ISTH/ANRS 0409s INTEGRATE Lassa Fever Study

Phase 3RecruitingNCT06212336

Irrua Specialist Teaching Hospital1,755 enrolled

Overview

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

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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 2.4 ARN-75039 subprotocols Exclusion criteria • History of severe gastrointestinal disease • History of chronic generalized pruritus * History of severe chronic liver disease * History of severe cardiac disorder

Locations (4)

Phebe Hospital

Suacoco, Bong County, Liberia

NOT_YET_RECRUITING

Irrua Specialist Teaching Hospital

Irrua, Edo, Nigeria

RECRUITING

Federal Medical Center Owo

Owo, Ondo State, Nigeria

RECRUITING

Abubakar Tafawa Balewa University Teaching Hospital

Bauchi, Nigeria

NOT_YET_RECRUITING

Outcomes

Primary Outcomes

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.).

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: Between Day 0 and Day 10

Secondary Outcomes

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

Time frame: 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

Time frame: Day 0, Day 28

Organ failure from composite primary endpoint

Proportion of participants with a newly occurring component of the composite primary endpoint

Time frame: Between Day 0 and Day 10

New onset of Acute Kidney Injury

Proportion of participants meeting KDIGO ≥ 2 or initiation of renal replacement therapy parameters

Time frame: Between Day 0 and discharge

New onset of CVPU or seizure

Proportion of participants with CVPU or seizure

Time frame: Between Day 0 and Discharge

New onset of Bleeding

Proportion of participants meeting WHO bleeding scale grade 2 or above

Time frame: Between Day 0 and Discharge

New onset of Severe anaemia

Proportion of participants with Hb level \< 8 g/dL

Time frame: Between Day 0 and Discharge

New onset of liver failure

Proportion of participants with AST or ALT ≥ 3 ULN

Time frame: Between Day 0 and Discharge

New onset of clinical severity score

Proportion of participants with a NEWS2 score ≥7

Time frame: Between Day 0 and Discharge

Intensive care strategies - oxygen therapy

Proportion of participants having received oxygen therapy

Time frame: Between Day 0 and Discharge

Intensive care strategies - RRT

Proportion of participants having received RRT

Time frame: Between Day 0 and Discharge

Intensive care strategies - blood transfusion

Proportion of participants having received blood transfusion

Time frame: Between Day 0 and Discharge

Intensive care strategies- inotropes or vasopressors

Proportion of participants having received inotropes or vasopressors

Time frame: Between Day 0 and Discharge

the viral clearance - Change in LF RT-PCR Ct

value (for each target gene) from D0

Time frame: Day 3, Day 5, Day 7, Day 9

the viral clearance - Change in LASV viral

titer from D0

Time frame: D01-D10

viral clearance - LASV RT-PCR

\<LLQ

Time frame: D01- D10

Pharmacokinetics (phase II only)

• Peak concentration (Cmax)

Time frame: Between Day 0 and Day 10

Pharmacokinetics (phase II only)

• Time to peak concentration (Tmax)

Time frame: Between Day 0 and Day 10

Pharmacokinetics (phase II only)

• Area under the curve

Time frame: Between Day 0 and Day 10

Pharmacokinetics (phase II only)

• Half-life

Time frame: Between Day 0 and Day 10

Pharmacokinetics (phase II only)

• Clearance

Time frame: Between Day 0 and Day 10

Pharmacokinetics (phase II only)

• Volume(s) of distribution

Time frame: Between Day 0 and Day 10

PK/PD (phase II only)

• Prediction of initial viral load and slope of decline

Time frame: Between Day 0 and Day 10

PK/PD (phase II only)

• Optimal dosing regimen with PK/PD modelling

Time frame: Between Day 0 and Day 10

LASV RT-PCR

LASV RT-PCR (Ct value)

Time frame: D28 if participants have a positive RT PCR at discharge

Peak CRP (Phase II stage only)

Peak CRP level (mg/L)

Time frame: D01-D10

Time to first LASV RT-PCR <LLOQ

Time to first LASV RT-PCR \<LLOQ (days)

Time frame: D01-D10

ISTH/ANRS 0409s INTEGRATE Lassa Fever Study

Overview

Conditions

Interventions

Eligibility

Locations (4)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts