HCV Infection
Conditions
Brief summary
The primary objective of this study is to evaluate the pharmacokinetics (PK), safety, and tolerability of a single dose of voxilaprevir (formerly GS-9857) in participants with normal hepatic function, moderate hepatic impairment and severe hepatic impairment. Participants in the healthy control group will be matched to participants with impaired hepatic function by gender, age (± 10 years), and body mass index (± 15%).
Interventions
DRUGVoxilaprevir
100 mg tablet administered orally
Sponsors
Gilead Sciences
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
Key Inclusion Criteria: * All individuals: * Screening laboratory values within defined thresholds for group * Use of two effective contraception methods if female of childbearing potential or sexually active male * For individuals with moderate hepatic impairment: * Diagnosis of chronic (\> 6 months) hepatic impairment * Score on the Child-Pugh-Turcotte (CPT) scale of 7-9 at screening (Child Pugh Class B). * For individuals with severe hepatic impairment: * Diagnosis of chronic (\> 6 months) hepatic impairment * Score on the CPT scale of 10-15 at screening (Child Pugh Class C) * For individuals with normal hepatic function: * Hepatitis C Virus (HCV) antibody and hepatitis B surface antigen negative Key
Exclusion criteria
* All individuals: * Pregnant or nursing female or male with pregnant female partner * HIV infection * History of clinically significant illness or any other medical disorder that may interfere with the individual's treatment, assessment or compliance with the protocol * For individuals with moderate or severe hepatic impairment: * Active HCV infection * Current hepatic encephalopathy * Variceal bleeding in the last 6 months unless banded * Prior placement of a portosystemic shunt * History of hepatorenal or hepatopulmonary syndrome * Spontaneous bacterial peritonitis currently or within the last 6 months * Hospitalization within the last 2 months related to cirrhosis * Confirmed hypotension * Suspicion of hepatocellular carcinoma Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic (PK) Parameter of Voxilaprevir: AUClast | 0 (pre-dose ≤ 5 minutes), 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, 96, and 120 hours post-dose | AUClast is defined as the area under the plasma concentration versus time curve from time zero to the last quantifiable concentration. Data presented are unadjusted geometric means and confidence intervals. |
| PK Parameter of Voxilaprevir: AUCinf | 0 (pre-dose ≤ 5 minutes), 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, 96, and 120 hours postdose | AUCinf is defined as the area under the plasma concentration versus time curve extrapolated to infinite time. Data presented are unadjusted geometric means and confidence intervals. |
| PK Parameter of Voxilaprevir: Cmax | 0 (pre-dose ≤ 5 minutes), 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, 96, and 120 hours postdose | Cmax is defined as the maximum observed plasma concentration of drug.Data presented are unadjusted geometric means and confidence intervals. |
Countries
Germany, New Zealand, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in United States, Germany, and New Zealand. The first participant was screened on 24 March 2015. The last study visit occurred on 04 March 2016.
Pre-assignment details
54 participants were screened. 33 participants were enrolled, 14 participants with normal hepatic function, 10 with Moderate Hepatic Impairment (MHI), and 9 with Severe Hepatic Impairment (SHI). Five of the same participants with normal hepatic function served as matched controls for the MHI and SHI Arms/Groups.
Participants by arm
| Arm | Count |
|---|---|
| Normal Hepatic Function Participants with normal hepatic function received single dose of voxilaprevir 100 mg tablet orally on Day 1. | 14 |
| Moderate Hepatic Impairment (MHI) Participants with moderate hepatic impairment received single dose of voxilaprevir 100 mg tablet orally on Day 1. | 10 |
| Severe Hepatic Impairment (SHI) Participants with severe hepatic impairment received single dose of voxilaprevir 100 mg tablet orally on Day 1. | 9 |
| Total | 33 |
Baseline characteristics
| Characteristic | Moderate Hepatic Impairment (MHI) | Severe Hepatic Impairment (SHI) | Normal Hepatic Function | Total |
|---|---|---|---|---|
| Age, Continuous | 55 years STANDARD_DEVIATION 6.7 | 55 years STANDARD_DEVIATION 7 | 53 years STANDARD_DEVIATION 9.8 | 54 years STANDARD_DEVIATION 8 |
| Body Mass Index (BMI) | 27.6 kg/m^2 STANDARD_DEVIATION 3.9 | 28.4 kg/m^2 STANDARD_DEVIATION 3.86 | 27.6 kg/m^2 STANDARD_DEVIATION 2.21 | 27.8 kg/m^2 STANDARD_DEVIATION 3.18 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black | 1 Participants | 0 Participants | 3 Participants | 4 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 3 Participants | 5 Participants | 7 Participants | 15 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Pacific Islander | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 7 Participants | 4 Participants | 7 Participants | 18 Participants |
| Race/Ethnicity, Customized Not Permitted | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 8 Participants | 9 Participants | 9 Participants | 26 Participants |
| Region of Enrollment Germany | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Region of Enrollment New Zealand | 2 Participants | 1 Participants | 3 Participants | 6 Participants |
| Region of Enrollment United States | 8 Participants | 6 Participants | 11 Participants | 25 Participants |
| Sex: Female, Male Female | 4 Participants | 2 Participants | 5 Participants | 11 Participants |
| Sex: Female, Male Male | 6 Participants | 7 Participants | 9 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 10 | 0 / 9 |
| other Total, other adverse events | 2 / 14 | 3 / 10 | 1 / 9 |
| serious Total, serious adverse events | 0 / 14 | 0 / 10 | 0 / 9 |
Outcome results
Primary
Pharmacokinetic (PK) Parameter of Voxilaprevir: AUClast
AUClast is defined as the area under the plasma concentration versus time curve from time zero to the last quantifiable concentration. Data presented are unadjusted geometric means and confidence intervals.
Time frame: 0 (pre-dose ≤ 5 minutes), 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, 96, and 120 hours post-dose
Population: PK Analysis Set included all enrolled participants who took at least 1 dose of study drug and had at least 1 nonmissing postdose concentration value reported by the PK laboratory for the corresponding analyte. Five of the same participants with normal hepatic function served as matched controls for the MHI and SHI Arms/Groups.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Moderate Hepatic Impairment (MHI) | Pharmacokinetic (PK) Parameter of Voxilaprevir: AUClast | 2058.5 h*ng/mL |
| Severe Hepatic Impairment (SHI) | Pharmacokinetic (PK) Parameter of Voxilaprevir: AUClast | 3872.5 h*ng/mL |
| Normal Hepatic Function (Matched Control for MHI) | Pharmacokinetic (PK) Parameter of Voxilaprevir: AUClast | 500.1 h*ng/mL |
| Normal Hepatic Function (Matched Controls for SHI) | Pharmacokinetic (PK) Parameter of Voxilaprevir: AUClast | 601.2 h*ng/mL |
Comparison: An analysis of variance (ANOVA) appropriate for a parallel design was fitted to the natural logarithmic transformation of voxilaprevir AUClast. A 90% confidence interval (CI) was constructed for the geometric least squares mean (GLSM) ratio of AUClast for the comparison groups using two 1-sided tests.90% CI: [214.72, 789.08]
Comparison: An ANOVA appropriate for a parallel design was fitted to the natural logarithmic transformation of voxilaprevir AUClast. A 90% CI was constructed for the GLSM ratio of AUClast for the comparison groups using two 1-sided tests.90% CI: [364.67, 1137.82]
Primary
PK Parameter of Voxilaprevir: AUCinf
AUCinf is defined as the area under the plasma concentration versus time curve extrapolated to infinite time. Data presented are unadjusted geometric means and confidence intervals.
Time frame: 0 (pre-dose ≤ 5 minutes), 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, 96, and 120 hours postdose
Population: Participants in the PK Analysis Set were analyzed. Five of the same participants with normal hepatic function served as matched controls for the MHI and SHI Arms/Groups.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Moderate Hepatic Impairment (MHI) | PK Parameter of Voxilaprevir: AUCinf | 2227.1 h*ng/mL |
| Severe Hepatic Impairment (SHI) | PK Parameter of Voxilaprevir: AUCinf | 4107.5 h*ng/mL |
| Normal Hepatic Function (Matched Control for MHI) | PK Parameter of Voxilaprevir: AUCinf | 557.8 h*ng/mL |
| Normal Hepatic Function (Matched Controls for SHI) | PK Parameter of Voxilaprevir: AUCinf | 685 h*ng/mL |
Comparison: An ANOVA appropriate for parallel design was fitted to the natural logarithmic transformation of voxilaprevir AUCinf. A 90% CI was constructed for the GLSM ratio of AUClast for the comparison groups using two 1-sided tests.90% CI: [210.89, 755.81]
Comparison: An ANOVA appropriate for parallel design was fitted to the natural logarithmic transformation of voxilaprevir AUCinf. A 90% CI was constructed for the GLSM ratio of AUCinf for the comparison groups using two 1-sided tests.90% CI: [342.36, 1050.22]
Primary
PK Parameter of Voxilaprevir: Cmax
Cmax is defined as the maximum observed plasma concentration of drug.Data presented are unadjusted geometric means and confidence intervals.
Time frame: 0 (pre-dose ≤ 5 minutes), 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, 96, and 120 hours postdose
Population: Participants in the PK Analysis Set were analyzed. Five of the same participants with normal hepatic function served as matched controls for the MHI and SHI Arms/Groups.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Moderate Hepatic Impairment (MHI) | PK Parameter of Voxilaprevir: Cmax | 189.7 ng/mL |
| Severe Hepatic Impairment (SHI) | PK Parameter of Voxilaprevir: Cmax | 370.8 ng/mL |
| Normal Hepatic Function (Matched Control for MHI) | PK Parameter of Voxilaprevir: Cmax | 56.1 ng/mL |
| Normal Hepatic Function (Matched Controls for SHI) | PK Parameter of Voxilaprevir: Cmax | 51.9 ng/mL |
Comparison: An ANOVA appropriate was fitted to the natural logarithmic transformation of voxilaprevir Cmax. A 90% CI was constructed for the GLSM ratio of AUClast for the comparison groups using two 1-sided tests.90% CI: [168.96, 677.79]
Comparison: An ANOVA appropriate was fitted to the natural logarithmic transformation of voxilaprevir Cmax. A 90% CI was constructed for the GLSM ratio of AUClast for the comparison groups using two 1-sided tests.90% CI: [384.07, 1327.06]