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Interest of Ribavirin in the Maintenance Treatment of Liver Fibrosis Using Low Dose Pegylated Interferon alpha2b in Patients With Chronic Hepatitis C Non Responders to Previous Antiviral Therapy.

This study has been completed.
Sponsor:
Collaborators:
Merck Sharp & Dohme Corp.
Rennes University Hospital
Information provided by (Responsible Party):
French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
ClinicalTrials.gov Identifier:
NCT00323804
First received: May 9, 2006
Last updated: September 3, 2014
Last verified: August 2014

May 9, 2006
September 3, 2014
May 2006
February 2013   (final data collection date for primary outcome measure)
Rate of patients with at least a one point improvement in Metavir fibrosis score between the inclusion and the end-of-study liver biopsies. [ Time Frame: Screen visit and M36 ] [ Designated as safety issue: No ]
Rate of patients with at least a one point improvement in Metavir fibrosis score between the inclusion and the end-of-study liver biopsies.
Complete list of historical versions of study NCT00323804 on ClinicalTrials.gov Archive Site
  • Distribution of the Metavir scoring on the end-of-study biopsy [ Time Frame: M36 ] [ Designated as safety issue: No ]
  • Distribution of the Chevallier fibrosis score [ Time Frame: Screen visit and M36 ] [ Designated as safety issue: No ]
  • Evolution of the area of fibrosis between the inclusion and the end-of -study biopsies [ Time Frame: Screen visit and M36 ] [ Designated as safety issue: No ]
  • Fibrosis serum markers [ Time Frame: Screen, day0, M6, M12, M24, M36 ] [ Designated as safety issue: No ]
  • Liver elasticity before and after treatment [ Time Frame: Screen,M12, M24, M36 ] [ Designated as safety issue: No ]
  • Safety of treatment and quality of life [ Time Frame: day0, M6, M12, M24, M36 ] [ Designated as safety issue: No ]
  • Frequency of occurrence of hepatic complications and/or liver transplantations [ Time Frame: Day 0 to M36 ] [ Designated as safety issue: Yes ]
  • Evolution of the hepatitis C viral load [ Time Frame: Screen to M36 ] [ Designated as safety issue: No ]
  • Rate of patients with loss of detectable hepatitis C virus RNA [ Time Frame: Day 0 to M36 ] [ Designated as safety issue: No ]
  • Distribution of the Metavir scoring on the end-of-study biopsy
  • Distribution of the Chevallier fibrosis score
  • Evolution of the area of fibrosis between the inclusion and the end-of -study biopsies
  • Fibrosis serum markers
  • Liver elasticity before and after treatment
  • Safety of treatment and quality of life
  • Frequency of occurrence of hepatic complications and/or liver transplantations
  • Evolution of the hepatitis C viral load
  • Rate of patients with loss of detectable hepatitis C virus RNA
Not Provided
Not Provided
 
Interest of Ribavirin in the Maintenance Treatment of Liver Fibrosis Using Low Dose Pegylated Interferon alpha2b in Patients With Chronic Hepatitis C Non Responders to Previous Antiviral Therapy.
Randomized, Double-blind, Placebo-controlled Multicenter Study Evaluating the Interest of a Long-term (3 Years) Treatment With Peginterferon Alfa-2b and Ribavirin on Liver Fibrosis in Non-responder Chronic Hepatitis C Patients.

Patients with chronic hepatitis C who did not respond to previous antiviral treatment develop liver fibrosis leading to cirrhosis. Maintenance low dose pegylated interferon therapy of fibrosis is currently under investigation in large multicenter trials. The aim of our study is to assess if peginterferon alpha2b plus ribavirin is more efficient than peginterferon alpha2b alone. 454 patients will be randomized between the 2 arms and the efficacy will be assessed, after 3 years of treatment, on Metavir liver fibrosis score improvement.

Up to 45% of patients with chronic hepatitis C do not respond to pegylated interferon/ribavirin combination therapy. These patients are prone to develop liver fibrosis leading to cirrhosis and its complications. Interferon has proven to be efficient in liver fibrosis treatment even in case of virological non response. Maintenance low dose pegylated interferon therapy is currently under investigation in large multicenter trials. The aim of our study is to assess wether peginterferon alpha 2 b (0.5 µg/kg/week) plus ribavirin (800-1200 mg according to body weight) is more efficient than peginterferon alpha 2 b alone in a long term 3 years treatment of liver fibrosis. 454 patients, non responders (VHC RNA positive after 24 weeks of treatment or absence of ≥ 2 log HCV RNA drop after 12 weeks of treatment) to a previous peginterferon/ribavirin antiviral treatment will be randomized between the 2 arms, with a double-blind masking of ribavirin. The efficacy will be assessed on Metavir liver fibrosis score improvement between pre and post therapeutic liver biopsy.

Interventional
Phase 2
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
  • Hepatitis C, Chronic
  • Liver Fibrosis
  • Biological: Peginterferon alfa-2b
    PegIFN alfa 2b in addition to ribavirin or ribavirin-placebo, from day 0 to M36
  • Drug: Ribavirin
    Ribavirin in addition to PegIFN alfa 2b, from day 0 to M36
  • Drug: Ribavirin-Placebo
    Ribavirin-placebo in addition to PegIFN alfa 2b, from day 0 to M36
  • Experimental: Randomised PegIFN alfa 2b + ribavirin (RBV) arm
    Combination of ribavirin capsules 200 mg, weight-based daily dose ( <75 kg : 1000 mg ; ≥ 75 kg : 1200 mg), and low-dose PegIFN alfa 2b by subcutaneous injection 0.5 μg / kg / week, from day 0 to M36
    Interventions:
    • Biological: Peginterferon alfa-2b
    • Drug: Ribavirin
  • Placebo Comparator: Randomised PegIFN alfa 2b + ribavirin-placebo arm
    Combination of ribavirin-placebo capsules 200 mg, weight-based daily dose ( <75 kg : 1000 mg ; ≥ 75 kg : 1200 mg), and low-dose PegIFN alfa 2b by subcutaneous injection 0.5 μg / kg / week, from day 0 to M36
    Interventions:
    • Biological: Peginterferon alfa-2b
    • Drug: Ribavirin-Placebo
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
372
March 2013
February 2013   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Adults over 18
  • With a hepatitis C virus infection (HCV RNA and anti-HCV antibodies in serum)
  • Not responders to a previous antiviral treatment using the interferon plus ribavirin combination
  • With a wash-out of treatment for at least 6 months
  • With an active chronic hepatitis C and a Metavir fibrosis score ≥ 2
  • Serum ALT levels > upper limit of the laboratory on two occasions within 6 months before inclusion
  • Accepting to undergo a liver biopsy at the end of the study
  • Negative pregnancy test for women
  • With a social security cover
  • Written informed consent

Exclusion Criteria:

  • History of hepatic complications
  • History of transplantation
  • History of severe seizures
  • History of severe psychiatric disorders
  • Drug addiction within the last 12 months
  • Associated condition susceptible to be responsible for liver fibrosis
  • Hepatocellular carcinoma
  • Cardiovascular disease unstable under treatment
  • Uncontrolled diabetes
  • Retinopathy
  • Thyroid disease unstable under treatment
  • Epilepsy and/or central nervous system functional disorders
  • Autoimmune disease
  • Regular alcohol consumption
  • Pregnancy, breast-feeding or absence of contraception
  • Haemoglobin <12 g/dl
  • platelets <50000/mm3
  • Neutrophils < 1200/ mm3
  • Severe hepatocellular failure (prothrombin index lower than 60%)
  • Renal failure (creatinine clearance lower than 50 mL/Mn)
  • Associated immunosuppressive drugs, corticosteroids, antiviral drugs (other than study ones)
  • Treatment with drugs likely to have an effect on fibrosis
  • Anticonvulsants
  • Inability to tolerate interferon
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
Belgium,   France
 
NCT00323804
ANRS HC15 NRfi, 2005-002937-11
Yes
French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
  • Merck Sharp & Dohme Corp.
  • Rennes University Hospital
Principal Investigator: Dominique Guyader, MD, PhD CHU Rennes
Study Chair: Eric Bellissant, MD, PhD CHU Rennes
French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
August 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP