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.

September 3, 2014 updated by: ANRS, Emerging Infectious Diseases

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

372

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Belgium
      • Bruxelles, Belgium, 1070
        • Hôpital Erasme
      • Bruxelles, Belgium, 1020
        • CHU Brugmann
      • Bruxelles, Belgium, 1070
        • Hôpital Bracops
      • La Louvière, Belgium, 7100
        • Hopital de Jolimont
      • Liège, Belgium, 4000
        • Chu Sart Tilman
  • France
      • Aix en Provence, France, 13616
        • Service d'Hépatogastroentérologie et d'endoscopie digestive - CH du Pays d'Aix
      • Amiens, France, 80054
        • Hôpital Nord
      • Amiens, France, 80054
        • Service d'Hépatogastroentérologie - Hôpital Nord
      • Angers, France, 49100
        • Service d'Hépatologie - Gastroentérologie - Cancérologie digestive - CHU Angers
      • Argenteuil, France, 95100
        • Centre Hospitalier Victor Dupouy
      • Bobigny, France, 93009
        • Service d'Hépatogastroentérologie - Hôpital Avicenne
      • Bondy, France, 93143
        • Service d' Hépatogastroentérologie - Hôpital Jean Verdier
      • Bordeaux Pessac, France, 33604
        • Service d'Hépatogastroentérologie et d'Assistance nutritive - Hôpital Haut-Lévêque
      • Bourgoin-Jallieu, France, 38317
        • CH Pierre Oudot
      • Brest, France, 29200
        • Service d'Hépatogastroentérologie - Hôpital de la Cavale Blanche
      • Caen, France, 14000
        • Service d'Hépatologie - Gastroentérologie - Nutrition -Hôpital de la Côte de Nacre
      • Châteauroux, France, 36000
        • Centre hospitalier
      • Clermont-Ferrand, France, 63003
        • Service d'Hépatogastroentérologie - CHU d'ESTAING
      • Clichy, France, 92110
        • Service d'Hépatogastroentérologie - Hôpital Beaujon
      • Corbeil-Essonnes, France, 91106
        • Service d'Hépatogastroentérologie - CH Sud Francilien
      • Dijon, France, 21079
        • Service d'Hépatogastroentérologie - Hôpital du Bocage
      • Grenoble, France, 38043
        • Hôpital Nord
      • La Roche sur Yon, France, 85925
        • Service d'Hépatogastroentérologie - CH La Roche sur Yon
      • Le Kremlin-Bicêtre, France, 94275
        • Service des Maladies du Foie et de l'appareil Digestif - Hôpital de Bicêtre
      • Le Mans, France, 72037
        • Département d'Hépatogastroentérologie - CH Le Mans
      • Lille, France, 59000
        • Service d'Hépatogastroentérologie - CHRU - Hôpital Claude Huriez
      • Lyon, France, 69004
        • Service d'Hépatogastroentérologie - Hotel de la Croix Rousse
      • Marseille, France, 13285
        • Service d'Hépatogastroentérologie - Hôpital Saint Joseph
      • Montauban, France, 82000
        • Service d'Hépatogastroentérologie - CH Montauban
      • Montelimar, France, 26200
        • Service d'Hépatogastroentérologie - CH Montélimar
      • Montpellier, France, 34295
        • Service d'Hépatogastroentérologie - Hôpital Saint Eloi
      • Nantes, France, 44093
        • Service d'Hépatogastroentérologie - Hôtel Dieu
      • Nice, France, 06202
        • Hopital de l'archet
      • Orléans, France, 45067
        • Service d'Hépatogastroentérologie - Hôpital de la Source
      • Paris, France, 75013
        • Service d'Hépatogastroentérologie - Hôpital La Pitié Salpétrière
      • Paris, France, 75020
        • Service d'Hépatogastroentérologie - Hôpital Tenon
      • Rennes, France, 35033
        • Service d'Hépatogastroentérologie - Hôpital Pontchaillou
      • Rouen, France, 76031
        • Service d'Hépatogastroentérologie - CHU Rouen
      • Saint Quentin, France, 02321
        • Centre hospitalier
      • Strasbourg, France, 67000
        • Service d'Hépatogastroentérologie, Clinique médicale B - Hôpital Civil
      • Toulouse, France, 31059
        • Hopital Purpan
      • Toulouse, France, 31059
        • Service d'Hépatogastroentérologie - Hôpital Purpan
      • Tours, France, 37044
        • Service d'Hépatogastroentérologie - Hôpital Trousseau
      • Vandoeuvre les Nancy, France, 54500
        • Service d'Hépatogastroentérologie - Hôpital Brabois
      • Villejuif, France, 94804
        • Hôpita Paul Brousse

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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
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
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
Biological: Peginterferon alfa-2b
PegIFN alfa 2b in addition to ribavirin or ribavirin-placebo, from day 0 to M36
Drug: Ribavirin-Placebo
Ribavirin-placebo in addition to PegIFN alfa 2b, from day 0 to M36

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
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
Screen visit and M36

Secondary Outcome Measures

Outcome Measure
Time Frame
Distribution of the Metavir scoring on the end-of-study biopsy
Time Frame: M36
M36
Distribution of the Chevallier fibrosis score
Time Frame: Screen visit and M36
Screen visit and M36
Evolution of the area of fibrosis between the inclusion and the end-of -study biopsies
Time Frame: Screen visit and M36
Screen visit and M36
Fibrosis serum markers
Time Frame: Screen, day0, M6, M12, M24, M36
Screen, day0, M6, M12, M24, M36
Liver elasticity before and after treatment
Time Frame: Screen,M12, M24, M36
Screen,M12, M24, M36
Safety of treatment and quality of life
Time Frame: day0, M6, M12, M24, M36
day0, M6, M12, M24, M36
Frequency of occurrence of hepatic complications and/or liver transplantations
Time Frame: Day 0 to M36
Day 0 to M36
Evolution of the hepatitis C viral load
Time Frame: Screen to M36
Screen to M36
Rate of patients with loss of detectable hepatitis C virus RNA
Time Frame: Day 0 to M36
Day 0 to M36

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

ANRS, Emerging Infectious Diseases

Collaborators

Merck Sharp & Dohme LLC
Rennes University Hospital

Investigators

  • Principal Investigator: Dominique Guyader, MD, PhD, CHU Rennes

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2006

Primary Completion (Actual)

February 1, 2013

Study Completion (Actual)

March 1, 2013

Study Registration Dates

First Submitted

May 9, 2006

First Submitted That Met QC Criteria

May 9, 2006

First Posted (Estimate)

May 10, 2006

Study Record Updates

Last Update Posted (Estimate)

September 4, 2014

Last Update Submitted That Met QC Criteria

September 3, 2014

Last Verified

August 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ANRS HC15 NRfi
  • 2005-002937-11 (EudraCT Number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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