Efficacy, Tolerability and Safety of New or Repurposed Drugs Against Lassa Fever in West African Countries
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 1,755
- 试验地点
- 4
- 主要终点
- Death
研究概览
简要总结
Lassa fever (LF) is a viral haemorrhagic fever responsible of 5000 deaths per year in West Africa, with in-hospital mortality at 12%. Transmission to humans occurs mainly via direct or indirect exposure to excreta from the rodent reservoir, mainly made up of Mastomys natalensis . Less frequently, LASV may also be transmitted from human to human and cause nosocomial outbreaks. Ribavirin is the only treatment available with worrying toxicity, questionable efficacy and low access because of its high cost. Consequently, there is an urgent need for new drugs to treat LF patients. The Research and Development (R&D) Blueprint of the World Health Organization (WHO) has included LF in the list of priority diseases for urgent research and development.
The INTEGRATE consortium is an unprecedented international collaboration on Lassa fever of 15 partners from 10 countries across West Africa, Europe and North America and across several disciplines (epidemiological researchers, social scientists, medical health facility professionals, humanitarian actors, etc.).
详细描述
The INTEGRATE study is a platform, multinational, multicentre, sequential, seamless phase II-III, controlled, randomised, superiority trial in open-label parallel arms. Three arms will be assessed and compared to the SCD. Its primary objective is to compare the efficacy of each Investigational Medical Product (IMP) to Standard of Care Drug (SCD) to prevent death or organ failure in hospitalized patients with confirmed LF. Secondary objectives will be i) to compare the safety and tolerability of each IMP and SCD, ii) to compare the efficacy of each IMP and SCD on clinical, virological and biological parameters, iii) to describe the pharmacokinetics of each IMP and iv) to develop a pharmacokinetics / pharmacodynamics model for each IMP informing about optimal dosing regimens and dose-response relationship.
- Objectives
1.1 Primary objective The primary objective of the trial is to compare the efficacy of each IMP and SCD to prevent death or organ failure in hospitalized participants with confirmed LF.
1.2. Secondary objectives
- To compare the safety and tolerability of each IMP and SCD
- To compare the efficacy of each IMP and SCD on clinical, virological and biological parameters
- To describe the pharmacokinetics of each IMP
- To develop a pharmacokinetics / pharmacodynamics model for each IMP informing about optimal dosing regimens and dose-response relationship
- Design
- Phase II: comparative controlled design
- Phase III: Whitehead's sequential double triangular design
- Sample size:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
Participant, Investigator, Outcomes Assessor
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
- •Inclusion criteria
- •Clinical disease with signs and symptoms suggestive for LF
- •Positive plasma LASV RT-PCR
- •Participant requires hospitalization per the local guidelines
- •Participant or their legally authorized representative is able and willing to sign the informed consent
排除标准
- •Unwilling to provide informed consent
- •Positive pregnancy test
- •Unwilling to provide informed consent
- •History of allergic reaction or other contra-indication to ribavirin according to the Reference safety document
- •Received drug therapy for Lassa fever (excluding supportive care) prior to inclusion
- •Has received a vaccine against LF
- •Sub-protocols
- •2.1 Favipiravir high dose sub-protocol
- •Inclusion criteria • Age ≥ 18 years old
- •Exclusion criteria • Pregnancy (evidenced by positive urine pregnancy test in women of child-bearing potential)
- •Treatment contraindicated with favipiravir according to the Reference safety document
- •Pre-existing liver failure
- •Severe symptomatic gout/hyperuricemia
- •History of QT prolongation or arrhythmia or other cardiac disorders
- •PR interval ≥ 200 ms
- •Hypersensitivity to excipients
- •Inability to take oral drug (e.g. encephalopathy, severe vomiting)
- •Favipiravir-Ribavirin sub-protocol
- •Inclusion criteria
- •Age ≥ 18 years old
- •Exclusion criteria
- •Pregnancy (evidenced by positive urine pregnancy test in women of child-bearing potential)
- •Treatment contraindicated with favipiravir according to the Reference safety document
- •Pre-existing liver failure
- •Severe symptomatic gout/hyperuricemia
- •History of QT prolongation or arrhythmia or other cardiac disorders
- •PR interval ≥ 200 ms
- •Hypersensitivity to excipients
- •Inability to take oral drug (e.g. encephalopathy, severe vomiting)
- •Dexamethasone sub-protocol
- •Inclusion criteria • Age ≥ 12 years old
- •Exclusion criteria
- •Pregnancy (evidenced by positive urine pregnancy test in women of child-bearing potential)
- •Known intolerance and contra-indications to ribavirin or dexamethasone
- •Patients who already received a corticosteroid within the preceding 7 days
- •2.4 ARN-75039 subprotocols
- •Exclusion criteria • History of severe gastrointestinal disease
- •History of chronic generalized pruritus
- •History of severe chronic liver disease
- •History of severe cardiac disorder
研究组 & 干预措施
Ribavirin
Intravenous ribavirin (Irrua regimen - 100 mg/kg Day 1 (dose is divided: 2/3 stat, 1/3 8 hours later, maximum dose is 7g/day) then 25 mg/kg single dose days 2-7, 12.5 mg/kg single dose days 8-10).
