Activity of MK-8504 in Anti-retroviral-naïve, Human Immunodeficiency Virus 1 (HIV-1) Infected Participants (MK-8504-002)

Study Overview
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Brief Summary
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This study aims to evaluate the safety, tolerability, pharmacokinetics (PK), and anti-retroviral therapy (ART) activity of monotherapy with MK-8504 (a tenofovir pro-drug), in ART-naïve Human Immunodeficiency Virus (HIV)-1 infected participants. The primary hypothesis is that MK-8504, at a dose that is sufficiently safe and well tolerated, has superior antiretroviral activity compared to placebo, as measured by change from baseline in plasma HIV-1 ribonucleic acid (RNA) at 168 hours post-dose.

Official Title
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A Single-Dose Clinical Trial to Study the Safety, Tolerability, Pharmacokinetics, and Anti-Retroviral Activity of MK-8504 Monotherapy in Anti-Retroviral Therapy (ART)-Naïve, HIV-1 Infected Patients

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: MK-8504


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or non-pregnant and non-breast feeding female Have a Body Mass Index (BMI) ≤35 kg/m^2 Other than HIV infection, have stable baseline health based on medical history, physical examination, vital sign measurements, and laboratory safety test Is documented HIV-1 positive Is diagnosed with HIV-1 infection 3 months prior to screening Is ART-naïve Has not received an investigational agent or marketed ART within 30 days of study drug administration and is willing to receive no other ART for the duration of this study Agree to follow smoking and other trial restrictions Exclusion Criteria: Is mentally or legally institutionalized / incapacitated, has significant emotional problems at the time of pretrial (screening) visit or expected during the conduct of the trial 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 or major neurological (including stroke and chronic seizures) abnormalities or diseases Has a history of cancer (malignancy) Has a history of significant multiple and/or severe allergies (e.g. food, drug, latex allergy), or has had an anaphylactic reaction or significant intolerability (i.e. systemic allergic reaction) to prescription or non-prescription drugs or food Is positive for hepatitis B surface antigen Has a history of chronic Hepatitis C Has had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to the pretrial (screening) visit. Has participated in another investigational trial within 4 weeks or 5 half-lives, whichever is greater, prior to the Day 1 Dosing visit Is unable to refrain from or anticipates the use of any medication, including prescription and non-prescription drugs or herbal remedies beginning approximately 2 weeks (or 5 half-lives) prior to administration of the initial dose of trial drug, throughout the trial, until the post-trial visit Consumes greater than 3 glasses of alcoholic beverages or distilled spirits per day Consumes excessive amounts, defined as greater than 6 servings of coffee, tea, cola, energy-drinks, or other caffeinated beverages per day Is an excessive smoker (i.e., more than 10 cigarettes/day) and is unwilling to restrict smoking to ≤10 cigarettes per day Have clinically significant abnormality on the electrocardiogram (ECG) performed at the prestudy (screening) visit and/or prior to administration of the initial dose of study drug Has a positive urine drug screen (except for cannabis) at screening and/or predose, rechecks are allowed

