Institute for Stroke and Dementia Research, Klinikum der Universität München, Feodor-Lynen-Straße 17, 81377 Munich, Germany. Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany.
Department of Brain Ischemia and Neurodegeneration, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), 08036 Barcelona, Spain. Àrea de Neurociències, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
Sci Transl Med. 2015 Aug 5;7(299):299ra121. doi: 10.1126/scitranslmed.aaa9853.
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.
已有大量治疗方法被报道在实验性动物中风模型中提供了有益的结果；然而，这些治疗方法（组织型纤溶酶原激活物除外）在临床试验中均告失败。为了提高从实验室到临床的治疗效果转化率，我们进行了一项临床前随机对照多中心试验（pRCT），以在更接近临床试验设计和严格要求的情况下测试一种潜在的中风治疗方法。抗 CD49d 抗体可抑制白细胞向大脑迁移，先前已在实验性中风模型中由个别实验室进行了研究。尽管四项阳性和一项不确定的临床前研究结果存在冲突，但仍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中央协调、随机和盲法的方式，在两种不同的中风小鼠模型中研究了抗 CD49d 抗体的疗效。所有研究中心汇总的结果表明，CD49d 特异性抗体治疗可显著减少大脑中动脉永久性远端闭塞引起的小皮质梗塞后的白细胞浸润和梗塞体积。相比之下，抗 CD49d 治疗并未减少短暂性大脑中动脉近端闭塞引起的大病灶中的病灶大小或白细胞浸润。这些结果表明，免疫靶向方法的益处可能取决于梗塞的严重程度和部位。本研究支持进行 pRCT 的可行性。
