Clinical Trial Result Information

Title of Study:
TRIPEG STUDY: Randomized, double-blind, placebo controlled, multicenter study to compare the efficacy and tolerability of pegylated interferon alfa (PEG-IFN) plus ribavirin with and without amantadine sulfate in patients with chronic hepatitis C and subtype 1

Fast Facts:

Protocol number:	M78023
Sponsor:	Roche Austria GmbH
Company division:	Pharmaceutical
Product name:	PEGASYS
Generic name:	peginterferon alfa-2a (40KD)
Phase of development:	III
Therapeutic area, approved indication:	Hepatitis C, Chronic
Date of report:	11/1/2005

Clinical study summary:
This randomized, double-blind, placebo controlled, multicenter trial compared the efficacy and tolerability of peginterferon alfa-2a (40KD) (PEGASYS) plus oral ribavirin tablets with or without amantadine sulfate, in patients with chronic hepatitis C (CHC). After 48 weeks of treatment, there was a 24 week period of treatment-free follow-up.

Study center(s) :
17 centers in Austria

Objectives:
Primary: To compare the response rates (virologic) of the 2 therapy regimens at Week 24 of treatment in patients unlikely to respond to combination therapy (strata II and III).

Secondary: (1) To compare sustained response rates at the end of follow-up (Week 72); (2) To compare response rates at Week 4, 12, 36 and 48 and at the various follow-up visits; (3) To investigate the influence of initial viral decline and fibrosis grade on response; (4) To compare time to response; (5) To compare time to relapse in responders; (6) To evaluate safety and tolerability; (7) To compare patients’ quality of life.

Methodology:
A total of 211 patients were randomly allocated to 1 of 2 treatment regimens: (A) PEGASYS + ribavirin + amantadine 48 weeks, plus an untreated 24-week follow-up period; (B) PEGASYS + ribavirin + placebo for 48 weeks, plus an untreated 24-week follow-up period. PEGASYS was administered sc once weekly, ribavirin and amantadine/placebo were taken po daily in split doses. .In the event of intolerance to study medication, dose adjustment guidelines were provided. Following the initiation of test drug dosing, patients returned for evaluation at Weeks 2 and 4, and then monthly until the end of therapy at Week 48. After completing therapy, patients were seen after 4, 12, and 24 weeks. Patients who did not have an undetectable HCV-RNA by Roche AMPLICOR HCV test, v 2.0 (<50 IU/mL) after 24 weeks of study treatment were considered non-responders and were to stop therapy at Week 28 or as soon as the PCR results became available. For safety reasons, patients who prematurely stopped taking study medication for any reason were to be followed for ≥12 weeks after the last dose of test medication.

Number of patients (planned/analyzed):
220 planned; 211 included.

Diagnosis and main criteria for inclusion:
Men and women >18–65 years of age with serologically proven CHC subtype 1. Patients without pre-treatment with any (pegylated) interferon (IFN) and detectable hepatitis C virus (HCV)-RNA, elevated alanine aminotransferase levels, and a liver biopsy within 6 months of study therapy consistent with CHC and compensated liver disease were included. Patients with other forms of liver disease, active HAV or HBV infection, hepatocellular carcinoma or human immunodeficiency virus were excluded.

Test product, dose and mode of administration or test procedure:
PEGASYS, 180 μg sc/once weekly; ribavirin, 1000–1200 mg/po/day in split doses; amantadine sulfate, 100mg/po/twice daily

Duration of treatment:
48 weeks.

Reference therapy, dose and mode of administration or reference procedure:
PEGASYS 180μg sc/once weekly; ribavirin, 1000-1200mg/po/day in split doses; placebo, po/ twice daily

Criteria for evaluation (efficacy, safety):
Primary Efficacy Parameters: Clearance of HCV viremia (PCR results) after 24 weeks of treatment Secondary Efficacy Parameters: (1) End of treatment response; (2) Sustained response; (3) Time to response; (4) Time to relapse in responders; (5) Prognostic factors for response; and (6) Quality of life (Short Form 36 [SF-36]) and Fatigue Severity Scale (FSS).

Statistical methods:
All statistical tests were 2-sided with a significance level of 5%. The primary efficacy parameter (24-week response) was analyzed using a Cochran-Mantel-Haenszel (CMH) test stratified for initial viral decline and fibrosis grade. A similar analysis was used for all secondary endpoints. For patients in stratum I, a descriptive analysis of response rates and a 2-sided 95% confidence interval for the treatment effect was used. Time to response and time to relapse in responders (stratum I–III) were summarized using product limit estimates calculated by the Kaplan-Meier method, and a Cox regression model with the above-mentioned factors as covariates was applied. Quality of life (Short Form-36) and the FSS were analyzed using a repeated measures analysis and contrasted with baseline values. A total sample size of 112 patients was calculated to be sufficient to compare 24 weeks’ response rates between treatment groups with a 2-sided significance level of 5%, a statistical power of 80%, and an estimated difference of 11% vs 35% in patients in strata II and III. The sample size estimation did not consider stratum I because only exploratory analyses were planned within this stratum. Together with an estimated rate of 35% in stratum I and a dropout rate of 20%, approximately 220 patients were planned to be recruited for this trial.

Summary (efficacy, safety, other results):
Efficacy: A total of 211 patients were recruited for this trial, 209 of whom were evaluable for the intention-to-treat analysis (186 per protocol). Twenty-one patients (10%; 8 placebo, 13 amantadine) dropped out of the study before visit Week 24; 65% of patients attended the last treatment visit at Week 48 and 64% attended the follow-up visit at Week 72. The PCR analysis after 24 weeks of treatment was negative in 146 patients (LOCF, 70%; 72% placebo, 68% amantadine), the primary comparison (Week-24 response in strata II and III, stratified for initial response and fibrosis grade) between treatment groups being non-significant (66% placebo vs 64% amantadine, P=0.908). Differences in other secondary response endpoints were also not statistically significant.

Safety: In 160 patients (77%; 73 placebo, 87 amantadine) ≥1 treatment-emergent adverse event was reported after initial PEGASYS administration. A total of 968 (placebo, 461 events; amantadine, 507 events) adverse events were reported in the ITT safety population; most were mild to moderate in intensity. The most frequently reported adverse events were anemia, leucopenia, gastrointestinal complaints, flu-like symptoms, fatigue, hair loss, skin diseases, arthralgia, myalgia, sleeping disorders, cephalea and depression.

Conclusions:
Amantadine did not improve the outcome of treatment with PEGASYS plus ribavirin in de novo patients with CHC genotype 1 infection. Adverse event profiles were similar in the presence and absence of amantadine, and admantadine did not improve health-related quality of life compared with placebo. Furthermore, it was shown that IFN sensitivity is the single most important predictor of response to IFN-based antiviral therapy in patients with CHC genotype 1.

Publications (references, if available):
Ferenci P et al; Randomized, double-blind, placebo-controlled study of peginterferon alfa-2a (40KD) with or without amantadine in treatment-naïve patients with chronic hepatitis C genotype 1 infection. J Hepatol. 44: 275-282 (2005)