Safety, Pharmacokinetics, and Pharmacodynamics of MK-2248 in Participants With Hepatitis C (MK-2248-002)

A Multiple Dose Study to Evaluate Safety, Pharmacokinetics, and Pharmacodynamics of MK-2248 in Subjects With Hepatitis C Infection

The objective of this study is to identify a safe dose of MK-2248 in participants with Hepatitis C Virus (HCV) that mediates at least a 3 log10 reduction in viral load (VL) from baseline. It is anticipated that once-daily administration of a safe and well tolerated dose of MK-2248 will reduce VL by at least 3 log10 IU/mL.

Study Overview

• Status: Completed
• Conditions: Hepatitis C
• Intervention / Treatment: Drug: MK-2248

Detailed Description

In this Phase 1b study, the pharmacokinetic (PK), pharmacodynamic (PD), and safety profile of MK-2248 in HCV-infected participants will be evaluated as follows: Part I will assess sequentially ascending MK-2248 doses from 200 mg to ≤800 mg over 4 panels (A, B, C, and D). Part II will assess sequentially ascending MK-2248 doses from 200 mg to ≤800 mg over 4 panels (E, F, G, and H). Part III will assess sequentially ascending MK-2248 doses ranging up to ≤800 mg in 2 panels (I and J). The potential relationship between plasma MK-2248 levels and VL reduction will be determined.

• Study Type: Interventional
• Enrollment (Actual): 13
• 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: All

Description

Inclusion Criteria:

• clinical diagnosis of chronic HCV defined by positive serology for HCV or positive HCV RNA for at least 6 months and detectable HCV RNA in peripheral blood ≥10^5 IU/mL at screening
• Body Mass Index (BMI) ≥18 to <37 kg/m^2
• in good health other than HCV infection with normal laboratory values

Exclusion Criteria:

• history of clinically significant and not stably controlled endocrine, gastrointestinal, cardiovascular, hematological, hepatic (excepting HCV infection), immunological, renal, respiratory, genitourinary, or major neurological abnormalities or disease
• history of cancer other than adequately treated non-melanomatous skin carcinoma, malignancies which have been successfully treated ≥10 years prior with no recurrence, or cancer that is unlikely to sustain a recurrence for the duration of the trial
• 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
• positive for hepatitis B surface antigen or human immunodeficiency virus
• had major surgery or lost 1 unit of blood within 4 weeks prior to screening
• QTc interval ≥470 msec (males) or ≥480 msec (females)
• received prior treatment with other HCV inhibitors
• clinical or laboratory evidence of decompensated liver disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part I: MK-2248 200 mg (Panel A); HCV participants will take MK-2248 200 mg by mouth once daily for 7 days.	Drug: MK-2248; MK-2248 in once-daily oral doses of 200-≤800 mg for 7 days
Experimental: Part I: MK-2248 ≤800 mg (Panel B); Based on safety, PK, and PD data from the preceding panel, HCV participants will take MK-2248 at approximately ≤800 mg by mouth once daily for 7 days.	Drug: MK-2248; MK-2248 in once-daily oral doses of 200-≤800 mg for 7 days
Experimental: Part I: MK-2248 ≤800 mg (Panel C); Based on safety, PK, and PD data from the preceding panel, HCV participants will take MK-2248 at approximately ≤800 mg by mouth for 7 days.	Drug: MK-2248; MK-2248 in once-daily oral doses of 200-≤800 mg for 7 days
Experimental: Part I: MK-2248 ≤800 mg (Panel D); Based on safety, PK, and PD data from the preceding panel, HCV participants will take MK-2248 at approximately ≤800 mg by mouth once daily for 7 days.	Drug: MK-2248; MK-2248 in once-daily oral doses of 200-≤800 mg for 7 days
Experimental: Part II: MK-2248 200 mg (Panel E); HCV participants will take MK-2248 200 mg by mouth once daily for 7 days.	Drug: MK-2248; MK-2248 in once-daily oral doses of 200-≤800 mg for 7 days
Experimental: Part II: MK-2248 ≤800 mg (Panel F); Based on safety, PK, and PD data from the preceding panel, HCV participants will take MK-2248 at approximately ≤800 mg by mouth once daily for 7 days.	Drug: MK-2248; MK-2248 in once-daily oral doses of 200-≤800 mg for 7 days
Experimental: Part II: MK-2248 ≤800 mg (Panel G); Based on safety, PK, and PD data from the preceding panel, HCV participants will take MK-2248 at approximately ≤800 mg by mouth once daily for 7 days.	Drug: MK-2248; MK-2248 in once-daily oral doses of 200-≤800 mg for 7 days
Experimental: Part II: MK-2248 ≤800 mg (Panel H); Based on safety, PK, and PD data from the preceding panel, HCV participants will take MK-2248 at approximately ≤800 mg by mouth once daily for 7 days.	Drug: MK-2248; MK-2248 in once-daily oral doses of 200-≤800 mg for 7 days
Experimental: Part III: MK-2248 ≤800 mg (Panel I); Based on safety, PK, and PD data from the preceding panel, HCV participants will take MK-2248 at approximately ≤800 mg by mouth once daily for 7 days.	Drug: MK-2248; MK-2248 in once-daily oral doses of 200-≤800 mg for 7 days
Experimental: Part III: MK-2248 ≤800 mg (Panel J); Based on safety, PK, and PD data from the preceding panel, HCV participants will take MK-2248 at approximately ≤800 mg by mouth once daily for 7 days.	Drug: MK-2248; MK-2248 in once-daily oral doses of 200-≤800 mg for 7 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum change from baseline in VL	Up to Day 42
Number of participants experiencing an adverse event (AE)	Up to Day 42
Number of participants who discontinue from study treatment due to an AE	Up to Day 7

Secondary Outcome Measures

Outcome Measure	Time Frame
Plasma concentration at 24 hours post-dose (C24hr) of MK-2248 and circulating metabolite(s)	Up to Day 10
Area under the plasma-concentration curve at zero to 24 hours post-dose (AUC[0-24hr]) of MK-2248 and circulating metabolite(s)	Up to Day 10
Maximum observed post-dose plasma concentration (Cmax) of MK-2248 and circulating metabolite(s)	Up to Day 10
Time post-dose at which the maximum observed plasma concentraton (Tmax) of MK-2248 and circulating metabolite(s) occurs	Up to Day 10
Time required for Cmax to decrease by half (apparent t1/2) of MK-2248 and circulating metabolite(s) in plasma	Up to Day 10
Accumulation ratio of MK-2248 and circulating metabolite(s) in plasma	Up to Day 10
Total clearance (amount of drug cleared relative to the total systemically available amount per unit time [CL/F]) of MK-2248 in plasma	Up to Day 10
Apparent volume of distribution (V/F) of MK-2248 in plasma	Up to Day 10

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Study record dates

Study Major Dates

• Study Start: July 1, 2014
• Primary Completion (Actual): November 1, 2014
• Study Completion (Actual): April 1, 2015

Study Registration Dates

• First Submitted: June 10, 2014
• First Submitted That Met QC Criteria: June 10, 2014
• First Posted (Estimate): June 11, 2014

Study Record Updates

• Last Update Posted (Estimate): June 8, 2015
• Last Update Submitted That Met QC Criteria: June 5, 2015
• Last Verified: June 1, 2015

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: 2248-002; 2014-001494-14 (EudraCT Number)