ISTH/ANRS 0409s INTEGRATE Lassa Fever Study

Официальное название

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

Обзор

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.).

Подробное описание

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

Вмешательства

• Препарат Favipiravir
  Interventional Medicinal Product (IMP)
• Препарат Ribavirin
  Control arm
• Препарат Dexamethasone
  Interventional Medicinal Product (IMP)
• Препарат ARN-75039 high dose
  Investigational Medicinal Product
• Препарат ARN-75039 low dose
  Investigational Medicinal Product

Первичные конечные точки

• Death [Срок оценки: Day 28]
• New onset of acute kidney failure [Срок оценки: Between Day 0 and Day 10]
• New onset of acute respiratory failure [Срок оценки: Between Day 0 and Day 10]
• New onset of shock [Срок оценки: Between Day 0 and Day 10]

Вторичные конечные точки (12)

• Safety of each IMP and SCD [Срок оценки: Between Day 0 and Day 10]
• Safety of each IMP and SCD [Срок оценки: Day 0, Day 28]
• Organ failure from composite primary endpoint [Срок оценки: Between Day 0 and Day 10]
• New onset of Acute Kidney Injury [Срок оценки: Between Day 0 and discharge]
• New onset of CVPU or seizure [Срок оценки: Between Day 0 and Discharge]
• New onset of Bleeding [Срок оценки: Between Day 0 and Discharge]
• New onset of Severe anaemia [Срок оценки: Between Day 0 and Discharge]
• New onset of liver failure [Срок оценки: Between Day 0 and Discharge]
• New onset of clinical severity score [Срок оценки: Between Day 0 and Discharge]
• Intensive care strategies - oxygen therapy [Срок оценки: Between Day 0 and Discharge]
• Intensive care strategies - RRT [Срок оценки: Between Day 0 and Discharge]
• Intensive care strategies - blood transfusion [Срок оценки: Between Day 0 and Discharge]

Критерии участия

• General

Критерии включения

• 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

Критерии исключения

• 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
• 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

Критерии включения

• Age ≥ 18 years old

Критерии исключения

• 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

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Последовательный дизайн

Маскирование

Тройное слепое

Основная цель

Лечение

Центры проведения

Nigeria · 3 центра

• Irrua Specialist Teaching Hospital — Irrua
• Federal Medical Center Owo — Owo
• Abubakar Tafawa Balewa University Teaching Hospital — Bauchi

Liberia · 1 центр

• Phebe Hospital — Suacoco

Идентификаторы

NCT: NCT06212336 · ISTH/ANRS 0409s INTEGRATE

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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