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

Phase 1

Completed

• Conditions: Hepatitis C
• Interventions: Drug: MK-3281; Drug: Placebo to MK-3281

• Registration Number: NCT00635804
• Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2008-02-19
• Study First Submitted: 2008-02-28
• Study First Submitted QC: 2008-03-07
• Study First Posted: 2008-03-14
• Primary Completion: 2009-12-22
• Study Completion: 2009-12-22
• Results First Submitted: 2016-02-18
• Results First Submitted QC: 2016-03-31
• Results First Posted: 2016-05-04
• Status Verified: 2018-08
• Last Update Submitted: 2018-08-06
• Last Update Posted: 2018-09-05

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 60

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).

Read More

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

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Pt 1: MK-3281 100 mg BID (Panel A)	MK-3281	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.
Pt 1: MK-3281 200 mg BID (Panel B)	MK-3281	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.
Pt 1: MK-3281 400 mg BID (Panel C)	MK-3281	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.
Pt 2: MK-3281 800 mg BID (Panel F)	MK-3281	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.
Pt 1: MK-3281 800 mg BID (Panel D)	MK-3281	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.
Placebo	Placebo to MK-3281	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).
Pt 2: MK-3281 800 mg BID (Panel E)	MK-3281	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.
Pt 2: MK-3281 1200 mg BID (Panel G)	MK-3281	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants Experiencing Adverse Events (AEs)	Up to 14 days after the last dose of study drug (up to 24 days maximum)	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.
Number of Participants Who Discontinued Study Medication Due to AEs	Up to 14 days after the last dose of study drug (up to 24 days maximum)	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.

Secondary Outcome Measures

Name	Time	Method
Maximum Plasma Concentration (Cmax) of MK-3281	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)	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.
12-Hour Concentration of MK-3281 in Plasma (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)	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.
Apparent Half-Life (t ½) of MK-3281	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)	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.
Area Under the Plasma Concentration Versus Time Curve From Time Zero to Time 12 Hours (AUC[0-12]) of MK-3281	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)	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.
AUC (0-12hr) Accumulation Ratio of MK-3281	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)	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).
Time To Reach Cmax (Tmax) of MK-3281	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)	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.
Cmax Accumulation Ratio of MK-3281	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)	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.
C12hr Accumulation Ratio of MK-3281	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)	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.
Maximum HCV Viral Load Change From Baseline Over Study Following MK-3281 Dosing For 7 Days	Baseline (pre-dose Day 1), Day 2, Day 3, Day 4, Day 5, Day 6, Day 7	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.