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Clinical Trial Result Information
Protocol number
M78018
Title of Study
An open-label, multicentre pilot study evaluating the efficacy and safety of high dose peginterferon alfa-2a in combination with ribavirin in patients with chronic hepatitis C, genotype 1 who did not respond to previous IFN/ribavirin combination therapy
Sponsor
Roche Farma SA
Company division
Pharmaceutical
Product name
PEGASYS
Generic name
peginterferon alfa-2a (40KD)
Therapeutic area
Hepatitis C, Chronic
Clinical study summary
This multicenter, randomized, open-label, parallel group, pilot study assessed the efficacy and safety of high-dose subcutaneous (sc) induction with peginterferon alfa-2a (40KD) (PEGASYS) in patients with chronic hepatitis C (CHC), genotype 1 who had not responded to previous treatment with an interferon plus ribavirin. Patients were randomized to 3 groups, to receive 3 different doses of PEGASYS (plus ribavirin) for 12 weeks, followed by the standard dose for the subsequent 36 weeks.
Study center(s)
7 centers in Spain.
Phase of development
IV
Objectives
Primary: (1) To evaluate the effect of PEGASYS 180, 270, or 360 µg once weekly in combination with ribavirin (1000–1200 mg/day) on the clearance of hepatitis C virus (HCV) viremia after 12 weeks of treatment (on-treatment virologic response) in patients with CHC virus infection genotype 1 who did not respond to previous combination therapy.
Secondary: (1) To evaluate the effect of PEGASYS 180, 270, or 360 µg once weekly for 12 weeks followed by 180 µg once weekly for 36 weeks in combination with ribavirin (1000–1200 mg/day) for 48 weeks on the clearance of HCV viremia 24 weeks after treatment end (sustained virological response [SVR]); (2) To evaluate 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 effect of PEGASYS plus ribavirin on the reduction of HCV viremia after 4, 12, 24, and 48 weeks of treatment; (4) To evaluate the safety of high-dose PEGASYS plus ribavirin in patients with CHC and (5) To evaluate the viral kinetics and pharmacokinetic (PK) characteristics of PEGASYS.
Methodology
After screening, patients were randomized to one of 3 groups. During the first 12 weeks of treatment, Group A received 180μg, Group B 270μg, and Group C 360μg subcutaneous PEGASYS, respectively. During the subsequent 36 weeks of treatment, all groups received the standard 180μg dose of PEGASYS. Ribavirin was administered for the entire 48 weeks at a dose of 1000-1200mg/day orally, according to body weight. Treatment was followed by a 24 week treatment-free follow-up period. Patients were stratified according to viral load at screening (≤ or >800,000 IU/mL). HCV-RNA and serum ALT were measured at intervals during the study, and 24 weeks after treatment, and serial blood samples were taken for a pharmacokinetic evaluation.
Number of patients (planned/analyzed)
Total of 75 patients, 25 in each of 3 treatment groups.
Diagnosis and main criteria for inclusion
Men and women ≥18 years old with serologically proven CHC, genotype 1, who had not responded to a previous ≥22-week treatment with PEGASYS/ribavirin combination, and who had discontinued previous treatment ≥24 weeks prior to study enrollment. During screening, HCV-RNA was to be quantifiable (>1000 IU/mL) and ALT level elevated. A liver biopsy was required within 36 calendar months prior to baseline that was consistent with the diagnosis of CHC virus infection without cirrhosis, and patients had to have compensated liver disease (Child-Pugh Grade A). Patients with other forms of liver disease, human immunodeficiency virus (HIV) infection, serologic evidence of HAV or HBV infection or hepatocellular carcinoma were to be excluded.
Test product, dose and mode of administration or test procedure
PEGASYS once weekly sc, 180 µg in 0.5- or 1mL solution, 270 µg in 1- or 2-mL solution, 360 µg in 1.5- or 3-mL solution for 12 weeks. 180μg in 0.5- or 1mL solution for 36 weeks.
Ribavirin 200 mg/tablet, 1000–1200 mg/day/po according to body weight (< or ≥75 kg) in split doses (2–3 tablets bid with morning and evening meals).
Duration of treatment
48 weeks
Reference therapy, dose and mode of administration or reference procedure
Not applicable.
Criteria for evaluation (efficacy, safety)
αPrimary efficacy parameters: (1) On-treatment virologic response rate defined as percentage of patients with non-detectable HCV-RNA, as measured by the Roche AMPLICOR HCV Test, version 2.0 (<50 IU/mL), after 12 weeks of treatment.
Secondary efficacy parameters: (1) SVR rate defined as the percentage of patients with non-detectable HCV-RNA (<50 IU/mL by the Roche AMPLICOR HCV Test, version 2.0) at 24 weeks after completion of the 48-week treatment period; (2) SBR rate defined as the percentage of patients with normal serum ALT levels at 24 weeks after completion of the 48-week treatment period; (3) Percentage of patients with non-detectable HCV-RNA at study Weeks 4, 12, 24, and 48, as measured by the Roche AMPLICOR HCV Test, version 2.0 (<50 IU/mL); (4) Viral kinetic profile; and (5) PEGASYS PK.
Safety parameters: (1) Adverse event (AE) rate and profile; (2) Hemoglobin; and (3) Other laboratory tests.
