Roche trials database

Protocol number:

BV16210

Title of Study:

Safety and tolerability of peginterferon alfa-2a (Ro25-8310) monotherapy and combination therapy with ribavirin (Ro20-9963) in patients with chronic hepatitis C.

Sponsor:

Hoffmann-La Roche

Company division:

Pharmaceutical

Product name:

PEGASYS

Generic name:

peginterferon alfa-2a (40KD)

Therapeutic area:

• Hepatitis C, Chronic

Clinical study summary:

This was an open label study designed to evaluate the safety and efficacy of peginterferon alfa-2a (40KD) (PEGASYS) given alone or in combination with ribavirin in patients with chronic hepatitis C. Allocation to the treatment arms was at the discretion of the investigator.

Study center(s):

35 centers in Germany

Phase of development:

IV

Objectives:

Primary: to evaluate the safety and tolerability of PEGASYS given alone for 48 weeks, or in combination with ribavirin for 24 weeks or 48 weeks, in patients with chronic hepatitis C.
Secondary: to evaluate the effect of PEGASYS alone and in combination with ribavirin given for 24 or 48 weeks on the clearance of HCV viremia 24 weeks after treatment end (sustained virological response) in patients with chronic hepatitis C; to evaluate the effect of study treatment on serum ALT 24 weeks after treatment end (sustained biochemical response); to evaluate the effect of PEGASYS alone and in combination with ribavirin on the clearance of HCV viremia after 24 and 48 weeks treatment.

Methodology:

Patients were allocated to one of 3 treatment groups, to receive PEGASYS monotherapy (3 patients), PEGASYS +ribavirin for 24 weeks (90 patients), or PEGASYS + ribavirin for 48 weeks (219 patients) The treatment period was followed by a 24 week treatment-free period.

Number of patients (planned/analyzed):

320 screened, 312 treated

Diagnosis and main criteria for inclusion:

Adult patients ≥18 years old with serologically proven chronic hepatitis C who were either naïve to any therapy or who had had a breakthrough or relapse during or after previous treatment which must have been discontinued at least 24 weeks prior to enrolment into this trial

Test product, dose and mode of administration or test procedure:

PEGASYS (peginterferon alfa-2a (40KD)180 micrograms sc once weekly for 24 or 48 weeks. Ribavirin 400mg po bid for 24 or 48 weeks.

Duration of treatment:

24 or 48 weeks

Reference therapy, dose and mode of administration or reference procedure:

PEGASYS (peginterferon alfa-2a (40KD) 180 micrograms sc once weekly for 48 weeks

Criteria for evaluation (efficacy, safety):

Primary (safety) parameter: Adverse events Secondary(efficacy) parameter: HCV viremia after a 24 week treatment-free period; serum ALT after a 24 week treatment-free period; clearance of HCV viremia after 24 and 48 weeks treatment. Secondary (safety) parameters: Safety laboratory measurements (including neutrophil counts, platelet counts, hemoglobin)

Statistical methods:

The incidence of the adverse events was summarized by treatment group and by body system and event within each body system.
Response rates together with the 95% confidence intervals from the binomial distributions were provided for sustained virological response, sustained biochemical response and end of treatment response. A logistic regression analysis was performed to examine the effects of various prognostic factors on the sustained virological response rate.
For all other variables descriptive statistics were performed.

Summary (efficacy, safety, other results):

Sustained virological response (SVR) rate was 64% in the PEGASYS+ribavirin 24 week group and 42% in the PEGASYS+ribavirin 48 week group. The sustained biochemical response rates (SBR) were in accordance with the SVRs. In patients with genotype 2 or 3 the longer duration of treatment (48 vs 24 weeks) did not result in any additional benefit. In patients with genotype 1 SVR was higher when treated for 48 weeks (40% versus 17%). Multiple logistic regression analysis revealed genotype as the only independent baseline factor having a statistically significant effect on sustained virological response. Patients with genotype non 1 were more likely to achieve a sustained virological response than patients with genotype 1. Response rates were alike in treatment naïve patients and in relapsers. At the end of treatment 86% of patients in the PEGASYS+ribavirin 24 week group were responders compared to 67% in the 48 week group. Not all patients maintained their treatment response.
SVR and SBR were slightly higher in the PP-analysis, otherwise the results were identical to the ITT-analysis.

Safety: A total of 86% of patients in the 24 week treatment group and 59% in the 48 week group completed treatment. The most frequently reported adverse events were those commonly associated with interferon treatment, with the incidence of these events being similar in both treatment groups. More than 96% of patients in each group experienced at least one adverse event; the majority of which were considered treatment related.
One patient died during treatment, and two during the follow up period. One patient in the PEGASYS monotherapy group died in a traffic accident, and one patient in the PEGASYS+ribavirin 24 week group who suffered from psychotic disorder committed suicide. In the PEGASYS +ribavirin 48 week group one patient was prematurely withdrawn from study treatment due to leucopenia, thrombopenia, elevated ALT levels, and signs of cholestasis. Thereafter the patient developed sepsis and died during the follow up period.
A total of 9% of patients experienced at least one serious adverse event (SAE). The proportion of patients with at least one SAE was higher in the PEGASYS +ribavirin 48 week group (10.5%) than in the PEGASYS+ribavirin 24 week group (4.4%). The most frequent SAEs (≥2% in any treatment group) were psychiatric disorders, infections, and cardiac and gastrointestinal disorders. Of those SAEs considered related to treatment, only psychiatric disorders were reported ≥2% in any treatment group.
In general, the most frequently reported adverse events were general disorders, skin and subcutaneous disorders, nervous system and psychiatric disorders, gastrointestinal disorders, respiratory disorders, infections, and disorders of the musculoskeletal and connective tissue. These disorders were reported in more than 40% of patients. The incidence rate of AEs, including depression, was highest during the first 12 weeks of therapy. Generally AEs were self limiting and resolved after the end of treatment.
Median numbers of white blood count and platelets and median hemoglobin concentration decreased in all groups alike during treatment and returned to baseline after treatment. Median ALT and AST levels decreased during treatment and were within or slightly above the normal range by the end of treatment. Median decrease was slightly more pronounced in the 24 week group thus reflecting the better therapy response of genotype 2 and 3 which accounted for the majority of the 24 week group. Median triglyceride serum level increased slightly from baseline to levels marginally above normal. During the treatment period marked laboratory abnormalities included high levels of ALT, AST, total bilirubin, alkaline phosphatase, triglycerides, and markedly high and low glucose concentrations. The percentage of patients with markedly high ALT levels was slightly lower in the 24 week group, whereas the percentage of patients with markedly high AST, total bilirubin, and alkaline phosphatase levels was lower in the 48 week group, although the differences were small. The incidence of grade 4 neutropenia (<0.5x10⁹/L) was 3.6% in the 48 week group versus 8.1% in the 24 week group during treatment, whereas the percentage of patients experiencing grade 2 or 3 neutropenia (1.0 to <1.5x10⁹/L or 0.5 to <1.0x10⁹/L) was slightly lower in the 24 week group. Platelet counts were graded normal during the whole treatment period in the majority of patients (64% and 67%). None of the patients had grade 4 thrombocytopenia (<20x10⁹/L), and only patients in the 48 week group experienced grade 3 thrombocytopenia (20 to <50x10⁹/L). The vast majority of patients presented with hemoglobin concentrations of ≥10 g/dL during treatment.  The incidence of anemia was similar in the 24 week and the 48 week group.

 

Conclusions:

In patients with genotype non-1, 24 weeks of treatment was as efficacious as 48 weeks with the same dosage, irrespective of baseline viral load. For patients with genotype 1, irrespective of baseline viral load, 48 weeks treatment resulted in a higher sustained viral response.
No unexpected safety concerns were observed; the most common adverse events were those usually related to interferon treatment. The incidence of adverse events was highest during the first 12 weeks of therapy. Treatment for 24 weeks was better tolerated than 48 weeks.
The recommended therapy regimens for the genotype 1 and genotype non-1 populations in this study were highly efficacious, and were shown to have a reasonable benefit/risk ratio.

Publications (references, if available):

Witthoft Th., Moller B, Wiedmann K H et al. Journal of Viral Hepatitis, 2007

Date of report:

01.06.2005

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