Repair of Acute Respiratory Distress Syndrome by Stromal Cell Administration (REALIST): An Open Label Dose Escalation Phase 1 Trial Followed by a Randomised, Double-blind, Allocation Concealed, Placebo-controlled Trial.
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 129
- 试验地点
- 1
- 主要终点
- Oxygenation index (OI)
研究概览
简要总结
Acute Respiratory Distress Syndrome (ARDS) causes the lungs to fail due to the collection of fluid in the lungs (pulmonary oedema). ARDS is common in severely ill patients in Intensive Care Units and is associated with a high mortality and a high morbidity in those who survive. ARDS occurs in approximately 20% case of COVID-19 and respiratory failure is the leading cause of mortality. There is a large economic burden with direct healthcare costs, but also indirectly due to the impact on the carer and patient through the patients inability to return to full time employment. There is little evidence for effective drug (pharmacological) treatment for ARDS. There is increasing information that mesenchymal stem cells (MSCs) might be important in treating ARDS. REALIST will investigate if a single infusion of MSCs will help in the treatment of ARDS. The first step will be to first of all determine what dose of MSCs is safe and then divide patients suffering from ARDS into two groups, one of which will get MSCs and the other a harmless dummy (or placebo) infusion, who will then be followed up to determine if lung function improves. If effective this may lead to further research to determine if MSCs are effective in patients with ARDS.
详细描述
The role of MSCs as a novel treatment in ARDS. Mesenchymal Stem Cells (MSCs) are a mononuclear cell population that have the potential to differentiate into multiple lineages, and bone, cartilage and adipocyte cells in particular. Cell-based therapies have been termed the "next pillar of Medicine". MSCs constitute an innovative approach with substantial therapeutic promise for ARDS. MSCs possess several favorable biological characteristics, including convenient isolation, ease of expansion in culture while maintaining genetic stability, minimal immunogenicity and feasibility for allogenic transplantation.
MSCs reduce inflammation and enhance bacterial clearance during rodent and murine bacterial pneumonia, and augment repair of the animal and human lung. Large animal studies have also replicated these beneficial effects. Bone marrow derived (BM) hMSCs decreased acute lung injury (ALI), without producing organ toxicity, in endotoxin injured pigs. Two randomised small phase 1 studies of plastic adherent MSCs in patients with ARDS have taken place. In Japan, investigators used adipose-derived plastic adherent cells in a small cohort (n=12) of patients with ARDS randomized 1:1 to MSCs or placebo: showing that the cells were safe and well-tolerated in this patient group, and were associated with reduced plasma levels of the alveolar epithelial cell injury marker SP-D. In the US Matthay has completed the phase 1 START trial, using a dose escalation study of plastic adherent bone marrow derived MSCs, in patients with moderate to severe ARDS. START showed that marrow derived MSCs at similar doses to those proposed in this study are safe and well-tolerated, (n=9), with a trend to reduced lung injury in the group treated with the highest (10x10^6cells/kg) compared with the lower doses, 1-5x10^6cells/kg.
Current (20 March 2020) data on novel coronavirus disease (COVID-19) suggests that it causes a mortality rate of ~3.4%, compared with <0.1% with seasonal influenza. ARDS occurs in approximatel 20% cases of COVID-19 and respiratory failure is the leading cause of mortality. In a restropective multi-centre study of 150 confirmed cases in Wuhan, China, ARDS occured in significantly greater proportion of non-survivors 81% (55/68 patients) compared with only 9% survivors (7/82 patients); p<0.01. In another study of 193 confirmed COVID-19 cases, ARDS was observed at a significantly higher rate in non-survivors 93% (50/54 patients) compared with survivors, 7% (9/137) patients; p<0.0001.
During the current COVID-19 pandemic, MSCs have been administered in a pilot study of seven patients with COVID-19 pneumonia. A single infusion of 1 x 10^6 MSCs were administered intravenously when their condition was considered to be deteriorating despite other treatments, however only 1 of the 7 patients required critical care and mechanical ventilation. 4 patients were described as severe with compromise of respiratory function. Patients underwent follow up for 14 days and no infusional toxicity or adverse events were reported.
Trial design:
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)
盲法说明
The cell therapy facility and clinical trials pharmacist will be unblinded. The unblinded individuals will keep the treatment information confidential and will not discuss or release information on treatment allocation to the patient, the investigator, or other unauthorised personnel.
As in prior studies of MSCs, the infusion bag containing either the cell product or placebo will be masked at the time of preparation in the clinical site's cell therapy facility so that the contents of the infusion bag are not visible to the investigators or to the clinicians who are administering the study drug. The contents of the infusion bag will be administered through a masked infusion set.
入排标准
- 年龄范围
- 16 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •ARDS as defined by the Berlin definition.
- •Onset within 1 week of identified insult.
- •Within the same 24-hour time period i. Hypoxic respiratory failure (PaO2/ FiO2 ratio ≤ 27kPa on PEEP ≥ 5 cmH20) ii. Bilateral infiltrates on chest X-ray consistent with pulmonary oedema not explained by another pulmonary pathology iii. Respiratory failure not fully explained by cardiac failure or fluid overload
- •Patient is receiving invasive mechanical ventilation
- •COVID-19 based on clinical diagnosis or PCR result or other causes of ARDS.
排除标准
- •More than 72 hours from the onset of ARDS.
- •Age < 16 years.
- •Patient is known to be pregnant
- •Major trauma in the prior 3 days.
- •Presence of any active malignancy (other than non-melanoma skin cancer) that required treatment within the last year.
- •WHO Class III or IV pulmonary hypertension.
- •Venous thromboembolism currently receiving anti-coagulation or within the past 3 months
- •Currently receiving extracorporeal life support (ECLS).
- •Severe chronic liver disease with Child-Pugh score >
- •DNAR (Do Not Attempt Resuscitation) order (excluding advance directives) in place.
- •Treatment withdrawal imminent within 24 hours.
- •Consent declined.
- •Non-English speaking patients or those who do not adequately understand verbal or written information unless an interpreter is available.
- •Previously enrolled in the REALIST trial.
研究组 & 干预措施
Human umbilical cord derived CD362 enriched MSCs
Maximum tolerated dose from the phase 1 trial will be infused over 30 to 90 mins
干预措施: Human umbilical cord derived CD362 enriched MSCs (Biological)
Placebo (Plasma-Lyte 148) infusion
Plasma-Lyte 148 infused over 30 to 90 mins
干预措施: Placebo (Plasma-Lyte 148) (Biological)
结局指标
主要结局
Oxygenation index (OI)
时间窗: Day 7
OI is a physiological index of the severity of ARDS and measures both impaired oxygenation and the amount of mechanical ventilation delivered
Incidence of Serious Adverse Events (SAEs)
时间窗: 90 days
Incidence of SAEs
次要结局
- Oxygenation index(Days 4 and 14)
- Sequential Organ Failure Assessment (SOFA) score(Days 4, 7 and 14)
- Driving Pressure(Days 4, 7 and 14)
- Length of ICU and hospital stay(Until the patient is discharged or the patient dies)
- Partial pressure of arterial oxygen to the fraction of inspired oxygen ratio (P/F ratio)(Days 4, 7 and 14)
- Ventilation free days at day 28(Day 28)
- 28-day and 90-day mortality(Up to 28 and 90 days)
- Respiratory compliance (Crs)(Days 4, 7 and 14)
- Extubation and reintubation(Up to day 14 or until the patient is discharged from ICU or the patient dies)
研究者
Professor Danny McAuley
Professor and Consultant of Intensive Care Medicine
Belfast Health and Social Care Trust