Viral kinetics and PK: Determination of HCV RNA, and serum levels of PEGASYS
Statistical methods
Sample size calculation: A total of 75 patients were to be enrolled in the trial. With 25 patients per group, the precision (95% 2-sided confidence interval [CI] of the estimate of the on-treatment virologic response rate (Week 12) would be ±18% for a response of approximately 30% and ±20% for a response of 50%. The CI for a difference of approximately 20%, which is deemed clinically relevant in a patient group of previous non-responders, however, would be as broad as [–11% + 47%] (calculated by the program Power And Precision™ using the Cornfield/Gart method with Yates correction).
Analysis plan: The primary analysis of response rate was conducted on the intent-to-treat (ITT) population; patients without measurements at Week 12 of treatment were considered to be non-responders. Exact 95% CI from the binomial distribution was provided for response rate in individual treatment groups. All categorical variables for pairwise treatment comparisons were analyzed using the Cochran-Mantel-Haenszel test stratified by HCV viral load at screening. Odds ratios and corresponding 95% CIs were given for pairwise treatment comparisons. Change from baseline variables was analyzed using analysis of covariance (ANCOVA). Estimates of treatment differences using least squares means and corresponding 95% CIs were given.
Interim analysis: An interim analysis was performed after all patients had completed Visit 8 (Week 12: end of the high-dose therapy period).
Summary (efficacy, safety, other results)
Efficacy (ITT population) – A dose-response relationship for the qualitative viral response was observed at Week 12. The response rate in the high-dose group (360 µg PEGASYS) was 45.5%, compared to 21.4% in the group treated with the standard dose (180 µg PEGASYS), although this difference did not reach statistical significance (P=0.1739).Evolution of viral response rates throughout time were dose proportional and consistent with the initial PEGASYS dose until Week 12.
A dose-response relationship was also observed when the SVR (percentage of patients with non-detectable HCV-RNA at the end of follow-up) was considered. The highest SVR values were found in the group induced with 360 µg of PEGASYS plus ribavirin (37.5%), compared with 17.9% in the 180µg PEGASYS dose group (17.9%). Again, this difference did not reach statistical significance (P=0.2789). When the SVR by baseline viral load was considered, the major advantage was obtained among patients with heavy viral load (>800,000). The SBR rates (percentage of patients with normal serum ALT levels at 24 weeks after completion of the 48-week treatment period) were higher in the group treated with 270 µg than in the group treated with 360 µg; however, these differences did not reach statistical significance.
PEGASYS PK followed linear dose-related proportionality.
Safety – Up to 97.2% of patients had =1 related AE. Despite the considerable number of AEs, only 4 patients (5.6%) withdrew from the study because of an AE. Serious adverse events were recorded in a total of 5 patients during the study; of these only 1 was considered related to study medication and occurred in the low-dose group. The frequency of AEs was evenly distributed among groups. Doubling the dose of PEGASYS was not associated with an increase in the incidence of AEs.
Table 1. Summary of adverse events (AE) recorded during the study.
|
|
Peginterferon alfa-2a (40KD) dose* |
|
|
180 m g/week*
(n=28) |
270 m g/week
(n=20) |
360 m g/week
(n=24) |
|
AE |
27 (96.0%) |
20 (100.0%) |
23 (100%) |
|
Serious AE |
3 (10.7.0%) |
1 (5.0%) |
1 (4.2%) |
|
AE leading to withdrawal |
3 (10.7%)_ |
0% |
1 (4.2%) |
|
Most frequent AE |
|
|
|
|
Asthenia |
46.43% |
60% |
45.83% |
|
Fever |
28.57% |
25% |
41.67% |
|
Headache |
39.29% |
35% |
33.33% |
|
Nausea |
3.57% |
20% |
12.50% |
|
Myalgia |
25% |
30% |
33.33% |
|
Althralgia |
17.86% |
10% |
4.17% |
|
Depression |
25% |
10% |
20.83% |
|
Insomnia |
32.14% |
25% |
16.67% |
|
Irritability |
10.71% |
10% |
16.67% |
|
Anaemia |
17.86% |
30% |
4.17% |
|
Neutropenia |
28.57% |
15% |
12.50% |
|
Flu like symptoms |
21,43% |
20% |
12.50% |
|
Cough |
10.71% |
20% |
12.50% |
|
Chills |
10.71% |
0% |
8.33% |
|
Diarrhea |
7.14% |
10% |
8.33% |
|
Heartburn |
10.71% |
5% |
0% |
|
Hair loss |
10.71% |
0% |
16.67% |
|
Dermatitis |
3.57% |
5% |
12.50% |
|
Pruritus |
10.71% |
10% |
12.50% |
Conclusions
Initiating treatment of PEGASYS/ribavirin–resistant CHC with high-dose PEGASYS in combination with ribavirin increased early rates of virologic response and SVR (qualitative and quantitatively). This effect was more evident in patients with baseline viral loads >800,000 IU, suggesting that the benefits of beginning treatment with higher initial doses of PEGASYS are especially apparent in these “difficult to treat” patients. Importantly, treatment with higher initial doses of PEGASYS did not increase the incidence of side effects, including neutropenia and thrombocytopenia.
Date of report
5/11/2005
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