Efficacy of Favipiravir in Reducing Mortality in Individuals With Ebola Virus Disease in Guinea
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 126
- 试验地点
- 4
- 主要终点
- Mortality
研究概览
简要总结
There is no specific treatment for Ebola Virus Disease (EVD). Current EVD care are supportive, and includes intravenous or oral rehydration, nutrition, pain killers, treatment of coinfections with antibacterial and antimalarial drugs, and blood transfusion when appropriate. Despite these interventions, mortality remains high since the ongoing Ebola outbreak in West Africa was declared in April.
Potential anti-Ebola specific interventions include convalescent plasma, monoclonal and polyclonal antibodies, small inhibitory RNA (siRNA), synthetic adenosine analogues or RNA polymerase inhibitors. All these interventions are considered investigational due to lack of data in humans with EVD.
In this study, the investigators chose to study the efficacy of favipiravir because this drug:
- showed anti-Ebola efficacy in immunodeficient murine models;
- has been studied in thousands of adult humans participating in anti-influenza trials, with good tolerance; it has been approved for treating novel or resistant influenza infections in Japan;
- is immediately available;
- can be used orally, and can be easily given in both adults and children because pills can be crushed and mixed in food or liquids;
- has recently been used in Europe for treating several patients with EVD; the French drug safety agency (ANSM) has reviewed published data as well as data provided by the firm (Toyama Chemical Co., Ltd), and approved its compassionate use in EVD.
Here the investigators propose to assess the efficacy of high-dosed favipiravir in reducing mortality in humans with EVD.
In the present trial "JIKI" (means "Hope" in "Kissi" language), investigators, sponsor, scientific advisory board and safety monitoring board will be coordinated in a very reactive way, so that any new fact can be discussed rapidly and the research plan can be adapted accordingly (change in drug dosage; use of drug combination; combination with another strategy such as passive immunization with convalescent plasma, etc.).
详细描述
Hypotheses:
- The efficacy of antivirals in patients with EVD should correlate negatively with time since first symptoms. Thus, in this proof of concept trial, the main analysis will be done in adult patients with early symptoms in whom the efficacy is expected to be the highest;
- Favipiravir for EVD should be given at higher doses than that previously tested in studies in human with influenza. For this trial, the dose was calculated based on pharmacokinetics simulations, to rapidly reach plasma concentrations associated with anti-EBOV activity.
- A third assumption was made, given recent pre-trial data showing first a strong link between baseline viral load and mortality and second a higher mortality in children below 6 years: the efficacy of antivirals in patients with EVD should correlate negatively with viral load at start of treatment and with young age. Thus a secondary objective is the efficacy of favipiravir in adult patients and children >6 years with moderate baseline viral load (i.e. cycle threshold [Ct] ≥20 measured by RT-PCR) in whom the efficacy is expected to be the highest.
A comparative trial of favipiravir against a standard package of care (with or without placebo) has been deemed not appropriate because of: i) the highly sensitive social and political context; ii) the need to collect rapidly basic phase II evidence on the efficacy of high dosed favipiravir on EVD before choosing the best intervention(s) to be tested in phase III (favipiravir alone or in combination with other drugs; other therapeutic options including convalescent plasma).
Therefore, the investigators propose a non-comparative, proof-of-concept, phase II trial in patients with EVD, which will allow concluding within a few weeks:
- that mortality in patients starting favipiravir within 72 hours after the onset of first symptoms is inferior to mortality without treatment prior to the trial initiation;
- or that there is no trend that favipiravir brings significant benefit in terms of survival.
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
- 1 Year 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •age >1 year and weighting ≥10kg,
- •EVD confirmed by a positive qualitative PCR test,
- •signed informed consent (signed by the parents/adults guardians in case of minor patient).
- •Non inclusion-criteria:
- •pregnancy*,
- •inability to take the drug (encephalopathy, severe vomiting). * Emergency use of favipiravir in pregnant women outside of the trial is envisaged and under evaluation.
- •In this protocol, the investigators will refer to the following groups according to age and duration of symptoms**:
- •Group A1: adults with time between first symptoms and first dose of favipiravir ≤72h;
- •Group A2: adults with time between first symptoms and first dose of favipiravir >72h;
- •Group C: all children >1 year and weighting ≥10kg. Time of first symptom refers to the time of the beginning of any symptom considered to be related to EVD. **Symptoms to be considered will be: acute onset of fever, severe headache, myalgia, extreme fatigue, vomiting, diarrhoea, abdominal pain, or unexplained hemorrhage.
- •The division in groups is a matter of analysis, and will not be perceptible by the patients during the trial process. Patients in the three groups will receive the same treatment and will be followed under the same procedures, with only two exceptions: the number of additional blood sample collections will be lower in group A2 and C (n=2) than in group A1 (n=3) and daily dosages will be adapted to the body weight in group C.
排除标准
- 未提供
研究组 & 干预措施
Favipiravir
Favipiravir (oral administration, 200 mg light yellow, round-shaped, coated divisible tablets that can be crushed and mixed with liquid)
干预措施: Favipiravir (Drug)
结局指标
主要结局
Mortality
时间窗: Day-14
Day-0 is the day of the first dose of favipiravir
次要结局
- Mortality(Day-14 according to the second group definition (AC1, AC2, YC))
- Plasma trough concentrations of favipiravir(routine care venepuncture (Day-0; end of symptoms (EOS)+72h and EOS+96h if EOS >Day-9; or Day-12 and Day-13 if EOS <Day-9); (ii) additional trial venepuncture at: Day-2, Day-4 and Day-30 in group A1; Day-2 and Day-30 in group A2)
- Criteria for cure(Day-30)
- Evolution of EBOV plasma RNA and infectious loads(routine care venepuncture (Day-0; end of symptoms (EOS)+72h and EOS+96h if EOS >Day-9; or Day-12 and Day-13 if EOS <Day-9); (ii) additional trial venepuncture at: Day-2, Day-4 and Day-30 in group A1; Day-2 and Day-30 in group A2)
- Occurrence of grade 3 or 4 clinical or biological adverse events (Common Terminology Criteria for Adverse Events, CTAE, v3.0)(participants will be followed for the duration of hospital stay up to Day-14)
- Evolution of viral micro-diversity of EBOV (including potential resistance mutations)(routine care venepuncture (Day-0; end of symptoms (EOS)+72h and EOS+96h if EOS >Day-9; or Day-12 and Day-13 if EOS <Day-9); (ii) additional trial venepuncture at: Day-2, Day-4 and Day-30 in group A1; Day-2 and Day-30 in group A2)