Clinical Trial Result Information

Title of Study:
A prospective, randomized, multicenter, open-label, comparative safety study of Pegasys vs Pegasys plus Ribavirin treatment in patients with chronic hepatitis C virus

Fast Facts:

Protocol number:	NR16161
Sponsor:	Roche Laboratories Inc.
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:	11/16/2004

Clinical study summary:
This was a randomized, multicenter, comparative, open-label study to assess the safety of peginterferon alfa-2a (40KD) (PEGASYS) plus ribavirin, versus PEGASYS monotherapy in patients with chronic hepatitis C (CHC), either interferon naive, interferon non-responders, or interferon relapsers. Patients with CHC genotype-1 received PEGASYS 180μg/week.+ ribavirin 800 to 1200mg/day. Patients with non-1 CHC genotype received PEGASYS + 800mg /day ribavirin. All patients were originally to receive 48 weeks of therapy, followed by 24 weeks of treatment-free follow-up (see Amendment E, under Methodology).

Study center(s) :
223 centers in the United States and Puerto Rico.

Methodology:
This was a prospective, open-label, multicenter, safety study in CHC-infected patients. In the original study design, patients chose Cohort 1 (possible 12-week treatment delay) or Cohort 2 (no treatment delay) and were randomized 3:1:1 to Arm A (PEGASYS + ribavirin), Arm B (PEGASYS monotherapy), or if in the first cohort, Arm C (12 week treatment delay). After 12 weeks, patients in Arm C were randomized 3:1 to Arm A or B.

The design of the study was altered with Amendment D by eliminating Arm C, as few patients were willing to possibly delay treatment for 12 weeks. Arm B was also eliminated, and all new patients were to be enrolled into Arm A (PEGASYS + ribavirin. Previously enrolled patients not already in Arm A were switched to combination therapy after they had received at least 12 weeks if PEGASYS monotherapy.All patients were to receive a total of 48 weeks of PEGASYS therapy (total of monotherapy and combination therapy) and to be followed to Week 72, unless prematurely withdrawn.

With Amendment E to the protocol, the ribavirin dose and duration of treatment were altered, based on new information regarding efficacy in relation to CHC genotype and bodyweight. Patients infected with CHC genotype 1 were to receive 48 weeks of PEGASYS + ribavirin, using an increased ribavirin dose of 1000mg daily (if body weight was <75kg) or 1200mg daily (if body weight was ≥ 75kg). Patients with a non-1 CHC genotype were to receive PEGASYS + ribavirin 800mg daily.The criteria for continuing treatment after Week 24 also changed; patients with HCV RNA <600 IU/mL (quantitative test) or with a ≥ 2-log decrease from the screening or baseline value at Week 24 were to continue treatment for another 24 weeks if infected with genotype 1, or were to stop treatment if infected with a non-1 genotype (treatment considered complete). Patients with a non-1 genotype who did not meet the new criteria were to discontinue therapy (for non-response) at Week 24 or when possible, if already past Week 24. All patients who completed the treatment period (regardless of duration) were to be followed for 24 weeks post-treatment.

During the treatment and follow-up periods, patients were periodically assessed for vital signs, clinical laboratory tests, pregnancy, fatigue, and depression. HCV-RNA was also assessed. Serious adverse events and the selected adverse events of fatigue, depression, anemia, Grade 3 or 4 neutropenia, and clinically significant infections requiring treatment were continually reported.

Number of patients (planned/analyzed):
≤1900 planned, 1887 enrolled, and 1854 received study medication.(301 randomized in the PEGASYS® monotherapy group, 956 randomized in the PEGASYS® + ribavirin group under Protocol A-C, 597 enrolled in the PEGASYS® + ribavirin group under Protocol D.

Diagnosis and main criteria for inclusion:
Male and female outpatients ≥18 years old with serologic evidence of CHC (anti-HCV antibody test); detectable HCV-RNA in plasma; elevated serum alanine aminotransferase (ALT) activity within 6 months prior to the first dose of study medication; and chronic liver disease consistent with CHC, Child-Pugh Grade A classification.

