Clinical Trial Result Information

Title of Study:
A randomized, open-label, multicenter, efficacy and safety study examining the effects of duration of treatment and of a high induction dose of PEGASYS in combination with daily Copegus in patients with chronic hepatitis C who did not respond to previous peginterferon alfa-2b/ribavirin combination therapy.

Fast Facts:

Protocol number:	MV17150
Sponsor:	Hoffmann-La Roche Ltd/Inc/AG Roche Global Business
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:	12/3/2007

Clinical study summary:
This was a randomized, open-label, parallel-group trial. Patients with chronic hepatitis C (CHC) who failed to respond to a previous PEG-IFN alfa-2b and ribavirin combination therapy given for at least 12 weeks were treated with one of the combinations described below. Patients were then followed for an additional 24 weeks. The four treatment groups were:
Group A: 360μg of PEGASYS once weekly plus 1000/1200mg of ribavirin daily for 12 weeks, and thereafter 180μg of PEGASYS once weekly plus 1000/1200mg of ribavirin daily for 60 weeks, followed by an untreated follow-up period of 24 weeks.
Group B: 360μg of PEGASYS once weekly plus 1000/1200mg of ribavirin daily for 12 weeks, and thereafter 180μg of PEGASYS once weekly plus 1000/1200mg of ribavirin daily for 36 weeks, followed by an untreated follow-up period of 24 weeks.
Group C: 180μg of PEGASYS once weekly plus 1000/1200mg of ribavirin daily for 72 weeks, followed by an untreated follow-up period of 24 weeks.
Group D: 180μg of PEGASYS once weekly plus 1000/1200mg of ribavirin daily for 48 weeks, followed by an untreated follow-up period of 24 weeks.

Study center(s) :
A total of 106 centers in Belgium, Brazil, Canada, France, Germany, Greece, Italy, Portugal, Spain, Sweden, Switzerland, Turkey, UK and USA.

Objectives:
Primary: To compare the efficacy of the combination of an induction dose of PEGASYS, 360μg given for 12 weeks followed by 180μg for 60 weeks, and ribavirin, 1000 or 1200mg given for 72 weeks, with the combination of 180μg of PEGASYS plus 1000 or 1200mg of ribavirin given for 48 weeks in patients who did not respond to previous PEG-IFN alfa-2b and ribavirin combination therapy.

Secondary: To compare the efficacy of the pooled arms with the high induction 360μg dose to the pooled arms with the 180μg dose; to compare the efficacy of the pooled arms with 72 weeks of treatment to the pooled arms with 48 weeks of treatment; to evaluate the effect of PEGASYS and ribavirin combination therapy on the reduction of HCV viremia at the end of treatment; to evaluate the effect of PEGASYS and ribavirin combination therapy on the reduction of HCV viremia after 12, 24 and 48 weeks of treatment; to evaluate the safety of PEGASYS and ribavirin combination therapy given with a high induction dose of 360μg PEGASYS for the first 12 weeks; to evaluate the safety of PEGASYS and ribavirin combination therapy given for 72 weeks.

Methodology:
Qualitative HCV RNA tests (Amplicor HCV Test, v2.0, lower limit of detection: 50 IU/mL) were performed at weeks 12, 24, 48 and at the end of follow-up for patients in the two 48-week treatment groups (groups B and D) and at weeks 12, 24, 48, 72 and at the end of follow-up for patients in the two 72-week treatment groups (groups A and C). Quantitative HCV RNA titers (Amplicor HCV Monitor Test v2.0, lower limit of quantification: 600 IU/mL) were evaluated during screening, at baseline, and at weeks 12 and 24 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):
888 planned, 950 randomized and 942 dosed.

Diagnosis and main criteria for inclusion:
Male or female outpatients ≥18 years of age with serologically and histologically proven CHC, quantifiable HCV RNA (>600 IU/mL), compensated liver disease, and who had positive HCV RNA assessments after the start of appropriately dosed previous PEG-IFN alfa-2b and ribavirin combination therapy given for at least 12 weeks.

