Clinical Trial Result Information

Title of Study:
Randomized, multicenter, open-label, phase IV study evaluating the efficacy and safety of 16-week versus 24-week treatment with PEGASYS in combination with Copegus in interferon-naïve patients with chronic hepatitis C genotype 2 or 3 virus infection.

Fast Facts:

Protocol number:	NV17317
Sponsor:	Hoffmann-La Roche
Company division:	Pharmaceutical
Product name:	PEGASYS
Generic name:	peginterferon alfa-2a (40KD)
Phase of development:	IV
Therapeutic area, approved indication:	Hepatitis C, Chronic
Date of report:	2/1/2006

Clinical study summary:
This was a multicenter, open-label, randomized, parallel-group trial. Patients infected with HCV genotype 2 or 3 were treated with combination therapy for either 16 or 24 weeks and were then followed for an additional 24 weeks.

Study center(s) :
A total of 132 centers in Australia, Canada, France, Germany, Italy, New Zealand, Spain and United States.

Objectives:
Primary objective: To compare the efficacy of the combination of PEGASYS (peginterferon alfa-2a (40KD)) and Copegus (ribavirin) given for 16 weeks to the same combination given for 24 weeks in chronic hepatitis C (CHC) patients with hepatitis C virus (HCV) genotype 2 or 3.
Secondary objectives: To compare the safety of the combination of PEGASYS and ribavirin given for 16 weeks to the same combination given for 24 weeks in CHC patients with HCV genotype 2 or 3. To evaluate the effect of the combination of PEGASYS and ribavirin on fasting triglycerides (substudy – not reported here).

Methodology:
All patients were screened within 35 days prior to the first dose of study treatment. Patients’ disease status was assessed by monitoring serum HCV RNA titers. Qualitative HCV RNA tests were performed at weeks 4, 12, 16, 28, and 40 for patients in the 16-week group and at weeks 4, 12, 24, 36, and 48 for patients in the 24-week group. Quantitative HCV RNA titers were evaluated during screening and at weeks 4 and 12 when HCV RNA was detectable by the qualitative assay. Safety assessments were performed during treatment and the 24-week follow-up.

Number of patients (planned/analyzed):
1400 planned, 1469 randomized, 1465 dosed.

Diagnosis and main criteria for inclusion:
Male or female outpatients ≥ 18 years of age with serologically and histologically proven CHC, HCV genotype 2 or 3 infection, quantifiable HCV RNA (> 600 IU/mL), elevated ALT, and compensated liver disease. Patients previously treated with interferon, ribavirin, viramidine, levovirin, or amantadine and patients with other forms of liver disease, HIV infection or hepatocellular carcinoma were excluded.

Test product, dose and mode of administration or test procedure:
PEGASYS (peginterferon alfa-2a (40KD)) 180µg. Copegus (ribavirin) 200 mg.
180 µg of PEGASYS in 1-mL solution administered subcutaneously once weekly for 16 or 24 weeks. 800mg of ribavirin (200-mg tablets) administered orally twice daily in split doses (400 mg x2) for 16 or 24 weeks.

Duration of treatment:
16 or 24 weeks.

Reference therapy, dose and mode of administration or reference procedure:
None

Criteria for evaluation (efficacy, safety):
Efficacy: Primary efficacy parameter: Sustained virological response at 24 weeks after the completion of the scheduled study treatment. Secondary efficacy parameters: Virological response at the end of study treatment and virological response at 12 weeks after completion of study treatment. Safety: Adverse events, laboratory test results, vital signs, study drug dose modifications and treatment withdrawals for safety reasons.

Statistical methods:
Efficacy: Primary efficacy analyses used the standard population since for equivalence testing, analyses in the intent-to-treat population tend to dilute true treatment differences. Cochran-Mantel-Haenszel test stratified by country and genotype was used to compare sustained virological response, end-of-treatment virological response, and virological response 12 weeks after the end of treatment between the two treatment groups. The odds ratios and corresponding 95% confidence intervals are provided. Safety: Descriptive statistics were used to summarize safety parameters by treatment group.

Summary (efficacy, safety, other results):
Efficacy: The main efficacy results in the standard population are summarized below.

Treatment for 16 weeks was not equivalent to treatment for 24 weeks in patients infected with HCV genotype 2 or 3. Treatment for 16 weeks resulted in a statistically significantly lower sustained virological response (65%) than treatment for 24 weeks (76%) (p < 0.0001). In patients infected with HCV genotype 2, 16 weeks of treatment resulted in a statistically significantly lower sustained virological response (65%) than 24 weeks of treatment (82%) (p < 0.0001). In patients infected with HCV genotype 3, sustained virological response was numerically lower in the 16- (65%) than in the 24-week treatment group (69%) (p = 0.1565). End-of-treatment virological response in the 16-week treatment group was comparable to that in the 24-week treatment group (94% vs 92% regardless of HCV genotype: 94% vs 95% for HCV genotype 2, 93% vs 89% for HCV genotype 3, 16 vs 24 weeks of treatment). Virological response at 12 weeks post-treatment was significantly lower in the 16- (59%) than in the 24-week treatment arm (69%) (p = 0.0003). The percentage of patients who maintained their end-of-treatment virological response was lower in the 16- (69%) than in the 24-week treatment groups (81%). The difference was still present if patients infected with HCV genotype 2 and patients infected with HCV genotype 3 were compared separately. Safety: The safety profile of PEGASYS and ribavirin combination therapy for 16 or 24 weeks in CHC patients infected with HCV genotype 2 or 3 was similar to that reported previously, and no new safety concerns were identified. The most frequent adverse events were those known to be associated with interferon and ribavirin treatment, such as fatigue, headache, insomnia, and nausea, and these events, as well as severe adverse events, occurred less frequently in the 16-week treatment group than in the 24-week treatment group. Overall, depression was reported in a similar percentage of patients in the two treatment groups (20% and 23%). The overall frequency of serious adverse events was similar in the two arms, occurring in 5% and 6% of patients in the 16- and 24-week treatment groups, respectively. Serious infection occurred in 2% of the patients in each treatment group, and none of the serious infections were associated with a concomitant severe neutropenia or lymphopenia. Serious cardiovascular and bleeding events were reported in a few patients in each group, and these events were not associated with severe anemia or thrombocytopenia. A total of 4 patients died during the study; all 4 deaths were considered unrelated to study drug. Dose modifications of PEGASYS and ribavirin for safety occurred less frequently in the 16- than in the 24-week treatment group. The majority of PEGASYS dose modifications were for laboratory abnormalities, whereas the majority of ribavirin dose modifications were for adverse events. The percentage of patients who prematurely discontinued PEGASYS treatment for adverse events or laboratory abnormalities was lower in the 16-week treatment group (3%) than in the 24-week treatment group (5%). A similar trend was seen in the percentage of patients who prematurely discontinued ribavirin treatment (4% and 5%, respectively). The most frequent marked laboratory abnormalities were low neutrophil, lymphocyte, and platelet counts; low hemoglobin concentration; high triglyceride concentration; and low phosphate concentration. These laboratory abnormalities generally returned toward the normal range after completion of study treatment. Severe neutropenia, lymphopenia, thrombocytopenia, and anemia were not common. Neutropenia (0.75 × 10⁹/L) and anemia (<10 g/dL) occurred at a similar frequency in the 16-week treatment group (14% and 4%) and in the 24-week treatment group (16% and 6%). No new safety concerns were observed in patients with liver cirrhosis. The safety profile was less favorable in patients with liver cirrhosis than in the overall patient population.

Conclusions:
In CHC patients infected with HCV genotype 2 or 3, 16 weeks of treatment with 180 μg of PEGASYS weekly and 800 mg of ribavirin daily resulted in a statistically significantly lower sustained virological response than the same treatment combination given for the current standard of 24 weeks. Treatment for 16 weeks appeared to have consistent but small safety advantages over treatment for 24 weeks.

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