Low Dose of IL-2 In Acute Respiratory DistrEss Syndrome Related to COVID-19
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 30
- 试验地点
- 2
- 主要终点
- The PaO2/FiO2 ratio at D11
研究概览
简要总结
The purpose is to demonstrate the efficacy of low-dose interleukin 2 (Ld-IL2) administration in improving clinical course and oxygenation parameters in patients with SARS-CoV2-related ARDS.
详细描述
About 25% of hospitalized patients with SARS-CoV2 infection presented life-threatening respiratory conditions. Of these, 60% met ARDS criteria leading to death in 25% to 63% of the cases. SARS-CoV2-related ARDS is caused by a massive inflammatory cell infiltration leading to dysregulated cytokine/chemokine responses with lung immunopathological changes. To date, there is no treatment available.
Regulatory T cells (Treg) are a subpopulation of CD4+ T cells playing a crucial role in the control of immune responses, in part by preventing excessive inflammation. Depletion of Treg cells in models of lung infection or after berylium exposure exacerbated lung inflammation. In contrast, a beneficial role for Treg during early ARDS and its resolution has been observed.
Low-dose interleukin 2 (Ld-IL2) is the first therapy driving Treg-specific expansion and activation. Ld-IL2 was successfully tested in a wide range of preclinical models of inflammatory diseases, including beryllium-induced lung inflammation. Moreover, Ld-IL2 has been shown to be safe and free of serious adverse events when administered in patients with various autoimmune diseases. Importantly, in our previous work, we observed only very low concentrations of IL-2 in the blood (0.1 pg/mL [0.0-2.0]) as well as in the BAL supernatant (0.8 pg/mL [0.4-1.3]) collected from patients during the early phase of ARDS, suggesting that additional IL-2 could be beneficial for Treg expansion/activation.
Our objective is therefore to investigate the therapeutic benefit of Ld-IL2 as a Treg inducer for controlling SARS-CoV2-related ARDS.
After admission of patients to the intensive care unit at one of the recruiting centers, the eligibility criteria will be checked by the investigating physician and participation in the study will be proposed to the patient or parent/family member/trusted person. If the patient is unable to consent and there is no parent/family member/trusted person, the patient may be included in the emergency procedure.
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
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female, age ≥ 18 years
- •Laboratory (RT-PCR) confirmed infection with SARS-CoV2
- •Patient is either under invasive or non-invasive mechanical ventilation (including high flow nasal oxygen therapy).
- •Diagnosis of ARDS according to the Berlin definition of ARDS
- •Onset of ARDS <96 hours
- •Patient with French Social Security System
- •A written informed consent by the designated substitute decision maker, if present. In the event of absence, the patient can be included by investigator's decision alone.
排除标准
- •Previous history of ARDS in the last month
- •Chronic respiratory diseases requiring long-term oxygen therapy and/or long-term respiratory assistance
- •History of organ allograft.
- •Active cancer
- •Liver cirrhosis with basal Child and Pugh of C
- •Pulmonary fibrosis
- •Patient with end-of-life decision
- •Patient not expected to survive for 24 hours
- •Woman known to be pregnant, lactating or with a positive (urine or serum test) or indeterminate (serum test) pregnancy test
- •Patient already enrolled in another interventional pharmacotherapy protocol on COVID-19
- •Patient with known hypersensitivity to natural or recombinant Interleukin-2 or to any of the excipients
- •Presence of any of the following abnormal laboratory values at screening: absolute neutrophil count (ANC) less than 1.5x109/L, AST or ALT greater than 5 x ULN, platelets <50,000 per mm3
- •Use of chronic oral corticosteroids > 10 mg prednisone equivalent a day for a non-COVID-19-related condition
- •Current uncontrolled autoimmune disease
- •Patients with uncontrolled suspected or known active systemic bacterial or fungal infections
- •Patient with severe, uncontrolled pre-existing (chronic) organ failure (myocardial, hepatic or renal)
- •Vaccination with live attenuated vaccines in the month preceding the inclusion
- •Patient with burns to ≥ 15% of their total body surface area
- •Patient receiving extra-corporeal membrane oxygenation, high-frequency oscillatory ventilation or any form of extra-corporeal lung support
- •Patient under legal protection (protection of the court, or in curatorship or guardianship).
结局指标
主要结局
The PaO2/FiO2 ratio at D11
时间窗: at Day11
次要结局
- Number of days alive outside ICU within 28 days(at Day28)
- Maximal oxygen rate within 28 days(at Day28)
- Number of days alive with oxygen therapy within 28 days(at Day28)
- Time (in days) from randomization to death(through study completion at day 28)
- Mortality rate at D28(at Day28)
- Changes in Tregs between Baseline and Day 7 (expressed in %)(at Day0 and Day7)
- Number of days alive free of invasive or non-invasive ventilation within 28 days(At Day28)
- Number of days alive outside hospital within 28 days(at Day28)
- Difference between CRP levels at randomization and at Day 7 (or at the time of discharge if occurs before Day 7)(at Day0 and Day7 or at the time of discharge)
- Use of antibiotics for respiratory (proved or suspected) infection within 28 days(at Day28)
- Number of prone positioning sessions(throughout the follow up period at day 28)
- Cytokines analysis on plasma samples at Day 0, 7 and 14(at Day 0, 7 and 14)
- Tregs numbers during induction period and throughout the follow up period at day 5, 7, 11, 14 and 28 compared to baseline before the first IL-2 injection.(at Day0, 5, 7, 11, 14 and Day28)
- Deep Immunophenotyping of Cellular components in blood samples at Day 0, 7, and 14(at Day0, 7 and Day14)
- T cell repertoire on Treg, after sorting from blood at Day 7 and Day 14 and compared to baseline(at Day0, 7 and Day14)
- Single cells sequencing will be performed in BAL at Day 7 and Day 14 and compared to baseline.(at Day0, 7 and Day14)
- Changes in Tregs during the different visits between baseline and day 28(at Day0, 5, 7, 11, 14 and Day28)
- Tregs percentages during induction period and throughout the follow up period at day 5, 7, 11, 14 and 28 compared to baseline before the first IL-2 injection.(at Day0, 5, 7, 11, 14 and Day28)
- T cell repertoire on Teff (CD4 and CD8) after sorting from blood at Day 7 and Day 14 and compared to baseline(at Day0, 7 and Day14)