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).
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
130
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
One single intravenous infusion
Department of General Pediatrics and Sickle Cell Center, Necker-Enfants malades Hospital
Paris, France
RECRUITINGTime to successful weaning from both supplemental oxygen and any respiratory support
Successful weaning from both supplemental oxygen and any respiratory support, defined as SpO2 ≥ 95% without oxygen during the next 24 hours, and spontaneous breathing without any respiratory support (non-invasive or invasive) during the next 48 hours
Time frame: During hospitalization for ACS, from randomization until day 28 after randomization
Adverse events during hospitalization and within 3 months following tocilizumab or placebo injection
Severe and not severe adverse events (including hypertension, hypersensitivity reactions, hypokalemia, neutropenia, thrombocytopenia, infections, pulmonary embolism/thrombosis, hepatic cytolysis, organ failure)
Time frame: Within 3 months after randomization
Time to discharge
Length of hospital stay
Time frame: From the date of randomization until the date of end of hospitalization, assessed up to 3 months
Mortality
Mortality
Time frame: Within 3 months after randomization
Need for transfusion
Need for red blood cell transfusion
Time frame: 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
Total number of red blood cell units received
Time frame: 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)
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Need for non-invasive ventilation (high flow nasal oxygen, continuous positive airway pressure, or bilevel non-invasive ventilation), for patients without ventilatory support at inclusion
Time frame: 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)
Need for invasive ventilation, for patients without invasive ventilation at inclusion
Time frame: 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
Readmission for vaso-occlusive crisis or ACS within 3 months following tocilizumab or placebo injection
Time frame: 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
C-reactive protein (CRP), procalcitonin (PCT), plasma and sputum IL-6 levels 48 (+/- 12) hours after tocilizumab or placebo injection
Time frame: 48 (+/- 12) hours after tocilizumab or placebo injection
Procalcitonin (PCT) level 48 (+/- 12) hours after tocilizumab or placebo injection
Procalcitonin (PCT) level 48 (+/- 12) hours after tocilizumab or placebo injection
Time frame: 48 (+/- 12) hours after tocilizumab or placebo injection
Plasma IL-6 level 48 (+/- 12) hours after tocilizumab or placebo injection
Plasma IL-6 level 48 (+/- 12) hours after tocilizumab or placebo injection
Time frame: 48 (+/- 12) hours after tocilizumab or placebo injection
Sputum IL-6 level 48 (+/- 12) hours after tocilizumab or placebo injection
Sputum IL-6 level 48 (+/- 12) hours after tocilizumab or placebo injection
Time frame: 48 (+/- 12) hours after tocilizumab or placebo injection
Chest imaging improvement 48 (+/- 12) hours after tocilizumab or placebo injection
Improvement of chest imaging (chest X-ray or lung ultrasound) will be assessed by an investigator, who will have to choose between 3 possible answers: worsening, stability or improvement of ACS images.
Time frame: 48 (+/- 12) hours after tocilizumab or placebo injection
Tocilizumab level in the plasma 48 (+/- 12) hours after tocilizumab or placebo injection
Tocilizumab level in the plasma 48 (+/- 12) hours after tocilizumab or placebo injection
Time frame: 48 (+/- 12) hours after tocilizumab or placebo injection
Tocilizumab level in the sputum (or in the tracheal aspirations in case of invasive mechanical ventilation) 48 (+/- 12) hours after tocilizumab or placebo injection
Tocilizumab level in the sputum (or in the tracheal aspirations in case of invasive mechanical ventilation) 48 (+/- 12) hours after tocilizumab or placebo injection
Time frame: 48 (+/- 12) hours after tocilizumab or placebo injection