Trial Information

Combination of Alpha Interferon With Long Term Ribavirin Therapy for Patients With Chronic Hepatitis C

Between 60 and 90 patients with chronic hepatitis C will be enrolled in a study of the
combination of alpha interferon and ribavirin for 12 months with early discontinuation of
therapy and randomization to receive either ribavirin alone or placebo for patients who do
not respond within 6 months of starting therapy. Adult patients will be chosen who have
chronic hepatitis C, HCV RNA in serum, and elevations in serum aminotransferases. Patients
who have received alpha interferon in the past will be eligible if they did not have a
sustained response to their previous course of interferon. After medical evaluation and
liver biopsy, patients will begin receiving alpha interferon by subcutaneous injection in a
dose of 3 million units three times weekly. At the same time, patients will begin receiving
ribavirin orally in a dose of 1000 mg (if body weight is less than 75 kg) or 1200 mg daily
(two or three capsules of 200 mg twice daily). During the initial 24-week period of
combination therapy, patients will be seen in the outpatient clinic for medical interview,
physical examinations and blood tests at 2 to 4 week intervals. At 24 weeks, patients will
be classified as either responders or non-responders based upon HCV RNA testing of serum.
Responders will continue on the combination therapy for another 24 weeks (total treatment =
48 weeks). Non-responders will stop interferon therapy and will be randomized to receive
either ribavirin or identically appearing placebo capsules for 48 weeks (total treatment =
72 weeks). At the 72 week point (18 months after enrollment), all patients will be
readmitted for repeat medical evaluation and liver biopsy. At this point, ribavirin and
placebo will be stopped (unless the patient has had a clear histological and biochemical
response to therapy) and patients will be monitored with outpatient visits at 8 week
intervals for another 6 months.

Patients who exhibit a histological and biochemical response to ribavirin monotherapy will
be offered a one-year extension of treatment with ribavirin in a gradually reduced dosage.
These patients will be monitored at 8 week intervals and the dose will be reduced by 200 mg
per day every 16 weeks to a minimum dose of 600 mg per day. If the biochemical response is
maintained, patients will continue on therapy for one year and then undergo repeat medical
evaluation and liver biopsy. Continued therapy with ribavirin after this point will depend
upon whether safety and efficacy of ribavirin have been demonstrated and whether ribavirin
has been approved for use in hepatitis C.

The primary criterion for success of therapy overall will be sustained loss of HCV RNA as
assessed at 18 months. Primary criteria for response among the patients who are randomized
to receive ribavirin or placebo will be degree of histological improvement on liver biopsy.
Secondary criteria will be normalization of ALT levels. This study will allow for therapy
of all patients with chronic hepatitis C with the combination of alpha interferon and
ribavirin and will allow for therapy of patients with resistant forms of chronic hepatitis C
with ribavirin alone and will address whether monotherapy with ribavirin can sustain these
improvements and whether the biochemical improvements reflect amelioration of the underlying
liver disease as judged histologically.