Combination Drug Therapy for Patients With Hepatitis C
Combination Drug Therapy for Patients With Hepatitis C
Hepatitis C is a major cause of liver disease in the United States and leads to cirrhosis of
 the liver in approximately one-third of patients some of whom will ultimately suffer from
 liver failure or liver cancer. At present, the recommended therapy of hepatitis C is the
 combination of alpha interferon and ribavirin given for 6 to 12 months. Ribavirin is a
 antiviral drug that is given by mouth. Interferon is both an antiviral and an immune
 medication which must be given by injections (three times a week) and has many difficult side
 effects. The purpose of this study is to determine whether the combination of ribavirin and
 interferon improve the liver disease of hepatitis C and whether improvements can be
 maintained by continuing ribavirin therapy long-term. This study will take 100 to 120
 patients suffering from hepatitis C and place them under combination drug therapy with alpha
 interferon and ribavirin. The course of drug therapy is scheduled to last 6 to 12 months.
 Patients will be selected after appropriate screening for hepatitis C virus and elevated
 liver enzymes are conducted and liver biopsy shows chronic hepatitis with some degree of
 injury and scarring.

 During the first 6 months of the study, subjects will be asked to return to the outpatient
 clinic for routine check-ups and blood tests every 2 to 4 weeks. Blood tests will include
 tests for hepatitis C virus. If the virus test becomes negative on treatment, the therapy
 will be considered successful and will be continued for a full 6 or 12 months (depending upon
 the strain of virus).

 If the virus test does not become negative during the first six months of treatment, subjects
 will be considered "non-responders" and will stop taking interferon but will continue on
 ribavirin alone or an identically appearing placebo tablet. These non-responsive subjects
 will continue this therapy for an additional 12 months. (A year-and-a-half total).

 Upon completion of the drug therapies, subjects will be requested to submit blood samples and
 undergo a liver biopsy to determine if the therapy was successful. Test results that reveal a
 loss of hepatitis C antibodies or normal levels of liver enzymes will be deemed successful.

 Patients that have successful laboratory test results will be considered for continuation of
 ribavirin therapy. Patients that received placebo for a year will be eligible to receive
 ribavirin long-term at the end of the study.
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.
INCLUSION CRITERIA:

 Age above 18 years, male or female.

 Serum alanine or asparate aminotransferase activities that are above the upper limit of
 normal (ALT greater than 41 or AST greater than 31 U/L) on an average of three
 determinations taken during the previous 6 months. The mean of the three determinations
 will be defined as "baseline" levels.

 Presence of anti-HCV and HCV RNA in serum tested at least once during the previous six
 months.

 Evidence of chronic hepatitis on liver biopsy done within the previous 12 months with a
 histology activity index of at least 6 (out of a maximum of 22).

 Written informed consent.

 EXCLUSION CRITERIA:

 If previously treated with interferon or ribavirin, must not have a lack of sustained
 virological response as shown by the presence of HCV RNA in serum six months after stopping
 therapy. Patients must not have received the combination of alpha interferon and ribavirin
 in the past.

 Decompensated liver disease, as marked by bilirubin greater than 4 mg%, albumin less than
 3.0 gm%, prothrombin time greater than 2 sec prolonged, or history of bleeding esophageal
 varices, ascites or hepatic encephalopathy. Patients with ALT levels greater than 1000 U/L
 (greater than 25 times ULN) will not be enrolled but may be followed until three
 determinations are below this level.

 Pregnancy or, in women of child-bearing potential or spouses of such women, inability to
 practice adequate contraception, defined as vasectomy in men, tubal ligation in women, or
 use of condoms and spermacide, or birth control pills, or an intrauterine device.

 Significant systemic or major illnesses other than liver disease, including congestive
 heart failure, renal failure (creatinine clearance less than 50 ml/min), organ
 transplantation, serious psychiatric disease or depression, and angina pectoris.

 Pre-existing anemia (hematocrit less than 36% for men and less than 34% for women) or known
 history of hemolytic anemia.

 Antiviral or immunosuppressive therapy within the last 6 months.

 Evidence of another form of liver disease in addition to viral hepatitis (e.g., autoimmune
 liver disease, Wilson's disease, alcoholic liver disease, hemochromatosis,
 alpha-1-antitrypsin deficiency).

 Any evidence of coronary artery disease or cerebral vascular disease, including
 abnormalities on exercise stress testing in patients with defined risk factors who will be
 screened for evidence of underlying coronary artery disease.

 Active substance abuse, such as alcohol, inhaled or injection drugs within the previous one
 year.

 Evidence of hepatocellular carcinoma; either alphafetoprotein (AFP) levels greater than 50
 ng/ml (normal is less than 9 ng/ml) and /or ultrasound (or other imaging study)
 demonstrating a mass suggestive of liver cancer.

 Clinical gout.