Hepatitis C, Chronic
Conditions
Brief summary
This 4-arm study will compare the efficacy and safety of PEGASYS induction and maintenance dosing, versus standard fixed dosing in combination with Copegus, and the efficacy and safety of higher dose versus standard dose Copegus in combination with PEGASYS. Patients with chronic hepatitis C (CHC) genotype 1 infection of high viral titer, and baseline body weight ≥85 kg, will be randomized to one of 4 groups, to receive one of the following: a) PEGASYS 180 µg subcutaneously (sc) weekly plus Copegus 1200 mg orally (po) daily; b) PEGASYS 180 µg sc weekly plus Copegus 1400-1600 mg po daily; c)PEGASYS 360 µg sc weekly (induction) followed by 180 µg sc weekly (maintenance) plus Copegus 1200 mg po daily; or d) PEGASYS 360 µg sc weekly (induction) followed by 180 µg sc weekly (maintenance) plus Copegus 1400-1600 mg po daily. Following 48 weeks treatment, there will be a 24-week period of treatment-free follow-up. The anticipated time on study treatment is 3-12 months, and the target sample size is 500+ individuals.
Interventions
DRUGpeginterferon alfa-2a
180 µg sc weekly for 48 weeks
DRUGRibavirin
1200 mg po daily for 48 weeks
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult patients, ≥18 years of age * CHC infection, genotype 1 * Hepatitis C virus (HCV) RNA ≥400,000 IU/mL * Baseline body weight ≥85 kg * Liver biopsy (within 24 months of first dose) with results consistent with CHC
Exclusion criteria
* Previous treatment with interferon, ribavirin, viramidine, levovirin, HCV polymerase or protease inhibitors * Other forms of liver disease, including liver cancer * Human immunodeficiency virus infection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sustained Virological Response (SVR)-24 (Scheduled Treatment Period) | Week 72 | SVR-24 according to the scheduled treatment period was defined as the percentage of patients with undetectable HCV RNA at 24 weeks after completion of the treatment period (a single last HCV RNA PCR \<15 IU/mL measured at or after week 68 (ie, on or after study day 477). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| SVR-24 (Actual Treatment Period) | 24 weeks after end of treatment | SVR-24 according to the actual treatment period was defined as the percentage of patients with undetectable HCV RNA at least 20 weeks after the last dose of study drug. |
| SVR-12 (Scheduled Treatment Period) | 12 weeks after end of treatment | SVR-12 according to the scheduled treatment period was defined as the percentage of patients with undetectable HCV RNA at 12 weeks after the scheduled treatment period (a single last HCV RNA PCR \<15 IU/mL measured at or after week 60). |
| SVR-12 (Actual Treatment Period) | 12 weeks after end of treatment | SVR-12 according to the actual treatment period was defined as the percentage of patients with undetectable HCV RNA at least 12 weeks after the last dose of study drug. |
Countries
Belgium, Brazil, Canada, Denmark, France, Germany, Hungary, Netherlands, Poland, Puerto Rico, Romania, Russia, Sweden, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PEG-IFN 180 µg + Ribavirin 1200 mg PEG-IFN 180 µg administered subcutaneously once weekly in abdomen or thigh. Ribavirin 600 mg administered orally twice daily (total of 1200 mg daily). | 195 |
| PEG-IFN 180 µg + Ribavirin 1400/1600 mg PEG-IFN 180 µg administered subcutaneously once weekly in abdomen or thigh. Patients with a body weight of 85 kg to \<95 kg took 600 mg of ribavirin (3 tablets) in the morning and 800 mg (4 tablets) in the evening, or vice versa; total daily dose was 1400 mg. Patients with a body weight ≥ 95 kg took 800 mg of ribavirin (4 tablets) in the morning and evening; total daily dose was 1600 mg. | 196 |
| PEG-IFN 360/180 µg + Ribavirin 1200 mg PEG-IFN 360 or 180 µg administered subcutaneously once weekly in abdomen or thigh. Ribavirin 600 mg administered orally twice daily (total of 1200 mg daily). | 393 |
| PEG-IFN 360/180 µg + Ribavirin 1400/1600 mg PEG-IFN 360 or 180 µg administered subcutaneously once weekly in abdomen or thigh. Patients with a body weight of 85 kg to \<95 kg took 600 mg of ribavirin (3 tablets) in the morning and 800 mg (4 tablets) in the evening, or vice versa; total daily dose was 1400 mg. Patients with a body weight ≥ 95 kg took 800 mg of ribavirin (4 tablets) in the morning and evening; total daily dose was 1600 mg. | 391 |
| Total | 1,175 |
Baseline characteristics
| Characteristic | PEG-IFN 180 µg + Ribavirin 1200 mg | PEG-IFN 180 µg + Ribavirin 1400/1600 mg | PEG-IFN 360/180 µg + Ribavirin 1200 mg | PEG-IFN 360/180 µg + Ribavirin 1400/1600 mg | Total |
|---|---|---|---|---|---|
| Age Continuous | 46.1 years STANDARD_DEVIATION 9.86 | 45.1 years STANDARD_DEVIATION 9.5 | 45.7 years STANDARD_DEVIATION 9.64 | 46.0 years STANDARD_DEVIATION 10.18 | 45.7 years STANDARD_DEVIATION 9.83 |
| Gender Female | 37 Patients | 41 Patients | 90 Patients | 73 Patients | 241 Patients |
| Gender Male | 154 Patients | 148 Patients | 292 Patients | 310 Patients | 904 Patients |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 186 / 191 | 179 / 189 | 370 / 382 | 373 / 383 |
| serious Total, serious adverse events | 22 / 191 | 20 / 189 | 36 / 382 | 39 / 383 |
Outcome results
Primary
Sustained Virological Response (SVR)-24 (Scheduled Treatment Period)
SVR-24 according to the scheduled treatment period was defined as the percentage of patients with undetectable HCV RNA at 24 weeks after completion of the treatment period (a single last HCV RNA PCR \<15 IU/mL measured at or after week 68 (ie, on or after study day 477).
