Thymosin Plus PEG-Interferon in Hepatitis C Patients With Cirrhosis Who Did Not Respond to Interferon or Interferon Plus Ribavirin

Chronic hepatitis C infection is one of the leading causes of chronic liver disease in the United States. Approximately one-third of patients with hepatitis C infection develop cirrhosis of the liver, which can lead to liver failure or liver cancer. The current treatment for hepatitis C infection in previously untreated patients is successful in only about half of patients. There is no established therapy for non-responders.

This is a randomized, double-blinded, multicenter trial to determine the effectiveness of thymosin alpha 1 (thymalfasin) 1.6 mg twice weekly plus PEGinterferon alfa-2a 180 ug/wk compared to placebo plus PEGinterferon alfa-2a in adults with chronic hepatitis C with early cirrhosis or progression to cirrhosis who are non-responders to previous treatment with interferon or interferon plus ribavirin. The definition of non-response requires a positive HCV RNA test at the end of a course of at least 12 weeks of therapy. Patients will receive treatment for 12 months, and will be followed-up for a further 6 months after the end of therapy

Inclusion criteria:

• Signed written informed consent.
• Age over 18 years old.
• Presence of HCV RNA measured by qualitative PCR.
• Nonresponder to a previous course of therapy with either IFN alone or IFN plus ribavirin. The patient must have been treated for at least 3 months (12 weeks).
• Washout period of at least 6 months from previous therapy with IFN alone or IFN plus Ribavirin.
• Liver biopsy consistent with cirrhosis or progression to cirrhosis (METAVIR fibrosis score 3 to 4) due to chronic hepatitis C within the last 12 months before treatment starts, and at least 6 months after the end of the prior failed therapy.
• Cirrhosis classified as Child-Pugh "A" (no more than 6 points).
• Compensated liver disease with prothrombin time prolonged less than 3 seconds over control, total bilirubin < 2 mg/dl, and no history of hepatic encephalopathy, bleeding varices or a history of detection of stigmata of recent bleeding on existing varices or ascites.
• Ultrasound, CT scan, or MRI of the liver within 3 months of entry negative for HCC.
• Hematocrit > 30%, platelet count > 75,000, WBC > 2,500, and absolute neutrophil cell count > 1,500.
• Adequate renal function as demonstrated by serum creatinine level < 2.0 mg/dl.
• Normal TSH or adequately controlled thyroid function.
• If the patient is a woman, she is using a definitive method of birth control in consultation with her physician, or is surgically sterile, or post-menopausal.

Exclusion criteria:

• Use of systemic corticosteroids within 6 months of entry.
• Evidence of drug-induced liver injury.
• Current use of any drug known to have or suspected of having therapeutic activity in hepatitis C, or any immunosuppressive drug (including corticosteroids).
• Evidence of any other liver disease including hepatitis B, hepatitis delta, alcoholic liver disease, primary biliary cirrhosis, sclerosing cholangitis, autoimmune hepatitis, hemochromatosis, alpha 1-antitrypsin deficiency, or Wilson's disease.
• Alpha-fetoprotein > 200 ng/mL.
• Child-Pugh "B" or "C" cirrhosis (score of 7 or more points), either currently or at any occasion in the past.
• Decompensated liver disease based on a history of hepatic encephalopathy, bleeding varices or a history of detection of stigmata of recent bleeding on existing varices, or ascites.
• HIV infection diagnosed by HIV seropositivity and confirmed by Western blot.
• Concomitant or prior history of malignancy other than curatively treated skin cancer or surgically cured in situ carcinoma of the cervix.
• Active infectious process other than HCV that is not of a self-limited nature.
• Rheumatoid arthritis or other autoimmune disease (serum ANA > 1:160.).
• Pregnancy as documented by a urine pregnancy test.
• Alcohol or intravenous drug abuse within the previous 1 year.
• Chronic use of methadone.
• Patients who are poor medical risk or who have any non-malignant systemic disease that, in the opinion of the investigator, would make it unlikely that the patient could complete the protocol.
• Patients with a history of severe depression that required either hospitalization or electroshock therapy; or depression associated with suicide attempt.
• Patients with significant pre-existing cardiac or pulmonary disease.
• Recipients of transplants.
• Patients with uncontrolled seizure disorder.
• Any indication that the patient would not comply with the conditions of the study protocol.
• Previous treatment with thymosin alpha 1.
• Patients with known hypersensitivity to IFN a.
• Simultaneous participation in another investigational drug study, or participation in any clinical trial involving investigational drugs within 3 months of study entry.
• Family history of intracerebral hemorrhage.