Hepatitis C, Chronic
Conditions
Brief summary
The purpose of this study is to evaluate the safety, tolerability, and efficacy of vaniprevir given in combination with pegylated interferon alfa-2b (PegIntron®/peg-IFN) and ribavirin (RBV) in chronic hepatitis C (CHC) Genotype I (GT 1) participants who relapsed after previous therapy with interferon-based therapy. The primary efficacy hypothesis is that the percentage of participants achieving sustained virologic response 24 weeks after completion of all study therapy (SVR24) in at least one of the vaniprevir 300 mg twice daily treatment regimens is greater than 20% (historical data of standard of care treatment).
Interventions
DRUGvaniprevir
vaniprevir capsules containing 150 mg vaniprevir, orally, two in the morning and two in the evening for 12 or 24 weeks
BIOLOGICALpeg-IFN
peg-IFN 1.5 µg/kg once per week, subcutaneously (SC) for 24 weeks
DRUGribavirin
Capsules containing 200 mg ribavirin, orally, 3 to 5 capsules, dosage based on participant weight (600 mg/day to 1000 mg/day), for 24 weeks
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Japanese participant diagnosed with compensated CHC GT 1 * Absence of ascites, bleeding esophageal varices, hepatic encephalopathy, or other signs or symptoms of advanced liver disease * Has received and tolerated treatment with IFN-based therapy (IFN α, IFN β, or peg-IFN) with or without use of ribavirin, but failed to respond to the prior treatment (relapse or breakthrough) * No evidence of cirrhosis
Exclusion criteria
* Co-infection with human immunodeficiency virus (HIV) * Positive hepatitis B surface antigen or other evidence of active hepatitis B infection * Any other condition that is contraindicated or for which caution is required for treatment with peg-IFN or RBV * Any condition or pre-study laboratory abnormality, or history of any illness, that, in the opinion of the investigator, might confound the results of the study or pose additional risk in administering the study drugs, peg-IFN and RBV, to the participant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After Completion of All Study Therapy (SVR24) | 24 weeks after 24 weeks of study therapy (up to 48 weeks) | SVR24 was defined as having an undetectable HCV RNA level 24 weeks after completion of all study therapy. The percentage of participants achieving SVR24 were reported along with corresponding 95% Clopper-Pearson exact confidence intervals for each treatment regimen. |
| Percentage of Participants With One or More Specific Adverse Events (AEs) of Special Interest During the Study | From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks) | An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the product, was also an AE. For this study, safety parameters or AEs of special interest that were identified a priori included serious rash, anemia (anemia plus haemoglobin decreased), neutropenia (neutropenia plus neutrophil count decreased), bilirubin increased and gastrointestinal (GI) adverse experiences (vomiting, nausea, and diarrhea). The percentage of participants with ≥1 specific AEs were reported along with corresponding 95% Clopper-Pearson exact confidence intervals for each treatment regimen. |
| Percentage of Participants Who Discontinued Study Drug Due to an AE | From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks) | An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the product, was also an AE. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Undetectable HCV RNA at the End of Treatment (EOT) | At Week 24 | Participants were assessed for undetectable HCV RNA levels at the end of all study therapy. The percentage of participants with undetectable HCV RNA levels at EOT were reported along with corresponding 95% Clopper-Pearson exact confidence intervals for each treatment regimen. |
| Percentage of Participants Achieving SVR12 | 12 weeks after 24 weeks of study therapy (up to 36 weeks) | SVR12 was defined as having an undetectable HCV RNA level 12 weeks after completion of all study therapy. The percentage of participants achieving SVR12 were reported along with corresponding 95% Clopper-Pearson exact confidence intervals for each treatment regimen. |
| Mean Change From Baseline in HCV RNA (Log 10) | Baseline, Week 2, Week 4, Week 8, Week 12, Week 24 | HCV RNA levels were assessed at baseline (BL) and during treatment weeks 2, 4, 8, 12, and 24 using the Roche TaqMan HCV assay, and transformed to Log 10 values. HCV RNA values below the limit of reliable quantification (LoQ) or the limit of detection (LoD) at any time point were handled as follows (imputations done for computational purposes): values below the LoQ but above the LoD were imputed with the LoQ minus 0.1; values below the LoD were imputed with the value of 0 Log IU/mL. HCV RNA levels below the LoD were considered undetectable. |
| Percentage of Participants Achieving Rapid Virologic Response (RVR) | At Week 4 | RVR was defined as having an undetectable HCV RNA level at Week 4. The percentage of participants achieving RVR were reported along with corresponding 95% Clopper-Pearson exact confidence intervals for each treatment regimen. |
| Percentage of Participants Achieving Complete Early Virologic Response (cEVR) | At Week 12 | cEVR was defined as having an undetectable HCV RNA level at Week 12. The percentage of participants achieving cEVR were reported along with corresponding 95% Clopper-Pearson exact confidence intervals for each treatment regimen. |
Participant flow
Recruitment details
Japanese patients 20-70 years old (inclusive) with chronic, compensated, genotype 1 Hepatitis C (HCV) infection and HCV ribonucleic acid (RNA) levels ≥5.0 log IU/mL in peripheral blood at screening, who had failed to respond to prior treatment, were recruited from 22 sites in Japan.
Pre-assignment details
51 participants were randomized to receive 12 or 24 weeks of vaniprevir in combination with 24 weeks of peg-IFN α-2b (peg-IFN) and ribavirin (RBV).
Participants by arm
| Arm | Count |
|---|---|
| Vaniprevir 12 Week Arm Participants on this arm receive 12 weeks of vaniprevir (300 mg twice daily) along with 24 weeks of treatment with peg-IFN and RBV | 25 |
| Vaniprevir 24 Week Arm Participants on this arm receive 24 weeks of vaniprevir (300 mg twice daily) along with 24 weeks of treatment with peg-IFN and RBV | 26 |
| Total | 51 |
Baseline characteristics
| Characteristic | Vaniprevir 12 Week Arm | Vaniprevir 24 Week Arm | Total |
|---|---|---|---|
| Age, Continuous | 57.8 years STANDARD_DEVIATION 9 | 60.3 years STANDARD_DEVIATION 7.5 | 59.1 years STANDARD_DEVIATION 8.3 |
| Sex: Female, Male Female | 13 Participants | 14 Participants | 27 Participants |
| Sex: Female, Male Male | 12 Participants | 12 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 24 / 25 | 26 / 26 |
| serious Total, serious adverse events | 2 / 25 | 3 / 26 |
Outcome results
Primary
Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After Completion of All Study Therapy (SVR24)
SVR24 was defined as having an undetectable HCV RNA level 24 weeks after completion of all study therapy. The percentage of participants achieving SVR24 were reported along with corresponding 95% Clopper-Pearson exact confidence intervals for each treatment regimen.
Time frame: 24 weeks after 24 weeks of study therapy (up to 48 weeks)
Population: Full Analysis Set (FAS) population; all randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vaniprevir 12 Week Arm | Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After Completion of All Study Therapy (SVR24) | 92.0 percentage of participants |
| Vaniprevir 24 Week Arm | Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After Completion of All Study Therapy (SVR24) | 96.2 percentage of participants |
Comparison: The null hypothesis that the percentage of participants achieving SVR24 of vaniprevir treatment was 20% versus the alternative that the percentage of participants achieving SVR24 of vaniprevir treatment was over 20% was tested.p-value: <0.001exact test for binomial proportion
Comparison: The null hypothesis that the percentage of participants achieving SVR24 of vaniprevir treatment was 20% versus the alternative that the percentage of participants achieving SVR24 of vaniprevir treatment was over 20% was tested.p-value: <0.001exact test for binomial proportion
Primary
Percentage of Participants Who Discontinued Study Drug Due to an AE
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the product, was also an AE.
