Chronic Hepatitis C
Conditions
Brief summary
This study will evaluate the technical feasibility of using fine needle aspiration (FNA) of liver tissue to obtain vaniprevir (MK-7009) liver pharmacokinetic (PK) data, working towards identifying a minimally invasive, reproducible platform to measure liver PK. The study will be done in 2 parts. In Part 1, participants will be randomized to one of five FNA/core needle biopsy (CNB) time-point collection sequences. In Part 2, participants will be randomized to one of two possible doses of vaniprevir and will be assigned to one of five FNA/CNB time-point collection sequences; participants in Part 2 will also receive background therapy with pegylated interferon alpha-2b (Peg-IFN alpha-2b) and ribavirin (RBV). The primary hypothesis is that there is a greater than 80% posterior probability that vaniprevir concentrations are successfully obtained at least 60% of the time from FNA liver samples collected at 2 of 3 specified timepoints.
Interventions
DRUGVaniprevir 600 mg
Vaniprevir capsules, were administered orally, twice per day (BID) to achieve a final daily dose of 600 mg on Days 1 through 6; and a single dose of 600 mg, orally, on Day 7.
BIOLOGICALPeg-IFN alfa-2b
Peg-IFN alfa-2b was administered at 1.5 µg/kg per week by subcutaneous injections on Days 1, 8, 15 and 21
BIOLOGICALRibavirin
Ribavirin capsules were administered on Days 1-21, orally, twice daily for a total daily dose of 600 - 1400 mg, depending on the participant's weight
PROCEDURELiver samples from FNA
Liver samples were collected from Day 7 up to Day 10 by FNA at 3 of 5 specified postdose timepoints.
Vaniprevir capsules were administered orally, twice per day to achieve a final daily dose of 300 mg on Days 1 through 6; and a single dose of 300 mg, orally, on Day 7.
PROCEDURELiver samples from CNB
Liver samples were collected from Day 8 up to Day 10 by CNB at 1 of 3 specified postdose timepoints.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Body Mass Index (BMI) ≥18.5 kg/m\^2 and ≤32.0 kg/m\^2 * Under evaluation for treatment of chronic hepatitis C virus (HCV) * Chronic compensated, genotype 1 HCV infection * Treatment-naïve or previously treated and tolerated at least 12 weeks of continuous licensed interferon (including pegylated interferon) and ribavirin combination therapy with at least a partial response, or previously treated with investigational products and/or vaccines, other than HCV nonstructural proteins (NS) NS3/4A protease inhibitors, either alone or in combination with other licensed therapies * Able to avoid use of anticoagulants, nonsteroidal anti-inflammatory agents and aspirin for at least seven (7) days preceding the initial liver biopsy and continuing throughout the entire study * Female participants of childbearing potential or male participants with female sexual partners of childbearing potential must agree to use two acceptable methods of birth control from 2 weeks prior to the first dose through at least 6 months after last dose of study drug, or longer if dictated by local regulation
Exclusion criteria
* Pregnant, lactating, or intending to become pregnant or donate eggs, or intending to donate sperm * History of stroke, chronic seizures, or major neurological disorder * Did not achieve a viral response to prior treatment with licensed interferon-based therapy * Previously treated with an NS3/4A protease inhibitor (investigational or licensed) * 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 * Clinical or laboratory evidence of cirrhosis or other advanced liver disease * Decompensated liver disease as indicated by a history of ascites, hepatic encephalopathy, or bleeding esophageal varices * Diagnosed with or suspected of having hepatocellular carcinoma * Co-infection with human immunodeficiency virus (HIV) * Positive hepatitis B surface antigen or other evidence of active hepatitis B infection * History of gastric bypass surgery or bowel resection * History of clinically significant uncontrolled endocrine, gastrointestinal, cardiovascular, hematological, immunological, renal, respiratory, or genitourinary abnormalities or diseases * History of clinically significant neoplastic disease * Consumption of 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 * Regular user, including use of any illicit drugs, or has a history of drug (including alcohol) abuse within the last 3 months * Surgery or donation of 1 unit of blood (approximately 500 mL) or participation in another investigational study within a period of 4 weeks prior to the prestudy (screening) visit * History of multiple and/or severe allergies, or has had an anaphylactic reaction or intolerability to prescription or nonprescription drugs or food
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants From Whom Detectable Concentrations of Hepatic Vaniprevir Are Obtained by FNA | Day 7 up to Day 10 at 3 of the following timepoints: 3, 12, 24, 48 and 72 hours postdose | Liver samples were collected by FNA at 3 of 5 of the following specified postdose timepoints: 3, 12, 24, 48 and 72 hours after a single vaniprevir dose on Day 7. The technical success of the FNA procedure was established for a participant if vaniprevir was detected from at least 2 of the 3 FNA collection timepoints. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 600 mg Vaniprevir Participants received 600 mg vaniprevir only from Days 1-7; and had postdose liver biopsy from Day 7 up to Day 10 done by Fine Needle Aspiration (FNA) and Core Needle Biopsy (CNB). | 10 |
| 300 mg Vaniprevir + PegIFN/RBV Participants received 300 mg vaniprevir from Days 1-7; Pegylated Interferon (Peg-IFN) alpha-2b once weekly, Ribavirin (RBV) twice daily from Day 1 up to Day 21; and had postdose liver biopsy from Day 7 up to Day 10 done by FNA and CNB. | 10 |
| 600 mg Vaniprevir + PegIFN/RBV Participants received 600 mg vaniprevir from Days 1-7; Peg-IFN once weekly, RBV twice daily from Day 1 up to Day 21; and had postdose liver biopsy from Day 7 up to Day 10 done by FNA and CNB. | 11 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | 600 mg Vaniprevir | 300 mg Vaniprevir + PegIFN/RBV | 600 mg Vaniprevir + PegIFN/RBV | Total |
|---|---|---|---|---|
| Age, Continuous | 43.7 Years STANDARD_DEVIATION 10.6 | 43.9 Years STANDARD_DEVIATION 12.1 | 38.9 Years STANDARD_DEVIATION 8 | 42.1 Years STANDARD_DEVIATION 10.2 |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Male | 9 Participants | 8 Participants | 8 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 10 | 10 / 10 | 10 / 11 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 0 / 11 |
Outcome results
Primary
Number of Participants From Whom Detectable Concentrations of Hepatic Vaniprevir Are Obtained by FNA
Liver samples were collected by FNA at 3 of 5 of the following specified postdose timepoints: 3, 12, 24, 48 and 72 hours after a single vaniprevir dose on Day 7. The technical success of the FNA procedure was established for a participant if vaniprevir was detected from at least 2 of the 3 FNA collection timepoints.
Time frame: Day 7 up to Day 10 at 3 of the following timepoints: 3, 12, 24, 48 and 72 hours postdose
Population: Participants treated with vaniprevir who had hepatic FNA collected at 3 timepoints. One participant from the 300 mg Vaniprevir + Peg-IFN/RBV treatment group, and one participant from the 600 mg Vaniprevir + Peg-IFN/RBV treatment group discontinued treatment prior to collection of 3 FNAs, and were therefore excluded from the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 600 mg Vaniprevir | Number of Participants From Whom Detectable Concentrations of Hepatic Vaniprevir Are Obtained by FNA | 10 Participants |
| 300 mg Vaniprevir + PegIFN/RBV | Number of Participants From Whom Detectable Concentrations of Hepatic Vaniprevir Are Obtained by FNA | 9 Participants |
| 600 mg Vaniprevir + PegIFN/RBV | Number of Participants From Whom Detectable Concentrations of Hepatic Vaniprevir Are Obtained by FNA | 10 Participants |
Comparison: The posterior percentage probability of the true success rate of the FNA procedure for the 3 combined treatment groups (n=29) was determined by a Bayesian calculation, using a Jeffrey's prior distribution (i.e. Beta \[0.5,0.5\]) on the true success rate. Neither P-values, nor confidence intervals are estimated in this analysis. The primary hypothesis was met if the posterior percentage probability was \> 80% that the true success rate is at least 60%.