Back to resultsA Multiple Dose Study of Grazoprevir (MK-5172) in Hepatitis C-Infected Participants (MK-5172-010)
Primary Purpose
Hepatitis C
Status
Completed
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
Grazoprevir
Sponsored by
About this trial
This is an interventional treatment trial for Hepatitis C
Eligibility 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
Sites / Locations
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Grazoprevir 100 mg
Arm Description
Participants received GZR 100 mg once daily (q.d.) for 7 days. Liver FNA was performed on Day 7.
Outcomes
Primary Outcome Measures
Estimated Area Under the Liver Concentration-time Curve for 24 Hours Post-dose (AUC[H]0-24hr) of Grazoprevir
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)
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
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
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
Cmax is a measure of the maximum plasma concentration post-dose.
Lowest Plasma Concentration (Ctrough) of GZR
Ctrough is a measure of drug concentration 24 hours post-dose.
Time to Maximum Plasma Concentration (Tmax) of GZR
Tmax is a measure of time to reach maximum post-dose plasma drug concentration.
Plasma t½ of GZR
t1/2 is a measure of time for the maximum plasma concentration of GZR to decrease by 50%.
Full Information
NCT ID
NCT01537900
First Posted
February 17, 2012
Last Updated
August 16, 2018
Sponsor
Merck Sharp & Dohme LLC
1. Study Identification
Unique Protocol Identification Number
NCT01537900
Brief Title
A Multiple Dose Study of Grazoprevir (MK-5172) in Hepatitis C-Infected Participants (MK-5172-010)
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
Study Type
Interventional
2. Study Status
Record Verification Date
August 2018
Overall Recruitment Status
Completed
Study Start Date
October 1, 2013 (Actual)
Primary Completion Date
July 31, 2014 (Actual)
Study Completion Date
July 31, 2014 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Merck Sharp & Dohme LLC
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
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).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatitis C
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
4 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Grazoprevir 100 mg
Arm Type
Experimental
Arm Description
Participants received GZR 100 mg once daily (q.d.) for 7 days. Liver FNA was performed on Day 7.
Intervention Type
Drug
Intervention Name(s)
Grazoprevir
Other Intervention Name(s)
MK-5172
Intervention Description
GZR 100 mg tablet by mouth q.d. for 7 days.
Primary Outcome Measure Information:
Title
Estimated Area Under the Liver Concentration-time Curve for 24 Hours Post-dose (AUC[H]0-24hr) of Grazoprevir
Description
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.
Time Frame
4, 8, and 24 hours post-dose on Day 7
Title
Hepatic Concentration of GZR (C[H]Xhr)
Description
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.
Time Frame
4, 8, 24, and 72 hours post-dose on Day 7
Title
Apparent Terminal Hepatic Half-life (t[H]½ ) of GZR
Description
t(H)1/2 is a measure of the time required for the maximum post-dose liver concentration of GZR to decrease by 50%.
Time Frame
4, 8, 24, and 72 hours post-dose on Day 7
Secondary Outcome Measure Information:
Title
Plasma AUC[0-24 hr] of GZR
Description
AUC0-24hr is a measure of the mean concentration of drug in plasma after dosing to 24 hours post-dose.
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
Title
Maximum Plasma Concentration (Cmax) of GZR
Description
Cmax is a measure of the maximum plasma concentration post-dose.
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
Title
Lowest Plasma Concentration (Ctrough) of GZR
Description
Ctrough is a measure of drug concentration 24 hours post-dose.
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
Title
Time to Maximum Plasma Concentration (Tmax) of GZR
Description
Tmax is a measure of time to reach maximum post-dose plasma drug concentration.
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
Title
Plasma t½ of GZR
Description
t1/2 is a measure of time for the maximum plasma concentration of GZR to decrease by 50%.
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Director
Organizational Affiliation
Merck Sharp & Dohme LLC
Official's Role
Study Director
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf
IPD Sharing URL
http://engagezone.msd.com/ds_documentation.php
Learn more about this trial
A Multiple Dose Study of Grazoprevir (MK-5172) in Hepatitis C-Infected Participants (MK-5172-010)
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