efficacy and safety of tocilizumab for acute chest syndrome treatment in patients with sickle cell disease

Conditions: Sickle Cell Disease; Acute Chest Syndrome

Summary: 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.

Eligibility criteria:
inclusion criteria: 1. scd patient of all genotypes (ss, sc, s/β0 and s/β+) 2. age ≥ 2 years old 3. 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) 4. 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 5. negative pregnancy test for girls or women of childbearing age 6. freely given, informed and written consent of patient or legal representatives 7. affiliation to the social security (or health insurance) 8. effective contraception up to 3 months after the administration of treatment (tocilizumab or placebo) exclusion criteria: 1. impossibility to perform tocilizumab/placebo injection within the first 48 hours of supplemental oxygen 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. 2. known hypersensitivity to tocilizumab or its excipients 3. 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) 4. immunization with a live/attenuated vaccine within the last 4 weeks 5. immunomodulatory therapy, anti-rejection therapy, cell depleting therapies and investigational agents within the last 3 months 6. history of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies 7. 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 8. evidence of malignant disease or malignancies diagnosed within the last 3 years 9. pregnancy or breastfeeding 10. imminent and inevitable progression towards death in the opinion of the investigator 11. absolute neutrophil count \< 1.0 g/l or platelets \< 50 g/l 12. alt or ast \> 5-fold the upper limit of normal 13. glomerular filtration rate (gfr) \< 60 ml/min/1,73 m² 14. current enrolment in another interventional research concerning a medicinal product for human use

Keywords: sickle cell disease acute chest syndrome tocilizumab