Pharmacokinetics, Tolerability and Safety of Favipiravir Compared to Ribavirin for the Treatment of Lassa Fever: A Randomized Controlled Open Label Phase II Clinical Trial
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 40
- 试验地点
- 2
- 主要终点
- Pharmacokinetic parameter of favipiravir: Maximum plasma concentration (Cmax)
研究概览
简要总结
This exploratory, prospective, controlled, multisite, open label, randomized clinical trial with two treatment arms aims to compare favipiravir, a new treatment candidate for Lassa fever (LF), with the current standard of care, ribavirin.
The primary endpoints of this research are (1) the description of classical pharmacokinetic parameters of favipiravir in comparison with ribavirin standard treatment in patients suffering from LF and (2) the safety and tolerability of both study drugs in the investigated regimens.
详细描述
The currently used antiviral for the treatment of LF, which is also recommended by the World Health Organization (WHO) and the Nigeria Center for Disease Control, is ribavirin. However, evidence for ribavirin efficacy in LF patients adds up to the results of a single study with serious limitations. A promising new treatment candidate that showed efficacy against LF in preclinical studies is Favipiravir. It has further been evaluated for the treatment of Ebola Virus disease during the West-African Ebola outbreak and is approved for treatment of pandemic influenza virus infections in Japan.
The study will be conducted at two study sites in Nigeria: the Irrua Specialist Teaching Hospital (ISTH) and the Federal Medical Center of Owo (FMCO). Lassa fever patients of 18 years and older with LF confirmed by reverse-transcription polymerase chain reaction (RT-PCR) hospitalized at either ISTH or FMCO will be asked to participate in this study. A total of 40 evaluable participants will be randomized to two treatment arms (20 participants per arm): intravenous ribavirin standard of care treatment (Irrua regimen), oral favipiravir. Patients will be included in the study after giving written informed consent and if all inclusion criteria and no exclusion criteria are met. Multiple blood draws with the purpose of virologic, serologic and immunological analyses, hematological and biochemical analyses as well as pharmacokinetic analyses will be performed throughout the study duration of ten days. Adverse events (AEs), serious adverse events (SAEs) and pregnancy will be captured, monitored and followed-up. A medical monitor will be available for study investigators to assist with any clinical and safety related questions. An external data safety monitoring board (DSMB) will conduct periodic safety reviews.
Data will be captured on source documents and electronic case report forms (eCRFs). Informed consent forms will be stored in a lockable cabinet. Participants data will only be linked to the unique identifier to ensure pseudonymity.
Statistical analysis of study endpoints and pharmacokinetic parameters will be performed descriptively. Missing data will be treated as such, no imputation will be applied.
The study will be conducted in compliance with the protocol, the Declaration of Helsinki, the International Conference on Harmonisation-Good Clinical Practice (ICH-GCP) guideline and the Nigerian National Code for Health Research Ethics, in particular concerning the submission to the ethics committees and the protection of personal data as well as other national and regulatory requirements.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 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
- •Age ≥ 18 years
- •LF confirmed by RT-PCR (reverse-transcription polymerase chain reaction)
- •Written informed consent
排除标准
- •Inability to give consent (e.g. unconscious patients/ cognitively impaired patients)
- •Pregnancy/lactation (evidenced by negative urine pregnancy test in women of child-bearing potential)
- •Women who plan to get pregnant within the upcoming 6 months
- •Severe malnutrition (BMI<16)
- •Known intolerance to ribavirin or favipiravir
- •History of hemoglobinopathies (i.e., sickle-cell anaemia or thalassemia major) and/or haemophilia
- •Organ failure as evidenced by:
- •Creatinine ≥ 3x upper limit of normal (ULN)
- •Aspartate aminotransferase (AST/GOT) > 150 IU/l
- •Alert, confusion, voice, pain, unresponsive (ACVPU) score = V or P or U (corresponds to Glasgow Coma Scale (GCS) ≤ 12)
- •Severe central nervous system features (e.g. seizures, restlessness, confusion and coma)
- •O2 Saturation < 90%
- •Hematocrit <30 %
- •Severe anaemia requiring blood transfusion
- •Inability to take oral drug (e.g. encephalopathy, severe vomiting)
- •Patients who already received ribavirin or favipiravir within the preceding 7 days
研究组 & 干预措施
Intravenous ribavirin
standard treatment: Irrua regimen
- 100 mg/kg Day 1 (dose is divided: 2/3 stat, 1/3 8 hours later, maximum dose is 7g/day)
- 25 mg/kg days 2-7
- 12.5 mg/kg days 8-10
干预措施: Ribavirin iv (Drug)
Oral favipiravir
Oral favipiravir
- Day 1 2400mg(H0)-2400mg(H8)-1200mg(H16)
- Day 2-10 1200mg twice daily (BD)
干预措施: Favipiravir (Drug)
结局指标
主要结局
Pharmacokinetic parameter of favipiravir: Maximum plasma concentration (Cmax)
时间窗: Day 1, Day 2, Day 4, Day 6, Day 7, Day 8 and Day 10 of the study conduct
Maximum plasma concentration (Cmax) of favipiravir
Proportion of drug related AEs and SAEs of both study treatments
时间窗: throughout study completion (10 days per participant)
Safety and tolerability of ribavirin and favipiravir in investigated regimens by investigating the proportion of drug related AEs and SAEs
Pharmacokinetic parameter of favipiravir: Area under the concentration-time curve (AUC)
时间窗: Day 1, Day 2, Day 4, Day 6, Day 7, Day 8 and Day 10 of the study conduct
Area under the concentration-time curve (AUC) of favipiravir
Pharmacokinetic parameter of favipiravir: Half life (T1/2)
时间窗: Day 1, Day 2, Day 4, Day 6, Day 7, Day 8 and Day 10 of the study conduct
Half life (T1/2) of favipiravir
Pharmacokinetic parameter of favipiravir: Time to maximum concentration (Tmax)
时间窗: Day 1, Day 2, Day 4, Day 6, Day 7, Day 8 and Day 10 of the study conduct
Time to maximum concentration (Tmax) of favipiravir
次要结局
- Pharmacokinetic (PK) modelling and simulations(Day 1, Day 2, Day 4, Day 6, Day 7, Day 8 and Day 10 of the study conduct)
- Mutagenicity(10 days)
- Co-variates impacting on drug exposure(10 days)
- Change from baseline in Viral RNA loads(Day of enrollment - Day 10)
- Change from baseline in Lassa virus titers(Day of enrollment - Day 10)
- Change from baseline in Lassa virus serological status(10 days)
- Correlation between drug exposure and different parameters(10 days)