Clinical Trial Result Information
Protocol number
M78019
Title of Study
A multicentre, randomized, safety and efficacy clinical trial to evaluate the effects of the duration of treatment with peginterferon alfa-2a and ribavirin in naïve patients with chronic infection by hepatitis C virus and without an early virologic response
Sponsor
Roche Farma S.A.
Company division
Pharmaceutical
Product name
PEGASYS
Generic name
peginterferon alfa-2a (40KD)
Therapeutic area
Hepatitis C, Chronic
Clinical study summary
This was a multicenter, randomized, parallel group study of peginterferon alfa-2a (40KD) (PEGASYS administered by subcutaneous (sc) injection once weekly and oral ribavirin administered in split daily doses in patients with chronic hepatitis C (CHC) virus infection and without an early virologic response. The efficacy and safety of different treatment durations in early responders and non-responders was investigated.
Study center(s)
28 centers in Spain.
Phase of development
IV
Objectives
Primary: To compare the sustained virologic response (SVR) rate after 72 weeks of treatment versus 48 weeks of treatment in patients with no early virologic response (EVR). Secondary: 1) To compare the sustained biochemical response (SBR) rate after 72 weeks of treatment versus 48 weeks of treatment in patients with no EVR to treatment. 2) To compare the SVR and SBR rates caused by modifying the treatment duration (24, 48 and 72 weeks) according to the EVR, genotype, and initial viral load. 3) To compare overall SVR, end of treatment virologic response, and end of treatment biochemical response by treatment duration. 4) To compare the incidence of adverse events and laboratory abnormalities by treatment group. 5) To evaluate the safety of PEGASYS and ribavirin in patients treated for 72 weeks.
Methodology
All patients were treated with combined therapy PEGASYS 180 µg administered sc once weekly, and ribavirin 800 mg administered in split daily doses for 4 weeks. Patients then had to undergo a determination of HCV-RNA by polymerase chain reaction (PCR) testing. Patients not having a virologic response at Week 4 were randomized (1:1) to 1 of the following groups: Group A, PEGASYS 180 µg/wk + ribavirin 800 mg/day for an additional 44 weeks of treatment and 24 weeks of follow-up; or Group B, same treatment for an additional 68 weeks of treatment and 24 weeks of follow-up. Patients showing virologic response at Week 4 were assigned to 1 of the following groups: Group C, PEGASYS 180 µg/wk + ribavirin 800 mg/day for an additional 20 weeks (patients with no 1 and no 4 genotype, or with genotype 1 or 4 with viral load <800,000 IU/mL); or Group D, same treatment for another additional 44 weeks (patients with genotype 1 and 4 with viral load >800,000 IU/mL).
Number of patients (planned/analyzed)
510 enrolled.
Diagnosis and main criteria for inclusion
Men and women ≥18 years of age with serologic evidence of CHC, and no previous treatment with an interferon or ribavirin. Patients had to have quantifiable HCV-RNA, have maintained abnormal alanine aminotransferase (ALT) levels, and have a hepatic biopsy performed within 24 calendar months prior to baseline with results consistent with CHC virus infection. Patients with other forms of liver disease, human immunodeficiency virus (HIV) infection or hepatocellular carcinoma were excluded.
Test product, dose and mode of administration or test procedure
PEGASYS 180 µg/mL sc once weekly.
Ribavirin 800 mg/day/po in split doses (four 200mg tablets).
Duration of treatment
≤72 weeks.
Reference therapy, dose and mode of administration or reference procedure
Not applicable
Criteria for evaluation (efficacy, safety)
Primary efficacy parameter: (1) Proportion of patients showing virologic response at the end of the active treatment period and at the end of the 24-week follow-up period among those not showing rapid virologic response (positive HCV-RNA result determined by qualitative PCR testing: >50 IU/mL) at Week 4.
Secondary efficacy parameters: (1) Proportion of patients showing biochemical response at the end of treatment and at the end of a 24-week follow-up period among those not showing virologic response (positive HCV-RNA result determined by qualitative PCR testing: >50 IU/mL) at Week 4; (2) Proportions of patients showing virologic and biochemical responses at the end of treatment and at the end of a 24-week follow-up period based on treatment duration, genotype, and viral load among those showing virologic response at (negative HCV-RNA result determined by qualitative PCR testing: <50 IU/mL) Week 4.
Safety parameters: (1) Clinical adverse events; (2) Vital signs; (3) Serum biochemistry, hematology and urinalysis.
Statistical methods
All baseline variables were analyzed in descriptive fashion stratified by treatment group.
The following null and alternative hypotheses were tested by the Mentel-Haenszel test: H0*: odds ratio (probability of achieving a response with the PEGASYS 180 µg/wk plus ribavirin 800 mg/day for 48 weeks in patients not showing virologic response at Week 4) vs (probability of achieving a response with the PEGASYS 180 µg/wk plus ribavirin 800 mg/day for 72 weeks in patients not showing virologic response at Week 4) = 1. HA*: odds ratio (probability of achieving a response with the PEGASYS 180 µg/wk plus ribavirin 800 mg/day for 48 weeks in patients not showing virologic response at Week 4) vs (probability of achieving a response with the PEGASYS plus ribavirin for 72 weeks in patients not showing virologic response at Week 4) ≠ 1.
