ISTH/ANRS 0409s INTEGRATE Lassa Fever Study
- Conditions
- Lassa Fever
- Interventions
- Registration Number
- NCT06212336
- Lead Sponsor
- Irrua Specialist Teaching Hospital
- Brief Summary
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.).
- Detailed Description
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.
1. 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
2. Design
* Phase II: comparative controlled design
* Phase III: Whitehead's sequential double triangular design
3. Sample size:
In the current version of the protocol (if all sub-protocols start at once):
* 3 IMPs go into phase III: N= 732
* 2 IMPs go into phase III: N= 585
* 1 IMP go into phase III: N= 438
4. Duration
* Hospitalization: 10 days
* Follow-up: 28 days
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 1755
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Ribavirin Favipiravir 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). Favipiravir 1600 Ribavirin Oral favipiravir: 2400 mg BID D1; 1600 mg BID D2-D10 Favipiravir 1200 + ribavirin Favipiravir 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). Favipiravir 1200 + ribavirin 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). Ribavirin + dexamethasone Ribavirin 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.) Ribavirin + dexamethasone 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.)
- Primary Outcome Measures
Name Time Method Death 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 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 D0New onset of acute respiratory failure 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 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
- Secondary Outcome Measures
Name Time Method Safety of each IMP and SCD Day 0, Day 28 Proportion (events and participants with at least one event) of:
Adverse Event\* grade 3 and higher
* Serious Adverse Event
* Adverse Event of Special InterestOrgan failure from composite primary endpoint Between Day 0 and Day 10 Proportion of participants with a newly occurring component of the composite primary endpoint
Acute Kidney Injury Between Day 0 and Day 10 Proportion of participants meeting KDIGO ≥ 2 or initiation of renal replacement therapy parameters
Liver failure Between Day 0 and Day 10 Proportion of participants with AST or ALT ≥ 3 N
Clinical severity score Between Day 0 and Day 10 Proportion of participants with a NEWS2 score \> 7
Intensive care strategies - oxygen therapy Between Day 0 and Day 10 Proportion of participants having received oxygen therapy
Severe anaemia Between Day 0 and Day 10 Proportion of participants with Hb level \< 80 g/L
Encephalopathy Between Day 0 and Day 10 Proportion of participants with CVPU or seizure
Bleeding Between Day 0 and Day 10 Proportion of participants meeting WHO bleeding scale grade 2 or above
Intensive care strategies - RRT Between Day 0 and Day 10 Proportion of participants having received RRT
Intensive care strategies - blood transfusion Between Day 0 and Day 10 Proportion of participants having received blood transfusion
Intensive care strategies- inotropes Between Day 0 and Day 10 Proportion of participants having received inotropes
the viral clearance - Change in LF RT-PCR Ct Day 3, Day 5, Day 7, Day 9 value (for each target gene) from D0
the viral clearance - Change in LASV viral Day 3, Day 5, Day 7, Day 9 titer from D0
viral clearance - LASV RT-PCR Day 3, Day 5, Day 7, Day 9 \<LLQ
Pharmacokinetics (phase II only) Between Day 0 and Day 10 • Volume(s) of distribution
PK/PD (phase II only) Between Day 0 and Day 10 • Optimal dosing regimen with PK/PD modelling