ISTH/ANRS 0409s INTEGRATE Lassa Fever Study

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.).

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