Clinical Trial Result Information

Protocol number
M78015

Title of Study
Comparison of the efficacy and safety of 2 treatments regimens given for 22 weeks: Peginterferon alfa-2a (Pegasys) with ribavirin versus Pegasys alone in naïve patients with chronic hepatitis C and genotype 1 responding after a 24-week therapy of Pegasys in combination with ribavirin – An open, multi-center, national, and randomized study.

Sponsor
Roche SAS

Company division
Pharmaceutical

Product name
PEGASYS

Generic name
peginterferon alfa-2a (40KD)

Therapeutic area
Hepatitis C, Chronic

Clinical study summary
This phase III, open, multi-center, national, randomized study evaluated the efficacy and safety of pegylated interferon alfa-2a (40KD)(PEGASYS) plus ribavirin compared with PEGASYS alone in patients naïve to treatment with chronic hepatitis C virus (CHC) and genotype 1,, who responded after 24 weeks of PEGASYS plus ribavirin. Patients received PEGASYS 180 μg weekly sc, plus twice-daily oral ribavirin 400 mg for 24 weeks. Patients who were HCV RNA negative at week 24 (<50IU/mL) were rsndomized into PEGASYS alone or PEGASYS plus ribavirin for 22 weeks. Treatment was followed by a 24 week treatment-free follow-up period.

Study center(s)
80 centers in France.

Phase of development
IV

Objectives
Primary: To compare the efficacy of combination therapy of PEGASYS with ribavirin given for 22 weeks compared with PEGASYS monotherapy given for 22 weeks in patients with CHC, genotype 1, responding to PEGASYS plus ribavirin given for 24 weeks.

Secondary: (1) To compare the safety in both arms; (2) To assess quality of life of patients in both arms.

Methodology
Patients were treated for 24 weeks with sc PEGASYS plus oral ribavirin. Those responding after 24 weeks were randomized to receive a further 22 weeks of treatment, with either PEGASYS monotherapy, or PEGASYS plus ribavirin This was followed by 24 weeks of treatment-free follow-up.

Number of patients (planned/analyzed)
500 planned; 524 were included and received treatment.

Diagnosis and main criteria for inclusion
Male or female patients ≥18 years of age and naïve to treatment; serologic evidence of CHC by an anti-HCV test; genotype 1; Serum HCV-RNA at >600 IU/mL by Amplicor HCV Monitor; elevated serum alanine aminotransferase (ALT) activity above normal limit documented on ≥2 occasions within the past 6 months; Metavir Score of ≥A1 and ≥F1 on a biopsy obtained within the past 24 months.

Test product, dose and mode of administration or test procedure
Pegasys (1-mL solution) 180 μg/sc/week.

Duration of treatment
48 weeks for randomized patients.

Reference therapy, dose and mode of administration or reference procedure
Ribavirin 400 mg/po/bid.

Criteria for evaluation (efficacy, safety)
Primary efficacy parameter: The primary efficacy endpoint was sustained viral response (SVR), defined as undetectable serum HCV-RNA (<50 IU/mL) at 24 weeks post treatment in both arms. Secondary efficacy parameters: (1) Sustained biochemical response defined as normal serum ALT levels at 24 weeks post treatment in both arms; (2) Non-detectable HCV-RNA at study Weeks 24, 48, and 72 as measured by Roche AMPLICOR HCV Test (50 IU/mL); (3) Hepatitis Quality of Life Questionnaire (HQLQ) scores at baseline and Weeks 24, 48, and 72. Tolerance parameters: (1) Adverse event rate and profile; (2) Hematology; (3) Chemistry; and (4) Weight and vital signs.

Statistical methods
Results were compared between both treatment groups using appropriate statistical tests:
• Student’s t-test was used for normally distributed quantitative parameters; the Wilcoxon rank-sum test was used otherwise.
• Chi-squared test (or Fisher’s exact test if the chi-squared test turned out to be invalid) was used for qualitative data.
• Non-inferiority of the PEGASYS (Group B) arm compared with the PEGASYS plus ribavirin (Group A) arm would be demonstrated if the 95% confidence interval (CI) of the observed difference between both arms for the primary criteria was included in the non-inferiority interval –∞; 15%.