Time frame: Week 72
Population: Intent-to-treat population (all patients treated with at least one dose of either study medication)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PEG-IFN 180 µg + Ribavirin 1200 mg | Sustained Virological Response (SVR)-24 (Scheduled Treatment Period) | 37.7 Percentage of patients |
| PEG-IFN 180 µg + Ribavirin 1400/1600 mg | Sustained Virological Response (SVR)-24 (Scheduled Treatment Period) | 42.9 Percentage of patients |
| PEG-IFN 360/180 µg + Ribavirin 1200 mg | Sustained Virological Response (SVR)-24 (Scheduled Treatment Period) | 43.5 Percentage of patients |
| PEG-IFN 360/180 µg + Ribavirin 1400/1600 mg | Sustained Virological Response (SVR)-24 (Scheduled Treatment Period) | 40.7 Percentage of patients |
Comparison: This reflects the primary protocol-specified comparison (standard Pegasys induction dosing arms versus pooled Pegasys induction dosing arms). The study was designed to have at least 86% power for testing the null hypothesis of no difference between these two pooled groups, with assumed response rates of 28%, 32%, 36%, and 43% in the four treatment arms.p-value: 0.58495% CI: [0.831, 1.391]Cochran-Mantel-Haenszel
Secondary
SVR-12 (Actual Treatment Period)
SVR-12 according to the actual treatment period was defined as the percentage of patients with undetectable HCV RNA at least 12 weeks after the last dose of study drug.
Time frame: 12 weeks after end of treatment
Population: Intent-to-treat population (all patients treated with at least one dose of either study medication)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PEG-IFN 180 µg + Ribavirin 1200 mg | SVR-12 (Actual Treatment Period) | 40.3 Percentage of patients |
| PEG-IFN 180 µg + Ribavirin 1400/1600 mg | SVR-12 (Actual Treatment Period) | 45.5 Percentage of patients |
| PEG-IFN 360/180 µg + Ribavirin 1200 mg | SVR-12 (Actual Treatment Period) | 44.2 Percentage of patients |
| PEG-IFN 360/180 µg + Ribavirin 1400/1600 mg | SVR-12 (Actual Treatment Period) | 42.3 Percentage of patients |
Comparison: (PEG-IFN 180 µg + Ribavirin 1200 mg and PEG-IFN 180 µg + Ribavirin 1400/1600 mg) vs. (PEG-IFN 360/180 µg + Ribavirin 1200 mg and PEG-IFN 360/180 µg + Ribavirin 1400/1600 mg)p-value: 0.95195% CI: [0.78, 1.304]Cochran-Mantel-Haenszel
Secondary
SVR-12 (Scheduled Treatment Period)
SVR-12 according to the scheduled treatment period was defined as the percentage of patients with undetectable HCV RNA at 12 weeks after the scheduled treatment period (a single last HCV RNA PCR \<15 IU/mL measured at or after week 60).
Time frame: 12 weeks after end of treatment
Population: Intent-to-treat population (all patients treated with at least one dose of either study medication)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PEG-IFN 180 µg + Ribavirin 1200 mg | SVR-12 (Scheduled Treatment Period) | 40.3 Percentage of patients |
| PEG-IFN 180 µg + Ribavirin 1400/1600 mg | SVR-12 (Scheduled Treatment Period) | 45.0 Percentage of patients |
| PEG-IFN 360/180 µg + Ribavirin 1200 mg | SVR-12 (Scheduled Treatment Period) | 44.2 Percentage of patients |
| PEG-IFN 360/180 µg + Ribavirin 1400/1600 mg | SVR-12 (Scheduled Treatment Period) | 41.5 Percentage of patients |
Comparison: (PEG-IFN 180 µg + Ribavirin 1200 mg and PEG-IFN 180 µg + Ribavirin 1400/1600 mg) vs. (PEG-IFN 360/180 µg + Ribavirin 1200 mg and PEG-IFN 360/180 µg + Ribavirin 1400/1600 mg)p-value: 0.97395% CI: [0.777, 1.299]Cochran-Mantel-Haenszel
Secondary
SVR-24 (Actual Treatment Period)
SVR-24 according to the actual treatment period was defined as the percentage of patients with undetectable HCV RNA at least 20 weeks after the last dose of study drug.
Time frame: 24 weeks after end of treatment
Population: Intent-to-treat population (all patients treated with at least one dose of either study medication)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PEG-IFN 180 µg + Ribavirin 1200 mg | SVR-24 (Actual Treatment Period) | 38.2 Percentage of patients |
| PEG-IFN 180 µg + Ribavirin 1400/1600 mg | SVR-24 (Actual Treatment Period) | 43.9 Percentage of patients |
| PEG-IFN 360/180 µg + Ribavirin 1200 mg | SVR-24 (Actual Treatment Period) | 43.5 Percentage of patients |
| PEG-IFN 360/180 µg + Ribavirin 1400/1600 mg | SVR-24 (Actual Treatment Period) | 40.7 Percentage of patients |
Comparison: (PEG-IFN 180 µg + Ribavirin 1200 mg and PEG-IFN 180 µg + Ribavirin 1400/1600 mg) vs. (PEG-IFN 360/180 µg + Ribavirin 1200 mg and PEG-IFN 360/180 µg + Ribavirin 1400/1600 mg)p-value: 0.77595% CI: [0.803, 1.344]Cochran-Mantel-Haenszel