Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of MK-3281 in Healthy and Hepatitis C Infected Male Participants (MK-3281-002)

A 2-Part, Randomized, Double-Blind, Placebo-Controlled, Multiple-Rising Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of MK-3281 in Healthy Male Subjects and Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MK-3281 in Hepatitis C Infected Male Patients

This study will examine the safety, tolerability and plasma pharmacokinetics of multiple doses of MK-3281 in healthy male participants in Part I, and in Hepatitis C Virus (HCV)-infected male participants in Part II. The clinical efficacy of MK-3281, as measured by viral load reduction, will also be assessed in Part II. The primary hypothesis is that twice daily administration of MK-3281 for 10 days in healthy adult male participants and for 7 days in HCV-infected male participants is sufficiently safe and well tolerated, based on assessment of clinical and laboratory adverse experiences, to permit continued clinical investigation.

The results of this study will guide dose selection for future studies in both healthy participants and HCV-infected participants.

Study Overview

• Status: Completed
• Conditions: Hepatitis C
• Intervention / Treatment: Drug: MK-3281; Drug: Placebo to MK-3281

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Participant is judged to be in good/stable health based on medical history, physical examination, vital signs, and laboratory safety tests performed at the prestudy (screening) visit and/or prior to administration of the initial dose of study drug
• Participant has no clinically significant abnormality on electrocardiogram (ECG) performed at the prestudy (screening) visit and/or prior to administration of the initial dose of study drug
• Participants with female partner(s) of childbearing potential must agree to use a medically acceptable method of contraception during the study and for 90 days after the last dose of study drug
• Participant has a clinical diagnosis of chronic HCV infection (for Part II only).

Exclusion Criteria:

• Participant has a history of stroke, chronic seizures, or major neurological disorder
• Participant has a history of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, immunological, renal, respiratory, or genitourinary abnormalities or diseases
• Participant has a history of neoplastic disease (including leukemia, lymphoma, malignant melanoma), or myeloproliferative disease, regardless of the time since treatment
• Participant has positive Hepatitis B surface antigen (or other evidence of active Hepatitis B infection) at the prescreening (study) visit
• For Healthy Panel (Part I), participant has evidence of chronic Hepatitis C virus infection at the prescreening (study) visit
• Participant has a history of documented Human Immunodeficiency Virus (HIV) infection

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pt 1: MK-3281 100 mg BID (Panel A); Healthy male participants in this Part I serial panel receive 100 mg MK-3281 orally twice daily (BID) for 10 consecutive days for a total daily dose administered of 200 mg. The evening (PM) dose of MK-3281 was not administered on Day 10.	Drug: MK-3281; MK-3281 capsule administered orally BID for 7 or 10 consecutive days depending on randomized dose. The PM dose of MK-3281 was not administered on Day 7 (for HCV-infected males) or Day 10 (for healthy males)
Experimental: Pt 1: MK-3281 200 mg BID (Panel B); Healthy male participants in this Part I serial panel receive 200 mg MK-3281 orally BID for 10 consecutive days for a total daily dose administered of 400 mg. The PM dose of MK-3281 was not administered on Day 10.	Drug: MK-3281; MK-3281 capsule administered orally BID for 7 or 10 consecutive days depending on randomized dose. The PM dose of MK-3281 was not administered on Day 7 (for HCV-infected males) or Day 10 (for healthy males)
Experimental: Pt 1: MK-3281 400 mg BID (Panel C); Healthy male participants in this Part I serial panel receive 400 mg MK-3281 orally BID for 10 consecutive days for a total daily dose administered of 800 mg. The PM dose of MK-3281 was not administered on Day 10.	Drug: MK-3281; MK-3281 capsule administered orally BID for 7 or 10 consecutive days depending on randomized dose. The PM dose of MK-3281 was not administered on Day 7 (for HCV-infected males) or Day 10 (for healthy males)
Experimental: Pt 1: MK-3281 800 mg BID (Panel D); Healthy male participants in this Part I serial panel receive 800 mg MK-3281 orally BID for 10 consecutive days for a total daily dose administered of 1600 mg. The PM dose of MK-3281 was not administered on Day 10.	Drug: MK-3281; MK-3281 capsule administered orally BID for 7 or 10 consecutive days depending on randomized dose. The PM dose of MK-3281 was not administered on Day 7 (for HCV-infected males) or Day 10 (for healthy males)
Experimental: Pt 2: MK-3281 800 mg BID (Panel E); Genotype (GT)1 HCV-infected male participants in this Part II serial panel receive 800 mg MK-3281 orally BID for 7 consecutive days for a total daily dose administered of 1600 mg. The PM dose of MK-3281 was not administered on Day 7.	Drug: MK-3281; MK-3281 capsule administered orally BID for 7 or 10 consecutive days depending on randomized dose. The PM dose of MK-3281 was not administered on Day 7 (for HCV-infected males) or Day 10 (for healthy males)
Experimental: Pt 2: MK-3281 800 mg BID (Panel F); GT1a/GT1-nontypeable/GT3/GT1b HCV-infected male participants in this Part II serial panel receive 800 mg MK-3281 orally BID for 7 consecutive days for a total daily dose administered of 1600 mg. The PM dose of MK-3281 was not administered on Day 7.	Drug: MK-3281; MK-3281 capsule administered orally BID for 7 or 10 consecutive days depending on randomized dose. The PM dose of MK-3281 was not administered on Day 7 (for HCV-infected males) or Day 10 (for healthy males)
Experimental: Pt 2: MK-3281 1200 mg BID (Panel G); GT1a (and/or GT1 nontypeable) and GT1b HCV-infected male participants in this Part II serial panel receive 1200 mg MK-3281 orally BID for 7 consecutive days for a total daily dose administered of 2400 mg. The PM dose of MK-3281 was not administered on Day 7.	Drug: MK-3281; MK-3281 capsule administered orally BID for 7 or 10 consecutive days depending on randomized dose. The PM dose of MK-3281 was not administered on Day 7 (for HCV-infected males) or Day 10 (for healthy males)
Placebo Comparator: Placebo; Participants receive dose-matched placebo to MK-3281 orally BID for 7 or 10 consecutive days depending on randomization. The PM dose of matched placebo was not administered on Day 7 or 10 (depending upon allocation).	Drug: Placebo to MK-3281; Dose-matched placebo to MK-3281 capsule administered orally BID for 7 or 10 consecutive days depending on randomized dose of MK-3281 in serial panel. The PM dose of matched placebo was not administered on Day 7 or 10 (depending upon allocation).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Experiencing Adverse Events (AEs)	An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the SPONSOR's product, was also an AE.	Up to 14 days after the last dose of study drug (up to 24 days maximum)
Number of Participants Who Discontinued Study Medication Due to AEs	An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the SPONSOR's product, was also an AE.	Up to 14 days after the last dose of study drug (up to 24 days maximum)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Plasma Concentration Versus Time Curve From Time Zero to Time 12 Hours (AUC[0-12]) of MK-3281	Blood samples were obtained from participants and MK-3281 AUC(0-12) was calculated at Days 1 and 7 (for HCV+ participants) or Day 10 (for healthy participants) using the MK-3281 assay.	Predose daily on Days 2-9 (for healthy participants) and Days 2-6 (for HCV+ participants), and predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose on Day 1, Day 7 (HCV+ participants), and Day 10 (healthy participants)
