Pharmacokinetics of Vaniprevir (MK-7009) and Hepatitis C Virus RNA Levels After Vaniprevir Treatment (MK-7009-029)

A Multiple Dose Study to Evaluate Pharmacokinetics and Hepatitis C Virus RNA Following Administration of MK-7009 in Hepatitis C Infected Patients

This study will evaluate the hepatic (liver) and plasma pharmacokinetics of Vaniprevir (MK-7009) by evaluation of ribonucleic acid (RNA) of the hepatitis C virus (HCV) in genotype 1, HCV-infected participants.

Study Overview

• Status: Terminated
• Conditions: Chronic Hepatitis C Infection
• Intervention / Treatment: Drug: Vaniprevir

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Participant is a male or female between 40 to 65 years of age at the prestudy (screening) visit
• Participant has a Body Mass Index (BMI) ≥18.5 kg/m2 and ≤36.0 kg/m2.
• Participant requires a diagnostic biopsy, per local treatment guidelines, to monitor progression of liver disease.
• Participant has chronic compensated, genotype 1 HCV infection as defined by positive serology for HCV and detectable HCV RNA in peripheral blood
• Participant met pre-specified criteria based on laboratory values at screening for the following: -- Alanine aminotransferase (ALT): ≤400 U/L -- Aspartate aminotransferase (AST): ≤400 U/L -- Total bilirubin: ≤2.4 mg/dL -- Direct bilirubin: ≤1.0 mg/dL -- Creatinine clearance (Clcr): ≥60 mL/min (by the Cockcroft-Gault equation*) -- Albumin: ≥3.3 g/dL -- Alkaline phosphatase: ≤260 U/L -- Hemoglobin: ≥13 g/dL (men), ≥12 g/dL (women) -- White blood cell count: 3.8 to 10.7 ×103/μL -- Absolute neutrophil count: ≥1.5 ×103/μL -- Platelet count: ≥120 ×103/μL -- International normalized ratio (INR): ≤1.2 -- Thyroid stimulating hormone (TSH): 0.34 to 5.60 μIU/mL -- Alpha fetoprotein (AFP): <100 ng/mL
• Participant does not have cirrhosis as confirmed by FibroSure™/FibroTest®
• Participant is treatment-experienced, with regard to prior treatment for chronic HCV infection
• Participant has the ability to avoid use of anticoagulants, nonsteroidal anti-inflammatory agents and aspirin for at least five (5) days preceding the initial liver biopsy and continuing throughout the entire study

Exclusion Criteria:

• Participant is under the age of legal consent, is mentally or legally incapacitated/ institutionalized, has significant emotional problems at the time of prestudy screening visit or expected during the conduct of the study or has a history of a clinically significant psychiatric disorder which, in the opinion of the investigator, would interfere with the study procedures.
• Participant has a history of stroke, chronic seizures, or major neurological disorder
• Participant did not achieve a viral response to prior treatment with licensed interferon-based therapy (i.e., is a 'null responder'). Viral response is defined by a >= 2-log^10 decline in HCV viral RNA within the first 12 weeks of therapy.
• Participant has previously been treated with an NS3/4A protease inhibitor for chronic HCV infection
• Evidence of high grade bridging fibrosis (eg, METAVIR score >3, Ishak score >4 or Scheuer score >3) from prior liver biopsy within 3 years of study entry
• Participant has evidence or history of chronic hepatitis not caused by HCV including but not limited to non-HCV viral hepatitis, nonalcoholic steatohepatitis (NASH), drug-induced hepatitis or autoimmune hepatitis. Note: Participants with history of acute non-HCV-related hepatitis which resolved >6 months before study entry can be enrolled.
• Participant has clinical or laboratory evidence of cirrhosis or other advanced liver disease
• Participant has decompensated liver disease as indicated by a history of ascites, hepatic encephalopathy, or bleeding esophageal varices
• Participant has been diagnosed or suspected of hepatocellular carcinoma
• Participant has coinfection with human immunodeficiency virus (HIV)
• Participant has positive Hepatitis B surface antigen or other evidence of active Hepatitis B infection
• Participant has a history of gastric bypass surgery, bowel resection or other disorder that in the opinion of the investigator may interfere with the absorption of the study medication
• Participant has a history of clinically significant uncontrolled 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 consumes excessive amounts of alcohol, defined as greater than 3 glasses of alcoholic beverages (1 glass is approximately equivalent to: beer [284 mL], wine [125 mL], or distilled spirits [25 mL]) per day
• Participant is currently a regular user (including use of any illicit drugs or has a history of drug (including alcohol) abuse within the last 3 months
• Female participant is pregnant, lactating, expecting to conceive or donate eggs, or is of childbearing potential and unwilling to commit to two methods of birth control as outlined in inclusion criterion
• Male Participant is planning to impregnate or provide sperm donation or has a female sexual partner of childbearing potential and is unwilling to commit to using two methods of birth control as outlined in inclusion criterion

