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
Overview
- Phase
- Phase 1
- Intervention
- MK-8504
- Conditions
- HIV-1 Infection
- Sponsor
- Merck Sharp & Dohme LLC
- Enrollment
- 12
- Locations
- 2
- Primary Endpoint
- Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
- Status
- Completed
- Last Updated
- 6 years ago
Overview
Brief Summary
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.
Investigators
Eligibility Criteria
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
Arms & Interventions
MK-8504 100 mg (Panel A)
Participants receive a single oral dose of MK-8504 100 mg.
Intervention: MK-8504
MK-8504 240 mg (Panel B)
Participants receive a single oral dose of MK-8504 240 mg.
Intervention: MK-8504
MK-8504 ≤240 mg (Panel C)
Participants receive a single oral dose of MK-8504 ≤240 mg.
Intervention: MK-8504
MK-8504 ≤240 mg (Panel D)
Participants receive a single oral dose of MK-8504 ≤240 mg.
Intervention: MK-8504
Outcomes
Primary Outcomes
Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
Time Frame: Day 1
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.
Change From Baseline in Plasma HIV-1 Ribonucleic Acid (RNA) at 168 Hours Post-Dose
Time Frame: Baseline, 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).
Number of Participants Who Experienced At Least One Adverse Event (AE)
Time Frame: From Day 1 through Post-Trial Visit (up to 25 days)
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.
Secondary Outcomes
- Area Under the Concentration-Time Curve of MK-8504 in Plasma From Time 0 to Last Measurable Concentration (AUC0-last)(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)(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)(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)(Pre-dose, 4, 12, 24, 48, 72, 96, and 168 hours post-dose)
- Area Under the Concentration-Time Curve of MK-8504 in Plasma From Time 0 to 168 Hours (AUC0-168hr)(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)(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)(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)(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(Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose)
- Intracellular Maximum Concentration (Intracellular Cmax) of Tenofovir-Diphosphate (TFV-DP) In Peripheral Blood Mononuclear Cells (PBMCs)(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)(168 hours post-dose)
- Area Under the Concentration-Time Curve of Tenofovir in Plasma From Time 0 to Last Measurable Concentration (AUC0-last)(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 Infinity (Intracellular AUC0-inf) In Peripheral Blood Mononuclear Cells (PBMCs)(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)(Pre-dose, 4, 12, 24, 48, 72, 96, 168, 240, 384, and 600 hours post-dose)
- Area Under the Concentration-Time Curve of Tenofovir in Plasma From Time 0 to Infinity (AUC0-inf)(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)(Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose)
- Intracellular Time to Maximum Concentration (Intracellular Tmax) of Tenofovir-Diphosphate (TFV-DP) In Peripheral Blood Mononuclear Cells (PBMCs)(Pre-dose, 4, 12, 24, 48, 72, 96, 168, 240, 384, and 600 hours post-dose)
- Maximum Concentration of Tenofovir in Plasma (Cmax)(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)(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)(Pre-dose, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36, 48, and 72 hours post-dose)