Time frame: From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Population: All Participants Treated (APaT) Population; all participants receiving at least one dose of study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vaniprevir 12 Week Arm | Percentage of Participants Who Discontinued Study Drug Due to an AE | 4.0 percentage of participants |
| Vaniprevir 24 Week Arm | Percentage of Participants Who Discontinued Study Drug Due to an AE | 0.0 percentage of participants |
Primary
Percentage of Participants With One or More Specific Adverse Events (AEs) of Special Interest During the Study
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the product, was also an AE. For this study, safety parameters or AEs of special interest that were identified a priori included serious rash, anemia (anemia plus haemoglobin decreased), neutropenia (neutropenia plus neutrophil count decreased), bilirubin increased and gastrointestinal (GI) adverse experiences (vomiting, nausea, and diarrhea). The percentage of participants with ≥1 specific AEs were reported along with corresponding 95% Clopper-Pearson exact confidence intervals for each treatment regimen.
Time frame: From Day 1 (post-dose) through completion of Week 24 Follow-up (up to 48 weeks)
Population: All Participants Treated (APaT) Population; all participants receiving at least one dose of study treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vaniprevir 12 Week Arm | Percentage of Participants With One or More Specific Adverse Events (AEs) of Special Interest During the Study | bilirubin increased | 8.0 percentage of participants |
| Vaniprevir 12 Week Arm | Percentage of Participants With One or More Specific Adverse Events (AEs) of Special Interest During the Study | With ≥1 specific AEs | 88.0 percentage of participants |
| Vaniprevir 12 Week Arm | Percentage of Participants With One or More Specific Adverse Events (AEs) of Special Interest During the Study | GI AEs | 64.0 percentage of participants |
| Vaniprevir 12 Week Arm | Percentage of Participants With One or More Specific Adverse Events (AEs) of Special Interest During the Study | neutropenia | 40.0 percentage of participants |
| Vaniprevir 12 Week Arm | Percentage of Participants With One or More Specific Adverse Events (AEs) of Special Interest During the Study | anaemia | 56.0 percentage of participants |
| Vaniprevir 24 Week Arm | Percentage of Participants With One or More Specific Adverse Events (AEs) of Special Interest During the Study | neutropenia | 42.3 percentage of participants |
| Vaniprevir 24 Week Arm | Percentage of Participants With One or More Specific Adverse Events (AEs) of Special Interest During the Study | With ≥1 specific AEs | 84.6 percentage of participants |
| Vaniprevir 24 Week Arm | Percentage of Participants With One or More Specific Adverse Events (AEs) of Special Interest During the Study | bilirubin increased | 3.8 percentage of participants |
| Vaniprevir 24 Week Arm | Percentage of Participants With One or More Specific Adverse Events (AEs) of Special Interest During the Study | GI AEs | 65.4 percentage of participants |
| Vaniprevir 24 Week Arm | Percentage of Participants With One or More Specific Adverse Events (AEs) of Special Interest During the Study | anaemia | 61.5 percentage of participants |
Secondary
Mean Change From Baseline in HCV RNA (Log 10)
HCV RNA levels were assessed at baseline (BL) and during treatment weeks 2, 4, 8, 12, and 24 using the Roche TaqMan HCV assay, and transformed to Log 10 values. HCV RNA values below the limit of reliable quantification (LoQ) or the limit of detection (LoD) at any time point were handled as follows (imputations done for computational purposes): values below the LoQ but above the LoD were imputed with the LoQ minus 0.1; values below the LoD were imputed with the value of 0 Log IU/mL. HCV RNA levels below the LoD were considered undetectable.
