Results of a preclinical randomized controlled multicenter trial (pRCT): Anti-CD49d treatment for acute brain ischemia
Results of a preclinical randomized controlled multicenter trial (pRCT): Anti-CD49d treatment for acute brain ischemia
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DOI：
10.1126/scitranslmed.aaa9853
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发表时间：
2015-08-05
影响因子：
17.1
通讯作者：
Liesz, Arthur
中科院分区：
文献类型：
--
作者：
Llovera, Gemma;Hofmann, Kerstin;Liesz, Arthur
据报道，许多治疗在实验性动物中风模型中提供了有益的结果;然而，这些治疗（组织纤溶酶原激活剂除外）在临床试验中失败。为了改善治疗效果从实验室到临床的转化，我们进行了一项临床前随机对照多中心试验（pRCT），以在更接近临床随机对照试验设计和严格性的情况下测试潜在的卒中治疗。抗CD 49 d抗体，抑制白细胞迁移到大脑中，以前研究了实验性中风模型的个别实验室。尽管四项阳性和一项不确定的临床前研究的结果相互矛盾，但还是启动了一项临床试验。为了确认临床前结果并测试进行pRCT的可行性，六个独立的欧洲研究中心以集中协调、随机和设盲的方法研究了抗CD 49 d抗体在两种不同的中风小鼠模型中的疗效。来自所有研究中心的汇总结果显示，在大脑中动脉永久性远端闭塞后，CD 49 d特异性抗体治疗显著降低了白细胞浸润和梗死体积，这导致了小的皮质梗死。相比之下，抗CD 49 d治疗并没有减少病变大小或影响大脑中动脉短暂近端闭塞后的白细胞浸润，这会诱导大病变。这些结果表明，免疫靶向方法的好处可能取决于梗死的严重程度和定位。本研究支持进行pRCT的可行性。
Numerous treatments have been reported to provide a beneficial outcome in experimental animal stroke models; however, these treatments (with the exception of tissue plasminogen activator) have failed in clinical trials. To improve the translation of treatment efficacy from bench to bedside, we have performed a preclinical randomized controlled multicenter trial (pRCT) to test a potential stroke therapy under circumstances closer to the design and rigor of a clinical randomized control trial. Anti-CD49d antibodies, which inhibit the migration of leukocytes into the brain, were previously investigated in experimental stroke models by individual laboratories. Despite the conflicting results from four positive and one inconclusive preclinical studies, a clinical trial was initiated. To confirm the preclinical results and to test the feasibility of conducting a pRCT, six independent European research centers investigated the efficacy of anti-CD49d antibodies in two distinct mouse models of stroke in a centrally coordinated, randomized, and blinded approach. The results pooled from all research centers revealed that treatment with CD49d-specific antibodies significantly reduced both leukocyte invasion and infarct volume after the permanent distal occlusion of the middle cerebral artery, which causes a small cortical infarction. In contrast, anti-CD49d treatment did not reduce lesion size or affect leukocyte invasion after transient proximal occlusion of the middle cerebral artery, which induces large lesions. These results suggest that the benefits of immune-targeted approaches may depend on infarct severity and localization. This study supports the feasibility of performing pRCTs.