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

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

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.

Study Overview

• Status: Completed
• Conditions: Carcinoma, Hepatocellular
• Intervention / Treatment: Biological: Peginterferon alfa-2b; Other: Observation (no treatment)

• Study Type: Interventional
• Enrollment (Actual): 150
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proliferating Cell Nuclear Antigen Labeling Index (PCNA-LI) at Baseline	Liver tissues 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

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Study record dates

Study Major Dates

• Study Start: March 1, 2002
• Primary Completion (Actual): November 1, 2009
• Study Completion (Actual): November 1, 2009

Study Registration Dates

• First Submitted: August 26, 2008
• First Submitted That Met QC Criteria: September 23, 2008
• First Posted (Estimate): September 25, 2008

Study Record Updates

• Last Update Posted (Actual): April 7, 2017
• Last Update Submitted That Met QC Criteria: March 9, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Liver Neoplasms; Hepatitis; Carcinoma; Carcinoma, Hepatocellular; Hepatitis C; Anti-Infective Agents; Antiviral Agents; Peginterferon alfa-2b
• Other Study ID Numbers: P02733

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

http://www.merck.com/clinical-trials/pdf/Merck%20Procedure%20on%20Clinical%20Trial%20Data%20Access%20Final_Updated%20July_9_2014.pdf

http://engagezone.msd.com/ds_documentation.php