ISTH/ANRS 0409s INTEGRATE Lassa Fever Study

Efficacy, Tolerability and Safety of New or Repurposed Drugs Against Lassa Fever in West African Countries

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.).

Study Overview

• Status: Not yet recruiting
• Conditions: Lassa Fever
• Intervention / Treatment: Drug: Ribavirin; Drug: Favipiravir; Drug: Dexamethasone

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

• Study Type: Interventional
• Enrollment (Estimated): 1755
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Camille FRITZELL, PHD; Phone Number: +33 6 58 80 90 12; Email: camille.fritzell@coral.alima.ngo
• Study Contact Backup: Name: Sylvain JUCHET; Phone Number: +33 6 58 80 90 12; Email: sylvain.juchet@coral.alima.ngo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Favipiravir 1600; Oral favipiravir: 2400 mg BID D1; 1600 mg BID D2-D10	Drug: Ribavirin; Control arm; Other Names: Standard of care
Active Comparator: 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).	Drug: Favipiravir; Interventional Medicinal Product (IMP)
Experimental: 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).	Drug: Ribavirin; Control arm; Other Names: Standard of care; Drug: Favipiravir; Interventional Medicinal Product (IMP)
Experimental: 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.)	Drug: Ribavirin; Control arm; Other Names: Standard of care; Drug: Dexamethasone; Interventional Medicinal Product (IMP)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death	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.).	Day 28
New onset of acute kidney failure	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	Between Day 0 and Day 10
New onset of acute respiratory failure	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	Between Day 0 and Day 10
New onset of shock	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	Between Day 0 and Day 10

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of each IMP and SCD	Proportion (events and participants with at least one event) of: Adverse Event* grade 3 and higher; Serious Adverse Event; Adverse Event of Special Interest	Between Day 0 and Day 10
Safety of each IMP and SCD	Proportion (events and participants with at least one event) of: Adverse Event* grade 3 and higher; Serious Adverse Event; Adverse Event of Special Interest	Day 0, Day 28
Organ failure from composite primary endpoint	Proportion of participants with a newly occurring component of the composite primary endpoint	Between Day 0 and Day 10
Acute Kidney Injury	Proportion of participants meeting KDIGO ≥ 2 or initiation of renal replacement therapy parameters	Between Day 0 and Day 10
Encephalopathy	Proportion of participants with CVPU or seizure	Between Day 0 and Day 10
Bleeding	Proportion of participants meeting WHO bleeding scale grade 2 or above	Between Day 0 and Day 10
Severe anaemia	Proportion of participants with Hb level < 80 g/L	Between Day 0 and Day 10
Liver failure	Proportion of participants with AST or ALT ≥ 3 N	Between Day 0 and Day 10
Clinical severity score	Proportion of participants with a NEWS2 score > 7	Between Day 0 and Day 10
Intensive care strategies - oxygen therapy	Proportion of participants having received oxygen therapy	Between Day 0 and Day 10
Intensive care strategies - RRT	Proportion of participants having received RRT	Between Day 0 and Day 10
Intensive care strategies - blood transfusion	Proportion of participants having received blood transfusion	Between Day 0 and Day 10
Intensive care strategies- inotropes	Proportion of participants having received inotropes	Between Day 0 and Day 10
the viral clearance - Change in LF RT-PCR Ct	value (for each target gene) from D0	Day 3, Day 5, Day 7, Day 9
the viral clearance - Change in LASV viral	titer from D0	Day 3, Day 5, Day 7, Day 9
viral clearance - LASV RT-PCR	<LLQ	Day 3, Day 5, Day 7, Day 9
Pharmacokinetics (phase II only)	• Peak concentration (Cmax)	Between Day 0 and Day 10
Pharmacokinetics (phase II only)	• Time to peak concentration (Tmax)	Between Day 0 and Day 10
Pharmacokinetics (phase II only)	• Area under the curve	Between Day 0 and Day 10
Pharmacokinetics (phase II only)	• Half-life	Between Day 0 and Day 10
Pharmacokinetics (phase II only)	• Clearance	Between Day 0 and Day 10
Pharmacokinetics (phase II only)	• Volume(s) of distribution	Between Day 0 and Day 10
PK/PD (phase II only)	• Prediction of initial viral load and slope of decline	Between Day 0 and Day 10
PK/PD (phase II only)	• Optimal dosing regimen with PK/PD modelling	Between Day 0 and Day 10

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Viral resistance parameters	Frequency of LASV resistance mutations	Between Day 0 and Day 10

Collaborators and Investigators

• Sponsor: Irrua Specialist Teaching Hospital
• Collaborators: University of Bordeaux; Médecins Sans Frontières, Belgium; ANRS, Emerging Infectious Diseases; University of Hamburg-Eppendorf; Centre de Recherche Médicale de Lambaréné; Bernhard Nocht Institute for Tropical Medicine; University of North Carolina; Programme PAC-CI, Site ANRS-MIE de Côte d'Ivoire; Alex Ekwueme Federal University Teaching Hospital; Federal Medical Centre, Owo; Alliance for International Medical Action; Fondation pour la Recherche Scientifique, Benin; Donka Hospital, Conakry; Phebe Hospital, Liberia
• Investigators: Study Director: Marie MD JASPARD, MD, ALIMA - The Alliance for International Medical Action - Paris, France; Principal Investigator: Sylvanus OKOGBENIN, MD, Irrua Specialist Teaching Hospital Irrua - Edo State, Nigeria; Study Chair: Michael RAMHARTER, MD, Bernhard Nocht Institute for Tropical Medicine Bernhard-Nocht-Hamburg, Germany

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2024
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2027

Study Registration Dates

• First Submitted: September 22, 2023
• First Submitted That Met QC Criteria: January 8, 2024
• First Posted (Actual): January 18, 2024

Study Record Updates

• Last Update Posted (Actual): January 18, 2024
• Last Update Submitted That Met QC Criteria: January 8, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: adult; adolescent; viral hemorrhagic fever; emerging infectious diseases; AFRICA
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Body Temperature Changes; Hemorrhagic Fevers, Viral; Arenaviridae Infections; Fever; Lassa Fever; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Antiviral Agents; Anti-Inflammatory Agents; Antimetabolites; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Favipiravir; Dexamethasone; Ribavirin
• Other Study ID Numbers: ISTH/ANRS 0409s INTEGRATE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No