Clinical trial NCT06818266: Efficacy and Safety of Tocilizumab for Acute Chest Syndrome Treatment in Patients With Sickle Cell Disease
Official title: Efficacy and Safety of Tocilizumab for Acute Chest Syndrome Treatment in Pediatric and Adult Patients With Sickle Cell Disease
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Sickle Cell Disease
Acute Chest Syndrome
Keywords: Sickle cell disease
Acute chest syndrome
Tocilizumab
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2025-02-10
Enrollment: 130
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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).

Detailed description: 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

Primary outcomes:
measure: Time to successful weaning from both supplemental oxygen and any respiratory support
timeFrame: During hospitalization for ACS, from randomization until day 28 after randomization
Secondary outcomes:
measure: Adverse events during hospitalization and within 3 months following tocilizumab or placebo injection
timeFrame: Within 3 months after randomization
measure: Time to discharge
timeFrame: From the date of randomization until the date of end of hospitalization, assessed up to 3 months
measure: Mortality
timeFrame: Within 3 months after randomization
measure: Need for transfusion
timeFrame: From the date of randomization until the date of end of hospitalization, assessed up to 3 months
measure: Total number of red blood cell units received
timeFrame: From the date of randomization until the date of end of hospitalization, assessed up to 3 months
measure: Need for non-invasive ventilation (for patients without ventilatory support at inclusion)
timeFrame: From the date of randomization until the date of end of hospitalization, assessed up to 3 months
measure: Need for invasive ventilation (for patients without invasive ventilation at inclusion)
timeFrame: From the date of randomization until the date of end of hospitalization, assessed up to 3 months
measure: Readmission for vaso-occlusive crisis or ACS within 3 months following tocilizumab or placebo injection
timeFrame: Within 3 months after randomization
measure: C-reactive protein (CRP), procalcitonin (PCT), plasma and sputum IL-6 levels 48 (+/- 12) hours after tocilizumab or placebo injection
timeFrame: 48 (+/- 12) hours after tocilizumab or placebo injection
measure: Procalcitonin (PCT) level 48 (+/- 12) hours after tocilizumab or placebo injection
timeFrame: 48 (+/- 12) hours after tocilizumab or placebo injection
measure: Plasma IL-6 level 48 (+/- 12) hours after tocilizumab or placebo injection
timeFrame: 48 (+/- 12) hours after tocilizumab or placebo injection
measure: Sputum IL-6 level 48 (+/- 12) hours after tocilizumab or placebo injection
timeFrame: 48 (+/- 12) hours after tocilizumab or placebo injection
measure: Chest imaging improvement 48 (+/- 12) hours after tocilizumab or placebo injection
timeFrame: 48 (+/- 12) hours after tocilizumab or placebo injection
measure: Tocilizumab level in the plasma 48 (+/- 12) hours after tocilizumab or placebo injection
timeFrame: 48 (+/- 12) hours after tocilizumab or placebo injection
measure: Tocilizumab level in the sputum (or in the tracheal aspirations in case of invasive mechanical ventilation) 48 (+/- 12) hours after tocilizumab or placebo injection
timeFrame: 48 (+/- 12) hours after tocilizumab or placebo injection
Other outcomes:
Locations:
city: Paris
country: France
facility: Department of General Pediatrics and Sickle Cell Center, Necker-Enfants malades Hospital
Study officials:
affiliation: Department of General Pediatrics and Sickle Cell Center, Necker-Enfants malades Hospital, Paris, France
name: Slimane ALLALI, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: