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
  Purpose

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.


Condition Intervention Phase
Hepatitis C, Chronic
Liver Fibrosis
Biological: Peginterferon alfa-2b
Drug: Ribavirin
Drug: Ribavirin-Placebo
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: 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.

Resource links provided by NLM:


Further study details as provided by French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS):

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Enrollment: 372
Study Start Date: May 2006
Study Completion Date: March 2013
Primary Completion Date: February 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  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.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00323804

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

No publications provided

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     History of Changes
Other Study ID Numbers: ANRS HC15 NRfi, 2005-002937-11
Study First Received: May 9, 2006
Last Updated: September 3, 2014
Health Authority: France: ANSM - Agence Nationale de Sécurité du Médicament

Keywords provided by French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS):
Maintenance therapy
Non-responder patients
Ribavirin/peginterferon combination therapy
Hepatitis C, Chronic

Additional relevant MeSH terms:
Hepatitis C, Chronic
Fibrosis
Hepatitis
Hepatitis A
Hepatitis C
Hepatitis, Chronic
Liver Cirrhosis
Pathologic Processes
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Flaviviridae Infections
Ribavirin
Peginterferon alfa-2b
Interferon-alpha
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 22, 2014