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

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01537900
• Collaborator: (none)
• Enrollment: 4
• Arm: 1
• Actual Duration (Months): 10

Study Details

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).

Condition or Disease	Intervention/Treatment	Phase
Hepatitis C	Drug: Grazoprevir	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 4 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (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
• Actual Study Start Date: Oct 1, 2013
• Actual Primary Completion Date: Jul 31, 2014
• Actual Study Completion Date: Jul 31, 2014

Arms and Interventions

Arm	Intervention/Treatment
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 Names: MK-5172

Outcome Measures

Primary Outcome Measures

1. Estimated Area Under the Liver Concentration-time Curve for 24 Hours Post-dose (AUC[H]0-24hr) of Grazoprevir [4, 8, and 24 hours post-dose on Day 7]

   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.

2. Hepatic Concentration of GZR (C[H]Xhr) [4, 8, 24, and 72 hours post-dose on Day 7]

   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.

3. Apparent Terminal Hepatic Half-life (t[H]½ ) of GZR [4, 8, 24, and 72 hours post-dose on Day 7]

   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

1. Plasma AUC[0-24 hr] of GZR [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]

   AUC0-24hr is a measure of the mean concentration of drug in plasma after dosing to 24 hours post-dose.

2. Maximum Plasma Concentration (Cmax) of GZR [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]

   Cmax is a measure of the maximum plasma concentration post-dose.

3. Lowest Plasma Concentration (Ctrough) of GZR [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]

   Ctrough is a measure of drug concentration 24 hours post-dose.

4. Time to Maximum Plasma Concentration (Tmax) of GZR [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]

   Tmax is a measure of time to reach maximum post-dose plasma drug concentration.

5. Plasma t½ of GZR [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]

   t1/2 is a measure of time for the maximum plasma concentration of GZR to decrease by 50%.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

No locations specified.

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Director, Merck Sharp & Dohme LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT01537900
• Other Study ID Numbers: 5172-010; 2011-000435-83
• First Posted: Feb 23, 2012
• Last Update Posted: Sep 14, 2018
• Last Verified: Aug 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Hepatitis A; Hepatitis C; Hepatitis; Grazoprevir

Study Results

Participant Flow

Arm/Group Title	Grazoprevir 100 mg
Arm/Group Description	Participants received GZR 100 mg once daily (q.d.) for 7 days. Liver FNA was performed on Day 7.
Period Title: Overall Study
STARTED	4
COMPLETED	4
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Grazoprevir 100 mg
Arm/Group Description	Participants received GZR 100 mg q.d. for 7 days. Liver FNA was performed on Day 7.
Overall Participants	4
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	42.5 (12.9)
Sex: Female, Male (Count of Participants)
Female	1 25%
Male	3 75%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

The per protocol population (PPP) includes all participants (4, 8, and 24 hr time points) who complied with the protocol sufficiently to ensure that the data were likely to exhibit the effects of treatment. As each data point was obtained from unique participants, there is no measure of variability.

Arm/Group Title	Grazoprevir 100 mg
Arm/Group Description	Participants received GZR 100 mg q.d. for 7 days. Liver FNA was performed on Day 7.
Measure Participants	3
Number [µM*hr]	19800

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

The PPP includes all participants who complied with the protocol sufficiently to ensure that the data were likely to exhibit the effects of treatment.

Arm/Group Title	Grazoprevir 100 mg
Arm/Group Description	Participants received GZR 100 mg q.d. for 7 days. Liver FNA was performed on Day 7.
Measure Participants	4
Hepatic concentration at 4 hours (C[H]4hr)	390 (186)
Hepatic concentration at 8 hours (C[H]8hr)	1340 (1335)
Hepatic concentration at 24 hours (C[H]24hr)	575 (505)
Hepatic concentration at 72 hours (C[H]72hr)	434 (108)

3. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Apparent t(h)1/2 could not be estimated due to insufficient data in the terminal phase.

Arm/Group Title	Grazoprevir 100 mg
Arm/Group Description	Participants received GZR 100 mg q.d. for 7 days. Liver FNA was performed on Day 7.
Measure Participants	0

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Plasma PK data were not collected due to liver PK results being deemed physiologically impossible.

Arm/Group Title	Grazoprevir 100 mg
Arm/Group Description	Participants received GZR 100 mg q.d. for 7 days. Liver FNA was performed on Day 7.
Measure Participants	0

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Plasma PK data were not collected due to liver PK results being deemed physiologically impossible.

Arm/Group Title	Grazoprevir 100 mg
Arm/Group Description	Participants received GZR 100 mg q.d. for 7 days. Liver FNA was performed on Day 7.
Measure Participants	0

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Plasma PK data were not collected due to liver PK results being deemed physiologically impossible.

Arm/Group Title	Grazoprevir 100 mg
Arm/Group Description	Participants received GZR 100 mg q.d. for 7 days. Liver FNA was performed on Day 7.
Measure Participants	0

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Plasma PK data were not collected due to liver PK results being deemed physiologically impossible.

Arm/Group Title	Grazoprevir 100 mg
Arm/Group Description	Participants received GZR 100 mg q.d. for 7 days. Liver FNA was performed on Day 7.
Measure Participants	0

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Plasma PK data were not collected due to liver PK results being deemed physiologically impossible.

Arm/Group Title	Grazoprevir 100 mg
Arm/Group Description	Participants received GZR 100 mg q.d. for 7 days. Liver FNA was performed on Day 7.
Measure Participants	0

Adverse Events

Time Frame	From Screening up to 14 days after final dose (up to Day 21)
Arm/Group Title	Grazoprevir 100 mg
Arm/Group Description	Participants received GZR 100 mg q.d. for 7 days. Liver FNA was performed on Day 7.
All Cause Mortality
	Grazoprevir 100 mg
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Grazoprevir 100 mg
	Affected / at Risk (%)	# Events
Total	1/4 (25%)
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	1/4 (25%)	1
Other (Not Including Serious) Adverse Events
	Grazoprevir 100 mg
	Affected / at Risk (%)	# Events
Total	1/4 (25%)
Gastrointestinal disorders
Diarrhoea	1/4 (25%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The SPONSOR must have the opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/presentation.