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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.

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ClinicalTrials.gov Identifier: NCT00323804
Recruitment Status : Completed
First Posted : May 10, 2006
Last Update Posted : September 4, 2014
Sponsor:
Collaborators:
Merck Sharp & Dohme Corp.
Rennes University Hospital
Information provided by (Responsible Party):
ANRS, Emerging Infectious Diseases

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.

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

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 372 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, 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.
Study Start Date : May 2006
Actual Primary Completion Date : February 2013
Actual Study Completion Date : March 2013

Resource links provided by the National Library of Medicine


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




Primary Outcome Measures :
  1. 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 ]

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


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00323804


Locations
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Sponsors and Collaborators
ANRS, Emerging Infectious Diseases
Merck Sharp & Dohme Corp.
Rennes University Hospital
Investigators
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Principal Investigator: Dominique Guyader, MD, PhD CHU Rennes
Study Chair: Eric Bellissant, MD, PhD CHU Rennes
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Responsible Party: ANRS, Emerging Infectious Diseases
ClinicalTrials.gov Identifier: NCT00323804    
Other Study ID Numbers: ANRS HC15 NRfi
2005-002937-11 ( EudraCT Number )
First Posted: May 10, 2006    Key Record Dates
Last Update Posted: September 4, 2014
Last Verified: August 2014
Keywords provided by ANRS, Emerging Infectious Diseases:
Maintenance therapy
Non-responder patients
Ribavirin/peginterferon combination therapy
Hepatitis C, Chronic
Additional relevant MeSH terms:
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Hepatitis A
Hepatitis C
Hepatitis C, Chronic
Hepatitis
Liver Cirrhosis
Fibrosis
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Pathologic Processes
Flaviviridae Infections
Hepatitis, Chronic
Ribavirin
Peginterferon alfa-2b
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents