Pilot Study to Assess Efficacy and Safety of a Quadruple Therapy With Asunaprevir, Daclatasvir, Ribavirin and Pegylated Interferon Alpha-2a in HCV Genotype 4-infected Patients Non-responders to Pegylated Interferon-Ribavirin Regimen
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 60
- 试验地点
- 49
- 主要终点
- SVR12 Rate
研究概览
简要总结
Success rates, after retreatment with Peg-Interferon/Ribavirin bitherapy, in patients infected with HCV (hepatitis C virus) genotype 4 and non-responders to a first standard treatment, are disappointing. The association of Asunaprevir and Daclatasvir in combination with the standard-of-care bitherapy has been shown to increase the efficacy of the treatment in non-responders genotype 1-infected patients.
Given the absence of current solutions and urgent therapeutic needs for HCV genotype 4-infected patients previously treated with pegylated Interferon/Ribavirin, this pilot study aims to evaluate the efficacy and safety of a quadritherapy associating Asunaprevir, Daclatasvir, pegylated Interferon alpha-2a and Ribavirin, in this very difficult to treat population.
60 subjects will be enrolled.
The primary endpoint will be the rate of sustained virological response (SVR), defined by an undetectable HCV RNA, at Week 36 (12 weeks after the end of a 24 weeks quadritherapy).
详细描述
The population studied presents the maximum of factors of non-response to the retreatment of hepatitis C: non-response to well followed prior treatment with pegylated Interferon and Ribavirin, infection with HCV genotype 4, and the presence of cirrhosis (in less than 50% of the included patients) that could diminish the chances of SVR to a standard bitherapy.
The likelihood of SVR with standard bitherapy in this study population is thus considered low, around 15%.
The principal objective of this multicentric, national, single-arm, open-labeled, non-randomized phase II pilot study in 60 patients, is to assess the rate of SVR 12 weeks after 24 weeks of quadritherapy and to determine whether this rate is significantly greater than 20%.
The proportion of patients presenting with cirrhosis (defined by a METAVIR F4 score on liver biopsy or with hepatic impulse elastometry ≥ 15 kPa) will be limited to 50% of all patients included.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult ≥18 years
- •Infection with HCV genotype 4, confirmed by detectable HCV RNA ≥ 1000 IU/ml at pre-inclusion
- •Non-responders to a prior treatment with pegylated Interferon and Ribavirin, with non-response being defined as follows:
- •Null-response: reduction of less than 2 log10 IU/ml of HCV viral load between D0 of the treatment and week 12
- •Partial response: reduction of at least 2 log10 IU/ml of HCV viral load between D0 of the treatment and week 12 but detectable HCV RNA at week 12 and week 24 and without an undetectable viral load by 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, and/or
- •good quality (length ≥ 15 mm and ≥ 6 portal spaces) liver puncture biopsy from less than 18 months to establish the METAVIR, and/or
- •hepatic impulse elastometry (Fibroscan®) from less than 6 months and of good quality (at least 10 measurements on an incidence with an IQR of less than 30% of the mean elastometry measured and a success rate of 60%)
- •Body weight ≥ 40 kg and ≤125 kg
- •Men and women of child-bearing age and their heterosexual partners must use two adequate contraceptions from 1 month before initiation of treatment up to 7 months after the end of treatment for men and up to 4 months after treatment for women.
- •Written informed consents (2) 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)
- •Patients with Health insurance (Sécurité Sociale or Couverture Médicale Universelle)
排除标准
- •CHILD B or C cirrhosis or a history of decompensated cirrhosis. If Child A cirrhosis, presence of varices presenting an hemorrhagic risk (grade II with red spots or grade III) on a fibroscopy dating from less than 3 years
- •Previous HCV therapy including HCV NS3 protease inhibitor, and/or HCV NS5A replication complex inhibitor and/or HCV NS5B polymerase inhibitor
- •Positive HBs Antigen
- •Confirmed HIV-1 or HIV-2 infection
- •Pregnant or breast-feeding women
- •Severe heart or lung disease
- •Transplant recipient
- •Uncontrolled dysthyroidism
- •Uncontrolled diabetes
- •Any evolutive ongoing malignant disease, including hepatocellular carcinoma, which will be specifically screened for before inclusion
- •Consumption of alcohol which, in the opinion of the investigator, will be an obstacle to participation of the patient and to his remaining in the study
- •Drug addiction which, in the the investigator's opinion, will be an obstacle to the patient's participation and to his or her remaining in the study. Patients included in a programme of substitution with methadone or buprenorphine could be included. The opinion of a consultant in addictology 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 preceding inclusion.
- •Patient under guardianship, trusteeship or judicial protection
- •Hb < 110 g/L
- •Platelets < 80 000/mm3
- •Polynuclear neutrophils < 1000 /mm3 (for European patients) and < 750 /mm3 (for African patients)
- •Kidney failure defined by creatinine clearance < 50mL/mn (MDRD formula)
- •Contra-indication for treatment with Ribavirin including a history of hypersensitivity to Ribavirin or to one of the excipients
- •Contra-indication for treatment with Daclatasvir or Asunaprevir including a history of hypersensitivity to one of the excipients
- •Contra-indication to treatment with Interferon including psychiatric contra-indications. A psychiatrist's opinion is compulsory in the following situations :
- •history of psychiatric disorders requiring hospitalisation of the patient or a consultation with a specialist
- •treatment with mood stabilizers or antipsychotics during the previous year
- •history of psychiatric disorders during prior treatment with Interferon alpha
- •evidence of depression episodes, a risk of suicide, bipolar disorder and/or current behavioral disorders. These patients can only be included after a psychiatric evaluation that specifically authorizes the use of Interferon.
- •History of previous HCV treatment premature cessation (in the first 6 months) for toxicity. Premature cessation for anemia or neutropenia will be authorized in the absence of the use of erythropoietin or polynuclear neutrophil growth factor, respectively.
- •Patients with a non-compliance history, who will be at risk of not complying with the study follow-up timetable
- •Associated treatment likely to interfere with the study drugs
研究组 & 干预措施
Asunaprevir, Daclatasvir, Ribavirin, Peg-Interferon alpha-2a
Quadritherapy from Day 0 to Week 24
干预措施: Pegylated Interferon alpha-2a (Drug)
Asunaprevir, Daclatasvir, Ribavirin, Peg-Interferon alpha-2a
Quadritherapy from Day 0 to Week 24
干预措施: Asunaprevir (Drug)
Asunaprevir, Daclatasvir, Ribavirin, Peg-Interferon alpha-2a
Quadritherapy from Day 0 to Week 24
干预措施: Ribavirin (Drug)
Asunaprevir, Daclatasvir, Ribavirin, Peg-Interferon alpha-2a
Quadritherapy from Day 0 to Week 24
干预措施: Daclatasvir (Drug)
结局指标
主要结局
SVR12 Rate
时间窗: Week 36
HCV RNA measured 12 weeks after the end of the HCV treatment (Week 36)
次要结局
- Self-reported symptoms(Day 0, Week 12, Week 36)
- Patients' adherence(Week 4, Week 12, Week 24)
- HCV viral load(Day 0, Weeks 1, 2, 4, 8, 12, 16, 20, 24, 28, 36, 48)
- Number of patients with adverse events(Up to Week 48)
- Number of patients with virological failure under treatment(Up to Week 24)
- Proportion of patients with resistance mutations to Asunaprevir and/or Daclatasvir in case of virological failure(Up to Week 48)
- Insulin resistance : HOMA-IR score(Day 0, Week 36)
- Treatment discontinuations(Up to Week 24)
- HCV subtypic distribution(Baseline)
- Cirrhosis evaluation(Baseline, Week 12, Week 24, Week 36, Week 48)
- SVR 24 rate(Week 48)
- Metabolic syndrome parameters(Day 0, Week 36)
- Polymorphism of the gene of IL28B(Day 0)
- Liver fibrosis(Between baseline and Week 48)