Clinical Trial Result Information

Protocol number
NV15942

Title of Study
A Phase III, Randomized, Multicenter, Efficacy and Safety Study Examining the Effects of Duration of Treatment and the Daily Dose of Ribavirin in Patients With Chronic Hepatitis C Virus Infection Treated With the Combination of Peginterferon alfa-2a (40KD) and Ribavirin

Sponsor
Hoffmann-La Roche Inc.

Company division
Pharmaceutical

Product name
PEGASYS

Generic name
peginterferon alfa-2a (40KD)

Therapeutic area
Hepatitis C, Chronic

Clinical study summary
This phase III, randomized, multicenter, partially blinded study compared the efficacy and safety of the combination of peginterferon alfa-2a (40KD) (PEGASYS) + ribavirin when either the treatment duration or the dose of ribavirin was varied.

Study center(s)
A total of 99 sites in Australia, Europe, New Zealand, North America, South America and Taiwan.

Phase of development
III

Objectives
Primary: To compare the efficacy and safety of the combination of PEGASYS + ribavirin given for 24 weeks to the same combination given for 48 weeks in patients with hepatitis C virus (HCV) infection.

Secondary: (1) To compare the efficacy and safety of 2 different doses of ribavirin (800 mg vs 1000 or 1200 mg) given in combination with PEGASYS; (2) To assess the influence of baseline variables on steady state concentrations by monitoring trough levels of ribavirin and peginterferon alfa-2a (40KD) in patients receiving either the high or the low dose of ribavirin.

Methodology
Eligible patients were randomized to 1 of 4 treatment groups, to receive 1) PEGASYS 180 µg + ribavirin 800 mg for 24 weeks; 2) PEGASYS 180 µg + ribavirin 1000 or 1200 mg for 24 weeks; 3) PEGASYS 180 µg + ribavirin 800 mg for 48 weeks and 4) PEGASYS 180 µg + ribavirin 1000 or 1200 mg for 48 weeks. Treatment was followed by a 24-week treatment-free follow-up period. During treatment and follow-up, HCV RNA concentrations and serum ALT levels were monitored. A liver biopsy was performed within 15 months of study entry in all patients, and at the end of follow-up in consenting patients. Patients were assessed for safety at intervals during the treatment period, and for 24 weeks after the end of treatment.

Number of patients (planned/analyzed)
1311 randomized; 1284 intent-to-treat.

Diagnosis and main criteria for inclusion
Male and female outpatients >=18 years of age with serologically and histologically proven chronic hepatitis C (CHC) infection, elevated levels of alanine aminotransferase (ALT), and detectable HCV RNA

Test product, dose and mode of administration or test procedure
PEGASYS, 180 µg/sc/once weekly. Ribavirin, 800 mg in Groups 1 and 3; 1000 mg (body weight <75 kg), or 1200 mg (body weight >=75 kg) in Groups 2 and 4/po/day, in split doses taken with food.

Duration of treatment
24 weeks in Groups 1 and 2; 48 weeks in Groups 3 and 4.

Reference therapy, dose and mode of administration or reference procedure
Ribavirin placebo administered as ribavirin.

Criteria for evaluation (efficacy, safety)
Primary efficacy parameters: Sustained virologic response (SVR) (undetectable HCV RNA <100 copies/mL) at the end of follow-up (Week 48 for Groups 1 and 2; Week 72 for Groups 3 and 4).

Secondary efficacy parameters: (1) Sustained biochemical response (normalization of serum ALT) at the end of follow-up (Week 48 or Week 72); (2) virologic and biochemical response at the end of treatment (Week 24 or 48); (3) maintenance of virologic and biochemical response; (4) histologic response at the end of follow-up (Week 48 or Week 72).

Pharmacokinetic (PK) parameters: Trough serum and trough plasma concentrations of peginterferon alfa-2a (40KD) and ribavirin.

Safety parameters: Clinical adverse events, laboratory test results, and vital signs.

Statistical methods
Efficacy: Treatment duration and different ribavirin doses were analyzed using the Mantel-Haenszel test. The Breslow-Day test was performed for each comparison to assess the homogeneity of the odds ratios over the different strata used in the analysis. Sustained virologic response (primary) and sustained biochemical response (secondary) were used as measures of efficacy. End-of-treatment virologic and biochemical responses, maintenance of virologic and biochemical responses, and histologic responses in the 4 treatment groups were analyzed using descriptive statistics.

PK: Trough concentrations of peginterferon alfa-2a (40KD) and ribavirin were analyzed using descriptive statistics.

Safety: Descriptive statistics were used to summarize safety parameters by treatment group.

Summary (efficacy, safety, other results)
Efficacy - Sustained virologic response (SVR): Overall, the SVR was higher in patients treated for 48 weeks than for 24 weeks (odds ratio, 1.32; P=0.0393), and patients receiving 1000 or 1200 mg of ribavirin had a higher SVR than those receiving 800 mg of ribavirin ( odds ratio, 1.35; P=0.0177). The overall SVR in patients treated for 48 weeks with 1000 or 1200mg ribavirin was 59% (63%, assessment reflecting current clinical practice).

