Hepatitis C, Chronic
Conditions
Brief summary
This 2-arm study was designed to evaluate the efficacy, safety, and tolerability of prophylactic PEGASYS plus COPEGUS after liver transplantation for hepatitis C, compared to initiation of antiviral therapy at the time of clinical recurrence of hepatitis C infection. The anticipated time on study treatment was 3-12 months, and the target sample size was 100-500 individuals.
Interventions
DRUGpeginterferon alfa-2a [Pegasys]
135 micrograms subcutaneously (SC) weekly for 4 weeks followed by 180 micrograms SC weekly for 44 weeks
DRUGCopegus
400 mg orally (PO) daily escalating to 1200 mg PO daily, for 48 weeks
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult patients at least 18 years of age * Positive hepatitis C virus RNA at pre-transplantation * Primary, single-organ recipient (cadaveric donor) * Liver transplant between 10 and 16 weeks before treatment initiation
Exclusion criteria
* Multi-organ or re-transplant recipient * Evidence of current hepatitis B infection * Seropositive for human immunodeficiency (HIV) infection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Histologically-confirmed Recurrence of Hepatitis C Virus (HCV) | 120 weeks postrandomization | Histologically-confirmed recurrence of HCV defined as Batts-Ludwig inflammation grade ≥3 and/or fibrosis stage ≥2. Inflammation(Grade): 0 No Activity,1 Minimal,2 Mild,3 Moderate,4 Severe. Fibrosis (Stage): 0 No fibrosis, Normal; 1 Portal fibrosis; 2 Periportal fibrosis or rare portal septa; 3 Septal fibrosis, Fibrous septa with architectural distortion, no obvious cirrhosis; 4 Cirrhosis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Summary of Virologic Response | After 4, 12, 24 and 48 weeks of therapy, and 24 weeks of follow-up | Rapid virologic responder (RVR): undetectable HCV-RNA at Week 4; complete early virologic responder (cEVR): undetectable HCV-RNA at Week 12; partial early virologic responder (pEVR): ≥2 log10 drop from baseline in HCV-RNA but positive at Week 12; early virologic responder (EVR): undetectable HCV-RNA or ≥2 log10 drop from baseline in HCV-RNA at Week 12; 24 weeks negative: undetectable HCV-RNA at Week 24; 48 weeks negative: undetectable HCV-RNA at Week 48; sustained virologic response (SVR): undetectable HCV-RNA at 24 weeks after the end of treatment. |
Countries
United States
Participant flow
Recruitment details
Patients were recruited from 24 study centers in the US over a period of 4 years (12-Oct-04 - 17-Oct-08)
Pre-assignment details
Eligible for the study were male or female patients ≥18 years of age with HCV infection who underwent orthotopic liver transplantation (OLT) because of liver cirrhosis attributed to HCV infection
Participants by arm
| Arm | Count |
|---|---|
| Prophylaxis Arm Pegylated interferon alfa-2a subcutaneously (SC) 135 μg/week for 4 weeks, then increased to 180 μg/week for the next 44 weeks, plus Ribavirin orally 400 mg/day (initial) to 1000 mg/day for patients \<75 kg or 1200 mg/day for patients ≥75 kg PO (escalated) (maximum) administered orally | 55 |
| Observation Arm No antiviral therapy for HCV unless recurrence of HCV was histologically demonstrated. Once histological recurrence was demonstrated, patients received the same antiviral regimen as patients in the prophylaxis arm (ie, 48 weeks of combined PEG-IFN alfa-2a and ribavirin) | 60 |
| Total | 115 |
Baseline characteristics
| Characteristic | Prophylaxis Arm | Observation Arm | Total |
|---|---|---|---|
| Age, Continuous | 51.3 years STANDARD_DEVIATION 6.09 | 53.6 years STANDARD_DEVIATION 5.37 | 52.5 years STANDARD_DEVIATION 5.82 |
| Region of Enrollment United States | 55 participants | 60 participants | 115 participants |
| Sex: Female, Male Female | 10 Participants | 12 Participants | 22 Participants |
| Sex: Female, Male Male | 45 Participants | 48 Participants | 93 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 54 / 54 | 58 / 60 |
| serious Total, serious adverse events | 25 / 54 | 21 / 60 |
Outcome results
Primary
Percentage of Patients With Histologically-confirmed Recurrence of Hepatitis C Virus (HCV)
Histologically-confirmed recurrence of HCV defined as Batts-Ludwig inflammation grade ≥3 and/or fibrosis stage ≥2. Inflammation(Grade): 0 No Activity,1 Minimal,2 Mild,3 Moderate,4 Severe. Fibrosis (Stage): 0 No fibrosis, Normal; 1 Portal fibrosis; 2 Periportal fibrosis or rare portal septa; 3 Septal fibrosis, Fibrous septa with architectural distortion, no obvious cirrhosis; 4 Cirrhosis.
Time frame: 120 weeks postrandomization
Population: Intent-to-treat population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Prophylaxis Arm | Percentage of Patients With Histologically-confirmed Recurrence of Hepatitis C Virus (HCV) | 61.8 percentage of participants |
| Observation Arm | Percentage of Patients With Histologically-confirmed Recurrence of Hepatitis C Virus (HCV) | 65.0 percentage of participants |
p-value: 0.72595% CI: [-20.8, 14.4]Cochran-Mantel-Haenszel
Secondary
Summary of Virologic Response
Rapid virologic responder (RVR): undetectable HCV-RNA at Week 4; complete early virologic responder (cEVR): undetectable HCV-RNA at Week 12; partial early virologic responder (pEVR): ≥2 log10 drop from baseline in HCV-RNA but positive at Week 12; early virologic responder (EVR): undetectable HCV-RNA or ≥2 log10 drop from baseline in HCV-RNA at Week 12; 24 weeks negative: undetectable HCV-RNA at Week 24; 48 weeks negative: undetectable HCV-RNA at Week 48; sustained virologic response (SVR): undetectable HCV-RNA at 24 weeks after the end of treatment.
Time frame: After 4, 12, 24 and 48 weeks of therapy, and 24 weeks of follow-up
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Prophylaxis Arm | Summary of Virologic Response | Rapid virologic responder (RVR) | 4 participants |
| Prophylaxis Arm | Summary of Virologic Response | 24 weeks negative | 20 participants |
| Prophylaxis Arm | Summary of Virologic Response | Partial early virologic responder (pEVR) | 13 participants |
| Prophylaxis Arm | Summary of Virologic Response | 48 weeks negative | 18 participants |
| Prophylaxis Arm | Summary of Virologic Response | Complete early virologic responder (cEVR) | 14 participants |
| Prophylaxis Arm | Summary of Virologic Response | Sustained virologic responder (SVR) | 12 participants |
| Prophylaxis Arm | Summary of Virologic Response | Early virologic responder (EVR) | 27 participants |
| Observation Arm | Summary of Virologic Response | Sustained virologic responder (SVR) | 3 participants |
| Observation Arm | Summary of Virologic Response | Complete early virologic responder (cEVR) | 4 participants |
| Observation Arm | Summary of Virologic Response | Partial early virologic responder (pEVR) | 3 participants |
| Observation Arm | Summary of Virologic Response | Early virologic responder (EVR) | 7 participants |
| Observation Arm | Summary of Virologic Response | 24 weeks negative | 6 participants |
| Observation Arm | Summary of Virologic Response | 48 weeks negative | 3 participants |
| Observation Arm | Summary of Virologic Response | Rapid virologic responder (RVR) | 0 participants |