Test product, dose and mode of administration or test procedure:
PEGASYS 180 µg was administered as weekly sc injections for 48 weeks (genotype 1) or 24-48 weeks (non-1 genotypes). Ribavirin was taken orally, with food, for the duration of PEGASYS treatment. Daily doses were 800 mg (non-1 CHC genotypes), 800mg to 1200mg (CHC genotype 1).

Duration of treatment:
Weekly for 48 weeks prior to Amendment E

Reference therapy, dose and mode of administration or reference procedure:
PEGASYS® 180μg sc weekly.

Criteria for evaluation (efficacy, safety):
Primary Safety Parameters: Relative risk of each of the selected adverse experiences (fatigue, depression, anemia, Grade 3 or 4 neutropenia, and any clinically significant infection requiring treatment) through Week 12.

Secondary Safety Parameters: (1) Safety profiles through follow-up regarding the selected adverse experiences; (2) Absolute and percentage change from baseline in Fatigue Severity Scale (FSS) and Beck Depression Inventory (BDI-II) scores; (3) Time to first PEGASYS dose reduction; (4) Number of patients with dose modification for adverse events or laboratory abnormalities; (5) Time to discontinuation of treatment and number of patients discontinued due to a safety reason; (6) Incidence of serious adverse events; (7) Number of patients who were discontinued due to a serious adverse event; (8) Number of patients with dose adjustment due to a serious adverse event; (9) Patient days at each dose level; and (10) In addition, deaths, protocol-specified adverse events, clinical laboratory test results, vital signs, and body weight were evaluated.

Secondary Efficacy Parameters: (1) Nondetectable serum HCV-RNA (< 60 IU/mL) at Week 12, Week 24, and 24 weeks post-treatment; (2) Nondetectable serum HCV-RNA (< 60 IU/mL or ≥a 2-long decrease from screening/baseline) at Week 12; and (3) Predictability of Week-12 HCV-RNA to treatment response (nondetectable HCV-RNA) at Week 24 and 24 weeks post-treatment.

Statistical methods:
The primary analyses were performed on the combined data from Cohorts 1 and 2 through Week 12 between patients randomized to Arm A and those randomized to Arm B. For each primary safety endpoint, a Cox proportional hazards model was used to estimate the relative risk of having one of the selected events between Arms A and B using the safety population. The Kaplan-Meier method was used to estimate the cumulative probability. Treatment group differences in observed and cumulative events were tested using a chi-squared test, and the Cochran-Mantel-Haenzel test stratified by genotype was used to test for group differences in the proportions.

Time-to-event data were analyzed using the log-rank test from the Kaplan-Meier procedure for survival analysis. Absolute values and percent change in FSS and BDI-II scores were analyzed using a mixed model for repeated measurements over study visits, and scores were compared between study groups using a one-way analysis of variance (ANOVA) model. Other safety variables were summarized descriptively. The chi-square test or an ANOVA model was used to test for differences between treatment groups at baseline.

Efficacy analyses were performed on the intent-to-treat and standard populations. Virologic response and sustained virologic response were compared between study groups using the Cochran-Mantel-Haenzel test. Week-12 positive and negative predictive values were summarized descriptively.

Summary (efficacy, safety, other results):
Safety – At Week 12, patients on PEGASYS + ribavirin had a significantly greater risk of anemia and neutropenia than patients on PEGASYS monotherapy (2.3 for anemia and 3.1 for neutropenia); risks of experiencing the other events analyzed were similar between treatment groups (primary endpoints). Anemia and neutropenia also had significantly greater cumulative event rates at Week 12 in patients on PEGASYS + ribavirin compared with patients on PEGASYS monotherapy (treatment differences of 33.36, P=0.000, and 2.07, P=0.034, respectively).

Over the 48-week treatment period, fatigue occurred in 69.6% and 71.1% of patients in the PEGASYS + ribavirin and PEGASYS groups, respectively, and was most likely to occur during the first 4 weeks of treatment. Depression occurred throughout the treatment period, reaching 9.7% and 9.6%, respectively, by Week 48, with clinically severe depression (BDI-II >=31) in 4.5% and 2.3%, respectively. Anemia and neutropenia were likely to appear during the first 12 weeks of treatment. By Week 48, anemia reached 58.1% in the PEGASYS + ribavirin group and 41.2% in the PEGASYS group), and neutropenia was observed in 3.0% and 2.0% of patients, respectively. Clinically significant infections occurred throughout the treatment period. By Week 48, 25.8% and 24.6% of patients, respectively, experienced a clinically significant infection and 2.0% and 1.7% a serious one. The first PEGASYS dose reduction was more likely to occur during the first 4 weeks of treatment. Dose modification was frequently required for neutropenia and anemia; for overall adverse events or laboratory abnormalities, dose modification was more frequent among patients in the PEGASYS + ribavirin group than in the PEGASYS group (39.9% vs 30.6%). Discontinuation of study treatment for safety reasons occurred throughout the treatment period in both study groups (cumulative probabilities of 13.4% and 12.7%, respectively). Serious adverse events were experienced by 9% and 10% of patients in the PEGASYS + ribavirin and PEGASYS groups, respectively. In each of the groups, a serious adverse event led to dose modification in 2% of patients and to discontinuation of treatment in 3% of patients.

Over the entire study (including the follow-up period), 14 deaths were reported (<1% of all patients), 10.4% of all patients experienced a serious adverse event, and 8.3% were withdrawn due to one of the reported adverse events. Decreases in hematology parameters during study treatment reversed during the follow-up period. The overall PEGASYS + ribavirin group had higher incidences of low hemoglobin, neutrophil count, and lymphocyte count,, whereas the PEGASYS group had a higher incidence of thrombocytopenia.. Mean ALT values decreased during the treatment period; marked abnormalities in ALT occurred in 19% and 30% of patients in the overall PEGASYS + ribavirin and PEGASYS groups, respectively, which only rarely required a dose modification of study treatment (0.7% in each group). In most cases, laboratory abnormalities were managed with a dose modification. Mean plasma triglycerides increased and total cholesterol decreased during the treatment period, and mean values for both parameters returned toward baseline during the follow-up period. No meaningful changes in vital signs were observed in any group; however, during treatment, mean body weights decreased by 4.9 kg and 4.6 kg in the overall PEGASYS + ribavirin and PEGASYS groups, respectively.

Efficacy – The secondary efficacy analysis was based on 1854 ITT patients, who were either interferon naive, interferon responders, or interferon-relapsers. Patints were predominantly CHC genotype 1, and included interferon non-responders and relapsers.  At Week 12, nondetectable HCV-RNA (<60 IU/mL) was observed in 40.0% of patients in both the PEGASYS + ribavirin and PEGASYS monotherapy randomized treatment groups, and nondetectable or a >=2-log decrease in HCV-RNA was observed in 56.7% and 56.5% of randomized patients, respectively. A sustained virologic response (SVR) was obtained in 30.8% and 24.3% of randomized patients, respectively (P=0.031), and 32.8% of patients direct-enrolled to the PEGASYS + ribavirin treatment group.

 Week-12 negative predictive values for SVR were >95% in both groups. Week-12 positive predictive values for SVR were 42.2% and 53.2% in the PEGASYS + ribavirin and PEGASYS groups, respectively. Virologic response rates were higher in the standard analysis than in the intent-to-treat analysis, and Week-12 predictive values were similar between the 2 populations.

A higher SVR was observed among patients with non-1 CHC genotypes than genotype 1 (47.0% vs 25.0%, respectively, in the PEGASYS + ribavirin group) and among IFN-naïve than experienced patients (38.3% vs 21.3%, respectively, in the PEGASYS + ribavirin group).

Conclusions:
The safety profile of 12 weeks of treatment with PEGASYS + ribavirin for CHC was similar to that of PEGASYS monotherapy, with the exception of an increased risk of anemia and a small but increased risk of neutropenia. These laboratory abnormalities usually occurred early during treatment and were frequently managed with a dose reduction in study medication. Small differences in other safety parameters were not significant, and there were no unexpected findings. Improved efficacy with the addition of ribavirin was evidenced by significantly greater sustained virologic response 24 weeks post-treatment. The improved efficacy compared with monotherapy and manageable safety profile of PEGASYS® + ribavirin demonstrated in this study support the use of combination therapy in the treatment of CHC.