Clinical Trial Result Information

Title of Study:
Open-label pilot study to measure early viral kinetics in patients with chronic hepatitis C infection and subtype 1 treated with (pegylated)-interferon *-2a.

Fast Facts:

Protocol number:	M78021
Sponsor:	Roche Austria Ges.m.b.H.
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:	9/1/2005

Clinical study summary:
This open-label, multi-center pilot study evaluated viral load in patients with chronic hepatitis C. Patients were given a single dose of interferon alfa-2a (Roferon-A) 9 MU subcutaneously, followed by peginterferon alfa-2a (40KD) (PEGASYS®) 180 μg subcutaneously once weekly for 3 weeks. Thereafter, oral ribavirin 800 mg/day was added for 24 weeks.. Virologic responders continued treatment for a further 24 weeks..

Study center(s) :
4 centers in Austria.

Objectives:
Primary: To compare the percentage decline in viral titer (IU/mL) in serum in virus elimination phase I and virus elimination phase II from baseline, measured by Roche AMPLICOR MONITOR.

Methodology:
Titers of hepatitis C were measured prior to and 24 hours after a dose of interferon alfa-2a (9 MU). Patients then received once-weekly doses of 180μg peginterferon alfa-2a (40KD) for 3 weeks, and viral load was evaluated weekly. Thereafter, daily ribavirin treatment was added (800 mg/day). Viral titer and biochemical response rates were assessed 12 weeks after the start of combination therapy and at the end of therapy (48 weeks after starting combination therapy). Patients with a decrease in viral load continued treatment for another 24 weeks and were assessed after end of combination therapy (Week 72). Safety and tolerability of combined peginterferon alfa-2a (40KD) and ribavirin treatment was also assessed.

Number of patients (planned/analyzed):
22 enrolled (8 females, 14 males)

Diagnosis and main criteria for inclusion:
Male and female patients between 19 and 65 years of age with chronic hepatitis C. At least 1 elevated serum alanine aminotransferase (ALT) level higher than normal in last 6 months before start of therapy; serologic evidence of hepatitis C by anti-HCV antibody test; positive HCV-RNA level in serum; chronic liver disease consistent with chronic hepatitis C infection. Excluded were patients who had interferon therapy at any previous time; Class B or C cirrhosis; history of conditions consistent with decompensated liver disease or of congenital liver disease.

Test product, dose and mode of administration or test procedure:
Interferon alfa-2a, 9 MU, subcutaneously once; peginterferon alfa-2a (40KD), 180 µg in 1 mL solution subcutaneously once weekly; oral ribavirin, 800 mg daily in split doses.

Duration of treatment:
24 or 48 weeks.

Reference therapy, dose and mode of administration or reference procedure:
28 patients treated with standard interferon/ribavirin treatment in a previous study with an analogous treatment protocol (historical control)

Criteria for evaluation (efficacy, safety):
Comparison of the percentage of decline of viral titer (IU/mL) in serum, virus elimination phase I, and virus elimination phase II to baseline.

Statistical methods:
Since this was a pilot study, no statistical tests of hypotheses were applicable. Descriptive analyses of the primary efficacy parameter were conducted, using Wilcoxon tests, with all analyses of secondary efficacy parameters also being descriptive in nature.. Descriptive statistics of the vital sign parameters and their differences from baseline were tabulated for each time point.

Summary (efficacy, safety, other results):
Efficacy: After 24 weeks of combination therapy, 15 (68.2%) patients were HCV-RNA negative; 8 (36.4%) had a sustained response. The decrease in viral load 24 hours after 9MU interferon alfa-2a was greater in viral responders (1.05 log [0.25-1.67]) than in non-responders (0.34 log [0.14-0.65]; p=0.003). In contrast, viral decline was not different between responders and nonresponders during the first 2 weeks on PEGASYS. All patients with an initial log decline in viral load >1.4 became sustained responders. Five of the 12 patients with a log change <0.8 became end of treatment responders; 2 had a sustained response. Safety: The most common adverse events reported in this study were fever, flu-like symptoms, fatigue and headache. No serious adverse events occurred.

Conclusions:
The initial virologic response to PEGASYS is less pronounced than to daily administration of standard interferon. This difference has no impact on the overall efficacy of PEGASYS/ribavirin combination therapy. In spite of the lower initial response, PEGASYS/ribavirin combination therapy may overcome predicted interferon unresponsiveness.

Publications (references, if available):
Jessner W, Stauber R, Hackl F et al. Early viral kinetics on treatment with pegylated interferon-α-2a in chronic hepatitis C virus genotype 1 infection. Journal of Viral Hepatitis 2003; 10:37-42