Clinical Trial Result Information

Protocol number
M78020

Title of Study
A randomized, open-label, multicenter study evaluating the efficacy and safety of the combination therapy of peginterferon alfa-2a with Ribavirin versus combination therapy of interferon alfa-2a (Roferon-A) with Ribavirin in naïve or relapse patients with chronic hepatitis C.

Sponsor
Roche SA

Company division
Pharmaceutical

Product name
PEGASYS

Generic name
peginterferon alfa-2a (40KD)

Therapeutic area
Hepatitis C, Chronic

Clinical study summary
This was a phase III, multicenter, randomized, open-label, active controlled, parallel group study comparing PEGASYS plus ribavirin, and Roferon-A plus ribavirin in treatment-naïve or relapsed patients with chronic hepatitis C.

Study center(s)
46 centers in Belgium.

Phase of development
III

Objectives
Primary: To evaluate the effect of PEGASYS (peginterferon alfa-2a (40KD)) plus ribavirin versus Roferon-A (interferon alfa-2a) plus ribavirin, both combination regimens given for 48 weeks, on the clearance of HCV viremia 24 weeks after treatment end (sustained virological response) in patients with chronic hepatitis C (CHC) virus infection.
Secondary: To compare the effect of PEGASYS plus ribavirin versus Roferon-A plus ribavirin therapy on serum ALT-24 weeks after treatment end (sustained biochemical response); to compare the efficacy of PEGASYS plus ribavirin versus Roferon-A plus ribavirin therapy on the reduction of HCV viremia after 12, 24 and 48 weeks of treatment; to compare the safety of PEGASYS plus ribavirin versus Roferon-A plus ribavirin therapy.

Methodology
Eligible patients were randomized to receive either PEGASYS s.c. plus ribavirin p.o. or Roferon-A s.c. plus ribavirin p.o. The dose of ribavirin was dependent upon body weight, and had to be given within 1 hour before or 2 hours after a normal meal. The 48 weeks of treatment was followed by a treatment-free 24 week period. Sustained virological and biochemical responses were measured 24 weeks after end of trial treatment and the reduction of HCV viremia was assessed after 12, 24 and 48 weeks of treatment.

Number of patients (planned/analyzed)
479 patients were entered into the study. The ITT population included 443 patients, the PP population 403 patients and the safety population 441.

Diagnosis and main criteria for inclusion
Target population: male and female patients with serologically proven chronic hepatitis C in the care of outpatient clinics specializing in hepatology were eligible for screening.

Test product, dose and mode of administration or test procedure
Combination of PEGASYS (peginterferon alfa-2a (40KD)) 180μg sc once weekly and ribavirin 1000mg po daily (for <75kg body weight) or 1200mg po daily (for ≥75kg body weight), with food.

Duration of treatment
48 weeks of treatment in both arms.

Reference therapy, dose and mode of administration or reference procedure
Combination of Roferon-A (interferon alfa-2a), 6 MIU sc 3 times weekly for 8 weeks, then 3 MIU 3 times weekly, and ribavirin (as above).

Criteria for evaluation (efficacy, safety)
Efficacy: The evaluation of efficacy was based on the occurance of sustained virological response, sustained biochemical response, and non-detectable HCV-RNA at study weeks 12, 24 and 48. The analysis was performed both on the ITT population and the PP population.

Safety: Adverse event rate and profile: Only treatment emergent adverse events were considered for analysis.

Laboratory tests: Abnormal laboratory values were classified as clinically relevant deviations not connected with the patient's underlying disease, potentially significant clinical abnormalities, and clinically abnormal values.

Vital Signs: Changes in systolic and diastolic blood pressure and heart rate were investigated.

Statistical methods
The objective of the study was to compare the efficacy and safety of the two treatments. The analysis was performed using two-tailed hypothesis tests. The primary analysis was conducted on the ITT population. The PP population excluded major protocol violators. All statistical tests were performed at the 5% level of significance.

Summary (efficacy, safety, other results)
Efficacy: In all the analyses performed, the efficacy of treatment with PEGASYS® plus ribavirin was shown to be greater than treatment with Roferon plus ribavirin. In the ITT population (n=230 for the PEGASYS group, n=213 for the Roferon-A group), sustained virological response was observed for 119 patients in the PEGASYS group (52%, 95% CI: [0.45; 0.58]) and 57 patients in the Roferon-A group (27%, 95% CI: [0.21; 0.33]). These frequencies were statistically significantly different (p<0.001). In the PP population (n=206 for the PEGASYS group, n=197 for the Roferon-A group) sustained virological response was observed for 114 patients in the PEGASYS group (55%, 95% CI: [0.48; 0.62]) and 56 patients in the Roferon-A group (28%, 95% CI: [0.22; 0.35]). These frequencies were statistically significantly different (p<0.001).
Conclusions from the analysis of the primary endpoint were further supported by the analysis of the secondary endpoints.
In the ITT population sustained biochemical response was observed for 123 patients in the PEGASYS group (53%, 95% CI: [0.47; 0.60]) and 72 patients in the Roferon-A group (34%, 95% CI: [0.27; 041]). These frequencies were statistically significantly different (p<0.001). In the PP population sustained biochemical response was observed for 117 patients in the PEGASYS group (57%, 95% CI: [0.50; 0.64]) and 71 patients in the Roferon-A group (36%, 95% CI [0.29; 0.43]). These frequencies were statistically significantly different (p<0.001).

Safety: The incidence of most of the most frequently reported treatment-emergent adverse events was similar across the 2 treatment groups. The most common adverse events were fatigue (37.1% patients in the PEGASYS group, and 36.3% in the Roferon-A group),headache (29.7% vs 30.2%), myalgia (25.3% vs 23.1%), asthenia (24.9% vs 22.2%) and depression (20.1% vs 17.9%).
Adverse events related to blood and lymphatic system disorders were more frequent in the PEGASYS group (52.8% vs. 27.8%) with reports of anemia in 29.7% of the patients, thrombocytopenia in 23.1%, leucopenia in 21.8% and neutropenia in 18.3%. This observation was supported by the analysis of the laboratory tests. It should be noted that anemia and lymphopenia are known AEs related to ribavirin. Nausea was more common in the PEGASYS group (21.0%) than in the Roferon-A group (11.8%), and influenza-like illness was more common in the Roferon-A group (27.4%) than in the PEGASYS group (19.7%).
A potentially serious increase or decrease in blood pressure during the treatment period was recorded in 12 patients in the PEGASYS group (5.6%) and 8 patients in the Roferon-A group (4.0%).
No difference in the frequency and intensity of serious adverse events was seen between the 2 groups. There were 2 deaths in the PEGASYS group, one due to esophageal variceal hemorrhage not related to treatment, and one due to a drug overdose, considered related to treatment.

Conclusions
A significantly higher proportion of patients who received PEGASYS plus ribavirin had a sustained virological response than patients who received standard combination therapy (52% vs. 27%, p<0.001).
The safety data were consistent with the expected safety profiles of the study drugs and the information contained in the SmPC. The study results raised no particular major safety concerns.

Date of report
10/2/2006