Test product, dose and mode of administration or test procedure:
PEGASYS (peginterferon alfa-2a (40KD)) 180 or 360μg administered subcutaneously once weekly for the first 12 weeks and PEGASYS 180μg administered subcutaneously once weekly for the rest of the treatment period.
Ribavirin 1000mg (for patients weighing <75kg) or 1200mg (for patients weighing >75kg) administered orally twice daily in split doses.

Duration of treatment:
48 or 72 weeks plus a 24 week untreated follow-up period.

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

Criteria for evaluation (efficacy, safety):
Primary Efficacy Endpoint: Sustained virological response (SVR) at 24 weeks after the end of the actual study treatment.

Secondary Efficacy Endpoint: Virological response at the end of the actual treatment period; virological response at weeks 12, 24 and 48; maintenance of actual end-of-treatment virological response; relapse of actual end-of-treatment virological response.

Safety Endpoints: Frequency of adverse events and serious events, abnormal laboratory test results, change in vital signs, frequency of study drug dose modifications and treatment withdrawals for safety reasons.

Statistical methods:
Efficacy: The primary analysis used the intent-to-treat population (ie all patients receiving at least 1 dose of study drug) to compare SVR between groups A and D assessed according to the actual treatment period. Cochran-Mantel-Haenszel test stratified by geographical region, HCV genotype, and cirrhosis status was used to compare SVR. The odds ratios and corresponding 95% confidence intervals were provided for between-group pairwise comparisons and for comparisons of pooled data assessing the effect of 48 and 72 weeks of treatment and the 180μg dose and 360μg induction dose of PEGASYS. Descriptive statistics were used to calculate the positive predictive values of a week 12 response.

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

Summary (efficacy, safety, other results):
There were no statistically significant differences in baseline characteristics between the study arms.
Efficacy: The main efficacy results in all patients treated according to the actual treatment period are summarized below.
SVR was statistically significantly higher in group A (16%) than in group D (9%) (odds ratio = 2.00, 95% CI 1.21-3.31, p=0.006), and statistically significantly higher in the two pooled groups (groups A + C) receiving 72 weeks of study treatment (16%) than in the two pooled groups (groups B + D) receiving 48 weeks of study treatment (8%) (odds ratio = 2.22, 95% CI 1.4-3.52, p=0.0006). SVR was not significantly different in the two pooled groups receiving the 360µg PEGASYS induction dose (groups A + B, 13%) and in the two pooled groups receiving 180µg PEGASYS (groups C + D, 10%) (odds ratio = 0.98, 95% CI 0.63-1.51, p=0.9228).
Virological response (undetectable HCV RNA) at the end of study treatment was similar in the four treatment groups (28% to 33%). Virological response at week 12 was significantly higher in group A (24%) than in group D (11%) (odds ratio = 2.64, 95% CI 1.66-4.18, p<0.0001), while the virological responses at week 24 and week 48 were not significantly different in groups A and D. Patients who achieved a negative HCV RNA at week 12 had SVR rates of 53%, 36%, 68% and 34% for arms A, B, C and D, respectively. SVR in all groups in patients with liver cirrhosis (Metavir Grade F3 and 4) was low (4% to 7%) and fewer patients became HCV RNA negative at week 12 (7%), but similar positive predictive values applied to those cirrhotic patients who were HCV RNA negative at week 12.
For the pooled 72 and 48 week arms, this value was 57% and 35%, respectively. The percentage of patients who relapsed after having achieved an end-of-treatment virological response was lower in patients receiving 72 weeks of treatment (group A: 49% and group C: 59%) than in patients receiving 48 weeks of treatment (group B: 78% and group D: 67%).

Safety: The safety profile of PEGASYS and ribavirin combination therapy with a higher PEGASYS induction dose of 360 μg or with a longer treatment duration of 72 weeks in the patient population studied was in general similar to the safety profile in treatment-naive patients reported previously for the approved PEGASYS and ribavirin combination therapy, and no new safety concerns were observed. Most patients in all four treatment groups had at least one adverse event and at least one treatment-related adverse event. 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 occurred with similar frequency across the four treatment groups.
The frequency of serious adverse events was higher in group C (18%) than in the other three groups (9% to 11%), and the frequency of treatment-related serious adverse events was lower in group B (1%) than in the other three groups (4% or 5%). The frequency of depression and the frequency of serious infections were comparable across the four treatment groups. A total of 5 patients died during the study; all 5 deaths were considered unrelated to study drug.
Dose modifications of PEGASYS or ribavirin for safety occurred with comparable frequency in the four treatment groups. In all treatment groups, laboratory abnormalities, mainly neutropenia and less frequently thrombocytopenia, were the main reason for dose modifications of PEGASYS, whereas, as expected, the majority of ribavirin dose modifications were for anemia.
Compared with 48 weeks of treatment (4% in group B and 6% in group D), 72 weeks of treatment, as would be expected with a longer treatment duration, resulted in a higher frequency of premature discontinuation of PEGASYS treatment for adverse events or laboratory abnormalities (12% in groups A and C), and a similar trend was seen in the percentage of patients who prematurely withdrew from ribavirin treatment (13% in groups A and C vs. 6% and 7% in groups B and D, respectively). The differences were largely accounted for by additional treatment withdrawals between treatment weeks 49 and 72.
The most frequent marked laboratory abnormalities were low neutrophil, white blood cell, lymphocyte, and platelet counts; low hemoglobin concentration; low hematocrit fraction, high ALT activity, and high triglyceride concentration. These laboratory abnormalities generally returned toward the normal range after completion of study treatment. The frequency of severe neutropenia was 7% in the two groups receiving the 360 μg PEGASYS induction dose, compared with 6% and 4% in the two groups receiving the 180 μg PEGASYS dose. Severe anemia occurred at a similar frequency in the four treatment groups (2% in group A, 4% in group B, and 3% in groups C and D). Thrombocytopenia occurred in 9% and 7% of patients in the two groups receiving the 360 μg PEGASYS induction dose, compared with 4% and 6% in the two groups receiving only 180 μg PEGASYS.
In general, during the first 12 weeks of treatment when the induction dose of PEGASYS was given, no obvious differences in safety parameters were observed between patients receiving 360 μg of PEGASYS and those receiving 180 μg of PEGASYS, except for a higher frequency of PEGASYS dose modifications during this period in the two groups receiving 360 μg of PEGASYS (17% and 18%) than in the two groups receiving 180 μg (12% each group).
The effects of the longer treatment duration of 72 weeks and the higher PEGASYS induction dose of 360 μg on the safety profile in patients with cirrhosis were similar to those observed in the overall safety population, and no new safety concerns were seen in patients with cirrhosis.
In an exploratory analysis to assess the AE profile across the four treatment groups adjusted for length of treatment, the average number of AEs per patient year was lowest in the two 72 week treatment groups A and C (6.37 and 5.77, respectively) compared to the two 48 week treatment groups B and D (7.42 and 6.86, respectively).
Therefore, compared with the standard combination therapy with PEGASYS and ribavirin, neither the longer treatment duration of 72 weeks nor the higher PEGASYS induction dose of 360 μg resulted in any significant safety concerns or considerably modified the safety profile of the PEGASYS and ribavirin combination treatment regimen in this patient population.

Conclusions:
In CHC patients who failed to clear HCV RNA during at least 12 weeks of previous PEG-IFN alfa-2b and ribavirin combination therapy, a sustained virological response could be achieved by re-treatment with PEGASYS and ribavirin combination therapy. Compared with the standard treatment regimen approved for treatment-naive patients, a longer treatment duration of 72 weeks, rather than the higher PEGASYS induction dose of 360μg for 12 weeks, was the primary driver for achieving a sustained virological response during re-treatment in this patient population.
The safety profile of PEGASYS and ribavirin combination therapy in this study was similar to that previously reported, and no new safety concerns were identified in the overall population or in patients with underlying liver cirrhosis. Compared with the standard combination therapy regimen with PEGASYS and ribavirin approved for treatment-naive patients, neither the longer treatment duration of 72 weeks nor the higher PEGASYS induction dose of 360μg resulted in any significant safety concerns or considerably modified the safety profile of the PEGASYS and ribavirin combination treatment in this patient population

Click here for the protocol registry listing of this trial.