Pegylated Alfa-2b Interferon Therapy of Patients With Hepatitis C-related Cirrhosis and High Liver Cell Proliferation (P02733/MK-4031-085)

Study Overview
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Brief Summary
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This study aims to compare the role of peginterferon α-2b (50 μg/week) vs. control (no treatment) in the prevention of hepatocellular carcinoma, in adult patients with cirrhosis and initial signs of portal hypertension who did not respond to previous combined therapy with interferon alfa + ribavirin or peginterferon alfa + ribavirin or to interferon alfa monotherapy and with a high proliferation rate before entering the study. The duration of treatment will be 3 years, and the follow-up period will be 2 years.

Official Title
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Long-term Pegylated Alfa-2b Interferon Therapy of Patients With Hepatitis C-related Cirrhosis and High Liver Cell Proliferation: a Multicenter Study of Hepatocellular Carcinoma Prevention in Patients Non-responders to Combined Therapy With Alpha Interferon + Ribavirin or Peginterferon Alpha + Ribavirin or to Interferon Monotherapy

Conditions
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Carcinoma, Hepatocellular

Intervention / Treatment
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* Biological: Peginterferon alfa-2b
* Other: Observation (no treatment)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cirrhotic participants, both sexes, Child Pugh A, B, HCV-RNA positive, age < 70 years Participants non-responders to IFN + Ribavirin or PegIFN + Ribavirin or IFN monotherapy Pre-therapy liver biopsy (< 36 months) with PCNA-LI > 2.0 Fibrosis score 5-6 (Ishak) Initial portal hypertension, such as gastroesophageal varices or one of the following US sign: Collateral circles Spleen longitudinal diameter > 12 cm Portal vein diameter at hilus > 12 mm Portal flow > 12 cm/sec Participants must have the following minimum hematologic and biochemical criteria: Hemoglobin >= 11 g/dL Granulocyte count > 1,000/mm^3 Platelets > 70,000/mm^3 Prothrombin activity > 50% Total bilirubin <3 mg/dL Albumin >= 3.5 g/dL Serum creatinine within normal limits Uric Acid within normal limits Thyroid Stimulating Hormone (TSH), within normal limits Antinuclear antibodies (ANA) < 1:160 Written informed consent Women of childbearing potential must have a negative pregnancy test Acceptance of patients of both sexes of proper contraceptive measures for the study period Exclusion Criteria: Pregnant or breast-feeding women Co-infection with HIV and/or HBV Autoimmune hepatitis or history of autoimmune disease Alcoholic liver disease Metabolic disease HCC Participants with liver and kidney transplants Evidence of decompensated liver disease such as history or presence of ascites, bleeding varices, spontaneous encephalopathy Chronic renal failure or creatinine clearance < 50 mL/min Pre-existing thyroid disease unless it can be controlled with conventional treatment History or presence of psychiatric condition, especially depression, or a history of severe psychiatric disorder, such as major psychoses, suicidal ideation and/or suicidal attempt Epilepsy and/or compromised central nervous system (CNS) function Significant cardiovascular dysfunction within the previous 6 months before the study starts (eg, angina, congestive heart failure, recent myocardial infarction, moderate or severe hypertension, significant arrhythmia) Hemoglobinopathies Poorly controlled diabetes mellitus Chronic pulmonary disease (eg, chronic obstructive pulmonary disease) Clinical gout Hypersensitivity to interferons or any component of the drug

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A - PegIntron<br>Participants randomized to Arm A received peginterferon α-2b (PegIntron), 50 μg, weekly, subcutaneously (SC), for a period of 3 years. | Biological: Peginterferon alfa-2b<br>* Peginterferon alfa-2b, 50 μg, weekly, SC, for a period of 3 years.<br>* Other names: SCH 054031;|
| Other: Arm B - Control<br>Participants randomized to Arm B were under observation and received no treatment. | Other: Observation (no treatment)<br>* No treatment was given to participants enrolled in the control arm (Arm B).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With the Development of Hepatocellular Carcinoma (HCC) | Participants were tested for focal lesions by liver ultrasound and for AFP levels every 6 months the during study (treatment and follow-up). The development of hepatocellular carcinoma was determined by: the appearance of a focal lesion detected by liver ultrasound with metastases confirmed by fine needle biopsy, or the appearance of a focal lesion detected by ultrasound + alphafetoprotein (AFP) levels in blood >400 ng/mL. | During 3 years of treatment and 2 years of follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Development of Hepatic Decompensation | The development of hepatic decompensation, defined as worsening of the hepatic function as measured by Child Pugh Score. The Child Pugh score was calculated based on biochemical changes (changes in serum albumin, serum bilirubin, prothrombin time) and clinical impairment (ascites, encephalopathies) or both. Each of the 5 parameters was scored from 1-3, and the Child Pugh Score represented the total score. The maximum score was 15, and a score of 10-15 represents the worst outcome and a life expectancy of 1-3 years. | Baseline, During 3 years of treatment and 2 years of follow-up | 
| Survival Time of Participants | Survival time was defined as time from screening visit to the death of the participant and was studied with Kaplan-Meier and Log-rank tests. If a participant did not die, he or she was censored with the last available date. | During 3 years of treatment and 2 years of follow-up | 
| Number of Patients With a Virological Response Rate | Virological Response rate was measured by the disappearance of Hepatitis C Virus from serum. Serum samples from participants were analyzed for the presence of HCV-RNA using a qualitative polymerase chain reaction (PCR). | Baseline and every year during 3 years of treatment | 
| Change in the Proliferating Cell Nuclear Antigen Labeling Index (PCNA-LI) | PCNA-LI was measured at baseline and at 18 months of treatment, and the change in PCNA-LI was calculated. To measure PCNA-LI, liver tissue samples obtained from biopsies were fixed and immunostained to detect PCNA. PCNA-LI is the percentage of immunohistochemically stained (PCNA positive) cells in 1,000 HCC cells counted. A higher PCNA-LI indicates a worse outcome. | Baseline and at 18 months of treatment |