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MK-8504 100 mg (Panel A)<br>Participants receive a single oral dose of MK-8504 100 mg. | Drug: MK-8504<br>* After at least an 8-hour fast, a single oral dose of MK-8504 will be administered in capsule form.<br>|
| Experimental: MK-8504 240 mg (Panel B)<br>Participants receive a single oral dose of MK-8504 240 mg. | Drug: MK-8504<br>* After at least an 8-hour fast, a single oral dose of MK-8504 will be administered in capsule form.<br>|
| Experimental: MK-8504 ≤240 mg (Panel C)<br>Participants receive a single oral dose of MK-8504 ≤240 mg. | Drug: MK-8504<br>* After at least an 8-hour fast, a single oral dose of MK-8504 will be administered in capsule form.<br>|
| Experimental: MK-8504 ≤240 mg (Panel D)<br>Participants receive a single oral dose of MK-8504 ≤240 mg. | Drug: MK-8504<br>* After at least an 8-hour fast, a single oral dose of MK-8504 will be administered in capsule form.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Plasma HIV-1 Ribonucleic Acid (RNA) at 168 Hours Post-Dose | Plasma samples were collected from participants after a single dose of MK-8504 to assess viral load. The log10 plasma HIV-RNA (copies/mL) measurements from participants in each panel were pooled and analyzed based on a longitudinal data analysis model. Change from baseline to 168 hours post-dose was determined for each treatment group. Results are expressed as change in HIV RNA log10 (copies/mL). | Baseline, 168 hours post-dose | 
| Number of Participants Who Experienced At Least One Adverse Event (AE) | An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of the Sponsor's product, was also an AE. The number of participants experiencing at least one AE was reported for each arm. | From Day 1 through Post-Trial Visit (up to 25 days) | 
| Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) | An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of the Sponsor's product, was also an AE. The number of participants that discontinued study treatment due to an AE was reported for each arm. | Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-Time Curve of MK-8504 in Plasma From Time 0 to Last Measurable Concentration (AUC0-last) | Plasma samples were collected in a fasted state pre- and post-dose and used to determine AUC0-last of plasma MK-8504. AUC0-last was defined as the area under the concentration time curve of plasma MK-8504 from time 0 to last measurement, following a single dose of MK-8504. | Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose | 
| Area Under the Concentration-Time Curve of MK-8504 in Plasma From Time 0 to Infinity (AUC0-inf) | Plasma samples were collected in a fasted state pre- and post-dose and used to determine AUC0-inf of plasma MK-8504. AUC0-inf was defined as the area under the concentration time curve of plasma MK-8504 from time 0 to infinite time, following a single dose of MK-8504. | Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose | 
| Area Under the Concentration-Time Curve of MK-8504 in Plasma From Time 0 to 168 Hours (AUC0-168hr) | Plasma samples were collected in a fasted state pre- and post-dose and used to determine AUC0-168hr of plasma MK-8504. Because plasma MK-8504 was expected to rapidly disappear from plasma based on prior experience with healthy participants, sampling was done until 72 hrs and AUC0-168 hr was computed from these data assuming 1) a mono-exponential concentration decline after 72hrs; 2) accurate estimation of the elimination rate based on available data; and 3) no involvement of other processes besides elimination after 72 hrs. | Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose | 
| Time to Maximum Concentration of MK-8504 in Plasma (Tmax) | Plasma samples were collected in a fasted state pre- and post-dose and used to determine Tmax of plasma MK-8504. Tmax was defined as the time at which maximum concentration of MK-8504 in plasma was observed, following a single dose of MK-8504. | Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose | 
| Maximum Concentration of MK-8504 in Plasma (Cmax) | Plasma samples were collected in a fasted state pre- and post-dose and used to determine Cmax of plasma MK-8504. Cmax was defined as the maximum concentration of MK-8504 in plasma observed, following a single dose of MK-8504. | Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose | 
| Apparent Terminal Half Life of MK-8504 in Plasma (t½) | Plasma samples were collected in a fasted state pre- and post-dose and used to determine t½ of plasma MK-8504. t½ was defined as the time required to divide the plasma concentration by two after reaching pseudo-equilibrium, following a single dose of MK-8504. | Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose | 
| Apparent Total Clearance of MK-8504 in Plasma (CL/F) | Plasma samples were collected in a fasted state pre- and post-dose and used to determine CL/F of plasma MK-8504. CL/F was defined as the apparent total clearance of the drug from plasma after oral administration, following a single dose of MK-8504. | Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose | 
| Apparent Volume of Distribution During Terminal Phase (Vz/F) of MK-8504 in Plasma | Plasma samples were collected in a fasted state pre- and post-dose and used to determine Vz/F of plasma MK-8504. Vz/F was defined as the apparent volume of distribution of the drug in plasma during the terminal phase after non-intravenous administration, following a single dose of MK-8504. | Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose | 
| Intracellular Area Under the Concentration-Time Curve of Tenofovir-Diphosphate (TFV-DP) From Time 0 to 168 Hours (Intracellular AUC0-168hr) In Peripheral Blood Mononuclear Cells (PBMCs) | Blood samples were collected in a fasted state pre- and post-dose, processed for PBMC samples, and used to determine the intracellular AUC0-168hr of TFP-DP in PBMCs. TFV-DP is formed via metabolism of MK-8504 in plasma, PBMC and in other tissues. Intracellular AUC0-168hr was defined as the area under the concentration time curve of TFV-DP in PBMCs from time 0 to 168 hours, following a single dose of MK-8504. | Pre-dose, 4, 12, 24, 48, 72, 96, and 168 hours post-dose | 
