Clinical trial NCT02309450: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Hepatitis C Virus Genotype 4 Infection
Lead sponsor: ANRS, Emerging Infectious Diseases
Sponsor class: OTHER_GOV
Collaborators: name: Bristol-Myers Squibb
First posted: 2014-12-05
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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)

Eligibility criteria: 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

Primary outcomes:
measure: HCV sustained virological response rate
timeFrame: week 24
Secondary outcomes:
measure: Number of patients with adverse events
timeFrame: up to week 36
measure: Treatment interruptions
timeFrame: from day 0 to week12
measure: Causes of treatment discontinuation
timeFrame: form day 0 to week 12
measure: Self-reported symptoms
timeFrame: Day 0, week 12, week 36
measure: Patients adherence rate
timeFrame: week 4, week 12
measure: HCV viral load
timeFrame: day 0, week 1, week 2, week 4, week 8, week 12, week 16, week 20, week 24, week 36.
measure: Evaluation of the relationship between HCV subtypic distribution at baseline (by sequencing of the HCV NS5B domain) and the virological kinetics and response
timeFrame: at screening
measure: Proportion of patients with resistance mutations to Asunaprevir and/or Daclatasvir and/or BMS in case of virological failure
timeFrame: up to week 12
measure: Child-Pugh score (composite measure)
timeFrame: at screening
measure: Insulin resistance measured using the HOMA-IR score
timeFrame: Day 0, week 36
measure: Parameters that define metabolic syndrome
timeFrame: Day 0, week 36
measure: Evolution of liver fibrosis
timeFrame: Day 0, week 36
measure: MELD score (composite measure)
timeFrame: at screening
Other outcomes:
Locations:
city: All the Regions of the Country
country: France
facility: France
Study officials:
affiliation: Hopital Avicenne, APHP
name: Dominique Roulot, MD
role: PRINCIPAL_INVESTIGATOR
References: