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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:
NCT00759109
First received: August 26, 2008
Last updated: August 11, 2014
Last verified: August 2014
  Purpose

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.


Condition Intervention Phase
Carcinoma, Hepatocellular
Biological: Peginterferon alfa-2b
Other: Observation (no treatment)
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Merck Sharp & Dohme Corp.:

Primary Outcome Measures:
  • Number of Participants With the Development of Hepatocellular Carcinoma (HCC) [ Time Frame: During 3 years of treatment and 2 years of follow-up ] [ Designated as safety issue: No ]

    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:

    1. the appearance of a focal lesion detected by liver ultrasound with metastases confirmed by fine needle biopsy, or
    2. the appearance of a focal lesion detected by ultrasound + alphafetoprotein (AFP) levels in blood >400 ng/mL.


Secondary Outcome Measures:
  • Number of Participants With Development of Hepatic Decompensation [ Time Frame: Baseline, During 3 years of treatment and 2 years of follow-up ] [ Designated as safety issue: No ]
    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.

  • Survival Time of Participants [ Time Frame: During 3 years of treatment and 2 years of follow-up ] [ Designated as safety issue: No ]
    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.

  • Number of Patients With a Virological Response Rate [ Time Frame: Baseline and every year during 3 years of treatment ] [ Designated as safety issue: No ]

    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).


  • Change in the Proliferating Cell Nuclear Antigen Labeling Index (PCNA-LI) [ Time Frame: Baseline and at 18 months of treatment ] [ Designated as safety issue: No ]

    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.



Other Outcome Measures:
  • Proliferating Cell Nuclear Antigen Labeling Index (PCNA-LI) at Baseline [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    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.


Enrollment: 150
Study Start Date: January 2002
Study Completion Date: November 2009
Primary Completion Date: November 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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:
  • PegIntron
  • Pegylated Alfa-2b
  • SCH 054031
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).

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

No Contacts or Locations Provided
  More Information

No publications provided

Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT00759109     History of Changes
Other Study ID Numbers: P02733
Study First Received: August 26, 2008
Results First Received: March 24, 2011
Last Updated: August 11, 2014
Health Authority: Italy: Ministry of Health

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Hepatocellular
Hepatitis C
Adenocarcinoma
Digestive System Diseases
Digestive System Neoplasms
Flaviviridae Infections
Hepatitis
Hepatitis, Viral, Human
Liver Diseases
Liver Neoplasms
Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Glandular and Epithelial
RNA Virus Infections
Virus Diseases
Interferon-alpha
Interferons
Peginterferon alfa-2b
Anti-Infective Agents
Antineoplastic Agents
Antiviral Agents
Immunologic Factors
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 29, 2014