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.

Hepatitis C, Chronic Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00323804
• Other study ID #: ANRS HC15 NRfi
• Secondary ID: 2005-002937-11
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: May 9, 2006
• Last updated: September 3, 2014
• Start date: May 2006
• Est. completion date: March 2013

Study information

• Verified date: August 2014
• Source: French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: ANSM - Agence Nationale de Sécurité du Médicament
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 372
• Est. completion date: March 2013
• Est. primary completion date: February 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Fibrosis
• Hepatitis
• Hepatitis A
• Hepatitis C
• Hepatitis C, Chronic
• Hepatitis, Chronic
• Liver Cirrhosis
• Liver Fibrosis

Intervention

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
• Ribavirin-Placebo
Ribavirin-placebo in addition to PegIFN alfa 2b, from day 0 to M36

Locations

Country	Name	City	State
Belgium	CHU Brugmann	Bruxelles
Belgium	Hôpital Bracops	Bruxelles
Belgium	Hôpital Erasme	Bruxelles
Belgium	Hôpital de Jolimont	La Louvière
Belgium	CHU Sart Tilman	Liège
France	Service d'Hépatogastroentérologie et d'endoscopie digestive - CH du Pays d'Aix	Aix en Provence
France	Hôpital Nord	Amiens
France	Service d'Hépatogastroentérologie - Hôpital Nord	Amiens
France	Service d'Hépatologie - Gastroentérologie - Cancérologie digestive - CHU Angers	Angers
France	Centre Hospitalier Victor Dupouy	Argenteuil
France	Service d'Hépatogastroentérologie - Hôpital Avicenne	Bobigny
France	Service d' Hépatogastroentérologie - Hôpital Jean Verdier	Bondy
France	Service d'Hépatogastroentérologie et d'Assistance nutritive - Hôpital Haut-Lévêque	Bordeaux Pessac
France	CH Pierre OUDOT	Bourgoin-Jallieu
France	Service d'Hépatogastroentérologie - Hôpital de la Cavale Blanche	Brest
France	Service d'Hépatologie - Gastroentérologie - Nutrition -Hôpital de la Côte de Nacre	Caen
France	Centre Hospitalier	Châteauroux
France	Service d'Hépatogastroentérologie - CHU d'ESTAING	Clermont-Ferrand
France	Service d'Hépatogastroentérologie - Hôpital Beaujon	Clichy
France	Service d'Hépatogastroentérologie - CH Sud Francilien	Corbeil-Essonnes
France	Service d'Hépatogastroentérologie - Hôpital du Bocage	Dijon
France	Hôpital Nord	Grenoble
France	Service d'Hépatogastroentérologie - CH La Roche sur Yon	La Roche sur Yon
France	Service des Maladies du Foie et de l'appareil Digestif - Hôpital de Bicêtre	Le Kremlin-Bicêtre
France	Département d'Hépatogastroentérologie - CH Le Mans	Le Mans
France	Service d'Hépatogastroentérologie - CHRU - Hôpital Claude Huriez	Lille
France	Service d'Hépatogastroentérologie - Hotel de la Croix Rousse	Lyon
France	Service d'Hépatogastroentérologie - Hôpital Saint Joseph	Marseille
France	Service d'Hépatogastroentérologie - CH Montauban	Montauban
France	Service d'Hépatogastroentérologie - CH Montélimar	Montelimar
France	Service d'Hépatogastroentérologie - Hôpital Saint Eloi	Montpellier
France	Service d'Hépatogastroentérologie - Hôtel Dieu	Nantes
France	Hôpital de l'Archet	Nice
France	Service d'Hépatogastroentérologie - Hôpital de la Source	Orléans
France	Service d'Hépatogastroentérologie - Hôpital La Pitié Salpétrière	Paris
France	Service d'Hépatogastroentérologie - Hôpital Tenon	Paris
France	Service d'Hépatogastroentérologie - Hôpital Pontchaillou	Rennes
France	Service d'Hépatogastroentérologie - CHU Rouen	Rouen
France	Centre Hospitalier	Saint Quentin
France	Service d'Hépatogastroentérologie, Clinique médicale B - Hôpital Civil	Strasbourg
France	Hôpital Purpan	Toulouse
France	Service d'Hépatogastroentérologie - Hôpital Purpan	Toulouse
France	Service d'Hépatogastroentérologie - Hôpital Trousseau	Tours
France	Service d'Hépatogastroentérologie - Hôpital Brabois	Vandoeuvre les Nancy
France	Hôpita Paul Brousse	Villejuif

Sponsors (3)

Lead Sponsor	Collaborator
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

Countries where clinical trial is conducted

Belgium,  France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rate of patients with at least a one point improvement in Metavir fibrosis score between the inclusion and the end-of-study liver biopsies.		Screen visit and M36	No
Secondary	Distribution of the Metavir scoring on the end-of-study biopsy		M36	No
Secondary	Distribution of the Chevallier fibrosis score		Screen visit and M36	No
Secondary	Evolution of the area of fibrosis between the inclusion and the end-of -study biopsies		Screen visit and M36	No
Secondary	Fibrosis serum markers		Screen, day0, M6, M12, M24, M36	No
Secondary	Liver elasticity before and after treatment		Screen,M12, M24, M36	No
Secondary	Safety of treatment and quality of life		day0, M6, M12, M24, M36	No
Secondary	Frequency of occurrence of hepatic complications and/or liver transplantations		Day 0 to M36	Yes
Secondary	Evolution of the hepatitis C viral load		Screen to M36	No
Secondary	Rate of patients with loss of detectable hepatitis C virus RNA		Day 0 to M36	No