Summary (efficacy, safety, other results)
Efficacy – All baseline characteristics, particularly characteristics of pathology, were comparable between the 2 treatment groups. In the per-protocol (PP) population, 72.4% of patients in the PEGASYS plus ribavirin group and 57.2% in the PEGASYS monotherapy group presented a negative HCV-RNA at Week 72. The 1-sided 95% CI for the difference between both groups was –8; 22.6%. In the intent-to-treat (ITT) population, the results followed the same trend: 69.3% of patients in the PEGASYS plus ribavirin group and 53.4% in the PEGASYS group presented a negative HCV-RNA at Week 72. The 1-sided 95% CI for the difference between both groups was –8; 23.5%. According to the Point to consider “Switching between non-inferiority and superiority” adopted by the CPMP in July 2000, because the 1-sided 95% CI for the difference between both treatment groups was not comprised in –8; 15% and because the 2 sided CIs in both PP and ITT populations did not contain 0, the non inferiority hypothesis was rejected in favor of superiority. All further analyses were carried out in the ITT population. Thus, the percentage of patients with a SVR at Week 72 was significantly higher in patients who received combination therapy with PEGASYS plus ribavirin than in those who received PEGASYS® alone (69.3 vs 53.4%; P=0.002).

The proportion of patients with detectable HCV-RNA increased over time during treatment and follow-up and was always significantly higher in patients receiving PEGASYS monotherapy than in patients receiving combination therapy, at each time point between Weeks 48 and 72.

HQLQ scores generally decreased during treatment and increased during the untreated follow up period. Scores on each domain were somewhat lower at Week 48 in patients treated with combination therapy than those given PEGASYS monotherapy. The scores on all domains improved in both groups during follow-up.

Safety – During the first 24 weeks of treatment (before randomization), 479 patients (91.4%) presented >=1 adverse event, 43 patients (8.2%) >=1 serious adverse event, 452 patients (86.3%) >=1 treatment-related adverse event, and 31 patients (5.9%) an adverse event that led to drug discontinuation. The frequency of adverse events and the incidence of withdrawal because of adverse events were lower during Weeks 26–72 (after randomization). However, the frequency of patients with >=1 treatment related adverse event was significantly greater in the combination group: 53.1% vs 41.6% in the monotherapy group (P=0.034).The profile of adverse events observed in this study was very similar to the AE profile previously described with PEGASYS in combination with ribavirin, and no unexpected AE was observed. The most common adverse events were skin and appendage disorders (19%), psychiatric disorders (18.5%) and gastrointestinal disorders (16.8%).During Weeks 26–48, the incidence of low hemoglobin levels was greater in patients treated with the combination of PEGASYS plus ribavirin than those given PEGASYS monotherapy. During the untreated follow-up period, the incidence of low hemoglobin levels was low and similar in both treatment groups.

Conclusions
In conclusion, this study has confirmed that treatment for a full 48 weeks with the combination of PEGASYS plus ribavirin is significantly more effective than PEGASYS monotherapy during the last 22 weeks of treatment in patients infected with CHC genotype 1 who have undetectable serum HCV-RNA after 24 weeks of combination therapy. Ribavirin contributes to the significantly higher SVR rates by preventing relapse by some, as yet, unknown mechanism. The risk-benefit profile of continued combination therapy was favorable, with significantly better efficacy and little difference in safety compared with monotherapy. It must be noted that higher weight-based ribavirin doses (1000/1200mg/d) are preferred in patients infected with CHC genotype 1. Thus, optimal treatment of patients infected with CHC genotype 1 consists of a full 48-week course of PEGASYS plus ribavirin combination therapy.

Date of report
2/15/2005