Clinical Trial Result Information

Title of Study:
Peginterferon alfa-2a in combination with ribavirin in patients with chronic hepatitis C not previously treated with interferon and ribavirin: a randomized, open-label study in patients with genotype 1 evaluating the efficacy and safety of a treatment duration of 24 weeks versus 48 weeks and an observational study in patients with genotype non-1

Fast Facts:

Protocol number:	M78017
Sponsor:	Produtos Roche Químicos e Farmacêuticos S.A.
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:	6/28/2004

Clinical study summary:
This was a Phase IV multicenter, multi-national, randomized, open-label, parallel group study of the efficacy and safety of peginterferon alfa-2a (40KD) (PEGASYS) plus ribavirin in patients with chronic hepatitis C (CHC). Patients received PEGASYS for 24 or 48 weeks, and all patients had an untreated follow-up period of 24 weeks.

Study center(s) :
21 centers in Brazil and Mexico.

Objectives:
Primary: To compare the efficacy of PEGASYS plus ribavirin combination therapy given for 24 versus 48 weeks in genotype 1 patients with CHC. Sustained virologic response (SVR) was defined as a HCV RNA negative 24 weeks after treatment end.

Secondary: (1) To compare the efficacy of the combination therapy in genotype 1 versus genotype non-1 patients on the clearance of HCV viremia 24 weeks after treatment end (SVR); (2) To compare the effect of PEGASYS plus ribavirin on serum alanine aminotransferase (ALT) levels 24 weeks after treatment end (sustained biochemical response [SBR]); (3) To evaluate the efficacy of PEGASYS plus ribavirin therapy on the reduction of HCV viremia after 4, 12, 24, 36, and 48 weeks of treatment (Weeks 36 and 48 for Group B only); and (4) To compare the safety of PEGASYS plus ribavirin therapy given for 24 weeks compared with 48 weeks.

Methodology:
After screening and enrollment, genotype-1 patients were randomized to receive subcutaneous (sc) PEGASYS 180 μg once weekly plus oral ribavirin 800 mg/day for 24 weeks (Group A) or 48 weeks (Group B). Genotype non-1 patients received the same treatment for 24 weeks. Treatment was followed by a 24 week treatment-free follow-up period. HCV-RNA and serum ALT were measured regularly during the study, and 24 weeks after treatment end.

Number of patients (planned/analyzed):
Total planned, 220: 65 in Group A, 65 in Group B, and 90 in Group C; total enrolled, 221: 67 in Group A, 67 in Group B, and 87 in Group C.

Diagnosis and main criteria for inclusion:
Men and women ≥18 years of age with serologically proven CHC, previously untreated. Patients had quantifiable HCV-RNA (>1000 IU/mL), persistently elevated ALT levels, compensated liver disease (Child-Pugh Grade A) and a liver biopsy within the past 18 months consistent with CHC without cirrhosis. Patients with other forms of liver disease, HAV or HBV infection, hepatocellular carcinoma or human immunodeficiency virus (HIV) were excluded.

Test product, dose and mode of administration or test procedure:
PEGASYS 180 µg, in a 1- or 0.5-mL solution, sc once weekly. Ribavirin 200mg/tablet; 800 mg/day orally.

Duration of treatment:
24 or 48 weeks

Reference therapy, dose and mode of administration or reference procedure:
Not applicable

Criteria for evaluation (efficacy, safety):
Primary efficacy parameter: (1) Sustained virologic response (SVR) rate, defined as percentage of patients with non-detectable HCV-RNA, as measured by the Roche AMPLICOR HCV Test (<50 IU/mL) at 24 weeks after completion of the 24-week (Group A) or 48-week (Group B) treatment period.

Secondary efficacy parameters: ( 1) SVR rate in genotype 1 versus genotype non-1 patients (2) sustained biochemical response (SBR) rate (3) percentage of patients with non-detectable HCV-RNA at study weeks 4, 12, 24 and 48 (4) safety of PEGASYS plus ribavirin after 24 and 48 weeks of treatment.

Statistical methods:
The SVR rate was calculated as the number of patients with non-detectable HCV-RNA, as measured by the Roche AMPLICOR HCV Test (<50 IU/mL) 24 weeks after completion of the 24-week (Group A and C) or 48-week (Group B) treatment period, divided by the number of patients randomized. The SBR rate was calculated as the number of patients with normal serum ALT level at 24 weeks after completion of the 24-week (Group A and C) or 48-week (Group B) treatment period, divided by the number of patients randomized.

The exact 95% confidence interval from the binomial distribution was provided for response rates in individual treatment groups. Responses rates were compared between Groups A and B and between Groups A and C using the Cochran-Mantel-Haenszel test, controlling by country. Relative risk was given for treatment group comparisons. Patients without measurements at the end of the 24-week untreated follow-up period were considered to be non-responders.

Summary (efficacy, safety, other results):
Efficacy – The results of the efficacy analyses are summarized in Tables 1 and 2.

Table 1.  Sustained Virologic Response (SVR) Rates in Groups A, B, and C, Intent-to-Treat Population

*Exact 95% confidence interval from the binomial distribution.

 Table 2. Sustained Biochemical Response (SBR) in Groups A, B, and C, Intent-to-Treat Population

*Exact 95% confidence interval from the binomial distribution.

The Cochran-Mantel-Haenszel test, controlled by country, showed that the SVR rate among genotype 1 patients was significantly higher (P=0.0234) in patients treated for 48 weeks (Group B) compared with those treated for 24 weeks (Group A). Among patients treated for 24 weeks, the higher SVR rate occurred in genotype non-1 patients (Group C vs Group A, P<0.0001).

The SBR rate was statistically higher (P=0.0311) in genotype 1 patients treated for 48 weeks (Group B) compared with those treated for 24 weeks (Group A). Among patients treated for 24 weeks, significantly more genotype non-1 patients had a SBR (Group C vs Group A, P<0.0001).

Safety – The majority of adverse events were of mild or moderate intensity. Adverse events reported by at least 10% of patients, in at least one treatment group, are summarized in Table 3. The most frequent reported adverse event was ‘influenza like illness’. No deaths occurred during the study. There were 12 serious adverse event episodes, 2 not related and 10 related to study drug (Table 4).

Twenty patients discontinued the study (7 due to adverse events). The number of patients withdrawn because of adverse events was similar in groups treated for 24 or 48 weeks (2, 1 and 4, respectively, in groups A, B and C). Five patients discontinued for personal reasons and 8 patients were lost to follow up.

Dose modification because of neutropenia occurred in 7 (10%), 13 (19%) and 11 (13%) patients, respectively, in groups A, B and C. Dose modification because of thrombocytopenia occurred in 1, 2 and 2 patient in groups A, B and C, respectively. No patient with neutropenia showed serious infection as none of the patients with severe thrombocytopenia had clinical relevant bleeding.

Table 3. Adverse Event by study group (including laboratory abnormalities), Safety Population (reported by at least 10% of patients)

Table 4. Serious Adverse Events Episodes – Safety population

Conclusions:
This study was initiated before the optimal treatment for genotype 1 patients had been determined. The currently recommended ribavirin dose for genotype 1 is 1000-1200mg/day, whereas results in this study were obtained with the suboptimal dose of 800mg/day. Overall, the results of the study confirm the efficacy and safety of PEGASYS and ribavirin therapy in patients with CHC. The data demonstrate that treatment response is primarily driven by the HCV genotype, and support the development of an individualized patient treatment algorithm.

Publications (references, if available):
Brandao CE, Perez-Gomez R, Pessoa MG et al. Prospective evaluation,of early virologic response associated with peginterferon alfa-2a (40KD) (PEGASYS®) and ribavirin from a phase IV, randomized study examining the effects of treatment duration in hepatitis C patients affected with HCV genotype 1. Poster at 53rd Annual Meeting of AASLD, November 2002.