Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial.
Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial.
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DOI：
10.1016/s2213-2600(18)30418-1
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发表时间：
2019-03
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影响因子：
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通讯作者：
Liu KD
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作者：
Matthay MA;Calfee CS;Zhuo H;Thompson BT;Wilson JG;Levitt JE;Rogers AJ;Gotts JE;Wiener-Kronish JP;Bajwa EK;Donahoe MP;McVerry BJ;Ortiz LA;Exline M;Christman JW;Abbott J;Delucchi KL;Caballero L;McMillan M;McKenna DH;Liu KD
用骨髓间充质干细胞（MSCs）治疗急性呼吸窘迫综合征（ARDS）的临床前模型已显示出益处。尚未确定在患有ARDS的危重患者中施用MSC的安全性。我们进行了一项2a期试验，以评估对中度至重度ARDS患者给予MSC后的安全性。我们进行了一项前瞻性、双盲、多中心、随机试验，以评估与安慰剂相比，静脉注射一剂MSC的治疗效果。我们在美国的五所大学医学中心招募了中度至重度ARDS（氧分压与吸入氧分数之比<27 kPa且呼气末正压[PEEP] ≥8 cm H2O）的通气患者。根据计算机生成的时间表，采用可变区组设计并按研究中心分层，将患者以2：1的比例随机分配接受10 × 106/kg预测体重的MSC或安慰剂。我们排除了年龄小于18岁的患者，患有创伤或中度至重度肝病的患者，以及在过去2年内接受过癌症治疗的患者。主要终点是安全性，所有的分析都是通过意向治疗进行的。我们还测量了血浆中的生物标志物。在事后分析中测试MSC活力。本试验在ClinicalTrials.gov注册，编号NCT 02097641。从2014年3月24日至2017年2月9日，我们筛选了1038例患者，其中60例符合条件并接受了治疗。无患者发生任何预定义的MSC相关血流动力学或呼吸不良事件。MSC组中的一名患者在MSC输注后24小时内死亡，但死亡被判定为可能无关。28-两组间的日死亡率无差异（MSC组为30%，安慰剂组为15%，比值比2.4，95% CI 0.5 - 15.1）。在基线时，MSC组的急性生理学和慢性健康评估III（APACHE III; 104 [SD 31] vs 89 [33]）、每分钟通气量（11.1 [3.2] vs 9.6 [2.4] L/min）和PEEP（12.4 [3.7] vs 10.8 [2.6] cm H2O）的平均评分在数值上高于安慰剂组。校正APACHE III评分后，28天死亡率的风险比为1.43（95% CI 0.40 - 5.12，p= 0.58）。MSC的活力范围为36%至85%。中重度ARDS患者单次静脉注射MSCs是安全的。需要进行更大规模的试验来评估疗效，并且必须提高MSC的活力。国家心肺血液研究所。
Treatment with bone-marrow-derived mesenchymal stromal cells (MSCs) has shown benefits in preclinical models of acute respiratory distress syndrome (ARDS). Safety has not been established for administration of MSCs in critically ill patients with ARDS. We did a phase 2a trial to assess safety after administration of MSCs to patients with moderate to severe ARDS. We did a prospective, double-blind, multicentre, randomised trial to assess treatment with one intravenous dose of MSCs compared with placebo. We recruited ventilated patients with moderate to severe ARDS (ratio of partial pressure of oxygen to fractional inspired oxygen <27 kPa and positive end-expiratory pressure [PEEP] ≥8 cm H2O) in five university medical centres in the USA. Patients were randomly assigned 2:1 to receive either 10 × 106/kg predicted bodyweight MSCs or placebo, according to a computer-generated schedule with a variable block design and stratified by site. We excluded patients younger than 18 years, those with trauma or moderate to severe liver disease, and those who had received cancer treatment in the previous 2 years. The primary endpoint was safety and all analyses were done by intention to treat. We also measured biomarkers in plasma. MSC viability was tested in a post-hoc analysis. This trial is registered with ClinicalTrials.gov, number NCT02097641. From March 24, 2014, to Feb 9, 2017 we screened 1038 patients, of whom 60 were eligible for and received treatment. No patient experienced any of the predefined MSC-related haemodynamic or respiratory adverse events. One patient in the MSC group died within 24 h of MSC infusion, but death was judged to be probably unrelated. 28-day mortality did not differ between the groups (30% in the MSC group vs 15% in the placebo group, odds ratio 2·4, 95% CI 0·5–15·1). At baseline, the MSC group had numerically higher mean scores than the placebo group for Acute Physiology and Chronic Health Evaluation III (APACHE III; 104 [SD 31] vs 89 [33]), minute ventilation (11·1 [3·2] vs 9·6 [2·4] L/min), and PEEP (12·4 [3·7] vs 10·8 [2·6] cm H2O). After adjustment for APACHE III score, the hazard ratio for mortality at 28 days was 1·43 (95% CI 0·40–5·12, p=0·58). Viability of MSCs ranged from 36% to 85%. One dose of intravenous MSCs was safe in patients with moderate to severe ARDS. Larger trials are needed to assess efficacy, and the viability of MSCs must be improved. National Heart, Lung, and Blood Institute.