干预措施: Favipiravir (Drug)
Favipiravir 1200 + ribavirin
Oral favipiravir: 2400 mg BID D1; 1200 mg BID D2-D10 Intravenous ribavirin (Irrua regimen - 100 mg/kg Day 1 (dose is divided: 2/3 stat, 1/3 8 hours later, maximum dose is 7g/day) then 25 mg/kg single dose days 2-7, 12.5 mg/kg single dose days 8-10).
干预措施: Favipiravir (Drug)
Favipiravir 1200 + ribavirin
Oral favipiravir: 2400 mg BID D1; 1200 mg BID D2-D10 Intravenous ribavirin (Irrua regimen - 100 mg/kg Day 1 (dose is divided: 2/3 stat, 1/3 8 hours later, maximum dose is 7g/day) then 25 mg/kg single dose days 2-7, 12.5 mg/kg single dose days 8-10).
干预措施: Ribavirin (Drug)
Ribavirin + dexamethasone
IV ribavirin, Irrua regimen IV or oral dexamethasone 6mg/day (For the first 48 hours, dexamethasone will be given intravenously (i. Afterwards, a switch to oral dexamethasone (same dosage) is permitted at the discretion of the study physician.)
干预措施: Ribavirin (Drug)
Ribavirin + dexamethasone
IV ribavirin, Irrua regimen IV or oral dexamethasone 6mg/day (For the first 48 hours, dexamethasone will be given intravenously (i. Afterwards, a switch to oral dexamethasone (same dosage) is permitted at the discretion of the study physician.)
干预措施: Dexamethasone (Drug)
Favipiravir 1600
Oral favipiravir: 2400 mg BID D1; 1600 mg BID D2-D10
干预措施: Favipiravir (Drug)
ARN-75039 high dose
• ARN-75039 high dose
- D1: 300mg (morning), 200mg (evening)
- D2: 200mg BID
- D3-10: 100mg BID
干预措施: ARN-75039 high dose (Drug)
ARN-75039 low dose
• ARN-75039 low dose
- D1: 150mg (morning), 100mg (evening)
- D2: 100mg BID
- D3-10: 50mg BID
干预措施: ARN-75039 low dose (Drug)
结局指标
主要结局
Death
时间窗: Day 28
Proportion of participants death definition by Y/N measure Clinical aggravation is defined as the first occurrence of one of the following conditions, at any time point between baseline and Day 14 (included): Death, or Increase (+1 or +2) in the number (0, 1 or 2) of organ failures among: Renal failure: KDIGO stage 3 Respiratory failure: SpO2/FiO2\* ≤ 315 Cardiovascular failure: MBP\*\* \< 65 mmHg or SBP \< 90 mmHg (measured twice with a time interval of 10 min) and lactate \> 2 mmol/L Analysis per component Proportion of participants with a newly occurring component of the composite primary endpoint between Day 0 and Day 14. Sensitivity analyses Proportion of participants presenting no clinical aggravation between baseline and Day 14, with varying thresholds on the definitions of organ failures or adding different organ failures definition (e.g. neurologic, hepatic, hematologic, etc.).
New onset of acute kidney failure
时间窗: Between Day 0 and Day 10
Proportion of participants a new onset of acute kidney failure . Definition by KDIGO 3 measure. 3.0 times baseline, OR increase in serum creatinine to ≥4.0 mg/dl (≥353.6 mmol/l). The composite endpoint assesses the new onset of an event from D0
New onset of acute respiratory failure
时间窗: Between Day 0 and Day 10
Proportion of participants a new onset of acute respiratory failure. Definition by SpO2/FiO2 ≤ 315 measure The composite endpoint assesses the new onset of an event from D0
New onset of shock
时间窗: Between Day 0 and Day 10
Proportion of participants a New onset of shock. Mean Blood Pressure (MBP) \< 65 mmHg or Systolic Blood Pressure (SBP) \< 90 mmHg (measured twice with a time interval of 10 min) and lactate \> 2 mmol/L measured at the same time The composite endpoint assesses the new onset of an event from D0
次要结局
- the viral clearance - Change in LF RT-PCR Ct(Day 3, Day 5, Day 7, Day 9)
- Safety of each IMP and SCD(Day 0, Day 28)
- Organ failure from composite primary endpoint(Between Day 0 and Day 10)
- Pharmacokinetics (phase II only)(Between Day 0 and Day 10)
- PK/PD (phase II only)(Between Day 0 and Day 10)
- Safety of each IMP and SCD(Between Day 0 and Day 10)
- New onset of Acute Kidney Injury(Between Day 0 and discharge)
- New onset of CVPU or seizure(Between Day 0 and Discharge)
- New onset of Bleeding(Between Day 0 and Discharge)
- New onset of Severe anaemia(Between Day 0 and Discharge)
- New onset of liver failure(Between Day 0 and Discharge)
- New onset of clinical severity score(Between Day 0 and Discharge)
- Intensive care strategies - oxygen therapy(Between Day 0 and Discharge)
- Intensive care strategies - RRT(Between Day 0 and Discharge)
- Intensive care strategies - blood transfusion(Between Day 0 and Discharge)
- Intensive care strategies- inotropes or vasopressors(Between Day 0 and Discharge)
- the viral clearance - Change in LASV viral(D01-D10)
- viral clearance - LASV RT-PCR(D01- D10)
- LASV RT-PCR(D28 if participants have a positive RT PCR at discharge)
- Peak CRP (Phase II stage only)(D01-D10)
- Time to first LASV RT-PCR <LLOQ(D01-D10)