Research ArticleStroke

Results of a preclinical randomized controlled multicenter trial (pRCT): Anti-CD49d treatment for acute brain ischemia

Science Translational Medicine  05 Aug 2015:
Vol. 7, Issue 299, pp. 299ra121
DOI: 10.1126/scitranslmed.aaa9853

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Tested, just like a human

Over the last few decades, clinical trial design and analysis have become increasingly stringent. These refinements—designed to ensure valid conclusions for formal drug approval—have improved clinical trial reliability. Now, Llovera et al. have applied the principles of the gold-standard randomized, controlled clinical trial to a preclinical investigation. They tested an antibody to CD49d, which inhibits leukocyte migration into the brain, in two mouse models of stroke. Data from their six-center, preclinical, randomized controlled trial in mice show that the antibody significantly reduced both leukocyte invasion and infarct volume after a small cortical stroke but that it did not have any effect in the other model, in which the animal suffered a larger injury. The authors outline the many lessons learned from their experience for further application of preclinical randomized controlled trials to translational research.

Abstract

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.

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