Clinical trial NCT06212336: ISTH/ANRS 0409s INTEGRATE Lassa Fever Study
Official title: Efficacy, Tolerability and Safety of New or Repurposed Drugs Against Lassa Fever in West African Countries
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
PHASE3
Conditions: Lassa Fever
Keywords: emerging infectious diseases
viral hemorrhagic fever
AFRICA
adult
adolescent
Lead sponsor: Irrua Specialist Teaching Hospital
Sponsor class: OTHER
Collaborators: name: Alliance for International Medical Action
name: University of Bordeaux
name: Bernhard Nocht Institute for Tropical Medicine
name: Federal Medical Centre, Owo
name: Programme PAC-CI, Site ANRS-MIE de Côte d'Ivoire
name: Fondation pour la Recherche Scientifique, Benin
name: Médecins Sans Frontières, Belgium
name: Alex Ekwueme Federal University Teaching Hospital
name: Donka Hospital, Conakry
name: Centre de Recherche Médicale de Lambaréné
name: University of Hamburg-Eppendorf
name: Phebe Hospital, Liberia
name: University of North Carolina
name: ANRS, Emerging Infectious Diseases
First posted: 2024-01-18
Enrollment: 1755
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: a) Arms

Intervention/ treatement

Arm 1: SCD: ribavirin Arm:2 Favirpiravir 1600 Arm 3: Favipiravir 1200+ribavirin Arm 4: Ribavirin + dexamethasone
Primary purpose: TREATMENT

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

Eligibility 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

   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)

   2.2. 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)

   2.3. 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

Primary outcomes:
measure: Death
timeFrame: Day 28
measure: New onset of acute kidney failure
timeFrame: Between Day 0 and Day 10
measure: New onset of acute respiratory failure
timeFrame: Between Day 0 and Day 10
measure: New onset of shock
timeFrame: Between Day 0 and Day 10
Secondary outcomes:
measure: Safety of each IMP and SCD
timeFrame: Between Day 0 and Day 10
measure: Safety of each IMP and SCD
timeFrame: Day 0, Day 28
measure: Organ failure from composite primary endpoint
timeFrame: Between Day 0 and Day 10
measure: Acute Kidney Injury
timeFrame: Between Day 0 and Day 10
measure: Encephalopathy
timeFrame: Between Day 0 and Day 10
measure: Bleeding
timeFrame: Between Day 0 and Day 10
measure: Severe anaemia
timeFrame: Between Day 0 and Day 10
measure: Liver failure
timeFrame: Between Day 0 and Day 10
measure: Clinical severity score
timeFrame: Between Day 0 and Day 10
measure: Intensive care strategies - oxygen therapy
timeFrame: Between Day 0 and Day 10
measure: Intensive care strategies - RRT
timeFrame: Between Day 0 and Day 10
measure: Intensive care strategies - blood transfusion
timeFrame: Between Day 0 and Day 10
measure: Intensive care strategies- inotropes
timeFrame: Between Day 0 and Day 10
measure: the viral clearance - Change in LF RT-PCR Ct
timeFrame: Day 3, Day 5, Day 7, Day 9
measure: the viral clearance - Change in LASV viral
timeFrame: Day 3, Day 5, Day 7, Day 9
measure: viral clearance - LASV RT-PCR
timeFrame: Day 3, Day 5, Day 7, Day 9
measure: Pharmacokinetics (phase II only)
timeFrame: Between Day 0 and Day 10
measure: Pharmacokinetics (phase II only)
timeFrame: Between Day 0 and Day 10
measure: Pharmacokinetics (phase II only)
timeFrame: Between Day 0 and Day 10
measure: Pharmacokinetics (phase II only)
timeFrame: Between Day 0 and Day 10
measure: Pharmacokinetics (phase II only)
timeFrame: Between Day 0 and Day 10
measure: Pharmacokinetics (phase II only)
timeFrame: Between Day 0 and Day 10
measure: PK/PD (phase II only)
timeFrame: Between Day 0 and Day 10
measure: PK/PD (phase II only)
timeFrame: Between Day 0 and Day 10
Other outcomes:
measure: Viral resistance parameters
timeFrame: Between Day 0 and Day 10
Locations:
Study officials:
affiliation: ALIMA - The Alliance for International Medical Action - Paris, France
name: Marie MD JASPARD, MD
role: STUDY_DIRECTOR
affiliation: Irrua Specialist Teaching Hospital Irrua - Edo State, Nigeria
name: Sylvanus OKOGBENIN, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Bernhard Nocht Institute for Tropical Medicine Bernhard-Nocht-Hamburg, Germany
name: Michael RAMHARTER, MD
role: STUDY_CHAIR
References: