Clinical Trial to Evaluate the Efficacy of Pegylated Interferon-Ribavirin-Boceprevir Triple Therapy in Patients Infected With Genotype 1 HCV With Cirrhosis and Awaiting Liver Transplantation (ANRS HC 29 BOCEPRETRANSPLANT)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
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) ( French National Agency for Research on AIDS and Viral Hepatitis )
ClinicalTrials.gov Identifier:
NCT01463956
First received: October 14, 2011
Last updated: January 7, 2014
Last verified: January 2014
  Purpose

Evaluation of efficacy of triple therapy with pegylated interferon, ribavirin, and boceprevir in patients with genotype 1 chronic hepatitis C, who are treatment-naive, have relapsed, or are non-responders with cirrhosis and awaiting liver transplantation, with a MELD score less than or equal to 18


Condition Intervention Phase
HCV Infection
Liver Cirrhosis, Experimental
Drug: Boceprevir
Biological: Peg-Interferon α-2b or Peg-Interferon α-2a
Drug: Ribavirin
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Pilot Study on the Efficacy of Pegylated Interferon-Ribavirin-Boceprevir Triple Therapy in Patients Infected With Genotype 1 HCV With Cirrhosis and Awaiting Liver Transplantation (ANRS HC 29 BOCEPRETRANSPLANT)

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:
  • Sustained Virologic Response (SVR) Rate [ Time Frame: Week 24 after the discontinuation of antiviral C treatment and at the time of liver transplantation or at the time of liver transplantation ] [ Designated as safety issue: No ]

    Evaluation of sustained virologic response to antiviral C treatment depends of time of liver transplantation that can be performed between week 16 and week 96 of the trial:

    • If the liver transplant is realized after the discontinuation of antiviral C treatment,sustained virologic response should be evaluated 6 months after the discontinuation of antiviral C treatment and at the time of liver transplantation.
    • If the liver transplant is realized before the discontinuation of antiviral C treatment,sustained virologic response should be evaluated at the time of liver transplantation.


Secondary Outcome Measures:
  • Number of participants with adverse events as a measure of safety and tolerability [ Time Frame: From week 0 to week 144 ] [ Designated as safety issue: Yes ]
    Information on adverse events will be collected by the investigator during medical visits and reported in the CRF. Adverse events will be classified as: a) Flu-like symptoms b) Musculoskeletal symptoms c) Neurologic symptoms d) Psychiatric symptoms e) Constitutional symptoms

  • Perceived symptoms [ Time Frame: at day 0, week 24, week 48 and every 24 week up liver transplant - post liver transplant: day 0, week 24 and week 48 ] [ Designated as safety issue: No ]
    Information on symptoms as perceived by the patients will be collected through self-administered questionnaires.

  • Compliance rate. [ Time Frame: week 12, week 24, week 36, week 48, week 72 - after Liver transplant:Day 0 ] [ Designated as safety issue: No ]
    Treatment compliance will be assesses through a self-administered questionnaire reporting the number of medication doses prescribed and taken by the participants

  • SVR prognosis factors [ Time Frame: Week-4 up week 144 ] [ Designated as safety issue: No ]
    Participants with undetectable plasma HCV-RNA 24 weeks after treatment cessation and/or liver transplantation will be considered as SVR. Factors potentially associated with SVR will be studied through a logistic regression analysis. These factors include demographical (age, gender), virological (baseline viral load), clinical (disease severity measured by MELD score) and genetic factors (IL28B polymorphism: TT, CT, or CC)

  • The predictive value of on-treatment HCV RNA on SVR [ Time Frame: During weeks 1, 4, 5, 6, 7, 8, 12, 16, 20, and 24 (before transplantation) ] [ Designated as safety issue: No ]
    Quantitative assessment of HCV RNA during treatment will be performed at weeks 1, 4, 5, 6, 7, 8, 12, 16, 20, and 24 and correlated to SVR

  • The percentage of virologic failure [ Time Frame: week 4 and week 48 ] [ Designated as safety issue: No ]
    Virological failure is defined as an increase of HCV RNA of at least 1 log IU/mL during treatment, or by the reappearance of positive viremia during treatment, after an initial negative result

  • The percentage of relapse after transplantation [ Time Frame: Between week 16 and week 144 ] [ Designated as safety issue: No ]
    Virological relapse is characterized by an HCV RNA negative at the end of treatment but becoming detectable after cessation of therapy. The proportion of patients with virological relapse will be determined

  • Boceprevir resistant mutations [ Time Frame: From week 5 to week 48 or after week 48 ] [ Designated as safety issue: No ]
    The proportion of patients with emergence of resistant mutations to boceprevir in case of detectable viral load during treatment (from W5) and after the discontinuation of treatment in the event of virologic failure will be assessed

  • Resistant mutations in plasma and liver samples (both explanted liver and graft) [ Time Frame: Week 16 up to week 96 ] [ Designated as safety issue: No ]
  • Sepsis according to Systemic Inflammatory Response System (SIRS) Criteria [ Time Frame: From day 0 to week 72 ] [ Designated as safety issue: Yes ]
  • Cirrhosis impairment [ Time Frame: From day 0 to week 72 ] [ Designated as safety issue: Yes ]

    Cirrhosis impairment will be assessed by studying:

    • the mean variation of MELD score between baseline and end of therapy
    • the proportion of patients with a MELD score increased by at least 3 points (in case of baseline MELD>15) or 5 points (in case of baseline MELD<15)

  • Survival after transplantation [ Time Frame: Week 16 up to week 96 ] [ Designated as safety issue: Yes ]
  • Survival rate within one year after liver transplantation [ Time Frame: week 64 up to week 144 ] [ Designated as safety issue: Yes ]
  • The mean time elapsed between registration on the transplantation list and the date of transplantation [ Time Frame: Week16 up to week 96 ] [ Designated as safety issue: No ]
  • Measurement of the residual plasma concentration (Cres) of ribavirin [ Time Frame: at Week 4 and Week 8 ] [ Designated as safety issue: No ]
  • Area Under the Plasma Concentration Time Curve (AUC) From 0-8h of Boceprevir [ Time Frame: At week 16 and at week 24 and if the MELD score has changed by more than three points ] [ Designated as safety issue: No ]
  • Maximum Plasma Concentration (Cmax) of Boceprevir [ Time Frame: At week 16 and at week 24 and if the MELD score has changed by more than three points ] [ Designated as safety issue: No ]
  • Time of Maximum Plasma Concentration (Tmax) of Boceprevir [ Time Frame: At week 16 and at week 24 and if the MELD score has changed by more than three points ] [ Designated as safety issue: No ]
  • Minimum Plasma Concentration (Cmin) of Boceprevir [ Time Frame: At week 16 and at week 24 and if the MELD score has changed by more than three points ] [ Designated as safety issue: No ]
  • Correlation study between the presence of an elevated level of IP-10 during triple therapy and the absence of sustained virologic response [ Time Frame: From week 4 to week 48 ] [ Designated as safety issue: No ]
    Plasma aliquots will be performed in all patients of the trial at day 0 before liver transplant and day 0 post liver transplant to measure IP10. Evaluation will be performed at the end of the trial for all patients recruited. The association between IP-10 level and SVR will be assessed

  • Histological severity of HCV recurrence after liver transplantation [ Time Frame: At week 20 up to week 100, at week 40 up to week 120, at week 64 up to week 144 ] [ Designated as safety issue: No ]

    Histological severity will be assessed by the METAVIR score at 1 month (if early recurrence), at 6 months, 1 year after transplantation in case of non-response/relapse before transplantation .

    Liver transplantation can be performed between week 16 and week 96


  • Insulin Resistance (HOMA-IR) [ Time Frame: At baseline, week 48 and at the last follow-up visit ] [ Designated as safety issue: No ]
  • Virological Response in participants with and without Insulin Resistance [ Time Frame: At week 4, 8, 16, 28 and 48 during therapy ] [ Designated as safety issue: No ]
  • Relationship between the presence of a polymorphism in the IL28B gene (donor and recipient) and SVR [ Time Frame: After week 144 ] [ Designated as safety issue: No ]
    Whole blood aliquots (DNA bank) will be performed at the Day 0 visit to measure IL28B polymorphism. Evaluation will be performed at the end of the trial for all patients recruited. The SVR rate will be compared between the different IL28B phenotypes (CC, CT and TT).

  • Relationship between the presence of a polymorphism to the ITPA gene and the onset of hemolytic anemia [ Time Frame: After week 144 ] [ Designated as safety issue: No ]
    Whole blood aliquots (DNA bank) will be performed at the Day 0 visit for ITPA gene measure. Evaluation will be performed at the end of the trial for all patients recruited. The proportion of patients with occurrence of hemolytic anemia will be compared according to the ITPA polymorphism


Enrollment: 58
Study Start Date: January 2012
Estimated Study Completion Date: May 2016
Estimated Primary Completion Date: November 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Boceprevir, Pegylated interferon and Ribavirin
  • Lead-in phase (4 week): Pegylated interferon + Ribavirin
  • Triple therapy regimen for 44 weeks :Boceprevir + Pegylated interferon + Ribavirin
  • Pegylated interferon + Ribavirin therapy until transplantation (less or equal to 24 weeks)
Drug: Boceprevir
Boceprevir 200 mg capsules at 2400mg/day (800mg 3 times a day) from week 4 until week 48 or until liver transplant (can be performed from week 16)
Biological: Peg-Interferon α-2b or Peg-Interferon α-2a
Peg-Interferon α-2b by subcutaneous injection, 1.5µg/kg/week, from day 0 until week 48 or until liver transplantation, or Peg-Interferon α-2a by subcutaneous injection, 180 µg, once weekly, from day 0 until week 48 or until liver transplantation
Other Names:
  • PegIntron
  • PEG
Drug: Ribavirin
Ribavirin: capsules 200 mg (weight-based daily dose: <65kg, 800 mg; 65-80kg, 1000mg; 81-105kg: 1200mg; >105kg: 1400mg), from day 0 until week 48 or until liver transplantation or, Ribavirin: Tablet Oral, weight-based dose, 1000 mg for subjects weighing below 75 kg or 1200 mg for subjects weighing equal or over75 kg, once daily, from day 0 until week 48 or until liver transplantation

Detailed Description:

Evaluation of sustained virological response defined as the proportion of patients with undetectable hepatitis C virus RNA 24 weeks after discontinuation of therapy and/or after liver transplantation in patients with genotype 1, who are treatment-naive, have relapsed, or are non-responders with cirrhosis and awaiting liver transplantation, with a MELD score less than or equal to 18

  Eligibility

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

Inclusion Criteria:

  • Adult 18 years and older
  • Chronic infection with hepatitis C virus proven with positive PCR for more than 6 months
  • Viral genotype 1
  • Cirrhosis while awaiting liver transplantation
  • MELD score < or equal to 18
  • With or without hepatocellular carcinoma
  • Naive to antiviral C treatment
  • Failure on a previous treatment. Failure is defined as the persistence of detectable HCV RNA. The previous HCV failure treatment profile must be able to be documented according to the following terminology:- Relapsing patient: HCV RNA undetectable at the end of treatment, becoming detectable again after the discontinuation of treatment- Breakthrough: increase of viremia of 1 log or more during the treatment - Non-responding patient with partial response: HCV RNA detectable at W24 without ever having been undetectable and with a decrease in HCV RNA ≥ 2 log at W12 - Non-responding patient with nul response: decrease in HCV RNA < 2 log at W12
  • No need for prior treatment wash-out
  • Negative pregnancy test in women of child-bearing age
  • Double method of contraception in men and women of child-bearing age during the entire duration of treatment and the 6 months following its discontinuation
  • Free, informed, and written consent (signed on the day of pre-enrollment at the latest and before all exams required by the study)
  • Person enrolled in or a beneficiary of a social security/Universal Health Insurance Coverage
  • Inclusion approved by the Decision Support Committee

Exclusion Criteria:

  • Previous HCV treatment with boceprevir or telaprevir
  • Alcohol consumption > 40 g/day
  • Toxicomania constituting a barrier for starting therapy according to the opinion of the investigator. Patients included in a methadone or buprenorphine replacement program may be enrolled
  • MELD > 18
  • Non controlled sepsis
  • Platelets < 50,000/mm3
  • Neutrophil granulocyte levels < 1000/mm3
  • Creatinine clearance < 50 mL/min (MDRD)
  • Hb < 10 g/dL
  • Uncontrolled psychiatric problems
  • Contraindications to boceprevir
  • Contraindication to interferon or ribavirin
  • Subject with major complications of cirrhosis
  • HIV coinfection
  • HBV coinfection (unless this is treated effectively with analogues, as proven by undetectable viremia for at least 12 months)
  • Other infectious disease underway
  • Neoplastic disease other than hepatocellular carcinoma during the previous year, or neoplastic disease for which the prognosis is less than 3 years
  • Treatment with immunosuppressors (including corticosteroids), antivirals other than those for the study, except aciclovir
  • Consumption of St. John's wort
  • Associated treatments including a molecule or substance that could interfere with the pharmacokinetic characteristics of boceprevir
  • History of a lactose allergy
  • Person participating in another study including an exclusion period that is still underway during pre-enrollment
  • So-called vulnerable populations (minors, people under guardianship or protection, or a private individual under protection from making legal or administrative decisions)
  • Pregnancy, breast-feeding
  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: NCT01463956

Locations
France
Haut-Lévêque Hospital
Bordeaux, France, 33601
Beaujon Hospital
Clichy, France, 92110
Henri Mondor Hospital
Creteil, France, 94010 Cedex
A Michallon Hospital
Grenoble, France, 38700
Claude Huriez hospital
Lille, France, 59037 cedex
La Croix-Rousse
Lyon, France, 69 317 CEDEX
La Conception Hospital
Marseille, France, 13285
Saint-Eloi Hospital
Montpellier, France, 34090
Archet Hospital
Nice, France, 06202 cedex 3
Staint Antoine Hospital
Paris, France, 75571 Cedex 12
Cochin Hospital
Paris, France, 75014
La Pitié Salpétrière Hospital
Paris, France, 75013
Pontchaillou Hospital
Rennes, France, 35033 cedex 9
Civil Hospital
Strasbourg, France, 67091 Cedex
Purpan Hospital Médecine interne
Toulouse, France, 31059 cedex
Purpan Hospital
Toulouse, France, 31059 cedex
Trousseau Hospital
Tours, France, 37044
Nancy Hospital
Vandoeuvre Les Nancy, France, 54500
Paul Brousse Hospital
Villejuif, France, 94804 cedex
Sponsors and Collaborators
French National Agency for Research on AIDS and Viral Hepatitis
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Didier Samuel, Pr Hepatobiliary Center of Paul Brousse Hospital. France
  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) ( French National Agency for Research on AIDS and Viral Hepatitis )
ClinicalTrials.gov Identifier: NCT01463956     History of Changes
Other Study ID Numbers: 2011- 001089 -17
Study First Received: October 14, 2011
Last Updated: January 7, 2014
Health Authority: France: ANSM - Agence Nationale de Sécurité du Médicament et des produits de santé (French national competent authority)

Keywords provided by French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS):
Boceprevir
HCV infection
Antiviral therapy
Liver transplantation

Additional relevant MeSH terms:
Liver Cirrhosis
Fibrosis
Liver Cirrhosis, Experimental
Liver Diseases
Digestive System Diseases
Pathologic Processes
Interferons
Ribavirin
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antiviral Agents
Anti-Infective Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 29, 2014