Time frame: Baseline, Week 2, Week 4, Week 8, Week 12, Week 24
Population: Participants in the FAS population (all randomized participants who received at least one dose of study treatment) that had HCV RNA data available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vaniprevir 12 Week Arm | Mean Change From Baseline in HCV RNA (Log 10) | Change From BL at Week 2 (n=25, 26) | -5.7 Log IU/ml | Standard Deviation 0.5 |
| Vaniprevir 12 Week Arm | Mean Change From Baseline in HCV RNA (Log 10) | Change From BL at Week 12 (n=25, 26) | -6.6 Log IU/ml | Standard Deviation 0.5 |
| Vaniprevir 12 Week Arm | Mean Change From Baseline in HCV RNA (Log 10) | Change From BL at Week 8 (n=25, 26) | -6.6 Log IU/ml | Standard Deviation 0.5 |
| Vaniprevir 12 Week Arm | Mean Change From Baseline in HCV RNA (Log 10) | Change From BL at Week 24 (n=24, 26) | -6.7 Log IU/ml | Standard Deviation 0.5 |
| Vaniprevir 12 Week Arm | Mean Change From Baseline in HCV RNA (Log 10) | Change From BL at Week 4 (n=25, 26) | -6.5 Log IU/ml | Standard Deviation 0.6 |
| Vaniprevir 24 Week Arm | Mean Change From Baseline in HCV RNA (Log 10) | Change From BL at Week 24 (n=24, 26) | -6.5 Log IU/ml | Standard Deviation 0.7 |
| Vaniprevir 24 Week Arm | Mean Change From Baseline in HCV RNA (Log 10) | Change From BL at Week 2 (n=25, 26) | -5.7 Log IU/ml | Standard Deviation 0.7 |
| Vaniprevir 24 Week Arm | Mean Change From Baseline in HCV RNA (Log 10) | Change From BL at Week 4 (n=25, 26) | -6.3 Log IU/ml | Standard Deviation 0.9 |
| Vaniprevir 24 Week Arm | Mean Change From Baseline in HCV RNA (Log 10) | Change From BL at Week 8 (n=25, 26) | -6.5 Log IU/ml | Standard Deviation 0.7 |
| Vaniprevir 24 Week Arm | Mean Change From Baseline in HCV RNA (Log 10) | Change From BL at Week 12 (n=25, 26) | -6.5 Log IU/ml | Standard Deviation 0.7 |
Secondary
Percentage of Participants Achieving Complete Early Virologic Response (cEVR)
cEVR was defined as having an undetectable HCV RNA level at Week 12. The percentage of participants achieving cEVR were reported along with corresponding 95% Clopper-Pearson exact confidence intervals for each treatment regimen.
Time frame: At Week 12
Population: FAS population; all randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vaniprevir 12 Week Arm | Percentage of Participants Achieving Complete Early Virologic Response (cEVR) | 100.0 Percentage of participants |
| Vaniprevir 24 Week Arm | Percentage of Participants Achieving Complete Early Virologic Response (cEVR) | 100.0 Percentage of participants |
Secondary
Percentage of Participants Achieving Rapid Virologic Response (RVR)
RVR was defined as having an undetectable HCV RNA level at Week 4. The percentage of participants achieving RVR were reported along with corresponding 95% Clopper-Pearson exact confidence intervals for each treatment regimen.
Time frame: At Week 4
Population: FAS population; all randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vaniprevir 12 Week Arm | Percentage of Participants Achieving Rapid Virologic Response (RVR) | 88.0 percentage of participants |
| Vaniprevir 24 Week Arm | Percentage of Participants Achieving Rapid Virologic Response (RVR) | 88.5 percentage of participants |
Secondary
Percentage of Participants Achieving SVR12
SVR12 was defined as having an undetectable HCV RNA level 12 weeks after completion of all study therapy. The percentage of participants achieving SVR12 were reported along with corresponding 95% Clopper-Pearson exact confidence intervals for each treatment regimen.
Time frame: 12 weeks after 24 weeks of study therapy (up to 36 weeks)
Population: FAS population; all randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vaniprevir 12 Week Arm | Percentage of Participants Achieving SVR12 | 88.0 percentage of participants |
| Vaniprevir 24 Week Arm | Percentage of Participants Achieving SVR12 | 92.3 percentage of participants |
Secondary
Percentage of Participants Achieving Undetectable HCV RNA at the End of Treatment (EOT)
Participants were assessed for undetectable HCV RNA levels at the end of all study therapy. The percentage of participants with undetectable HCV RNA levels at EOT were reported along with corresponding 95% Clopper-Pearson exact confidence intervals for each treatment regimen.
Time frame: At Week 24
Population: FAS population; all randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vaniprevir 12 Week Arm | Percentage of Participants Achieving Undetectable HCV RNA at the End of Treatment (EOT) | 100.0 Percentage of participants |
| Vaniprevir 24 Week Arm | Percentage of Participants Achieving Undetectable HCV RNA at the End of Treatment (EOT) | 100.0 Percentage of participants |