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Vaniprevir 600 mg - 300 mg; For each participant in period 1, 600 mg of Vaniprevir was taken twice daily on Days 1-3 and a single dose of Vaniprevir 600 mg was taken on Day 4. Period 1 was followed by a minimum 30-day, up to approximately 140 day, washout interval. In period 2, 300 mg of Vaniprevir was taken twice daily by each participant on Days 1-3 and a single dose of Vaniprevir 300 mg was taken on Day 4.

Drug: Vaniprevir; Period 1: Vaniprevir 600 mg twice daily on Days 1-3 and a single dose of Vaniprevir 600 mg on Day 4. Period 2: Vaniprevir 300 mg twice daily on Days 1-3 and a single dose of Vaniprevir 300 mg on Day 4. There was at least a 30-day (up to approximately 140-day) washout interval between periods 1 and 2.; Other Names: MK-7009

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Curve (AUC) (0-12 Hrs) of Vaniprevir in the Liver	Participants were treated with vaniprevir twice daily on days 1,2, and 3. On treatment Day 4 participants were treated once with vaniprevir; then core needle liver biopsies were to be collected at 6, 12 and 24 hours postdose to determine the AUC of vaniprevir. AUC is the integrated area under the curve for plasma concentration of vaniprevir over time.	6, 12 and 24 hours postdose on day 4 of each period (up to Day 148)
Concentration of Vaniprevir in the Liver	Participants were treated with vaniprevir on days, 1,2, and 3. On treatment Day 4 participants were treated once with vaniprevir; then core needle liver biopsies were collected at 6, 12, and 24 hours postdose to determine the concentration of vaniprevir in the liver.	6, 12 and 24 hours postdose on day 4 of each period (up to day 148)
Apparent Terminal Half-life (t-1/2) of Vaniprevir in the Liver	Participants were treated with vaniprevir twice daily on days 1,2, and 3. On treatment Day 4 participants were treated once with vaniprevir; then core needle liver biopsies were to be collected at 6, 12 and 24 hours postdose to determine the t-1/2 of vaniprevir. The t-1/2 is the time taken to eliminate half the amount of vaniprevir.	6, 12 and 24 hours postdose on day 4 of each period (up to day 148)

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Study record dates

Study Major Dates

• Study Start (Actual): January 13, 2010
• Primary Completion (Actual): March 4, 2011
• Study Completion (Actual): March 4, 2011

Study Registration Dates

• First Submitted: August 6, 2009
• First Submitted That Met QC Criteria: August 6, 2009
• First Posted (Estimate): August 7, 2009

Study Record Updates

• Last Update Posted (Actual): October 18, 2018
• Last Update Submitted That Met QC Criteria: September 21, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Keywords: Hepatitis C Virus (HCV); Vaniprevir; MK-7009
• 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, Chronic; Hepatitis; Hepatitis A; Hepatitis C; Hepatitis C, Chronic
• Other Study ID Numbers: 7009-029; 2009-013076-41 (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