Efficacy and Safety of Tocilizumab for Acute Chest Syndrome Treatment in Pediatric and Adult Patients With Sickle Cell Disease
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 130
- 试验地点
- 1
- 主要终点
- Time to successful weaning from both supplemental oxygen and any respiratory support
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 2 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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)
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Tocilizumab (RoActemra®, 20 mg/mL). (Drug)
Arm B : Placebo (NaCl 0.9%)
One single intravenous infusion
干预措施: Placebo (NaCl 0.9%) (Drug)
结局指标
主要结局
Time to successful weaning from both supplemental oxygen and any respiratory support
时间窗: During hospitalization for ACS, from randomization until day 28 after randomization
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
次要结局
- Adverse events during hospitalization and within 3 months following tocilizumab or placebo injection(Within 3 months after randomization)
- Time to discharge(From the date of randomization until the date of end of hospitalization, assessed up to 3 months)
- Mortality(Within 3 months after randomization)
- Need for 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(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)(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(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(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)
- 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)
- 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(48 (+/- 12) hours after tocilizumab or placebo injection)
- Chest imaging improvement 48 (+/- 12) hours after tocilizumab or placebo injection(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(48 (+/- 12) hours after tocilizumab or placebo injection)