RIBAJUSTE Clinical Trial Investigating the Efficacy and Safety of Dose Adaptation of Ribavirin (RIBAJUSTE)

Multicentric, Controlled and Randomised Open Clinical Trial Investigating the Efficacy and Safety of Dose Adaptation of Ribavirin Using Pharmacologic Measures of Ribavirin Exposition During Combination Peginterferon Alfa-2 and Ribavirin Treatment in Naive Patients With Chronic Hepatitis C of Genotype 1 on a First Combination Therapy

The aim of this study is to compare two therapeutical strategies concerning the combination therapy (peginterferon alfa-2a and ribavirin) in naïve patients with chronic hepatitis C of genotype 1. "Reference" strategy corresponding to standards of care recommended by the French consensus conference versus "Test" strategy corresponding to adaptation strategy of ribavirin dose during the first week according to AUC (area under the curve) of ribavirin plasmatic concentration after the first intake (Day 0) of 600 mg

Study Overview

• Status: Unknown
• Conditions: Chronic Hepatitis C
• Intervention / Treatment: Drug: Peg-interferon alpha 2a and ribavin; Drug: ribavirin with adaptation dose

• Study Type: Interventional
• Enrollment (Anticipated): 236
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Marianne Maynard, MD; Phone Number: 33 4 72 41 30 88; Email: marianne.maynard-muet@chu-lyon.fr
• Study Contact Backup: Name: Véronique LOUSTAUD-RATTI, MD; Phone Number: 33 5 55 05 66 84; Email: veronique.loustaud-ratti@unilim.fr

Study Locations

• France
  • Lyon, France, 69002
    • Recruiting
    • Marianne Maynard
    • Contact: Marianne Maynard, MD; Phone Number: 33 4 72 41 30 88; Email: marianne.maynard-muet@chu-lyon.fr
    • Principal Investigator: Christian Trépo, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 65 years >Age >= 18 years
• Chronic hepatitis C documented by PCR performed within 3 months and at liver biopsy within 18 months or with serum markers of fibrosis performed within 3 months before inclusion or FibroScan performed
• Naive patients for who the physician decided to initiate a combination treatment of chronic hepatitis C with pegylated interferon alfa-2a plus ribavirine
• Genotype VHC-1
• Compensated liver disease (Child-Pugh <=6)
• Negative HBsAg test and HIV-RNA test
• Negative pregnancy test at baseline in women in age of procreation and efficient contraception all along the treatment period, and up to 7 months after discontinuation for women and men
• Signed consent form
• Patient with a social cover

Exclusion Criteria:

• Non HCV liver disease
• Non-1 HCV genotype
• Organ transplant whatever the organ
• Clinical or radiological evidence of liver carcinoma
• Severe psychiatric disorder
• Non compensated thyroid dysfunction
• Woman pregnant or breast-feeding
• Recent history of epilepsy (less than 6 months)
• Absolute contraindications to one of the drug of combination therapy
• Biological abnormalities at pre-treatment check-up, such as:

Neutropenia (<1500/mm³); Haemoglobinemia (<13 g/dL for men et <12 g/dL for women); Thrombopenia (<90 000/mm³);

• Kidney failure (creatinine clearance>70 ml/min)
• Hypersensitivity to epoetin or one of its excipients
• Treatment by epoetin within 2 months prior inclusion
• Chronic cardiac failure (grade III or IV - NYHA classification)
• High blood pressure unwell-controlled (SBP > 180 mmHg during inclusion in spite of hypertension treatment)
• Previous history or risk of venous thrombosis
• Major surgery within the previous 3 months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: standard dose; the "reference" strategy : Peg-interferon alpha 2a (180 µg/week) and ribavine (1000 mg/day if weight < 75 kg and 1200 mg/day if weight ≥ 75 kg)	Drug: Peg-interferon alpha 2a and ribavin; Date of ribavirin AUC : Day 0 (beginning of treatment) Bitherapy : Peg-interferon alpha 2a (180 µg/week) with ribavirin (1000 mg/day if weight < 75 kg and 1200 mg/day if weight ≥ 75 kg). Duration of treatment : 48 weeks Duration of study for patients : 72 weeks
Experimental: adjusted dose; individual dose adjustment of ribavirin dose at D7, based on ribavirin abbreviated AUC-0-4H , estimated itself by two independent methods: multiple linear regression and bayesien estimation based on three ribavirin concentration measurements obtained at 0.5H, 1H, 2H after the first intake of 600 mg at D0.	Drug: ribavirin with adaptation dose; Date of ribavirin AUC : Day 0 (beginning of treatment) Bitherapy : Peg-interferon alpha 2a (180 µg/week) with ribavirin (dose adaptation) Dose adaptation : Day 7, dependant of result of AUC Ribavirin dose increments : 200 mg, 400 mg or 600 mg with a maximum of 50% of the initial dose (600 mg) applied every 4 days up to the adjusted dose proposed in order to reach the targeted AUC. The maximum daily dose will not exceed 3600 mg Duration of treatment : 48 weeks Duration of study for patients : 72 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Inter-group comparison of sustained virological response rates as defined by the proportion of subjects with a negative PCR HCV-RNA test at Week 72	72 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy endpoints	To compare the virological response rate between the two groups: Rapid Virological Response (RVR) at W4, Early Virological Response (EVR) at W12, Virological Response at W24, and End-Of-Treatment response (EOT) at W48 ; To determine the relapse rate (between W48 and W72) and to determine the proportion of patients reaching the target trough ribavirin concentration of 2 mg/L at W4 or W8 after ribavirin dose adjustment in the first 7 days of treatment.	72 weeks
safety endpoints	To investigate the clinical and biological tolerability in patients with dose-adjusted ribavirin compared to those with standard ribavirin doses, the proportion of patients needing EPO co-prescription due to secondary anemia in each group, to estimate the rate of treatment discontinuation due to serious or other relevant adverse events in each group and to determine the proportion of subjects reaching ribavirin trough plasma concentrations considered as "toxic" (> 3.5 mg/L) at W4 and W8, in each arm.	72 weeks
Economic endpoints	Comparaison of the "test" and "standard" strategies by a medico-economic analysis	72 weeks

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon
• Investigators: Principal Investigator: Christian Trépo, MD, Hospices Civils de Lyon

Study record dates

Study Major Dates

• Study Start: April 1, 2006
• Primary Completion (Anticipated): March 1, 2013
• Study Completion (Anticipated): March 1, 2013

Study Registration Dates

• First Submitted: June 8, 2007
• First Submitted That Met QC Criteria: June 8, 2007
• First Posted (Estimate): June 12, 2007

Study Record Updates

• Last Update Posted (Estimate): January 9, 2012
• Last Update Submitted That Met QC Criteria: January 6, 2012
• Last Verified: January 1, 2012

More Information

Terms related to this study

• Keywords: Chronic hepatitis C,Genotype1,Naïf,bitherapy,Ribavirin adaptation,ribavirin AUC
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Hepatitis; Hepatitis A; Hepatitis C; Hepatitis, Chronic; Hepatitis C, Chronic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites; Antineoplastic Agents; Immunologic Factors; Interferons; Interferon-alpha; Ribavirin; Peginterferon alfa-2a; Interferon alpha-2
• Other Study ID Numbers: 2005-400