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
Overview
- Phase
- Phase 1
- Intervention
- MK-8558
- Conditions
- HIV-1 Infection
- Sponsor
- Merck Sharp & Dohme LLC
- Enrollment
- 21
- Locations
- 2
- Primary Endpoint
- Change From Baseline in Plasma HIV-1 Ribonucleic Acid (RNA) Concentration
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
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.
Investigators
Eligibility Criteria
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
Arms & Interventions
Panel A. MK-8558 400 mg
Single oral dose of MK-8558 administered at 400 mg following a 10-hour fast.
Intervention: MK-8558
Panel B. MK-8558 at dose level 2
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.
Intervention: MK-8558
Panel C. MK-8558 at dose level 3
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.
Intervention: MK-8558
Panel D. MK-8558 at dose level 4
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.
Intervention: MK-8558
Outcomes
Primary Outcomes
Change From Baseline in Plasma HIV-1 Ribonucleic Acid (RNA) Concentration
Time Frame: Baseline and 168 hours post-dose
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.
Number of Participants Experiencing ≥1 Adverse Event (AE)
Time Frame: Up to 35 days post-dose
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.
Number of Participants Who Discontinued From the Study Due to an AE
Time Frame: Up to 35 days post-dose
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.
Secondary Outcomes
- Terminal Half Life (t1/2) for MK-8558(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 168 Hours (AUC0-168) for MK-8558 in Plasma(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(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(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(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(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(168 hours post-dose)
- Apparent Clearance (CL/F) for MK-8558(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(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)