Clinical trial NCT00323804: 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.
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Hepatitis C, Chronic
Liver Fibrosis
Keywords: Maintenance therapy
Non-responder patients
Ribavirin/peginterferon combination therapy
Hepatitis C, Chronic
Lead sponsor: ANRS, Emerging Infectious Diseases
Sponsor class: OTHER_GOV
Collaborators: name: Merck Sharp & Dohme LLC
name: Rennes University Hospital
First posted: 2006-05-10
Enrollment: 372
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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 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

Primary outcomes:
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.
timeFrame: Screen visit and M36
Secondary outcomes:
measure: Distribution of the Metavir scoring on the end-of-study biopsy
timeFrame: M36
measure: Distribution of the Chevallier fibrosis score
timeFrame: Screen visit and M36
measure: Evolution of the area of fibrosis between the inclusion and the end-of -study biopsies
timeFrame: Screen visit and M36
measure: Fibrosis serum markers
timeFrame: Screen, day0, M6, M12, M24, M36
measure: Liver elasticity before and after treatment
timeFrame: Screen,M12, M24, M36
measure: Safety of treatment and quality of life
timeFrame: day0, M6, M12, M24, M36
measure: Frequency of occurrence of hepatic complications and/or liver transplantations
timeFrame: Day 0 to M36
measure: Evolution of the hepatitis C viral load
timeFrame: Screen to M36
measure: Rate of patients with loss of detectable hepatitis C virus RNA
timeFrame: Day 0 to M36
Other outcomes:
Locations:
city: Bruxelles
country: Belgium
facility: CHU Brugmann
city: Bruxelles
country: Belgium
facility: Hôpital Bracops
city: Bruxelles
country: Belgium
facility: Hôpital Erasme
city: La Louvière
country: Belgium
facility: Hôpital de Jolimont
city: Liège
country: Belgium
facility: CHU Sart Tilman
city: Aix en Provence
country: France
facility: Service d'Hépatogastroentérologie et d'endoscopie digestive - CH du Pays d'Aix
city: Amiens
country: France
facility: Hôpital Nord
city: Amiens
country: France
facility: Service d'Hépatogastroentérologie - Hôpital Nord
city: Angers
country: France
facility: Service d'Hépatologie - Gastroentérologie - Cancérologie digestive - CHU Angers
city: Argenteuil
country: France
facility: Centre Hospitalier Victor Dupouy
city: Bobigny
country: France
facility: Service d'Hépatogastroentérologie - Hôpital Avicenne
city: Bondy
country: France
facility: Service d' Hépatogastroentérologie - Hôpital Jean Verdier
city: Bordeaux Pessac
country: France
facility: Service d'Hépatogastroentérologie et d'Assistance nutritive - Hôpital Haut-Lévêque
city: Bourgoin-Jallieu
country: France
facility: CH Pierre OUDOT
city: Brest
country: France
facility: Service d'Hépatogastroentérologie - Hôpital de la Cavale Blanche
city: Caen
country: France
facility: Service d'Hépatologie - Gastroentérologie - Nutrition -Hôpital de la Côte de Nacre
city: Châteauroux
country: France
facility: Centre Hospitalier
city: Clermont-Ferrand
country: France
facility: Service d'Hépatogastroentérologie - CHU d'ESTAING
city: Clichy
country: France
facility: Service d'Hépatogastroentérologie - Hôpital Beaujon
city: Corbeil-Essonnes
country: France
facility: Service d'Hépatogastroentérologie - CH Sud Francilien
city: Dijon
country: France
facility: Service d'Hépatogastroentérologie - Hôpital du Bocage
city: Grenoble
country: France
facility: Hôpital Nord
city: La Roche sur Yon
country: France
facility: Service d'Hépatogastroentérologie - CH La Roche sur Yon
city: Le Kremlin-Bicêtre
country: France
facility: Service des Maladies du Foie et de l'appareil Digestif - Hôpital de Bicêtre
city: Le Mans
country: France
facility: Département d'Hépatogastroentérologie - CH Le Mans
city: Lille
country: France
facility: Service d'Hépatogastroentérologie - CHRU - Hôpital Claude Huriez
city: Lyon
country: France
facility: Service d'Hépatogastroentérologie - Hotel de la Croix Rousse
city: Marseille
country: France
facility: Service d'Hépatogastroentérologie - Hôpital Saint Joseph
city: Montauban
country: France
facility: Service d'Hépatogastroentérologie - CH Montauban
city: Montelimar
country: France
facility: Service d'Hépatogastroentérologie - CH Montélimar
city: Montpellier
country: France
facility: Service d'Hépatogastroentérologie - Hôpital Saint Eloi
city: Nantes
country: France
facility: Service d'Hépatogastroentérologie - Hôtel Dieu
city: Nice
country: France
facility: Hôpital de l'Archet
city: Orléans
country: France
facility: Service d'Hépatogastroentérologie - Hôpital de la Source
city: Paris
country: France
facility: Service d'Hépatogastroentérologie - Hôpital La Pitié Salpétrière
city: Paris
country: France
facility: Service d'Hépatogastroentérologie - Hôpital Tenon
city: Rennes
country: France
facility: Service d'Hépatogastroentérologie - Hôpital Pontchaillou
city: Rouen
country: France
facility: Service d'Hépatogastroentérologie - CHU Rouen
city: Saint Quentin
country: France
facility: Centre Hospitalier
city: Strasbourg
country: France
facility: Service d'Hépatogastroentérologie, Clinique médicale B - Hôpital Civil
city: Toulouse
country: France
facility: Hôpital Purpan
city: Toulouse
country: France
facility: Service d'Hépatogastroentérologie - Hôpital Purpan
city: Tours
country: France
facility: Service d'Hépatogastroentérologie - Hôpital Trousseau
city: Vandoeuvre les Nancy
country: France
facility: Service d'Hépatogastroentérologie - Hôpital Brabois
city: Villejuif
country: France
facility: Hôpita Paul Brousse
Study officials:
affiliation: CHU Rennes
name: Dominique Guyader, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Rennes
name: Eric Bellissant, MD, PhD
role: STUDY_CHAIR
References: