Safety, Tolerability, Pharmacokinetics, and Anti-Retroviral Activity of MK-8558 Monotherapy in Anti-Retroviral-Naïve HIV-1 Infected Participants (MK-8558-002)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and anti-retroviral activity of MK-8558 monotherapy in anti-retroviral-naïve human immunodeficiency virus type 1 (HIV-1) infected participants. The primary hypothesis is that at a dose that exhibits an acceptable safety and tolerability profile, MK-8558 has superior anti-retroviral activity compared to historical placebo data.

Official Title
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A Single-Dose Clinical Trial to Study the Safety, Tolerability, Pharmacokinetics, and Anti-Retroviral Activity of MK-8558 Monotherapy in Anti-Retroviral-Naïve HIV-1 Infected Participants

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: MK-8558


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Other than having HIV infection, is in good health based on medical history, physical examination, vital sign (VS) measurements, and laboratory safety tests, at the pre-study (screening) visit and/or prior to administration of the study drug Is documented as being HIV-1 positive Has a screening plasma HIV-1 ribonucleic acid (RNA) ≥ 2,500 copies/mL within 30 days prior to the treatment phase of this study Has a screening plasma cluster of differentiation 4+ (CD4+) T-cell count of >200/mm^3 Is antiretroviral therapy (ART)-naïve Is willing to receive no other ART prior to Day 11 post-dose of the trial, unless the physician/Investigator believes that there is a strong indication to start ART before Day 11 Has a Body Mass Index (BMI) ≤35 kg/m^2 Males must agree to abstinence, or barrier contraception plus partner contraception, unless confirmed to be azoospermic due to vasectomy or medical cause, for at least 35 days after the last dose of MK-8558 Females must not be pregnant or breastfeeding, and must be a woman of nonchildbearing potential, or a woman of childbearing potential using highly effective birth control with low user dependency or who is abstinent on a long-term and persistent basis during the intervention period and at least 35 days after the last dose of study medication Exclusion Criteria: Has acute (primary) HIV-1 infection Has a history of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic (with the exception of Gilbert's disease), immunological (outside of HIV-1 infection), renal, respiratory, genitourinary, or major neurological (including stroke and chronic seizures) abnormalities or diseases Is mentally or legally incapacitated or has a history of a clinically significant psychiatric disorder (with the exception of situational depression) of the last 5 years Has a history of cancer unless disease is adequately treated and deemed cured Has an estimated creatinine clearance (CrCl) ≤ 90 mL/min Has a history of significant multiple and/or severe allergies, or has had an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food, or has hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption Is positive for hepatitis B surface antigen Has a history of chronic hepatitis C unless there has been documented cure Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to the pre-study (screening) visit Is unable to refrain from or anticipates the use of any medication, including prescription and nonprescription drugs or herbal remedies beginning approximately 2 weeks (or 5 half-lives) prior to administration of the initial dose of study drug, throughout the study, until the post-study visit. There may be certain medications that are permitted Has participated in another investigational study within 4 weeks (or 5 half-lives, whichever is greater) prior to the pre-study (screening) visit. The window will be derived from the date of the last visit in the previous study Is under the age of legal consent or not capable of giving consent Has been committed to an institution by way of official or judicial order Is an excessive smoker (i.e., more than 10 cigarettes/day) and is unwilling to restrict smoking to ≤10 cigarettes per day Consumes more than 3 glasses of alcoholic beverages (1 glass is approximately equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 mL/1 ounce]) per day. Participants who consume 4 glasses of alcoholic beverages per day may be enrolled at the discretion of the investigator Consumes excessive amounts, defined as more than 6 servings (1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or other caffeinated beverages per day Has a positive urine drug screen (except for cannabis) at screening and/or pre-dose; 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Panel A. MK-8558 400 mg<br>Single oral dose of MK-8558 administered at 400 mg following a 10-hour fast. | Drug: MK-8558<br>* Single dose of MK-8558 administered as a tablet at a dose up to 1600 mg.<br>|
| Experimental: Panel B. MK-8558 at dose level 2<br>Single oral dose of MK-8558 administered at dose level 2 following a 10-hour fast. Dose level 2 shall not exceed 900 mg. Per protocol, dose will be selected following review of data from panel A. | Drug: MK-8558<br>* Single dose of MK-8558 administered as a tablet at a dose up to 1600 mg.<br>|
| Experimental: Panel C. MK-8558 at dose level 3<br>Single oral dose of MK-8558 administered at dose level 3 following a 10-hour fast. Dose level 3 shall not exceed 1600 mg. Per protocol, dose will be selected following review of data from panel B. | Drug: MK-8558<br>* Single dose of MK-8558 administered as a tablet at a dose up to 1600 mg.<br>|
| Experimental: Panel D. MK-8558 at dose level 4<br>Single oral dose of MK-8558 administered at dose level 4 following a low-fat breakfast. Dose level 4 shall not exceed 1600 mg. Per protocol, Panel D is optional pending results of Panels A-C, and dose will be selected following review of data from panel C. | Drug: MK-8558<br>* Single dose of MK-8558 administered as a tablet at a dose up to 1600 mg.<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) Concentration | Plasma was collected at baseline and at 168 hours post-dose to determine the change from baseline in HIV-1 ribonucleic acid (RNA) concentration. The log10 plasma HIV-RNA was measured and analyzed based on a longitudinal data analysis (LDA) model containing fixed effects for dose level and time. | Baseline and 168 hours post-dose | 
| Number of Participants Experiencing ≥1 Adverse Event (AE) | An Adverse Event (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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. | Up to 35 days post-dose | 
| Number of Participants Who Discontinued From the Study Due to an 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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. | Up to 35 days post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-Time Curve From 0 to 168 Hours (AUC0-168) for MK-8558 in Plasma | Plasma was collected from pre-dose up to 168 hours post-dose in order to determine the AUC0-168 for MK-8558. Data were natural log transformed and analyzed based on a linear model containing a fixed effect for dose level. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 120, 168 hours post-dose | 
| Area Under the Concentration-Time Curve From 0 up to the Last Quantifiable Time-Point (AUC0-last) for MK-8558 in Plasma | Plasma was collected from pre-dose up to 504 hours post-dose in order to determine the AUC0-last for MK-8558. Data were natural log transformed and analyzed based on a linear model containing a fixed effect for dose level. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 120, 168, 240, 336, 504 hours post-dose | 
| Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) for MK-8558 in Plasma | Plasma was collected from pre-dose up to 504 hours post-dose in order to determine the AUC0-inf for MK-8558. Data were natural log transformed and analyzed based on a linear model containing a fixed effect for dose level. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 120, 168, 240, 336, 504 hours post-dose | 
| Maximum Observed Concentration (Cmax) for MK-8558 in Plasma | Plasma was collected from pre-dose up to 504 hours post-dose in order to determine the Cmax for MK-8558. Data were natural log transformed and analyzed based on a linear model containing a fixed effect for dose level. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 120, 168, 240, 336, 504 hours post-dose | 
| Time to Maximum Observed Concentration (Tmax) for MK-8558 in Plasma | Plasma was collected from pre-dose up to 504 hours post-dose in order to determine the Tmax for MK-8558. Data were natural log transformed and analyzed based on a linear model containing a fixed effect for dose level. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 120, 168, 240, 336, 504 hours post-dose | 
| Concentration at 168 Hours Post-Dose (C168hr) for MK-8558 in Plasma | Plasma was collected at 168 hours post-dose in order to determine the C168hr for MK-8558. Data were natural log transformed and analyzed based on a linear model containing a fixed effect for dose level. | 168 hours post-dose | 
| Apparent Clearance (CL/F) for MK-8558 | Plasma was collected from pre-dose up to 504 hours post-dose in order to determine the CL/F for MK-8558. Data were natural log transformed and analyzed based on a linear model containing a fixed effect for dose level. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 120, 168, 240, 336, 504 hours post-dose | 
| Apparent Volume of Distribution (Vz/F) for MK-8558 | Plasma was collected from pre-dose up to 504 hours post-dose in order to determine the Vz/F for MK-8558. Data were natural log transformed and analyzed based on a linear model containing a fixed effect for dose level. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 120, 168, 240, 336, 504 hours post-dose | 
| Terminal Half Life (t1/2) for MK-8558 | Plasma was collected from pre-dose up to 504 hours post-dose in order to determine the t1/2 for MK-8558. Data were natural log transformed and analyzed based on a linear model containing a fixed effect for dose level. | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72, 120, 168, 240, 336, 504 hours post-dose |