Pilot Study to Assess Efficacy and Safety of a Triple Therapy With Asunaprevir, Daclatasvir, and BMS-791325 in HCV Genotype 4-infected Patients After Failure of Pegylated Interferon-Ribavirin Regimen (QUATTROTURBO)

Pilot Study to Assess Efficacy and Safety of a Triple Therapy With Asunaprevir, Daclatasvir and BMS-791325 in HCV Genotype 4-infected Patients After Failure of Pegylated Interferon-Ribavirin Regimen

ANRS HC 33 is a pilot study to assess efficacy and safety of a DCV 3DAA therapy with Asunaprevir, Daclatasvir and BMS-791325 in HCV genotype 4-infected patients after failure of pegylated Interferon-Ribavirin regimen.

Proportion of patients with cirrhosis will be limited to 50% of all patients included, cirrhosis being defined as a METAVIR score of F4 on the liver biopsy or an hepatic impulse elastometry ≥ 14 kPa or a Fibrotest® result > 0,75.

Study Overview

• Status: Withdrawn
• Conditions: Hepatitis C Virus Genotype 4 Infection
• Intervention / Treatment: Drug: .Asunaprevir, Daclatasvir and BMS - 791325

Detailed Description

The clinical trial is multi-centre, national, Phase 2, open-label, single-arm. The primary objective of this study is to assess, in HCV genotype 4-infected patients in failure to prior treatment with pegylated Interferon and Ribavirin bitherapy, the rate of sustained virological response (SVR) 12 weeks after 12 weeks of treatment with an all-oral combination of 3 DAAs in a Fixed-Dose-Combination (Asunaprevir 200 mg, Daclatasvir 30 mg and BMS - 791325 75 mg) twice a day.

Estimated enrollment is 60 patients during the enrolment period (9 months).

Schedule of assessments:

w4-w8 : screening D0 : Start of anti-HCV tritherapy (Asunaprevir + Daclatasvir + BMS-791325) w12: stop tritherapy w24: Sustained virological response SVR12 assessment (12 weeks post treatment) w36 : Sustained virological response SVR24 assessment (24 weeks post treatment)

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • All the Regions of the Country, France
    • France

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adult ≥18 years
• Infection with HCV genotype 4, confirmed by detectable HCV RNA ≥ 1000 IU/ml at pre-inclusion

• Failure to a prior treatment with pegylated Interferon and Ribavirin, with failure being defined as follows:

  • Non-response: HCV viral load remaining detectable during and at the end of P/R treatment.
  • Relapse: undetectable HCV viral load during P/R treatment and detectable after the end of the treatment.
  • HCV breakthrough: undetectable HCV viral load during P/R treatment becoming detectable before the end of treatment.
• Anti-HCV treatment discontinued for at least the last 3 months

• Fibrosis at any stage, with documentation of the presence or absence of cirrhosis at the pre-inclusion visit:

  • history of liver biopsy showing cirrhosis lesions (METAVIR F4), at any time in the patient's history, or
  • good quality (length ≥ 1 cm and ≥ 5 portal spaces) liver biopsy dating from less than 18 months to establish the METAVIR, or
  • hepatic impulse elastometry (Fibroscan®) dating from less than 6 months and of good quality (at least 10 measurements on an incidence with IQR of less than 30% of the median elastometry measured and a success rate of 60%) or
  • interpretable Fibrotest® dating from less than 6 months The proportion of patients with cirrhosis will be limited to 50% of all patients included, cirrhosis being defined as a METAVIR score of F4 on the liver biopsy or an hepatic impulse elastometry ≥ 14 kPa or a Fibrotest® result > 0,75.
• Men and women of a child-bearing age and their heterosexual partners must use adequate contraception during treatment and up to 8 weeks after the end of treatment for women, 12 weeks after the end of treatment for men.
• 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:

Medical history

• CHILD B or C cirrhosis
• Previous HCV therapy including HCV NS3 protease inhibitor, and/or HCV NS5A replication complex inhibitor and/or HCV NS5B polymerase inhibitor

Current condition

• Positive HBs Antigen
• Confirmed HIV-1 or HIV-2 infection
• Pregnant or breast-feeding women
• Transplant recipients
• Any evolutive ongoing malignant disease, including hepatocellular carcinoma, which will be specifically screened for before inclusion
• 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 during the 30 days prior to inclusion
• Patient under guardianship, trusteeship or judicial protection

Biological criteria

• ALT ≥ 5xULN
• Total bilirubin ≥ 34 µmol/L, unless a documented history of Gilbert's disease
• Hb < 85 g/L
• Platelets < 50 000/mm3
• Kidney failure defined by creatinine clearance < 50mL/mn (MDRD formula)
• QTc > 440 msec for males or 460 msec for females

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Asunaprevir, Daclatasvir and BMS - 791325	Drug: .Asunaprevir, Daclatasvir and BMS - 791325; All patients will receive an all-oral HCV tritherapy with Asunaprevir (200mg), Daclatasvir (30mg) and BMS-791325 (75mg) in a fixed-dose combination (FDC) tablet, twice a day (1 tablet in the morning and 1 tablet in the evening) for 12 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HCV sustained virological response rate	The primary endpoint is the Sustained Virological Response Rate defined by an undetectable HCV RNA at W24, that is to say 12 weeks after the end of the DCV 3DAA therapy associating Asunaprevir, Daclatasvir and BMS - 791325 (SVR12). In case of premature total or partial interruption of HCV treatment, the primary endpoint will also be assessed at week 24.	week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with adverse events		up to week 36
Treatment interruptions	Number of patients who totally or partially interrupt,treatment	from day 0 to week12
Causes of treatment discontinuation	toxicity or side effects	form day 0 to week 12
Self-reported symptoms	self-questionnaire (ANRS AC24 perceived symptoms scale)	Day 0, week 12, week 36
Patients adherence rate	measured using the (ANRS) self -questionnaire	week 4, week 12
HCV viral load		day 0, week 1, week 2, week 4, week 8, week 12, week 16, week 20, week 24, week 36.
Evaluation of the relationship between HCV subtypic distribution at baseline (by sequencing of the HCV NS5B domain) and the virological kinetics and response		at screening
Proportion of patients with resistance mutations to Asunaprevir and/or Daclatasvir and/or BMS in case of virological failure		up to week 12
Child-Pugh score (composite measure)	For cirrhotic patients Encephalopathy None+1 Mild to moderate (grade 1 or 2)+2 Severe (grade 3 or 4)+3 Ascites None+1 Mild to moderate (diuretic responsive)+2 Severe (diuretic refractory)+3 Bilirubin (mg/dL) < 2+1 2-3+2 > 3+3 Albumin (g/dL) > 3.5+1 2.8-3.5+2 < 2.8+3 International normalized ratio < 1.7+1 1.7-2.3+2 > 2.3+3 Total score of 5-6 = Grade A (well compensated disease) Total score of 7-9 = Grade B (disease with significant functional compromise) Total score of 10-15 = Grade C (decompensated liver disease)	at screening
Insulin resistance measured using the HOMA-IR score		Day 0, week 36
Parameters that define metabolic syndrome		Day 0, week 36
Evolution of liver fibrosis	Fibrotest® or imaging Fibroscan®. Fibrosis will be evaluated with the same method (Fibroscan® or Fibrotest®) at baseline and week 36.	Day 0, week 36
MELD score (composite measure)	For cirrhotic patients MELDScore = 10 * ((0.957 * ln(Creatinine)) + (0.378 * ln(Bilirubin)) + (1.12 * ln(INR))) + 6.43	at screening

Collaborators and Investigators

• Sponsor: ANRS, Emerging Infectious Diseases
• Collaborators: Bristol-Myers Squibb
• Investigators: Principal Investigator: Dominique Roulot, MD, Hopital Avicenne, APHP

Study record dates

Study Major Dates

• Study Start: December 1, 2014
• Primary Completion (Anticipated): November 1, 2015
• Study Completion (Anticipated): August 1, 2016

Study Registration Dates

• First Submitted: October 31, 2014
• First Submitted That Met QC Criteria: December 3, 2014
• First Posted (Estimate): December 5, 2014

Study Record Updates

• Last Update Posted (Estimate): February 2, 2016
• Last Update Submitted That Met QC Criteria: February 1, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• 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; Hepatitis; Hepatitis C; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Asunaprevir
• Other Study ID Numbers: ANRSHC33QUATTROTURBO; 2014-002724-27 (EudraCT Number)