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Efficacy of PegInterferon-Ribavirin-Boceprevir Therapy in Patients Infected With G1 HCV With Cirrhosis, Awaiting Liver Transplantation

Primary Purpose

HCV Infection, Liver Cirrhosis, Experimental

Status
Completed
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Boceprevir
Peg-Interferon α-2b or Peg-Interferon α-2a
Ribavirin
Sponsored by
French National Agency for Research on AIDS and Viral Hepatitis
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for HCV Infection focused on measuring Boceprevir, HCV infection, Antiviral therapy, Liver transplantation

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Haut-Lévêque Hospital
  • Beaujon Hospital
  • Henri Mondor Hospital
  • A Michallon Hospital
  • Claude Huriez hospital
  • La Croix-Rousse
  • La Conception Hospital
  • Saint-Eloi Hospital
  • Archet Hospital
  • La Pitié Salpétrière Hospital
  • Cochin Hospital
  • Staint Antoine Hospital
  • Pontchaillou Hospital
  • Civil Hospital
  • Purpan Hospital Médecine interne
  • Purpan Hospital
  • Trousseau Hospital
  • Nancy Hospital
  • Paul Brousse Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Boceprevir, Pegylated interferon and Ribavirin

Arm Description

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)

Outcomes

Primary Outcome Measures

Sustained Virologic Response (SVR) Rate
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
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
Information on symptoms as perceived by the patients will be collected through self-administered questionnaires.
Compliance rate.
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
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
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
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
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
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)
Sepsis according to Systemic Inflammatory Response System (SIRS) Criteria
Cirrhosis impairment
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
Survival rate within one year after liver transplantation
The mean time elapsed between registration on the transplantation list and the date of transplantation
Measurement of the residual plasma concentration (Cres) of ribavirin
Area Under the Plasma Concentration Time Curve (AUC) From 0-8h of Boceprevir
Maximum Plasma Concentration (Cmax) of Boceprevir
Time of Maximum Plasma Concentration (Tmax) of Boceprevir
Minimum Plasma Concentration (Cmin) of Boceprevir
Correlation study between the presence of an elevated level of IP-10 during triple therapy and the absence of sustained virologic response
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
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)
Virological Response in participants with and without Insulin Resistance
Relationship between the presence of a polymorphism in the IL28B gene (donor and recipient) and SVR
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
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

Full Information

First Posted
October 14, 2011
Last Updated
January 23, 2017
Sponsor
French National Agency for Research on AIDS and Viral Hepatitis
Collaborators
Merck Sharp & Dohme LLC
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1. Study Identification

Unique Protocol Identification Number
NCT01463956
Brief Title
Efficacy of PegInterferon-Ribavirin-Boceprevir Therapy in Patients Infected With G1 HCV With Cirrhosis, Awaiting Liver Transplantation
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)
Study Type
Interventional

2. Study Status

Record Verification Date
January 2017
Overall Recruitment Status
Completed
Study Start Date
January 6, 2012 (undefined)
Primary Completion Date
June 2014 (Actual)
Study Completion Date
January 22, 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
French National Agency for Research on AIDS and Viral Hepatitis
Collaborators
Merck Sharp & Dohme LLC

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HCV Infection, Liver Cirrhosis, Experimental
Keywords
Boceprevir, HCV infection, Antiviral therapy, Liver transplantation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
58 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Boceprevir, Pegylated interferon and Ribavirin
Arm Type
Experimental
Arm Description
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)
Intervention Type
Drug
Intervention Name(s)
Boceprevir
Intervention Description
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)
Intervention Type
Biological
Intervention Name(s)
Peg-Interferon α-2b or Peg-Interferon α-2a
Other Intervention Name(s)
PegIntron, PEG
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Ribavirin
Intervention Description
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
Primary Outcome Measure Information:
Title
Sustained Virologic Response (SVR) Rate
Description
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.
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
Secondary Outcome Measure Information:
Title
Number of participants with adverse events as a measure of safety and tolerability
Description
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
Time Frame
From week 0 to week 144
Title
Perceived symptoms
Description
Information on symptoms as perceived by the patients will be collected through self-administered questionnaires.
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
Title
Compliance rate.
Description
Treatment compliance will be assesses through a self-administered questionnaire reporting the number of medication doses prescribed and taken by the participants
Time Frame
week 12, week 24, week 36, week 48, week 72 - after Liver transplant:Day 0
Title
SVR prognosis factors
Description
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)
Time Frame
Week-4 up week 144
Title
The predictive value of on-treatment HCV RNA on SVR
Description
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
Time Frame
During weeks 1, 4, 5, 6, 7, 8, 12, 16, 20, and 24 (before transplantation)
Title
The percentage of virologic failure
Description
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
Time Frame
week 4 and week 48
Title
The percentage of relapse after transplantation
Description
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
Time Frame
Between week 16 and week 144
Title
Boceprevir resistant mutations
Description
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
Time Frame
From week 5 to week 48 or after week 48
Title
Resistant mutations in plasma and liver samples (both explanted liver and graft)
Time Frame
Week 16 up to week 96
Title
Sepsis according to Systemic Inflammatory Response System (SIRS) Criteria
Time Frame
From day 0 to week 72
Title
Cirrhosis impairment
Description
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)
Time Frame
From day 0 to week 72
Title
Survival after transplantation
Time Frame
Week 16 up to week 96
Title
Survival rate within one year after liver transplantation
Time Frame
week 64 up to week 144
Title
The mean time elapsed between registration on the transplantation list and the date of transplantation
Time Frame
Week16 up to week 96
Title
Measurement of the residual plasma concentration (Cres) of ribavirin
Time Frame
at Week 4 and Week 8
Title
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
Title
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
Title
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
Title
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
Title
Correlation study between the presence of an elevated level of IP-10 during triple therapy and the absence of sustained virologic response
Description
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
Time Frame
From week 4 to week 48
Title
Histological severity of HCV recurrence after liver transplantation
Description
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
Time Frame
At week 20 up to week 100, at week 40 up to week 120, at week 64 up to week 144
Title
Insulin Resistance (HOMA-IR)
Time Frame
At baseline, week 48 and at the last follow-up visit
Title
Virological Response in participants with and without Insulin Resistance
Time Frame
At week 4, 8, 16, 28 and 48 during therapy
Title
Relationship between the presence of a polymorphism in the IL28B gene (donor and recipient) and SVR
Description
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).
Time Frame
After week 144
Title
Relationship between the presence of a polymorphism to the ITPA gene and the onset of hemolytic anemia
Description
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
Time Frame
After week 144

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Didier Samuel, Pr
Organizational Affiliation
Hepatobiliary Center of Paul Brousse Hospital. France
Official's Role
Principal Investigator
Facility Information:
Facility Name
Haut-Lévêque Hospital
City
Bordeaux
ZIP/Postal Code
33601
Country
France
Facility Name
Beaujon Hospital
City
Clichy
ZIP/Postal Code
92110
Country
France
Facility Name
Henri Mondor Hospital
City
Creteil
ZIP/Postal Code
94010 Cedex
Country
France
Facility Name
A Michallon Hospital
City
Grenoble
ZIP/Postal Code
38700
Country
France
Facility Name
Claude Huriez hospital
City
Lille
ZIP/Postal Code
59037 cedex
Country
France
Facility Name
La Croix-Rousse
City
Lyon
ZIP/Postal Code
69 317 CEDEX
Country
France
Facility Name
La Conception Hospital
City
Marseille
ZIP/Postal Code
13285
Country
France
Facility Name
Saint-Eloi Hospital
City
Montpellier
ZIP/Postal Code
34090
Country
France
Facility Name
Archet Hospital
City
Nice
ZIP/Postal Code
06202 cedex 3
Country
France
Facility Name
La Pitié Salpétrière Hospital
City
Paris
ZIP/Postal Code
75013
Country
France
Facility Name
Cochin Hospital
City
Paris
ZIP/Postal Code
75014
Country
France
Facility Name
Staint Antoine Hospital
City
Paris
ZIP/Postal Code
75571 Cedex 12
Country
France
Facility Name
Pontchaillou Hospital
City
Rennes
ZIP/Postal Code
35033 cedex 9
Country
France
Facility Name
Civil Hospital
City
Strasbourg
ZIP/Postal Code
67091 Cedex
Country
France
Facility Name
Purpan Hospital Médecine interne
City
Toulouse
ZIP/Postal Code
31059 cedex
Country
France
Facility Name
Purpan Hospital
City
Toulouse
ZIP/Postal Code
31059 cedex
Country
France
Facility Name
Trousseau Hospital
City
Tours
ZIP/Postal Code
37044
Country
France
Facility Name
Nancy Hospital
City
Vandoeuvre Les Nancy
ZIP/Postal Code
54500
Country
France
Facility Name
Paul Brousse Hospital
City
Villejuif
ZIP/Postal Code
94804 cedex
Country
France

12. IPD Sharing Statement

Learn more about this trial

Efficacy of PegInterferon-Ribavirin-Boceprevir Therapy in Patients Infected With G1 HCV With Cirrhosis, Awaiting Liver Transplantation

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