear cells and determine C168hr. | 168 hours after islatravir administration | 
| Time to Maximum Concentration (Tmax) of Islatravir Triphosphate in Peripheral Blood Mononuclear Cells | Blood was collected to measure intracellular islatravir triphosphate concentration in peripheral blood mononuclear cells and determine TMax. | 4, 12, 24, 96, 120, 144, and 168 hours after islatravir administration. Value at predose was inferred from plasma predose sample. | 
| Apparent Terminal Half-Life (t1/2) of Islatravir Triphosphate in Peripheral Blood Mononuclear Cells | Blood was collected to measure intracellular islatravir triphosphate concentration in peripheral blood mononuclear cells and determine apparent terminal t1/2. | 4, 12, 24, 96, 120, 144, and 168 hours after islatravir administration. Value at predose was inferred from plasma predose sample. | 
| Area Under the Plasma Concentration-Time Curve of Islatravir From Time 0 to 168 Hours (AUC0-168hr) | Blood was collected for the determination of AUC0-168hr of islatravir in plasma. | Predose and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, and 96 hours after islatravir administration. Value at 168 hours was extrapolated. | 
| Maximum Plasma Concentration (Cmax) of Islatravir | Blood was collected for the determination of Cmax of islatravir in plasma. | Predose and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, and 96 hours after islatravir administration | 
| Time to Maximum Plasma Concentration (Tmax) of Islatravir | Blood was collected for the determination of Tmax of islatravir in plasma. | Predose and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, and 96 hours after islatravir administration | 
| Apparent Terminal Half-Life (t1/2) of Islatravir in Plasma | Blood was collected for the determination of apparent terminal t1/2 of islatravir in plasma. | Predose and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, and 96 hours after islatravir administration |