A Multicentre Phase III Study of Interferon-Beta-1a for the Treatment of Chronic Hepatitis C in Asian Patients

The main objective of this study is to establish interferon-beta-1a as the treatment of choice for chronic hepatitis C with better efficacy & safety profiles in monotherapy or combination therapy.

This will be a multicentre, randomised, double-blind, placebo-controlled study with a placebo cross-over to combination of interferon-beta-1a and ribavirin or no treatment during an open-label extension phase. The duration of the trial will be 48 weeks, with a double-blind period of 12 weeks.

The study will recruit 250 eligible patients of either sex. It will be conducted by approximately 16 Investigators / investigational centres in 3 countries (China, Hong Kong and Singapore).

Inclusion Criteria:

• Age between 18 and 65 years.
• Chronic hepatitis C infection demonstrated by HCV-RNA assay or PCR, and a liver biopsy (within 1 year) showing histological features consistent with chronic hepatitis C. The liver biopsy must be available for central review.
• Elevated serum ALT with levels between 1.5 times and 10 times the upper limit of normal. This must be documented in the patient's history on at least two occasions, at least four weeks apart from each other, within a period of at least six months and at screening visit.
• Adequate bone marrow reserve and organ function:
• White Blood Count ³ 3,000/mm3
• Neutrophils ³ 1,500/mm3
• Platelet count ³ 100,000/mm3
• Haemoglobin ³ 12 g/dL (woman) and 13 g/dL (man)
• Creatinine £ upper limit of normal
• Bilirubin £ 27.4 mmol/L (except if known to have Gilbert's syndrome or if direct bilirubin level is ≤ 5 mmol/L))
• Alkaline Phosphatase £ 2 x upper limit of normal
• Prothrombin time £ 3 seconds (time prolonged) above control
• Albumin ³ 35 g/L
• Alpha foetoprotein < 100 ng/mL
• ANA titers of < 1:160
• If the patient is female, she must not be pregnant nor breast-feeding. If the patient has childbearing potential, she must agree to practice contraception with an oral contraceptive, intrauterine device, hormonal implant, diaphragm/spermicide or condom/spermicide, or to remain sexually inactive for the duration of the study. Lack of childbearing potential may be established by post-menopausal status or surgical or medical sterility.
• Willing and able to comply with the protocol for the duration of the study.
• Willing and able to give written informed consent, prior to any study-related procedure not part of the patient's normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.

Exclusion Criteria:

• Clinical evidence of liver cirrhosis or a diagnosis of definite cirrhosis on liver biopsy using the modified Knodell Histological Activity Index and whose Child-Pugh score is 7 and above.
• History of hepatic failure including variceal bleeding, ascites, hepatic encephalopathy or hepatorenal syndrome.
• Positive test at screening for HBsAg, IgM anti-HBc and anti-HIV.
• History of immunologically mediated disease (e.g. inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune haemolytic anaemia, scleroderma, severe psoriasis, rheumatoid arthritis requiring more than intermittent nonsteroidal anti-inflammatory medications for management etc).
• History or other evidence of severe retinopathy.
• Chronic renal impairment.
• Any cause for the liver disease based on patient history or biopsy other than chronic hepatitis C, including the following: primary biliary cirrhosis, alpha1-antitrypsin deficiency, hemochromatosis, sclerosing cholangitis, Wilson's disease, alcohol induced liver disease, drug or toxin induced liver dysfunction, autoimmune liver disease.
• Any evidence of liver cancer.
• Undergone previous systemic treatment for hepatitis C with an interferon (interferon-alpha, -beta or -gamma) or ribavirin.
• Known and ongoing alcohol or drug abuse. Alcohol consumption during the study should not exceed 10 g per day.
• History of cancer (except carcinoma in situ of the cervix or adequately treated basal or squameous cell carcinoma of the skin)
• Presence of systemic disease that might interfere with patient safety, compliance or evaluation of the condition under study. Specifically:
• Inadequate control of diabetes mellitus as indicated by an HbA1c > 8.0%.

• Any significant cardiac disease includes the following:

  1. New York Heart Classification III or IV.
  2. Ventricular dysrhythmias that require therapy with anti-arrhythmic drugs such as procainamide, quinidine or disopyramide (digitalis preparations are permitted).
  3. Angina pectoris that requires medication.
  4. Any other significant cardiovascular dysfunction within six months of the screening evaluation for this study (e.g. congestive heart failure, myocardial infarction, severe hypertension or significant arrhythmia).
• Psychiatric disorder that is unstable or which precludes safe participation in the protocol. Specifically, patients with a history of suicidal tendencies or severe depression.
• Epilepsy with a history of seizures not adequately controlled by treatment.
• Known allergies to acetaminophen (paracetamol), human serum albumin, or mannitol.
• Bearing organ transplants (except cornea).
• Need for emergency surgery (e.g, uncontrollable haemorrhage), or are scheduled for elective surgery (during the study period).
• Recovering from other serious infections (e.g., pneumonia) or major surgery (unless a four-week period has passed).
• Received glucocorticosteroids or other immunosuppressive drugs (unless a two-week wash-out period is observed).
• Any medical risks, which would compromise the ability to give informed consent or which render it unlikely that the patient may complete the study.

Participated in any other investigational study or received an experimental therapeutic procedure considered to interfere with the study (unless a three-month period has passed).