| Intracellular Area Under the Concentration-Time Curve of Tenofovir-Diphosphate (TFV-DP) From Time 0 to Infinity (Intracellular AUC0-inf) In Peripheral Blood Mononuclear Cells (PBMCs) | Blood samples were collected in a fasted state pre- and post-dose, processed for PBMC samples, and used to determine the intracellular AUC0-inf of TFV-DP in PBMCs. TFV-DP is formed via metabolism of MK-8504 in plasma, PBMC and in other tissues. Intracellular AUC0-inf was defined as the area under the concentration time curve of TFV-DP in PBMCs from time 0 to infinite time, following a single dose of MK-8504. | Pre-dose, 4, 12, 24, 48, 72, 96, 168, 240, 384, and 600 hours post-dose | 
| Intracellular Time to Maximum Concentration (Intracellular Tmax) of Tenofovir-Diphosphate (TFV-DP) In Peripheral Blood Mononuclear Cells (PBMCs) | Blood samples were collected in a fasted state pre- and post-dose, processed for PBMC samples, and used to determine the intracellular Tmax of TFV-DP. TFV-DP is formed via metabolism of MK-8504 in plasma, PBMC and in other tissues. Intracellular Tmax was defined as the time at which maximum intracellular concentration of TFV-DP in PBMCs was observed, following a single dose of MK-8504. | Pre-dose, 4, 12, 24, 48, 72, 96, 168, 240, 384, and 600 hours post-dose | 
| Intracellular Maximum Concentration (Intracellular Cmax) of Tenofovir-Diphosphate (TFV-DP) In Peripheral Blood Mononuclear Cells (PBMCs) | Blood samples were collected in a fasted state pre- and post-dose, processed for PBMC samples, and used to determine the intracellular Cmax of TFV-DP. TFV-DP is formed via metabolism of MK-8504 in plasma, PBMC and in other tissues. Intracellular Cmax was defined as the maximum intracellular concentration of TFV-DP in PBMCs observed, following a single dose of MK-8504. | Pre-dose, 4, 12, 24, 48, 72, 96, 168, 240, 384, and 600 hours post-dose | 
| Intracellular Apparent Terminal Half Life (Intracellular t½) of Tenofovir-Diphosphate (TFV-DP) In Peripheral Blood Mononuclear Cells (PBMCs) | Blood samples were collected in a fasted state pre- and post-dose, processed for PBMC samples, and used to determine the intracellular t½ of TFV-DP. TFV-DP is formed via metabolism of MK-8504 in plasma, PBMC and in other tissues. Intracellular t½ was defined as the time required to divide the intracellular concentration by two after reaching pseudo-equilibrium, following a single dose of MK-8504. | Pre-dose, 4, 12, 24, 48, 72, 96, 168, 240, 384, and 600 hours post-dose | 
| Intracellular Concentration of Tenofovir-Diphosphate (TFV-DP) at 168 Hours (Intracellular C168hr) In Peripheral Blood Mononuclear Cells (PBMCs) | Blood samples were collected in a fasted state, processed for PBMC samples, and used to determine the intracellular C168hr of TFV-DP. TFV-DP is formed via metabolism of MK-8504 in plasma, PBMC and in other tissues. Intracellular C168hr was defined as the intracellular concentration of TFV-DP in PBMCs at 168 hours, following a single dose of MK-8504. | 168 hours post-dose | 
| Area Under the Concentration-Time Curve of Tenofovir in Plasma From Time 0 to Last Measurable Concentration (AUC0-last) | Plasma samples were collected in a fasted state pre- and post-dose and used to determine AUC0-last of plasma tenofovir. AUC0-last was defined as the area under the concentration time curve of plasma tenofovir from time 0 to last measurement, following a single dose of MK-8504. | Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose | 
| Area Under the Concentration-Time Curve of Tenofovir in Plasma From Time 0 to Infinity (AUC0-inf) | Plasma samples were collected in a fasted state pre- and post-dose and used to determine AUC0-inf of plasma tenofovir. AUC0-inf was defined as the area under the concentration time curve of plasma tenofovir from time 0 to infinite time, following a single dose of MK-8504. | Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose | 
| Area Under the Concentration-Time Curve of Tenofovir in Plasma From Time 0 to 168 Hours (AUC0-168hr) | Plasma samples were collected in a fasted state pre- and post-dose and used to determine AUC0-168hr of plasma tenofovir. Because plasma tenofovir was expected to rapidly disappear from plasma based on prior experience with healthy participants, sampling was done until 72 hrs and AUC0-168 hr was computed from these data assuming 1) a mono-exponential concentration decline after 72hrs; 2) accurate estimation of the elimination rate based on available data; and 3) no involvement of other processes besides elimination after 72 hrs. | Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose | 
| Time to Maximum Concentration of Tenofovir in Plasma (Tmax) | Plasma samples were collected in a fasted state pre- and post-dose and used to determine Tmax of plasma tenofovir. Tmax was defined as the time at which maximum concentration of tenofovir in plasma was observed, following a single dose of MK-8504. | Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose | 
| Maximum Concentration of Tenofovir in Plasma (Cmax) | Plasma samples were collected in a fasted state pre- and post-dose and used to determine Cmax of plasma tenofovir. Cmax was defined as the maximum concentration of tenofovir in plasma observed, following a single dose of MK-8504. | Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose | 
| Apparent Terminal Half Life of Tenofovir in Plasma (t½) | Plasma samples were collected in a fasted state pre- and post-dose and used to determine t½ of plasma tenofovir. t½ was defined as the time required to divide the plasma concentration by two after reaching pseudo-equilibrium, following a single dose of MK-8504. | Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose |