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Study to Assess Efficacy and Safety of Grazoprevir/Elbasvir Associated With Sofosbuvir and Ribavirin in HCV Genotype 1 or 4-infected Patients Who Failed Direct Acting Antivirals (DAA) Bitherapy With Sofosbuvir

Primary Purpose

Hepatitis C

Status
Completed
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Grazoprevir/Elbasvir
Sofosbuvir
Ribavirin
Sponsored by
ANRS, Emerging Infectious Diseases
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hepatitis C focused on measuring HCV genotype 1 or 4, failure to DAA

Eligibility Criteria

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

Inclusion Criteria:

  • Adult ≥18 years
  • Infection with HCV genotype 1 or 4, confirmed by detectable HCV RNA at pre-inclusion
  • Failure to a prior therapy with Sofosbuvir +/- Ribavirin associated with Simeprevir or Daclatasvir or Ledipasvir, with documented presence of NS5A or NS3/4A RAVs (Resistance Associated Variants) at the time of failure (presence of RAVs on at least one sample since the time of failure).

The proportion of patients previously treated with Simeprevir will be limited to a third of all patients included.

  • Fibrosis at any stage
  • Men and women of child-bearing age and their heterosexual partners must use adequate contraceptions from 15 days before their inclusion in the study up to 7 months after the end of treatment for men and up to 4 months after the end of treatment for women
  • Written informed consent signed by the patient and the investigator (on the day of the pre-inclusion at the latest and before any examination required by the study) (article L1122-1-1 Public Health Code)
  • Patients with Health insurance (Sécurité Sociale or Couverture Médicale Universelle)

Exclusion Criteria:

  • Child B or C cirrhosis (or Child A patients with history of Child B)
  • Patients with documented presence of RAVs conferring resistance to sofosbuvir
  • Positive HBs Antigen
  • Confirmed HIV-1 or HIV-2 infection
  • Pregnant or breast-feeding women or men whose female partners are pregnant
  • Transplant recipients
  • Any evolutive ongoing malignant disease, including hepatocellular carcinoma, which will be specifically screened for before inclusion
  • History of severe rhythm disorders or cardiac disease (coronary artery disease, heart failure, arteriopathy,…): the opinion of a cardiologist is compulsory (< 6 months)
  • Consumption of alcohol which, in the investigator's opinion, will be an obstacle to the patient's participation and to his/her remaining in the study
  • Drug addiction which, in the investigator's opinion, will be an obstacle to the patient's participation and to his/her remaining in the study. Patients included in a programme of substitution with methadone or buprenorphine could be included. The opinion of an addictology consultant is recommended for patients presenting with current drug use or drug use in the past year
  • Patients taking part in another clinical trial within 30 days prior to inclusion
  • Patient under guardianship, trusteeship or judicial protection

Non-inclusion biological criteria

  • Hemoglobin < 11 g/dL
  • Platelets < 50 000/mm3
  • INR > 1.5 unless subject has known hemophilia or is stable on an anticoagulant regimen affecting INR
  • ALT or AST > 10xULN
  • Creatinine clearance < 50 mL/mn (MDRD formula)
  • Albumin < 30 g/L
  • HbA1c > 10% (only in diabetic patients)

Criteria related to study drugs

  • Contra-indication to treatment with Grazoprevir/Elbasvir, Sofosbuvir or Ribavirin including a history of hypersensitivity to one of their excipients
  • Patients with a non-compliance history, who will be at risk of not complying with the study follow-up timetable
  • Treatment with contra-indicated associated drugs

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Experimental

    Arm Label

    16 weeks of treatment

    24 weeks of treatment

    Arm Description

    Drug : Grazoprevir/Elbasvir + Sofosbuvir + Ribavirin during 16 weeks

    Drug : Grazoprevir/Elbasvir + Sofosbuvir + Ribavirin during 24 weeks

    Outcomes

    Primary Outcome Measures

    rate of the Sustained Virological Response 12 weeks after the end of the therapy (SVR12), i.e. at W28 or W36 for treatment duration of 16 weeks and 24 weeks respectively.
    The primary endpoint is the rate of the Sustained Virological Response defined as HCV RNA < LLOQ (either TD[u] or TND) 12 weeks after the end of the therapy associating Grazoprevir/Elbasvir, Sofosbuvir and Ribavirin (SVR12), i.e. at W28 or W36 for treatment duration of 16 weeks and 24 weeks respectively.

    Secondary Outcome Measures

    SVR rate 4 weeks after the end of treatment (i.e. at week 20 or week 28 for treatment duration of 16 weeks and 24 weeks respectively) and 24 weeks after the end of treatment (i.e. at week 40 or week 48).
    HCV viral load assessment
    Assessment of HCV subtypic distribution at baseline
    Numbers and proportions of patients presenting variants of resistance (RAV) at baseline
    The numbers and proportions of patients presenting variants of resistance (RAV) and their characteristics will be studied
    Assessment of liver fibrosis by Hepatic impulse elastometry (Fibroscan®), or biological parameters (FibroMeter® or Fibrotest®)
    For cirrhotic patients, description of the risk of cirrhosis evolution (decompensation, hepatocarcinoma)
    Cirrhosis evaluation (Child-Pugh)
    For cirrhotic patients, description of the risk of cirrhosis evolution (decompensation, hepatocarcinoma)
    Cirrhosis evaluation (MELD score)
    Clinical and biological adverse events occurring during the treatment and until 24 weeks after the end of the treatment
    Numbers and proportions of patients who interrupted the treatments of the study
    Patient's reported outcomes evaluation with questionnaires
    Evaluation of patient's quality of life
    Patient's reported outcomes evaluation with questionnaires
    Evaluation of perceived symptoms (ANRS questionnaire)

    Full Information

    First Posted
    December 16, 2015
    Last Updated
    June 28, 2017
    Sponsor
    ANRS, Emerging Infectious Diseases
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    1. Study Identification

    Unique Protocol Identification Number
    NCT02647632
    Brief Title
    Study to Assess Efficacy and Safety of Grazoprevir/Elbasvir Associated With Sofosbuvir and Ribavirin in HCV Genotype 1 or 4-infected Patients Who Failed Direct Acting Antivirals (DAA) Bitherapy With Sofosbuvir
    Official Title
    Study to Assess Efficacy and Safety of Grazoprevir/Elbasvir Associated With Sofosbuvir and Ribavirin in HCV Genotype 1 or 4-infected Patients Who Failed Direct Acting Antivirals (DAA) Bitherapy With Sofosbuvir
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    June 2017
    Overall Recruitment Status
    Completed
    Study Start Date
    January 2016 (undefined)
    Primary Completion Date
    January 2017 (Actual)
    Study Completion Date
    April 2017 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    ANRS, Emerging Infectious Diseases

    4. Oversight

    5. Study Description

    Brief Summary
    The primary objective of this study is to estimate, in HCV genotype 1 or 4-infected patients who failed a prior DAA bitherapy with Sofosbuvir, the efficacy of a treatment with Grazoprevir/Elbasvir, Sofosbuvir and Ribavirin in the two treatment groups and compare the rate of sustained virological response (SVR) 12 weeks after 16 or 24 weeks of this treatment. SVR12 is defined as HCV RNA < LLOQ (either TD[u] or TND).

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Hepatitis C
    Keywords
    HCV genotype 1 or 4, failure to DAA

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2
    Interventional Study Model
    Parallel Assignment
    Masking
    None (Open Label)
    Allocation
    Randomized
    Enrollment
    26 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    16 weeks of treatment
    Arm Type
    Experimental
    Arm Description
    Drug : Grazoprevir/Elbasvir + Sofosbuvir + Ribavirin during 16 weeks
    Arm Title
    24 weeks of treatment
    Arm Type
    Experimental
    Arm Description
    Drug : Grazoprevir/Elbasvir + Sofosbuvir + Ribavirin during 24 weeks
    Intervention Type
    Drug
    Intervention Name(s)
    Grazoprevir/Elbasvir
    Other Intervention Name(s)
    Grazoprevir/Elbasvir is also known as MK-5172A or Zepatier
    Intervention Type
    Drug
    Intervention Name(s)
    Sofosbuvir
    Other Intervention Name(s)
    Sofosbuvir is also known as Sovaldi
    Intervention Type
    Drug
    Intervention Name(s)
    Ribavirin
    Other Intervention Name(s)
    Ribavirin is also known as Rebetol
    Primary Outcome Measure Information:
    Title
    rate of the Sustained Virological Response 12 weeks after the end of the therapy (SVR12), i.e. at W28 or W36 for treatment duration of 16 weeks and 24 weeks respectively.
    Description
    The primary endpoint is the rate of the Sustained Virological Response defined as HCV RNA < LLOQ (either TD[u] or TND) 12 weeks after the end of the therapy associating Grazoprevir/Elbasvir, Sofosbuvir and Ribavirin (SVR12), i.e. at W28 or W36 for treatment duration of 16 weeks and 24 weeks respectively.
    Time Frame
    Week 28 (W28) or Week 36 (W36)
    Secondary Outcome Measure Information:
    Title
    SVR rate 4 weeks after the end of treatment (i.e. at week 20 or week 28 for treatment duration of 16 weeks and 24 weeks respectively) and 24 weeks after the end of treatment (i.e. at week 40 or week 48).
    Time Frame
    Week 20 (W20) or Week 28 (W28), and W40 or W48
    Title
    HCV viral load assessment
    Time Frame
    from Day 0 (D0) to Week 40 (W40) or Week 48 (W48)
    Title
    Assessment of HCV subtypic distribution at baseline
    Time Frame
    Pre-inclusion
    Title
    Numbers and proportions of patients presenting variants of resistance (RAV) at baseline
    Description
    The numbers and proportions of patients presenting variants of resistance (RAV) and their characteristics will be studied
    Time Frame
    Pre-inclusion
    Title
    Assessment of liver fibrosis by Hepatic impulse elastometry (Fibroscan®), or biological parameters (FibroMeter® or Fibrotest®)
    Time Frame
    Pre-inclusion, Week 40 or Week 48
    Title
    For cirrhotic patients, description of the risk of cirrhosis evolution (decompensation, hepatocarcinoma)
    Description
    Cirrhosis evaluation (Child-Pugh)
    Time Frame
    Pre-inclusion, Day 0 (D0), Week 16 (W16), W20, W24, W28, W36, W40 or W48
    Title
    For cirrhotic patients, description of the risk of cirrhosis evolution (decompensation, hepatocarcinoma)
    Description
    Cirrhosis evaluation (MELD score)
    Time Frame
    Pre-inclusion, Day 0 (D0), Week 16 (W16), W20, W24, W28, W36, W40 or W48
    Title
    Clinical and biological adverse events occurring during the treatment and until 24 weeks after the end of the treatment
    Time Frame
    from Day 0(D0) to Week 40 (W40) or W48
    Title
    Numbers and proportions of patients who interrupted the treatments of the study
    Time Frame
    from Day 0 (D0) to Week 40 (W40) or W48
    Title
    Patient's reported outcomes evaluation with questionnaires
    Description
    Evaluation of patient's quality of life
    Time Frame
    Day 0 (D0), Week 4 (W4), W16, W28, W40 or D0, W4, W16, W24, W36, W48 (24 weeks treatment-arm))
    Title
    Patient's reported outcomes evaluation with questionnaires
    Description
    Evaluation of perceived symptoms (ANRS questionnaire)
    Time Frame
    Day 0 (D0), Week 4 (W4), W16, W28, W40 or D0, W4, W16, W24, W36, W48 (24 weeks treatment-arm))

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Adult ≥18 years Infection with HCV genotype 1 or 4, confirmed by detectable HCV RNA at pre-inclusion Failure to a prior therapy with Sofosbuvir +/- Ribavirin associated with Simeprevir or Daclatasvir or Ledipasvir, with documented presence of NS5A or NS3/4A RAVs (Resistance Associated Variants) at the time of failure (presence of RAVs on at least one sample since the time of failure). The proportion of patients previously treated with Simeprevir will be limited to a third of all patients included. Fibrosis at any stage Men and women of child-bearing age and their heterosexual partners must use adequate contraceptions from 15 days before their inclusion in the study up to 7 months after the end of treatment for men and up to 4 months after the end of treatment for women Written informed consent signed by the patient and the investigator (on the day of the pre-inclusion at the latest and before any examination required by the study) (article L1122-1-1 Public Health Code) Patients with Health insurance (Sécurité Sociale or Couverture Médicale Universelle) Exclusion Criteria: Child B or C cirrhosis (or Child A patients with history of Child B) Patients with documented presence of RAVs conferring resistance to sofosbuvir Positive HBs Antigen Confirmed HIV-1 or HIV-2 infection Pregnant or breast-feeding women or men whose female partners are pregnant Transplant recipients Any evolutive ongoing malignant disease, including hepatocellular carcinoma, which will be specifically screened for before inclusion History of severe rhythm disorders or cardiac disease (coronary artery disease, heart failure, arteriopathy,…): the opinion of a cardiologist is compulsory (< 6 months) Consumption of alcohol which, in the investigator's opinion, will be an obstacle to the patient's participation and to his/her remaining in the study Drug addiction which, in the investigator's opinion, will be an obstacle to the patient's participation and to his/her remaining in the study. Patients included in a programme of substitution with methadone or buprenorphine could be included. The opinion of an addictology consultant is recommended for patients presenting with current drug use or drug use in the past year Patients taking part in another clinical trial within 30 days prior to inclusion Patient under guardianship, trusteeship or judicial protection Non-inclusion biological criteria Hemoglobin < 11 g/dL Platelets < 50 000/mm3 INR > 1.5 unless subject has known hemophilia or is stable on an anticoagulant regimen affecting INR ALT or AST > 10xULN Creatinine clearance < 50 mL/mn (MDRD formula) Albumin < 30 g/L HbA1c > 10% (only in diabetic patients) Criteria related to study drugs Contra-indication to treatment with Grazoprevir/Elbasvir, Sofosbuvir or Ribavirin including a history of hypersensitivity to one of their excipients Patients with a non-compliance history, who will be at risk of not complying with the study follow-up timetable Treatment with contra-indicated associated drugs
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Victor DE LEDINGHEN
    Organizational Affiliation
    Hôpital de Haut-Lévêque, CHU de Bordeaux
    Official's Role
    Principal Investigator
    First Name & Middle Initial & Last Name & Degree
    Eric BELLISSANT
    Organizational Affiliation
    Centre de Méthodologie et de Gestion, CHU de Rennes
    Official's Role
    Study Chair

    12. IPD Sharing Statement

    Citations:
    PubMed Identifier
    29077864
    Citation
    de Ledinghen V, Laforest C, Hezode C, Pol S, Renault A, Alric L, Larrey D, Metivier S, Tran A, Jezequel C, Samuel D, Zoulim F, Tual C, Pailhe A, Gibowski S, Bourliere M, Bellissant E, Pawlotsky JM. Retreatment With Sofosbuvir Plus Grazoprevir/Elbasvir Plus Ribavirin of Patients With Hepatitis C Virus Genotype 1 or 4 Who Previously Failed an NS5A- or NS3-Containing Regimen: The ANRS HC34 REVENGE Study. Clin Infect Dis. 2018 Mar 19;66(7):1013-1018. doi: 10.1093/cid/cix916.
    Results Reference
    derived

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    Study to Assess Efficacy and Safety of Grazoprevir/Elbasvir Associated With Sofosbuvir and Ribavirin in HCV Genotype 1 or 4-infected Patients Who Failed Direct Acting Antivirals (DAA) Bitherapy With Sofosbuvir

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