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

Primary Purpose

Carcinoma, Hepatocellular

Status
Completed
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
Peginterferon alfa-2b
Observation (no treatment)
Sponsored by
Merck Sharp & Dohme LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Carcinoma, Hepatocellular

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Other

    Arm Label

    Arm A - PegIntron

    Arm B - Control

    Arm Description

    Participants randomized to Arm A received peginterferon α-2b (PegIntron), 50 μg, weekly, subcutaneously (SC), for a period of 3 years.

    Participants randomized to Arm B were under observation and received no treatment.

    Outcomes

    Primary Outcome Measures

    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.

    Secondary Outcome Measures

    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.
    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.
    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).
    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.

    Full Information

    First Posted
    August 26, 2008
    Last Updated
    March 9, 2017
    Sponsor
    Merck Sharp & Dohme LLC
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    1. Study Identification

    Unique Protocol Identification Number
    NCT00759109
    Brief Title
    Pegylated Alfa-2b Interferon Therapy of Patients With Hepatitis C-related Cirrhosis and High Liver Cell Proliferation (P02733/MK-4031-085)
    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
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    March 2017
    Overall Recruitment Status
    Completed
    Study Start Date
    March 2002 (undefined)
    Primary Completion Date
    November 2009 (Actual)
    Study Completion Date
    November 2009 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Merck Sharp & Dohme LLC

    4. Oversight

    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Carcinoma, Hepatocellular

    7. Study Design

    Primary Purpose
    Prevention
    Study Phase
    Phase 3
    Interventional Study Model
    Parallel Assignment
    Masking
    None (Open Label)
    Allocation
    Randomized
    Enrollment
    150 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Arm A - PegIntron
    Arm Type
    Experimental
    Arm Description
    Participants randomized to Arm A received peginterferon α-2b (PegIntron), 50 μg, weekly, subcutaneously (SC), for a period of 3 years.
    Arm Title
    Arm B - Control
    Arm Type
    Other
    Arm Description
    Participants randomized to Arm B were under observation and received no treatment.
    Intervention Type
    Biological
    Intervention Name(s)
    Peginterferon alfa-2b
    Other Intervention Name(s)
    PegIntron, Pegylated Alfa-2b, SCH 054031
    Intervention Description
    Peginterferon alfa-2b, 50 μg, weekly, SC, for a period of 3 years.
    Intervention Type
    Other
    Intervention Name(s)
    Observation (no treatment)
    Intervention Description
    No treatment was given to participants enrolled in the control arm (Arm B).
    Primary Outcome Measure Information:
    Title
    Number of Participants With the Development of Hepatocellular Carcinoma (HCC)
    Description
    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.
    Time Frame
    During 3 years of treatment and 2 years of follow-up
    Secondary Outcome Measure Information:
    Title
    Number of Participants With Development of Hepatic Decompensation
    Description
    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.
    Time Frame
    Baseline, During 3 years of treatment and 2 years of follow-up
    Title
    Survival Time of Participants
    Description
    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.
    Time Frame
    During 3 years of treatment and 2 years of follow-up
    Title
    Number of Patients With a Virological Response Rate
    Description
    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).
    Time Frame
    Baseline and every year during 3 years of treatment
    Title
    Change in the Proliferating Cell Nuclear Antigen Labeling Index (PCNA-LI)
    Description
    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.
    Time Frame
    Baseline and at 18 months of treatment
    Other Pre-specified Outcome Measures:
    Title
    Proliferating Cell Nuclear Antigen Labeling Index (PCNA-LI) at Baseline
    Description
    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.
    Time Frame
    Baseline

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    70 Years
    Accepts Healthy Volunteers
    No
    Eligibility 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

    12. IPD Sharing Statement

    Plan to Share IPD
    Yes
    IPD Sharing 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

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

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