Cell Therapy Using Umbilical Cord-derived Mesenchymal Stromal Cells in SARS-CoV-2-related ARDS
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 47
- 试验地点
- 4
- 主要终点
- Respiratory efficacy evaluated by the increase in PaO2/FiO2 ratio from baseline to day 7 in the experimental group compared with the placebo group
研究概览
简要总结
Whereas the pandemic due do Covid-19 continues to spread, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Severe Acute Respiratory Distress Syndrome in 30% of patients with a 30%-60% mortality rate for those requiring hospitalization in an intensive care unit. The main physio-pathological hallmark is an acute pulmonary inflammation. Currently, there is no treatment.
Mesenchymal stem cells (MSC) feature several attractive characteristics: ease of procurement, high proliferation potential, capacity to home to inflammatory sites, anti-inflammatory, anti-fibrotic and immunomodulatory properties. If all MSC share several characteristics regardless of the tissue source, the highest productions of bioactive molecules and the strongest immunomodulatory properties are yielded by those from the Wharton's jelly of the umbilical cord. An additional advantage is that they can be scaled-up to generate banks of cryofrozen and thus readily available products. These cells have already been tested in several clinical trials with an excellent safety record.
The objective of this project is to treat intubated-ventilated patients presenting with a SARS-CoV2-related Acute Respiratory Distress Syndrome (ARDS) of less than 96 hours by three intravenous infusions of umbilical cord Wharton's jelly-derived mesenchymal stromal cells (UC-MSC) one every other day (duration of the treatment: one week). The primary endpoint is the PaO2/FiO2 ratio at day 7. The evolution of several inflammatory markers, T regulatory lymphocytes and donor-specific antibodies will also be monitored. The trial will include 40 patients, of whom 20 will be cell-treated while the remaining 20 patients will be injected with a placebo solution in addition to the standard of care. Given the pathophysiology of SARS-CoV2, it is thus sound to hypothesize that the intravenous administration of UC-MSC during the initial phase of ARDS could control inflammation, accelerate its recovery with improved oxygenation, reduced mechanical ventilation and ventilation weaning time and therefore reduced length of stay in intensive care.
The feasibility of the project is supported by the expertise of the Meary Cell and Gene Therapy Center, which is approved for the production of Advanced Therapy Medicinal Products and has already successfully prepared the first batches of cells, as well as by the involvement of a cardiac surgery team which will leverage its experience with stem cells for the treatment of heart failure to make it relevant to the Stroma-Cov-2 project.
详细描述
General context:
As of March 13, 2020, more than 145,000 cases of 2019-nCoV infection have been confirmed with 5,500 deaths worldwide. As of March 21, 14,469 cases have been confirmed in France, of which 562 have been fatal while 1,525 patients are currently hospitalized in intensive care units. Whereas the pandemic continues to spread, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Severe Acute Respiratory Distress Syndrome in 30% of patients (Murthy et al., 2020) with a 30%-60% mortality rate. The main physio-pathological hallmark is an acute pulmonary inflammation. Currently, there is no treatment.
The objective of this project is to treat intubated-ventilated patients presenting with a SARS-CoV2-related Acute Respiratory Distress Syndrome (ARDS) of less than 96 hours by three intravenous infusions of umbilical cord Wharton's jelly-derived mesenchymal stromal cells (UC-MSC) one every other day (duration of the treatment: one week). The primary endpoint is the PaO2/FiO2 variation from baseline at day 7. The evolution of several inflammatory markers, T regulatory lymphocytes and donor-specific antibodies will also be monitored. The trial will include 40 patients, of whom 20 will be randomized to cell-treatment administered via intravenous route while the remaining 20 patients will be randomized to receive a placebo solution in addition to the standard of care. Patients will be followed up to 12 months after treatment.
State of the art:
Mesenchymal stem cells feature several attractive characteristics: ease of procurement, high proliferation potential, capacity to home to inflammatory sites, anti-inflammatory, anti-fibrotic and immunomodulatory properties. Their therapeutic benefits have been demonstrated in > 100 animal models, including sheep. Specifically, the therapeutic effects of MSC have been demonstrated in ARDS models induced by H1N1, H5N1, H9N2 influenza virus-associated pneumoniae and were also shown to reduce bacterial-induced acute lung injury in a human model of ex vivo perfused lung (Lee et al., 2013). In the clinics, MSC have demonstrated an excellent tolerance in over 3,000 patients (Thompson et al., 2020), regardless of the dosing and delivery route. Three phase I/II trials have included patients with an ARDS and in one (START II), MSC significantly reduced pulmonary endothelial injury (Matthay et al., 2019). If all MSC share several characteristics regardless of the tissue source, the highest productions of bioactive molecules and the strongest immunomodulatory properties are yielded by those from the Wharton's jelly of the umbilical cord (Romanov et al., 2019) which can be scaled-up to generate banks of cryofrozen and thus readily available products.
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
- Triple (Participant, Care Provider, Investigator)
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 patient, age > 18 years,
- •Laboratory (RT-PCR)-confirmed infection with SARS-CoV2
- •Diagnosis of ARDS according to the Berlin definition of ARDS
- •Under invasive, non-invasive ventilation or high-flow nasal oxygen therapy (PEEP ≥ 5 cmH2O)
- •Onset of ARDS <96 hours
- •Patient with French Social Security System
- •Provision of 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
- •Allogeneic bone marrow transplantation
- •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
- •Patient who received an organ transplant
- •Woman known to be pregnant or lactating
- •Patient already enrolled in another interventional pharmacotherapy protocol on COVID-19
- •Patient has burns to ≥15% of their total body surface area
- •Patient is receiving extra-corporeal membrane oxygenation, high-frequency oscillatory ventilation or any form of extra-corporeal lung support
- •Patient under tutelage
结局指标
主要结局
Respiratory efficacy evaluated by the increase in PaO2/FiO2 ratio from baseline to day 7 in the experimental group compared with the placebo group
时间窗: From baseline to day 7
次要结局
- Mortality(At day 28)
- Lung injury score(From baseline to day 28)
- Oxygenation index(From baseline to day 28)
- In-hospital mortality(From baseline to day 28)
- Number of days between randomization and the first day the patient meets weaning criteria o Number of days between randomization and the first day the patient meets PaO2/FiO2 > 200 (out of a prone positioning session)(From baseline to day 28)
- Cumulative duration of use of neuromuscular blocking agents (other than used for intubation)(From baseline to day 28)
- ICU-acquired weakness and delirium(From baseline to day 28)
- Quality of life at one year (EQ5D-3L quality of life questionnaire)(At 6 months and 12 months)
- Measurements of plasmatic cytokines (IL1, IL6, IL8, TNF-alpha, IL10, TGF-beta, sRAGE, Ang2) level(At day 1, 3, 5, 7 and 14)
- Treatment-induced toxicity rate and adverse events up to day 28(From baseline to day 28)
- Anti-HLA antibodies plasmatic dosage(From baseline to day 14, and at 6 months)
- Ventilator-free days(From baseline to day 28)
- Cumulative use of sedatives(From baseline to day 28)
- Cumulative duration of use of sedatives(From baseline to day 28)
- Cumulative use of neuromuscular blocking agents (other than used for intubation)(From baseline to day 28)