Maximum Plasma Concentration (Cmax) of MK-3281	Blood samples were obtained from participants and MK-3281 Cmax was calculated at Days 1 and 7 (for HCV+ participants) or Day 10 (for healthy participants) using the MK-3281 assay.	Predose daily on Days 2-9 (for healthy participants) and Days 2-6 (for HCV+ participants), and predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose on Day 1, Day 7 (HCV+ participants), and Day 10 (healthy participants)
12-Hour Concentration of MK-3281 in Plasma (C12hr)	Blood samples were obtained from participants and MK-3281 plasma C12hr was calculated at Days 1 and 7 (for HCV+ participants) or Day 10 (for healthy participants) using the MK-3281 assay.	Predose daily on Days 2-9 (for healthy participants) and Days 2-6 (for HCV+ participants), and predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose on Day 1, Day 7 (HCV+ participants), and Day 10 (healthy participants)
Time To Reach Cmax (Tmax) of MK-3281	Blood samples were obtained from participants and MK-3281 Tmax was calculated at Days 1 and 7 (for HCV+ participants) or Day 10 (for healthy participants) using the MK-3281 assay.	Predose daily on Days 2-9 (for healthy participants) and Days 2-6 (for HCV+ participants), and predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose on Day 1, Day 7 (HCV+ participants), and Day 10 (healthy participants)
Apparent Half-Life (t ½) of MK-3281	Blood samples were obtained from participants and MK-3281 apparent t ½ was calculated at Day 7 (for HCV+ participants) or Day 10 (for healthy participants) using the MK-3281 assay. Harmonic mean t ½ and pseudo standard deviation were reported.	Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, and 96 hours post-dose on Day 7 (HCV+ participants) or Day 10 (healthy participants)
AUC (0-12hr) Accumulation Ratio of MK-3281	Blood samples were obtained from participants and the MK-3281 AUC(0-12hr) accumulation ratio was calculated for HCV+ participants and healthy participants. AUC(0-12hr) accumulation ratio calculated for healthy participants as Day 10 AUC (0-12hr) / Day 1 AUC (0-12hr). AUC(0-12hr) accumulation ratio calculated for HCV+ participants as Day 7 AUC (0-12hr) / Day 1 AUC (0-12hr).	Predose daily on Days 2-9 (for healthy participants) and Days 2-6 (for HCV+ participants), and predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose on Day 1, Day 7 (HCV+ participants), and Day 10 (healthy participants)
Cmax Accumulation Ratio of MK-3281	Blood samples were obtained from participants and the MK-3281 Cmax accumulation ratio was calculated for HCV+ participants and healthy participants. Cmax accumulation ratio calculated for healthy participants as Day 10 Cmax / Day 1 Cmax. Cmax accumulation ratio calculated for HCV+ participants as Day 7 Cmax / Day 1 Cmax.	Predose daily on Days 2-9 (for healthy participants) and Days 2-6 (for HCV+ participants), and predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose on Day 1, Day 7 (HCV+ participants), and Day 10 (healthy participants)
C12hr Accumulation Ratio of MK-3281	Blood samples were obtained from participants and the MK-3281 C12hr accumulation ratio was calculated for HCV+ participants and healthy participants. C12hr accumulation ratio calculated for healthy participants as Day 10 C12hr / Day 1 C12hr. C12hr accumulation ratio calculated for HCV+ participants as Day 7 C12hr / Day 1 C12hr.	Predose daily on Days 2-9 (for healthy participants) and Days 2-6 (for HCV+ participants), and predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose on Day 1, Day 7 (HCV+ participants), and Day 10 (healthy participants)
Maximum HCV Viral Load Change From Baseline Over Study Following MK-3281 Dosing For 7 Days	For evaluation of MK-3281 antiviral activity, the maximum reduction in HCV ribonucleic acid (RNA) levels over the course of the study was assessed by MK-3281 dose group in HCV+ participants and the mean maximum viral load reduction was summarized. HCV RNA levels were measured at predose and 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24 hours postdose on Day 1 and Day 7; pre-morning (AM) and pre-evening (PM) dose Day 2; and pre AM dose Days 3-6. For each participant, baseline measurement was defined as the measurement obtained pre-dose on the first day of dosing, and change from baseline (difference) was calculated at each time point. The response for that participant was defined as: - (postbaseline time point - baseline) at the time point with the lowest HCV RNA level.	Baseline (pre-dose Day 1), Day 2, Day 3, Day 4, Day 5, Day 6, Day 7

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Study record dates

Study Major Dates

• Study Start (Actual): February 19, 2008
• Primary Completion (Actual): December 22, 2009
• Study Completion (Actual): December 22, 2009

Study Registration Dates

• First Submitted: February 28, 2008
• First Submitted That Met QC Criteria: March 7, 2008
• First Posted (Estimate): March 14, 2008

Study Record Updates

• Last Update Posted (Actual): September 5, 2018
• Last Update Submitted That Met QC Criteria: August 6, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Hepatitis; Hepatitis A; Hepatitis C
• Other Study ID Numbers: 3281-002; 2008_507 (Other Identifier: Merck Registration Number); 2007-006245-40 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf

Study Data/Documents

1. CSR Synopsis