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

HIV-1 Infection Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03859739
• Other study ID #: 8558-002
• Secondary ID: MK-8558-002
• Status: Completed
• Phase: Phase 1
• Start date: April 26, 2019
• Est. completion date: May 29, 2020

Study information

• Verified date: May 2021
• Source: Merck Sharp & Dohme Corp.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 21
• Est. completion date: May 29, 2020
• Est. primary completion date: May 29, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• HIV-1 Infection

Intervention

Drug:
• MK-8558
Single dose of MK-8558 administered as a tablet at a dose up to 1600 mg.

Locations

Country	Name	City	State
Germany	Charite Research Organisation GmbH ( Site 0001)	Berlin
Romania	Matei Bals Infectious Diseases Institute ( Site 0002)	Bucharest	Bucuresti

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme Corp.

Countries where clinical trial is conducted

Germany,  Romania, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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