Thymosin Plus PEG-Interferon in Non-Cirrhotic Hepatitis C Patients 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 without 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 12 weeks.
• Washout period of at least 6 months from previous therapy with IFN alone or IFN plus Ribavirin.
• Liver biopsy consistent with chronic hepatitis C within the last 12 months before treatment starts, and at least 6 months after the end of the prior failed therapy.
• No clinical or histological evidence of cirrhosis (METAVIR fibrosis score 0 to 3).
• Compensated liver disease with prothrombin time prolonged less than 3 seconds over control, serum albumin stable and within normal limits, total bilirubin < 2 mg/dl, and no history of hepatic encephalopathy, esophageal varices or ascites.
• Ultrasound, CT scan, or MRI of the liver within 3 months of entry negative for HCC.
• Hematocrit > 30%, platelet count > 100 x 109/L, WBC > 3 x 109/L, and polymorphonuclear white cell count > 1.5 x 109/L.
• 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.
• Current use of any drug known to be hepatotoxic, any drug (other than the study drugs) known to have or suspected of having therapeutic activity in hepatitis C or of any immunosuppressive drug (including corticosteroids).
• Any other liver disease including hepatitis B, hepatitis delta, alcoholic liver disease, drug-induced liver injury, primary biliary cirrhosis, sclerosing cholangitis, autoimmune hepatitis, hemochromatosis, alpha 1-antitrypsin deficiency, or Wilson's disease.
• Alpha-fetoprotein > 200 ng/mL.
• Current or past diagnosis of cirrhosis.
• Evidence of portal hypertension either by Doppler ultrasonography or gastrointestinal endoscopy.
• Decompensated liver disease based on a history of hepatic encephalopathy, esophageal 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 (eg. TB or AIDS).
• 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.
• 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 IFNa.
• Simultaneous participation in another investigational drug study, or participation in any clinical trial involving investigational drugs with 3 months before study entry.
• Family history of intracerebral hemorrhage.