Identical analysis was employed for the secondary variables.
Summary (efficacy, safety, other results)
Efficacy (ITT population) – After 4 weeks of treatment, 326 of 510 (64%) patients had a positive qualitative PCR test and were randomized to treatment for an additional 44 (Group A; n=165) or 68 weeks (Group B; n=161). The remaining 184 patients with a rapid virologic response (negative values on PCR testing by Week 4) were entered into Group C (n=148) or Group D (n=36), according to the study protocol. Sustained virologic response (SVR) rates at the end of follow-up were significantly higher in patients with a positive qualitative PCR result at Week 4 who were treated for the longer duration with combination therapy (45% vs 32%, P=0.0144) . In those treated for a total of 48 weeks, the virologic response rate declined from 61% at completion of treatment to 32% at the end of follow-up. In contrast, the virologic response rate declined from 52% at completion of treatment to 45% at the end of follow-up in patients who received a total of 72 weeks of treatment. Extended treatment was particularly beneficial in patients infected with HCV genotype 1. SVR rates of 28% and 44% were obtained in these patients after treatment for a total of 48 and 72 weeks, respectively. SVR rates were also consistently higher in patients treated for 72 weeks when data are grouped by baseline HCV-RNA level. In patients with an HCV-RNA-negative result at Week 4, SVR was obtained in 79% of patients treated for a total of 24 weeks (Group C) and 64% treated for a total of 48 weeks (Group D). The higher response rate in Group C reflects the inclusion of patients with genotypes 2 or 3 and low HCV-RNA levels. In patients with an HCV-RNA-positive result at Week 4, there was a significant difference in the maintenance of virologic response rates during follow-up.
Tolerability – The type and incidence of AEs were generally similar in Groups A and B (Table 1). In particular, the incidence of neutropenia and thrombocytopenia was similar in the 2 groups.
Table 1. Adverse Events During Treatment in Patients With an HCV-RNA–Positive Result at Week 4 (Events Reported by =10% of Patients Are Included)
|
Adverse event |
Pegasys 180 µg/wk + Ribavirin 800 mg/day
|
|
Group A, 48 weeks
n=165 |
Group B, 72 weeks
n=161 |
|
Asthenia |
60 |
59 |
|
Headache |
30 |
33 |
|
Fever |
27 |
28 |
|
Flu-like symptoms |
24 |
17 |
|
Neutropenia |
24 |
25 |
|
Anorexia |
21 |
14 |
|
Pruritus |
21 |
25 |
|
Anemia |
18 |
21 |
|
Insomnia |
18 |
25 |
|
Irritability |
17 |
22 |
|
Myalgia |
14 |
14 |
|
Alopecia |
13 |
17 |
|
Thrombocytopenia |
13 |
9 |
|
Depression |
12 |
19 |
|
Coughing |
8 |
10 |
|
Injection site reaction |
7 |
12 |
|
Anxiety |
5 |
12 |
The proportion of patients who withdrew for adverse events or laboratory abnormalities was similar between the 2 groups (Table 2).
Table 2. Treatment Discontinuation (%) in Patients With an HCV-RNA–Positive Result at Week 4
|
Reason |
PEGASYS 180 µg/wk + Ribavirin 800 mg/day
|
|
Group A, 48 weeks
n=165 |
Group B, 72 weeks
n=161 |
|
Adverse events |
10.3 |
13.0 |
|
Laboratory abnormalities |
0 |
1.2 |
|
Voluntary withdrawal |
4.2 |
17.3 |
|
Other |
2.4 |
4.3 |
Withdrawal rates were similar between groups until Week 24 of treatment, but a higher proportion of patients in Group B decided to withdraw voluntarily from the study after having an HCV-RNA–positive result at Week 24.
Conclusions
Extending the treatment duration with PEGASYS plus ribavirin from 48 to 72 weeks in patients who did not achieve a negative HCV-RNA result at Week 4 significantly reduced the relapse rate and increased the SVR rate. This effect was evident in patients with genotype 1 infection. Thus, the benefits of extended treatment were especially apparent in these “difficult to treat” patients. Examination of end-of-treatment and end-of-follow-up virologic response rates revealed that extended treatment considerably reduced the relapse rate after the end of treatment. Viral load was reduced to a greater degree in the group treated for 72 weeks than in the group treated for 48 weeks.. The relapse rate was significantly lower in the group treated for 72 weeks than in the group treated for 48 weeks. The proportion of patients showing biochemical responses was also higher in the group treated for 72 weeks than in the group treated for 48 weeks. Importantly, extended treatment did not increase the incidence of side effects, including neutropenia and thrombocytopenia. It must be noted that the 800-mg/day dose of ribavirin used in the trial is optimal in patients with HCV genotypes 2 or 3 but not in those with genotype 1 who require a standard weight-based dosage of 1000 or 1200 mg/day; this information was not available when the trial was initiated.
Date of report
3/1/2004
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