Clinical Trial Result Information

Protocol number
M23156

Title of Study
An open-label, multi-center, randomized, comparative clinical trial to evaluate the efficacy and safety of interferon alpha-2a (Roferon A injection) vs combination of oral amantadine (Viregyt K capsules) and interferon alpha-2a (Roferon A injection) in interferon- and amantadine-naïve patients with chronic hepatitis C.

Sponsor
Roche Hungary Ltd.

Company division
Pharmaceutical

Product name
Roferon-A

Generic name
interferon alfa-2a

Therapeutic area
Hepatitis C, Chronic

Clinical study summary
This was an open-label, multi-center, randomized, comparative clinical trial to evaluate the efficacy and safety of Roferon A injection vs a combination of Viregyt K capsules (oral amantadine) and Roferon A injection in interferon (IFN)- and amantadine-naïve patients with chronic hepatitis C (CHC). Twelve months of treatment was followed by 6 months of treatment-free follow-up.

Study center(s)
10 centers in Hungary.

Phase of development
III

Objectives
Primary: To assess the efficacy of Roferon A monotherapy vs the combination of amantadine and Roferon A based on the proportion of responding patients, taking into consideration normalization of alanine aminotransferase (ALT) and a negative HCV-RNA polymerase chain reaction (PCR) result together, at the end of the study (at Month 18). Secondary: To assess the safety of Roferon A monotherapy vs combination therapy with amantadine and Roferon A based on the occurrence of adverse events and laboratory findings.

Methodology
After screening, patients were randomized into 2 groups to receive either monotherapy with Roferon A or combination treatment with Roferon A and amantadine. Group A received Roferon A 3x6 MIU/week for 3 months, then Roferon A 3x3 MIU/week for a further 9 months by subcutaneous (sc) or intramuscular (im) injection. Group B received Roferon A 3x6 MIU/week plus 2x100mg/day amantadine for 3 months, then Roferon A 3x3 MIU/week plus amantadine 2x100mg/day for a further 9 months.

Number of patients (planned/analyzed)
160 planned; 77 randomized .

Diagnosis and main criteria for inclusion
Male and female patients 18–65 years of age, IFN- and amantadine-naïve CHC present for ≥6 months, demonstrated by liver biopsy and with or without Class A cirrhosis (Child-Pugh classification). Patients with a positive result on anti-HCV testing (IIIrd generation) and on HCV-RNA PCR. ALT ≥ the upper limit of normal (≥2 times during a 6-month period in the history, and within one week before the start of therapy).

Test product, dose and mode of administration or test procedure
Roferon A 3 or 6 MIU, 1-mL injectable solution sc or im + amantadine chloride 100mg po.

Duration of treatment
12 months.

Reference therapy, dose and mode of administration or reference procedure
Roferon A 3 or 6 MIU, 1 mL Injectable solution sc or im.

Criteria for evaluation (efficacy, safety)
Primary efficacy parameter: Biochemical response. Normalization of ALT by the end of Month 12 (biochemical response) and still normal 6 months after terminating treatment (sustained biochemical response). Secondary efficacy parameters: (1) Viral response: Negative for HCV-RNA on qualitative PCR at the end of Month 12 of treatment (viral response) and negative PCR at 6 months after treatment (sustained viral response). (2) Histologic response: In responder patients (biochemical and/or viral response) liver biopsy was performed at Month 6 after terminating treatment, when possible, to evaluate histologic response. Improvement: minimum 1 grade reduction of histologic activity on the histology activity index.

Statistical methods
For efficacy evaluations, the response rates in the 2 treatment arms were compared using the chi-squared test. To evaluate a possible gender effect, the Cochran-Mantel-Haenszel test was applied for response frequencies. Safety parameters were evaluated using a similar approach.

Summary (efficacy, safety, other results)
Results of an interim analysis showed a lack of the expected additive effect, and this observation was confirmed by scientific papers published after the launch of the study. Furthermore, ribavirin had become commercially available. Therefore, the collaborating investigators and the sponsor jointly declined Roferon A monotherapy as unethical and agreed to discontinue the trial prematurely, ie, before enrollment of the contemplated number of patients (n=160) ended. On discontinuation of the study, the study population comprised 77 patients, 66 of whom completed 48 weeks of treatment and 24 weeks of follow-up. This proportion of the study population thus was considered eligible for appraisal. No additive effect could be ascertained. Efficacy outcomes are listed in Table 1. Adverse events are listed in Table 2.

Table 1

Table 2

These data reflect a lower incidence of moderately severe or severe (Grade 2 and 3) flu-like reactions, headache, and nausea in Group B. No depressive episodes occurred, the number of adverse events related to global metabolism was lower, and the number of allergic reactions (Grade 1) was lower in this treatment group. Complete lack of any adverse event was observed in 27% of patients undergoing combination treatment vs in only 6% of patients receiving monotherapy.

Eleven patients were withdrawn from the study for the following reasons: lack of compliance (n=4), patient’s decision (n=1), and occurrence of a treatment-related adverse event (3 patients in each group).

Conclusions
In patients with CHC, amantadine added to Roferon A failed to enhance clinical or virologic efficacy compared with Roferon A monotherapy. Add-on amantadine augmented the tolerability of Roferon A and mitigated its flu-like and depressive adverse effects. Health-related quality of life improved during combination treatment. Amantadine was almost devoid of any adverse effects when administered in doses tested during this trial.

Publications (references, if available)
Roferon vs Roferon and Amantadine: Results of the M23156 study, Annual Meeting of the Hungarian Gastroenterology Society. Balatonaliga, 2003

Date of report
3/31/2003