Clinical Trial Result Information
Title of Study:
A Phase IV, Multicenter and Randomized Study Evaluating the Efficacy and Safety of PEG-Interferon α-2a plus Ribavirin and Amantadine or plus Ribavirin in the Treatment of Patients with Chronic Hepatitis C Previously Non Responders and Relapsers to IFNα plus Ribavirin.
Fast Facts:
| Protocol number: | ML16869 |
| Sponsor: | Produtos Roche Químicos e Farmacêuticos S A, Brazil |
| 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: | 10/1/2007 |
Clinical study summary:
This was a multicenter, randomized study evaluating PEGASYS 180μg sc weekly plus ribavirin 1000/1200mg po qd and amantadine 200mg po qd (groups A and C) versus PEGASYS 180μg sc weekly plus ribavirin 1000/1200mg po qd (groups B and D) in patients with chronic hepatitis C. Non-responders were randomized to groups A and B, and relapsers to groups C and D. After 48 weeks treatment, there was a 24 week treatment free follow-up period.
Study center(s) :
13 centers in Brazil.
Objectives:
To compare the efficacy and the safety/tolerability of PEGASYS 180μg sc weekly plus ribavirin and amantadine versus PEGASYS 180μg weekly plus ribavirin over a 48 week treatment period followed by a 24 week untreated follow-up period in the following patients:
1) Non responders, defined as patients with chronic hepatitis C without virological response at the end of at least 24 weeks treatment with conventional interferon (IFN α-2a or IFN α-2b) and ribavirin;
2) Relapsers, defined as patients with chronic hepatitis C with virological response at the end of at least 24 weeks treatment with conventional interferon (IFN α-2a or IFN α-2b) and ribavirin, but who had a virological positive test (HCV RNA) at the end of the 24 week follow-up period.
Methodology:
Eligible patients (non-responders and relapsers after previous treatment with IFN-α + ribavirin) were randomized to treatment in 1:1 proportion, to receive:
Group A (non responders): PEGASYS, ribavirin and amantadine;
Group B (non responders): PEGASYS and ribavirin;
Group C (relapsers): PEGASYS, ribavirin and amantadine;
Group D (relapsers): PEGASYS and ribavirin.
After 48 weeks treatment there was a 24 week treatment-free period.
Number of patients (planned/analyzed):
Planned:180. Enrolled: 186.
Diagnosis and main criteria for inclusion:
Men and women ≥18 years previously treated with conventional interferon and ribavirin for at least 24 weeks with an end-of-treatment virological test (HCV RNA) positive (non-responders) or with virological test (HCV RNA) negative at the end of treatment, but with virological test (HCV RNA) positive at the end of 24 weeks treatment free follow-up period (relapsers).
Test product, dose and mode of administration or test procedure:
Groups A and C (PEGASYS, ribavirin and amantadine).
PEGASYS (peginterferon alfa-2a (40KD)): 180μg sc once weekly.
Copegus (ribavirin): 1000-1200mg po daily according to body weight (1000mg to patients ≤75kg and 1200mg to patients >75kg) in split doses (morning/evening).
Mantidan (amantadine): 200mg po daily in split doses (morning/evening).
Duration of treatment:
48 weeks
Reference therapy, dose and mode of administration or reference procedure:
Groups B and D (PEGASYS and ribavirin).
PEGASYS (peginterferon alfa-2a (40KD)): 180μg sc once weekly.
Copegus (ribavirin): 1000-1200mg po daily according to body weight (1000mg to patients ≤75kg and 1200mg to patients >75kg) in split doses (morning/evening).
Criteria for evaluation (efficacy, safety):
Primary: Sustained virological response rate defined as percentage of patients with non-detectable HCV-RNA as measured by Roche AMPLICOR HCV Test, v2.0 (<50 IU/mL) at 24 weeks post completion of the 48 week treatment period.
Sustained biochemical response rate defined as percentage of patients with normal serum ALT levels at 24 weeks after completion of the 48 week treatment period.
Early virological response defined as patients with negative HCV RNA at week 12 of treatment or decrease of at least 2 log10 in viral load at week 12 relative to baseline viral load.
Safety: Clinical adverse experiences, laboratory tests, vital signs, ECG.
Statistical methods:
It was calculated that 120 patients, randomized in 1:1:1:1 proportion, would be sufficient to detect a significant difference when the sustained virological response was at least 20%. To take into account protocol violations and dropouts, which might occur in about 15% of the recruited patients, the numbers of patients were increased to:
Group A: 50 patients; Group B: 50 patients; Group C: 40 patients and group D: 40 patients.
The primary analysis plan had an intent-to-treat approach. Response rate was calculated as the number of patients with a sustained virological response divided by the number of patients who received at least one dose of study medication. Patients without measurements at the end of the 24-week untreated follow-up period were considered as non-responders. An exact confidence interval of 95% from the binomial distribution was provided for response rate in individual treatment groups.
Summary (efficacy, safety, other results):
Efficacy: The observed rates of sustained virological responses (SVRs) were: 23% for group A (95% CI 12.3; 36.2), 31% for group B (95% CI 18.7; 45.1), 56% for group C (95% CI 39.6; 72.2) and 61% for group D (95% CI 43.4; 76.0). The addition of amantadine did not increase the chances of achieving a SVR in the non-responders (A vs B, p value = 0.3306), or in the relapsers (C vs D, p value = 0.8525). Overall, non-responder patients showed a combined SVR of 27% (groups A and B) and relapser patients showed a combined SVR of 58% (groups C and D). The 27% SVR observed among non-responder patients was much higher than the investigators' null hypothesis of 5% maximum response. The SVR of 58% in the conventional IFN and ribavirin relapsers was comparable to the SVR seen in naive patients.
There was no statistically significant difference between groups A and B, and C and D, regarding early virological response rate, end of treatment virological response rate, and sustained biochemical response rate.
Safety: Adverse events occurred in a similar distribution among all groups. Fatigue and headache followed by flu-like syndrome were the most common adverse events and most of them were of mild intensity and resolved after treatment end. There were 14 serious adverse events and, among them, 10 were considered related to the study medications. However, none was considered new in the PEGASYS plus ribavirin tolerability profile. One cirrhotic patient from group A presented with a left ventricular dysfunction resulting in death. This serious adverse event was considered by the investigator to be related to PEGASYS, based on published reports of cardiac dysfunction associated with conventional interferon therapy. Leukopenia was the most frequent laboratory abnormality, with grade 4 leukopenia seen in 3% of patients. There was no association between this laboratory abnormality and clinical relevant outcomes.
Conclusions:
This study did not demonstrate benefit from adding amantadine to the combination of PEGASYS and ribavirin in hepatitis C patients, previously non responders and relapsers to conventional interferon and ribavirin treatment. However, the overall sustained virological response of 27% in the non responders group and 58% in the relapsers group is compelling evidence in favour of retreating this group of patients.
Publications (references, if available):
Cheinquer H et al. EASL 2006
Click here for the protocol registry listing of this trial.