In patients infected with genotype non-1 and with high or low baseline viral titers, treatment with 800 mg of ribavirin for 24 weeks was as efficacious (SVR=78%) as treatment with 1000 or 1200 mg of ribavirin for 48 weeks.

In patients infected with genotype 1, irrespective of baseline viral titers, the highest SVR was achieved among patients treated for 48 weeks with 1000 or 1200mg ribavirin. In this group, 46% of patients with high baseline viral titers and 60% of patients with low baseline viral titers achieved an SVR.

Sustained biochemical response: The sustained biochemical response for the overall population and for the populations defined by genotype and baseline viral titer was similar to the SVR.

Maintenance of virologic response: The percentage of patients who maintained their end-of-treatment virologic response was high in patients infected with genotype non-1, with either high or low baseline viral titers, and was similar in all 4 treatment groups (84% to 92%).

In patients infected with genotype 1, irrespective of baseline viral titer, maintenance of an end-of-treatment virologic response was highest in patients receiving treatment for 48 weeks. In patients with high baseline viral titer, maintenance of virologic response was higher in the 1000 or 1200mg ribavirin group than in the 800mg ribavirin group (70% and 57%, respectively). In patients with low baseline viral titers, maintenance of virologic response was not affected by the dose of ribavirin (79% and 77%, respectively, in the 800mg ribavirin, and 1000 or 1200mg ribavirin groups, respectively).

PK - Steady state trough concentrations of peginterferon alfa-2a (40KD) and ribavirin were characterized in approximately 220 patients with CHC infection. For peginterferon alfa-2a (40KD), steady state trough concentrations of approximately 21 ng/mL were reached by Week 8. Steady state trough peginterferon alfa-2a (40KD) concentrations were lower in patients with cirrhosis or transition to cirrhosis compared with those in non-cirrhotic patients. Steady state appeared to be reached before Week 8 in most patients.

Safety - More than 90% of patients treated for 24 weeks completed treatment. In the 48 week treatment groups, the percentage of patients who completed treatment was lower (68% in the 800mg ribavirin group, and 74% in the 1000 or 1200mg group,).

The most frequently reported adverse events were those commonly associated with interferon treatment, with the incidence of these events being similar in all 4 treatment groups.

Three patients died during treatment: 1 in the 24 week, 1000 or 1200mg ribavirin group, (overdose of opiates), 1 in the 48 week, 800mg ribavirin group (septicemia), and 1 in the 48 week, 1000 or 1200mg ribavirin group (suicide). A second patient in this group died as a result of consumption of multiple illicit drugs 5 months after he had stopped study medication.

The incidence of serious adverse events was lowest in the 24 week, 800mg ribavirin group (3%) compared with 7% in the 24 week, 1000 or 1200mg ribavirin group, 9% in the 48 week, 800mg group, and 10% in the 48 week, 1000 or 1200mg ribavirin group. Infections were the most common serious adverse events, with the incidence of serious infections being lowest in the 24 week, 800mg rivavirin group.

The percentage of patients withdrawing from treatment due to an adverse event or laboratory abnormality was lower among patients in the 24 week treatment groups (5%, taken together) than among patients in the 48 week treatment groups (16%). More patients in the groups treated for 48 weeks, and more patients treated for 1000 or 1200mg ribavirin had their dose of ribavirin modified for adverse events or laboratory abnormalities, with anemia being the most frequent laboratory abnormality resulting in a reduction of the ribavirin dose. The percentage of patients with anemia was lowest in the group of patients treated for 24 weeks with 800mg ribavirin; accordingly, the percentage of patients requiring a reduction of their dose of ribavirin due to anemia was lowest in this group. The percentage of patients requiring a reduction of their dose of PEGASYS was slightly lower in the groups treated for 24 weeks than in those treated for 48 weeks.

Conclusions
In patients with genotype non-1, irrespective of baseline viral titer, treatment with PEGASYS and a daily dose of 800 mg of ribavirin for 24 weeks was as efficacious as treatment with a daily dose of ribavirin of 1000 or 1200 mg for 48 weeks, and resulted in a decrease in treatment-limiting adverse events, premature withdrawals for safety reasons, and dose modifications of either PEGASYS or ribavirin. For patients with genotype 1, irrespective of baseline viral titer, treatment for 48 weeks with a daily dose of 1000 or 1200 mg of ribavirin resulted in the highest sustained virologic response.. In this harder-to-treat patient population, therapy with 180 µg PEGASYS and a daily dose of 1000 or 1200 mg of ribavirin for 48 weeks represents a highly efficacious treatment with an acceptable safety profile.

Publications (references, if available)
Hadziyannis S, Sette H, Morgan T et al. Peginterferon-α 2a and Ribavirin Combination Therapy in Chronic Hepatitis C. Ann. Intern. Med. 140: 346-355 (2004)

Date of report
9/23/2002