Efficacy and Safety of Tocilizumab for Acute Chest Syndrome Treatment in Patients With Sickle Cell Disease

Официальное название

Efficacy and Safety of Tocilizumab for Acute Chest Syndrome Treatment in Pediatric and Adult Patients With Sickle Cell Disease

Обзор

The purpose of this study is to determine whether a single infusion of tocilizumab is effective in reducing the time to successful weaning from both supplemental oxygen and any respiratory support, in pediatric and adult patients with sickle cell disease (SCD) during acute chest syndrome (ACS).

Подробное описание

SCD is a severe hemoglobinopathy, considered the first monogenic disease in the world. ACS, one of the most frequent and serious complications of SCD, is the first cause of hospitalization and mortality of SCD patients in intensive care unit. However, its pathophysiology has long been poorly understood and therapeutic options are limited.

A major increase has been recently reported in the level of interleukin-6 (IL-6), unlike other main pro-inflammatory cytokines, in the sputum (or bronchoalveolar fluid) from SCD children during ACS, positively correlated with the severity of ACS. Also, the observations of a very rapidly favorable outcome after administration of tocilizumab (anti-human IL-6 receptor monoclonal antibody) in SCD patients hospitalized for ACS with or without SARS-CoV-2 infection, suggest that tocilizumab may be a key therapy for ACS.

Вмешательства

• Препарат Tocilizumab (RoActemra®, 20 mg/mL).
  One single intravenous infusion at 8 mg/kg (up to a maximum of 800 mg) for patients ≥ 30 kg and 12 mg/kg for patients \< 30 kg
• Препарат Placebo (NaCl 0.9%)
  One single intravenous infusion

Первичные конечные точки

• Time to successful weaning from both supplemental oxygen and any respiratory support [Срок оценки: During hospitalization for ACS, from randomization until day 28 after randomization]

Вторичные конечные точки (12)

• Adverse events during hospitalization and within 3 months following tocilizumab or placebo injection [Срок оценки: Within 3 months after randomization]
• Time to discharge [Срок оценки: From the date of randomization until the date of end of hospitalization, assessed up to 3 months]
• Mortality [Срок оценки: Within 3 months after randomization]
• Need for transfusion [Срок оценки: From the date of randomization until the date of end of hospitalization, assessed up to 3 months]
• Total number of red blood cell units received [Срок оценки: From the date of randomization until the date of end of hospitalization, assessed up to 3 months]
• Need for non-invasive ventilation (for patients without ventilatory support at inclusion) [Срок оценки: From the date of randomization until the date of end of hospitalization, assessed up to 3 months]
• Need for invasive ventilation (for patients without invasive ventilation at inclusion) [Срок оценки: From the date of randomization until the date of end of hospitalization, assessed up to 3 months]
• Readmission for vaso-occlusive crisis or ACS within 3 months following tocilizumab or placebo injection [Срок оценки: Within 3 months after randomization]
• C-reactive protein (CRP), procalcitonin (PCT), plasma and sputum IL-6 levels 48 (+/- 12) hours after tocilizumab or placebo injection [Срок оценки: 48 (+/- 12) hours after tocilizumab or placebo injection]
• Procalcitonin (PCT) level 48 (+/- 12) hours after tocilizumab or placebo injection [Срок оценки: 48 (+/- 12) hours after tocilizumab or placebo injection]
• Plasma IL-6 level 48 (+/- 12) hours after tocilizumab or placebo injection [Срок оценки: 48 (+/- 12) hours after tocilizumab or placebo injection]
• Sputum IL-6 level 48 (+/- 12) hours after tocilizumab or placebo injection [Срок оценки: 48 (+/- 12) hours after tocilizumab or placebo injection]

Критерии участия

Критерии включения

• SCD patient of all genotypes (SS, SC, S/β0 and S/β+ or other major SCD syndrome)
• Age ≥ 2 years old
• Hospitalized for ACS, defined by the WHO as the association of fever and/or acute respiratory symptoms with a new pulmonary infiltrate on chest imaging, (X-ray, lung ultrasound, or CT scan)
• Requiring supplemental oxygen ≥ 2 L/min for SpO2 ≥ 95% or non-invasive respiratory support (high flow nasal oxygen or continuous positive airway pressure or bilevel non-invasive ventilation) or invasive mechanical ventilation or ECMO, for less than 48 hours
• Negative pregnancy test for girls or women of childbearing age
• Freely given, informed and written consent of patient or legal representatives
• Affiliation to the social security (or health insurance)
• Effective contraception up to 3 months after the administration of treatment (tocilizumab or placebo)

Критерии исключения

• Impossibility to perform tocilizumab/placebo injection within the first 48 hours of supplemental oxygen ≥2L/min for SpO2≥95% and/or respiratory support (as defined in inclusion criteria n°4). If exchange transfusion is indicated at inclusion, it has to be performed before the injection of tocilizumab/placebo.
• Known hypersensitivity to tocilizumab or its excipients
• Known active current severe bacterial, viral, fungal, mycobacterial, or other infections (including but not limited to tuberculosis and atypical mycobacterial disease, hepatitis B and C, and herpes zoster)
• Immunization with a live/attenuated vaccine within the last 4 weeks
• Immunomodulatory therapy, anti-rejection therapy, cell depleting therapies and investigational agents within the last 3 months
• History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies
• History of diverticulitis, diverticulosis requiring antibiotic treatment, or chronic ulcerative lower gastrointestinal disease such as Crohn's disease, ulcerative colitis, or other symptomatic lower gastrointestinal conditions that might predispose a patient to perforations
• Evidence of malignant disease or malignancies diagnosed within the last 3 years
• Pregnancy or breastfeeding
• Imminent and inevitable progression towards death in the opinion of the investigator
• Absolute neutrophil count < 1.0 G/L or platelets < 50 G/L
• ALT or AST > 5-fold the upper limit of normal
• Glomerular Filtration rate (GFR) < 60 mL/min/1,73 m²
• Current enrolment in another interventional research concerning a medicinal product for human use

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

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Лечение

Центры проведения

Франция · 1 центр

• Department of General Pediatrics and Sickle Cell Center, Necker-Enfants malades Hospital — Paris

Идентификаторы

NCT: NCT06818266 · APHP220797 · 2023-505109-17-00

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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