Lassa Fever
Conditions
Keywords
emerging infectious diseases, viral hemorrhagic fever, AFRICA, adult, adolescent
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
Interventions
DRUGFavipiravir
Interventional Medicinal Product (IMP)
DRUGRibavirin
Control arm
DRUGDexamethasone
Interventional Medicinal Product (IMP)
DRUGARN-75039 high dose
Investigational Medicinal Product
DRUGARN-75039 low dose
Investigational Medicinal Product
Sponsors
Irrua Specialist Teaching Hospital
Alliance for International Medical Action
University of Bordeaux
Bernhard Nocht Institute for Tropical Medicine
Federal Medical Centre, Owo
Programme PAC-CI, Site ANRS-MIE de Côte d'Ivoire
Fondation pour la Recherche Scientifique, Benin
Médecins Sans Frontières, Belgium
Alex Ekwueme Federal University Teaching Hospital
Donka Hospital, Conakry
Centre de Recherche Médicale de Lambaréné
University of Hamburg-Eppendorf
Phebe Hospital, Liberia
University of North Carolina
ANRS, Emerging Infectious Diseases
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
Participant, Investigator, Outcomes Assessor
Intervention model description
a) Arms Intervention/ treatement Arm 1: SCD: ribavirin Arm:2 Favirpiravir 1600 Arm 3: Favipiravir 1200+ribavirin Arm 4: Ribavirin + dexamethasone Arm 5: ARN-75039 high dose (100) Arm 6: ARN-75039 low dose (50)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. General 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
Exclusion criteria
* 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 2. Sub-protocols 2.1 Favipiravir high dose sub-protocol Inclusion criteria • Age ≥ 18 years old
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 D0 |
| New 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
| Measure | Time frame | Description |
|---|---|---|
| Safety of each IMP and SCD | Between Day 0 and Day 10 | Proportion (events and participants with at least one event) of: * Adverse Event\* grade 3 and higher * Serious Adverse Event * Adverse Event of Special Interest |
| Organ failure from composite primary endpoint | Between Day 0 and Day 10 | Proportion of participants with a newly occurring component of the composite primary endpoint |
| New onset of Acute Kidney Injury | Between Day 0 and discharge | Proportion of participants meeting KDIGO ≥ 2 or initiation of renal replacement therapy parameters |
| New onset of CVPU or seizure | Between Day 0 and Discharge | Proportion of participants with CVPU or seizure |
| New onset of Bleeding | Between Day 0 and Discharge | Proportion of participants meeting WHO bleeding scale grade 2 or above |
| New onset of Severe anaemia | Between Day 0 and Discharge | Proportion of participants with Hb level \< 8 g/dL |
| New onset of liver failure | Between Day 0 and Discharge | Proportion of participants with AST or ALT ≥ 3 ULN |
| New onset of clinical severity score | Between Day 0 and Discharge | Proportion of participants with a NEWS2 score ≥7 |
| Intensive care strategies - oxygen therapy | Between Day 0 and Discharge | Proportion of participants having received oxygen therapy |
| Intensive care strategies - RRT | Between Day 0 and Discharge | Proportion of participants having received RRT |
| Intensive care strategies - blood transfusion | Between Day 0 and Discharge | Proportion of participants having received blood transfusion |
| Intensive care strategies- inotropes or vasopressors | Between Day 0 and Discharge | Proportion of participants having received inotropes or vasopressors |
| 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 | D01-D10 | titer from D0 |
| viral clearance - LASV RT-PCR | D01- D10 | \<LLQ |
| Pharmacokinetics (phase II only) | Between Day 0 and Day 10 | • Peak concentration (Cmax) |
| PK/PD (phase II only) | Between Day 0 and Day 10 | • Prediction of initial viral load and slope of decline |
| LASV RT-PCR | D28 if participants have a positive RT PCR at discharge | LASV RT-PCR (Ct value) |
| Peak CRP (Phase II stage only) | D01-D10 | Peak CRP level (mg/L) |
| Time to first LASV RT-PCR <LLOQ | D01-D10 | Time to first LASV RT-PCR \<LLOQ (days) |
Countries
Liberia, Nigeria
Contacts
CONTACTCamille FRITZELL, PHD
CONTACTSylvain JUCHET
STUDY_DIRECTORMarie MD JASPARD, MD
ALIMA - The Alliance for International Medical Action - Paris, France
PRINCIPAL_INVESTIGATORSylvanus OKOGBENIN, MD
Irrua Specialist Teaching Hospital Irrua - Edo State, Nigeria
STUDY_CHAIRMichael RAMHARTER, MD
Bernhard Nocht Institute for Tropical Medicine Bernhard-Nocht-Hamburg, Germany
Outcome results
None listed