Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA, USA.
Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Lancet Neurol. 2017 May;16(5):360-368. doi: 10.1016/S1474-4422(17)30046-7. Epub 2017 Mar 17.
Multipotent adult progenitor cells are a bone marrow-derived, allogeneic, cell therapy product that modulates the immune system, and represents a promising therapy for acute stroke. We aimed to identify the highest, well-tolerated, and safest single dose of multipotent adult progenitor cells, and if they were efficacious as a treatment for stroke recovery.
We did a phase 2, randomised, double-blind, placebo-controlled, dose-escalation trial of intravenous multipotent adult progenitor cells in 33 centres in the UK and the USA. We used a computer-generated randomisation sequence and interactive voice and web response system to assign patients aged 18-83 years with moderately severe acute ischaemic stroke and a National Institutes of Health Stroke Scale (NIHSS) score of 8-20 to treatment with intravenous multipotent adult progenitor cells (400 million or 1200 million cells) or placebo between 24 h and 48 h after symptom onset. Patients were ineligible if there was a change in NIHSS of four or more points during at least a 6 h period between screening and randomisation, had brainstem or lacunar infarct, a substantial comorbid disease, an inability to undergo an MRI scan, or had a history of splenectomy. In group 1, patients were enrolled and randomly assigned in a 3:1 ratio to receive 400 million cells or placebo and assessed for safety through 7 days. In group 2, patients were randomly assigned in a 3:1 ratio to receive 1200 million cells or placebo and assessed for safety through the first 7 days. In group 3, patients were enrolled, randomly assigned, and stratified by baseline NIHSS score to receive 1200 million cells or placebo in a 1:1 ratio within 24-48 h. Patients, investigators, and clinicians were masked to treatment assignment. The primary safety outcome was dose-limiting toxicity effects. The primary efficacy endpoint was global stroke recovery, which combines dichotomised results from the modified Rankin scale, change in NIHSS score from baseline, and Barthel index at day 90. Analysis was by intention to treat (ITT) including all patients in groups 2 and 3 who received the investigational agent or placebo. This study is registered with ClinicalTrials.gov, number NCT01436487.
The study was done between Oct 24, 2011, and Dec 7, 2015. After safety assessments in eight patients in group 1, 129 patients were randomly assigned (67 to receive multipotent adult progenitor cells and 62 to receive placebo) in groups 2 and 3 (1200 million cells). The ITT populations consisted of 65 patients who received multipotent adult progenitor cells and 61 patients who received placebo. There were no dose-limiting toxicity events in either group. There were no infusional or allergic reactions and no difference in treatment-emergent adverse events between the groups (64 [99%] of 65 patients in the multipotent adult progenitor cell group vs 59 [97%] of 61 in the placebo group). There was no difference between the multipotent adult progenitor cell group and placebo groups in global stroke recovery at day 90 (odds ratio 1·08 [95% CI 0·55-2·09], p=0·83).
Administration of multipotent adult progenitor cells was safe and well tolerated in patients with acute ischaemic stroke. Although no significant improvement was observed at 90 days in neurological outcomes with multipotent adult progenitor cells treatment, further clinical trials evaluating the efficacy of the intervention in an earlier time window after stroke (<36 h) are planned.
Athersys Inc.
多能成体祖细胞是一种骨髓来源的同种异体细胞疗法产品，可调节免疫系统，是急性中风治疗的一种有前途的方法。我们旨在确定多能成体祖细胞的最高耐受和最安全的单次剂量，如果它们作为中风恢复的治疗有效。
我们在英国和美国的 33 个中心进行了一项 2 期、随机、双盲、安慰剂对照、剂量递增试验，对年龄在 18-83 岁之间、患有中度严重急性缺血性中风和 NIHSS 评分为 8-20 的患者进行了静脉注射多能成体祖细胞治疗。我们使用计算机生成的随机序列和交互式语音和网络响应系统，将在症状出现后 24-48 小时内随机分配给接受静脉注射多能成体祖细胞（4 亿或 1.2 亿个细胞）或安慰剂的患者。如果在筛选和随机化之间至少 6 小时内 NIHSS 评分有 4 分或更多的变化、有脑干或腔隙性梗死、严重合并症、无法进行 MRI 扫描或有脾切除术史，则患者不符合条件。在第 1 组中，患者被招募并以 3:1 的比例随机分配接受 4 亿个细胞或安慰剂，并通过 7 天评估安全性。在第 2 组中，患者以 3:1 的比例随机分配接受 1.2 亿个细胞或安慰剂，并通过前 7 天评估安全性。在第 3 组中，患者被招募、随机分配，并按基线 NIHSS 评分分层，在 24-48 小时内以 1:1 的比例接受 1.2 亿个细胞或安慰剂。患者、研究者和临床医生对治疗分配进行了盲法。主要安全性结果是剂量限制毒性作用。主要疗效终点是全球中风恢复，它结合了改良 Rankin 量表的二分结果、从基线 NIHSS 评分的变化和第 90 天的巴氏指数。分析采用意向治疗（ITT），包括接受研究药物或安慰剂的第 2 和第 3 组的所有患者。这项研究在 ClinicalTrials.gov 注册，编号为 NCT01436487。
该研究于 2011 年 10 月 24 日至 2015 年 12 月 7 日进行。在第 1 组的 8 名患者进行了安全性评估后，129 名患者被随机分配（67 名接受多能成体祖细胞，62 名接受安慰剂）在第 2 和第 3 组（1.2 亿个细胞）。ITT 人群包括 65 名接受多能成体祖细胞和 61 名接受安慰剂的患者。两组均无剂量限制毒性事件。两组之间输注和过敏反应没有差异，治疗中出现的不良事件也没有差异（多能成体祖细胞组 65 名患者中 64 名[99%]，安慰剂组 61 名患者中 59 名[97%]）。多能成体祖细胞组和安慰剂组在第 90 天的全球中风恢复方面没有差异（比值比 1.08[95%CI 0.55-2.09]，p=0.83）。
多能成体祖细胞在急性缺血性中风患者中是安全且耐受良好的。尽管在第 90 天，多能成体祖细胞治疗在神经功能结局方面没有明显改善，但计划在中风后（<36 小时）更早的时间窗内评估该干预措施的疗效的进一步临床试验。
Athersys Inc.
