Clinical Trial Result Information
Title of Study:
Multicenter, open-label, expanded access program of peginterferon alfa-2a monotherapy and combination therapy with ribavirin in patients with chronic hepatitis C.
Fast Facts:
| Protocol number: | BV16209 |
| Sponsor: | F Hoffmann-La Roche Ltd./Inc/AG/Roche Global Business |
| 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: | 3/3/2008 |
Clinical study summary:
This was a multicenter, open-label, multinational, parallel-group trial designed as an expanded access program. Patients infected with hepatitis C virus (HCV) were assigned to one of three treatment groups according to the discretion of the investigator: PEGASYS (peginterferon alfa-2a (40KD)) monotherapy for 48 weeks, or PEGASYS combination therapy with ribavirin for 24 or 48 weeks. Patients were followed for 24 weeks after the end of treatment.
Study center(s) :
A total of 652 centers in 55 countries worldwide.
Objectives:
To evaluate the safety and tolerability of PEGASYS monotherapy given for 48 weeks and PEGASYS in combination with ribavirin given for 24 weeks or 48 weeks in patients with chronic hepatitis C (CHC).
Methodology:
After receiving the first dose of study drug, patients returned for evaluation at weeks 2, 4, 8, 16 and 24 and in addition at weeks 32, 40 and 48 for patients assigned to 48 weeks of treatment. After completing therapy patients were seen after 8 and 24 weeks for evaluation of safety. Patients who prematurely stopped taking study medication were followed for safety for at least 12 weeks after their last dose of study medication.
In a Canadian subpopulation (cohort 2), only ribavirin was provided as study drug (PEGASYS was prescribed), and therefore non-serious adverse events associated with PEGASYS were not collected.
Number of patients (planned/analyzed):
10,000 planned; 10,436 enrolled; 9,802 treated (at least one dose of either study drug).
Diagnosis and main criteria for inclusion:
Male or female outpatients ≥18 years of age with serologically and histologically proven CHC, detectable HCV RNA, elevated ALT, and compensated liver disease.
Test product, dose and mode of administration or test procedure:
180μg of PEGASYS (peginterferon alfa-2a (40KD)) administered subcutaneously once weekly.
800mg or 1000-1200mg of ribavirin according to genotype (non-1 or 1) and body weight (< or ≥75kg) administered orally twice daily in split doses.
Duration of treatment:
24 or 48 weeks
Reference therapy, dose and mode of administration or reference procedure:
N/A.
Criteria for evaluation (efficacy, safety):
Efficacy: No efficacy parameters were evaluated in this study.
Safety: Serious adverse events; non-serious adverse events of special interest, which were defined as AEs leading to dose reduction or discontinuation of study drug, neutropenia (neutrophil count <750 cells/mm3), thrombocytopenia (platelet count <50,000 cells/mm3), and anemia (hemoglobin <10 g/dL), ALT elevation leading to dose modification, and unknown or unexpected AEs; study drug dose modifications; and treatment withdrawals for safety reasons.
Statistical methods:
Descriptive statistics were used to summarize safety parameters. The safety population was split into four cohorts and analyzed by treatment group within each cohort:
Cohort 1 included the vast majority of patients.
Cohort 2 was comprised of a Canadian subgroup of patients (ribavirin access program) receiving PEGASYS as a prescribed commercially packaged drug (see below) and ribavirin as an investigational drug.
Cohort 3 and 4 were comprised of 9 and 12 patients, respectively, enrolled under local amendments of the protocol in Canada and South Africa.
Summary (efficacy, safety, other results):
Safety: A total of 9188 patients were included in cohort 1; 45% of these patients reported at least one adverse event (a serious adverse even or a non-serious adverse event of special interest). Cohort 2 comprised 593 patients; due to the restricted reporting rules, a lower percentage of patients (25%) in cohort 2 reported at least one adverse event than in cohort 1. The majority of the reported adverse events were assessed as related to study drug by the investigator. The most frequently reported types of adverse events were blood and lymphatic system disorders (32% in cohort 1 and 15% in cohort 2), mainly neutropenia, anemia and thrombocytopenia, which represented the majority of adverse events of special interest. Overall, depression was reported in a similar percentage of patients (1.2% and 1.0%) in cohorts 1 and 2. In most of these patients depression was considered related to study drug.
Serious infections were the most frequent type of serious adverse events and occurred in 1.5% and 1.0% of patients in cohorts 1 and 2, respectively. In cohort 1, serious cardiac disorders were reported in 28 patients (0.3%) and serious vascular disorders in 14 patients (0.2%). In cohort 2, two serious cardiovascular events were reported (angina pectoris and deep vein thrombosis).
A total of 44 patients died during the study, 42 patients in cohort 1 and two in cohort 2. In six patients in cohort 1, the adverse event leading to death was assessed by the investigator as related to study drug. These six patients died of thrombocytopenia and gastrointestinal hemorrhage (combined reason for death in one patient), pneumonia, hepatic cirrhosis, hypoglycemia and cerebrovascular accident (combined reason for death in one patient), B-cell lymphoma, and sepsis. None of the adverse events leading to death in cohort 2 was assessed as related to study drug.
The type of non-serious adverse events of special interest reported with the highest incidence were blood and lymphatic system disorders (31% in cohort 1 and 14% in cohort 2) and mainly consisted of neutropenia, anemia and thrombocytopenia.
PEGASYS was prematurely discontinued in 9.8% of patients in cohort 1 and 6.9% of patients in cohort 2. In cohort 1, the most frequent reason for premature discontinuation of PEGASYS was blood and lymphatic system disorders (2.9%), mainly consisting of neutropenia (1.5%), thrombocytopenia (1.0%), and anemia (0.8%). In cohort 2, psychiatric disorders were the most frequent reason for premature discontinuation of PEGASYS (1.7% of patients), the most common reason being depression (0.7%)
In patients with liver cirrhosis the safety profile was less favorable. A higher occurrence of adverse events was observed than in the general population. The pattern of adverse events was otherwise very similar.
Conclusions:
In cohort 1, only the non SAEs of special interest were captured, but keeping in mind the limitations for the analysis, in cohort 1, which represented the vast majority of patients enrolled in the study, the safety profile of PEGASYS monotherapy given for 48 weeks and PEGASYS given in combination with ribavirin for 24 weeks or 48 weeks was similar to that previously reported, and no new safety concerns were identified either in the overall population or in those patients with underlying liver cirrhosis.
Click here for the protocol registry listing of this trial.
