Efficacy and Safety of Tocilizumab for Acute Chest Syndrome Treatment in Patients with Sickle Cell Disease (TOCIACS)

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

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).

Study Overview

• Status: Not yet recruiting
• Conditions: Sickle Cell Disease; Acute Chest Syndrome
• Intervention / Treatment: Drug: Tocilizumab (RoActemra®, 20 mg/mL).; Drug: Placebo (NaCl 0.9%)

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.

• Study Type: Interventional
• Enrollment (Estimated): 130
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Slimane ALLALI, MD, PhD; Phone Number: +33 01 44 49 48 96; Email: slimane.allali@aphp.fr
• Study Contact Backup: Name: Aminata TRAORE, Project advisor; Email: aminata.traore@aphp.fr

Study Locations

• France
  • Paris, France, 75015
    • Department of General Pediatrics and Sickle Cell Center, Necker-Enfants malades Hospital
    • Contact: Slimane ALLALI, MD, PhD; Phone Number: +33 01 44 49 48 96; Email: slimane.allali@aphp.fr
    • Contact: Aminata TRAORE, Project advisor
    • Contact: Slimane Allali, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arms A : 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.	Drug: 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
Placebo Comparator: Arm B : Placebo (NaCl 0.9%); One single intravenous infusion	Drug: Placebo (NaCl 0.9%); One single intravenous infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time 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	During hospitalization for ACS, from randomization until day 28 after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	Within 3 months after randomization
Time to discharge	Length of hospital stay	From the date of randomization until the date of end of hospitalization, assessed up to 3 months
Mortality	Mortality	Within 3 months after randomization
Need for transfusion	Need for red blood cell transfusion	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	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)	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	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	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	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	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	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	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	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.	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	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	48 (+/- 12) hours after tocilizumab or placebo injection

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Slimane ALLALI, MD, PhD, Department of General Pediatrics and Sickle Cell Center, Necker-Enfants malades Hospital, Paris, France

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2025
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): July 1, 2027

Study Registration Dates

• First Submitted: January 9, 2025
• First Submitted That Met QC Criteria: February 4, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 10, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Tocilizumab; Sickle cell disease; Acute chest syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Genetic Diseases, Inborn; Respiratory Tract Diseases; Disease; Lung Diseases; Respiration Disorders; Hematologic Diseases; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hemoglobinopathies; Syndrome; Anemia, Sickle Cell; Acute Chest Syndrome
• Other Study ID Numbers: APHP220797; 2023-505109-17-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No