Departments of Emergency Medicine and Anesthesia, University of California, San Francisco, CA, USA.
Departments of Medicine and Anesthesia and the Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
Lancet Respir Med. 2015 Jan;3(1):24-32. doi: 10.1016/S2213-2600(14)70291-7. Epub 2014 Dec 17.
No effective pharmacotherapy for acute respiratory distress syndrome (ARDS) exists, and mortality remains high. Preclinical studies support the efficacy of mesenchymal stem (stromal) cells (MSCs) in the treatment of lung injury. We aimed to test the safety of a single dose of allogeneic bone marrow-derived MSCs in patients with moderate-to-severe ARDS.
The STem cells for ARDS Treatment (START) trial was a multicentre, open-label, dose-escalation, phase 1 clinical trial. Patients were enrolled in the intensive care units at University of California, San Francisco, CA, USA, Stanford University, Stanford, CA, USA, and Massachusetts General Hospital, Boston, MA, USA, between July 8, 2013, and Jan 13, 2014. Patients were included if they had moderate-to-severe ARDS as defined by the acute onset of the need for positive pressure ventilation by an endotracheal or tracheal tube, a PaO2:FiO2 less than 200 mm Hg with at least 8 cm H2O positive end-expiratory airway pressure (PEEP), and bilateral infiltrates consistent with pulmonary oedema on frontal chest radiograph. The first three patients were treated with low dose MSCs (1 million cells/kg predicted bodyweight [PBW]), the next three patients received intermediate dose MSCs (5 million cells/kg PBW), and the final three patients received high dose MSCs (10 million cells/kg PBW). Primary outcomes included the incidence of prespecified infusion-associated events and serious adverse events. The trial is registered with ClinicalTrials.gov, number NCT01775774.
No prespecified infusion-associated events or treatment-related adverse events were reported in any of the nine patients. Serious adverse events were subsequently noted in three patients during the weeks after the infusion: one patient died on study day 9, one patient died on study day 31, and one patient was discovered to have multiple embolic infarcts of the spleen, kidneys, and brain that were age-indeterminate, but thought to have occurred before the MSC infusion based on MRI results. None of these severe adverse events were thought to be MSC-related.
A single intravenous infusion of allogeneic, bone marrow-derived human MSCs was well tolerated in nine patients with moderate to severe ARDS. Based on this phase 1 experience, we have proceeded to phase 2 testing of MSCs for moderate to severe ARDS with a primary focus on safety and secondary outcomes including respiratory, systemic, and biological endpoints.
The National Heart, Lung, and Blood Institute.
目前尚无针对急性呼吸窘迫综合征（ARDS）的有效药物治疗方法，死亡率仍然很高。临床前研究支持间充质干细胞（MSC）治疗肺损伤的疗效。我们旨在测试单次输注同种异体骨髓来源 MSC 在中重度 ARDS 患者中的安全性。
STem 细胞治疗 ARDS 试验（START）是一项多中心、开放标签、剂量递增、I 期临床试验。在美国加利福尼亚大学旧金山分校、斯坦福大学和马萨诸塞州总医院的重症监护病房招募患者，招募时间为 2013 年 7 月 8 日至 2014 年 1 月 13 日。符合以下标准的患者入选：ARDS 急性发作，需要经气管内或气管插管进行正压通气，氧合指数（PaO2：FiO2）<200mmHg，至少 8cmH2O 呼气末正压（PEEP），胸部正位 X 线片显示双侧浸润影符合肺水肿。前 3 例患者接受低剂量 MSC（100 万细胞/kg 预测体重[PBW]）治疗，接下来 3 例患者接受中剂量 MSC（500 万细胞/kg PBW）治疗，最后 3 例患者接受高剂量 MSC（1000 万细胞/kg PBW）治疗。主要结局包括预定输注相关事件和严重不良事件的发生率。该试验在 ClinicalTrials.gov 注册，编号为 NCT01775774。
9 例患者中均未报告预定输注相关事件或与治疗相关的不良事件。输注后数周内，3 例患者出现严重不良事件：1 例患者于研究第 9 天死亡，1 例患者于研究第 31 天死亡，1 例患者被发现脾脏、肾脏和大脑有多发性栓塞性梗死，年龄不明，但根据 MRI 结果认为这些梗死发生在 MSC 输注之前。这些严重不良事件均不认为与 MSC 相关。
9 例中重度 ARDS 患者单次静脉输注同种异体骨髓来源人 MSC 耐受性良好。基于这一 I 期经验，我们已开始对中重度 ARDS 进行 MSC 的 II 期试验，主要关注安全性和次要结局，包括呼吸、全身和生物学终点。
美国国立心肺血液研究所。
