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A Multiple Dose Study of Grazoprevir (MK-5172) in Hepatitis C-Infected Participants (MK-5172-010)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:
NCT01537900
First received: February 17, 2012
Last updated: February 3, 2016
Last verified: December 2015
  Purpose
The goal of this study was to compare hepatic pharmacokinetics (PK) derived from liver tissue to plasma PK after administration of grazoprevir (MK-5172) to participants with chronic hepatitis C virus (HCV) infection. Participants will be randomized to one of four different liver ultrasound-guided Fine Needle Aspirate (FNA) schedules (at 4-, 8-, 24-, or 72-hours after the Day 7 dose).

Condition Intervention Phase
Hepatitis C
Drug: Grazoprevir
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Multiple Dose Study to Evaluate Pharmacokinetics and Hepatitis C Virus RNA Dynamics Following Administration of MK-5172 in Hepatitis C Infected Patients

Resource links provided by NLM:


Further study details as provided by Merck Sharp & Dohme Corp.:

Primary Outcome Measures:
  • Estimated Area Under the Liver Concentration-time Curve for 24 Hours Post-dose (AUC[H]0-24hr) of Grazoprevir [ Time Frame: 4, 8, and 24 hours post-dose on Day 7 ] [ Designated as safety issue: No ]
    Each participant was assigned to undergo Fine Needle Aspiration (FNA) to obtain liver tissue at different time points. Specifically, one participant underwent FNA at 4 hr post-dose only, another participant underwent FNA at 8 hr post-dose only, and a third participant underwent FNA at 24 hr post-dose only. (The fourth participant underwent FNA at 72 hr post-dose and therefore was not included in the calculation of AUC0-24hr.) Therefore, in calculating AUC0-24hr, there were only 3 data points: 1 data point at 4 hr post-dose, 1 data point at 8 hr post-dose, and 1 data point at 24 hr post-dose. The model assumed that drug concentration was at steady-state, and that the concentration at 24 hr post-dose was equal to the concentration at 0 hr post-dose.

  • Hepatic Concentration of GZR (C[H]Xhr) [ Time Frame: 4, 8, 24, and 72 hours post-dose on Day 7 ] [ Designated as safety issue: No ]
    C(H)Xhr of GZR was expressed as liver concentration (μmol GZR/L liver) using the concentration of the extracted liver sample (mass of the liver biopsy/0.2 mL solvent), and assuming that liver has the specific gravity of water (1 g/mL). The arithmetic mean C(H)Xhr concentration is based on the means of 4 FNA passes per participant in all 4 participants.

  • Apparent Terminal Hepatic Half-life (t[H]½ ) of GZR [ Time Frame: 4, 8, 24, and 72 hours post-dose on Day 7 ] [ Designated as safety issue: No ]
    t(H)1/2 is a measure of the time required for the maximum post-dose liver concentration of GZR to decrease by 50%.


Secondary Outcome Measures:
  • Plasma AUC[0-24 hr] of GZR [ Time Frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 and 72 hours post-dose on Day 7 ] [ Designated as safety issue: No ]
    AUC0-24hr is a measure of the mean concentration of drug in plasma after dosing to 24 hours post-dose.

  • Maximum Plasma Concentration (Cmax) of GZR [ Time Frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 and 72 hours post-dose on Day 7 ] [ Designated as safety issue: No ]
    Cmax is a measure of the maximum plasma concentration post-dose.

  • Lowest Plasma Concentration (Ctrough) of GZR [ Time Frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 and 72 hours post-dose on Day 7 ] [ Designated as safety issue: No ]
    Ctrough is a measure of drug concentration 24 hours post-dose.

  • Time to Maximum Plasma Concentration (Tmax) of GZR [ Time Frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 and 72 hours post-dose on Day 7 ] [ Designated as safety issue: No ]
    Tmax is a measure of time to reach maximum post-dose plasma drug concentration.

  • Plasma t½ of GZR [ Time Frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 and 72 hours post-dose on Day 7 ] [ Designated as safety issue: No ]
    t1/2 is a measure of time for the maximum plasma concentration of GZR to decrease by 50%.


Enrollment: 4
Study Start Date: October 2013
Study Completion Date: July 2014
Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Grazoprevir 100 mg
Participants received GZR 100 mg once daily (q.d.) for 7 days. Liver FNA was performed on Day 7.
Drug: Grazoprevir
GZR 100 mg tablet by mouth q.d. for 7 days.
Other Name: MK-5172

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  • has a Body Mass Index (BMI) ≥18.5 kg/m² and ≤36.0 kg/m²
  • has chronic compensated, genotype 1 HCV infection
  • has no cirrhosis of the liver as confirmed by FibroSure®/Fibro Test® and/or local country procedure (e.g. transient elastography/Fibroscan)
  • does not require anticoagulants, nonsteroidal anti-inflammatory agents, and aspirin for at least fourteen (14) days preceding the initial liver biopsy and continuing throughout the entire study
  • if is a female participant of reproductive potential, is willing to use 2 medically acceptable forms of contraception for 2 weeks prior to start of treatment through 2 weeks after last study treatment
  • if is a male participant with a partner(s) of reproductive potential, is willing to use 2 medically acceptable forms of contraception from first dose to 90 days after last dose

Exclusion criteria:

  • has a history of stroke, chronic seizures, or major neurological disorder
  • has received previous treatment with a direct-acting antiviral (DAA)
  • has evidence of high grade bridging fibrosis from prior liver biopsy within 3 years of study entry
  • has evidence or history of chronic hepatitis not caused by HCV infection including but not limited to non-HCV viral hepatitis, nonalcoholic steatohepatitis (NASH), drug-induced hepatitis, or autoimmune hepatitis
  • has clinical or laboratory evidence of cirrhosis or other advanced liver disease
  • has decompensated liver disease as indicated by a history of ascites, hepatic encephalopathy, or bleeding esophageal varices
  • has been diagnosed with, or suspected of having, hepatocellular carcinoma (HCC)
  • has clinically significant abnormality on an electrocardiogram (ECG)
  • is co-infected with human immunodeficiency virus (HIV)
  • is positive for Hepatitis B surface antigen (HBsAg) or other evidence of active Hepatitis B infection
  • has a history of gastric bypass surgery, bowel resection or other disorder that may interfere with absorption
  • has a history of clinically significant uncontrolled endocrine, gastrointestinal, cardiovascular, hematological, immunological, renal, respiratory, or genitourinary abnormalities or diseases
  • has clinically significant neoplastic disease
  • uses alcohol to excess, defined as greater than 3 glasses of alcoholic beverages (1 glass is approximately equivalent to: beer [354 mL], wine [118 mL], or distilled spirits [29.5 mL]) per day
  • is a current regular user (including use of any illicit drugs) or history of drug (including alcohol) abuse within the last 3 months
  • has undergone surgery, donation of 1 unit of blood (approximately 500 mL) or participation in another investigational study within a period of 4 weeks prior to the screening visit
  • has a history of multiple and/or severe allergies, or anaphylactic reaction or intolerability to prescription or nonprescription drugs or food
  • is pregnant or lactating
  • is expecting to donate eggs or sperm
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01537900

Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
Study Director: Medical Director Merck Sharp & Dohme Corp.
  More Information

Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT01537900     History of Changes
Other Study ID Numbers: 5172-010  2011-000435-83 
Study First Received: February 17, 2012
Results First Received: February 3, 2016
Last Updated: February 3, 2016
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis C
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Flaviviridae Infections

ClinicalTrials.gov processed this record on September 27, 2016