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Sci Transl Med. 2015 Aug 5;7(299):299ra121. doi: 10.1126/scitranslmed.aaa9853.

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

Author information

1
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.
2
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.
3
Neuroscience Department, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy.
4
Department of Experimental Neurology and Center for Stroke Research Berlin (CSB), Charité-Universitätsmedizin Berlin; German Center for Neurodegenerative Diseases (DZNE) and German Center for Cardiovascular Diseases (DZHK), Berlin sites; Excellence Cluster NeuroCure, 10117 Berlin, Germany.
5
INSERM, UMR-S U919, Université de Caen Basse-Normandie, team Serine Proteases and Pathophysiology of the neurovascular Unit, GIP Cyceron, F-14074 Caen Cedex, France.
6
Experimental Stroke Research Platform (ESRP), IBiSA platform, Centre Universitaire de Ressources Biologiques (CURB), Université de Caen Basse-Normandie, F-14074 Caen Cedex, France.
7
INSERM, UMR-S U919, Université de Caen Basse-Normandie, team Serine Proteases and Pathophysiology of the neurovascular Unit, GIP Cyceron, F-14074 Caen Cedex, France. Experimental Stroke Research Platform (ESRP), IBiSA platform, Centre Universitaire de Ressources Biologiques (CURB), Université de Caen Basse-Normandie, F-14074 Caen Cedex, France.
8
Department of Biostatistics and Clinical Epidemiology, Charité-Universitätsmedizin Berlin, 12203 Berlin, Germany.
9
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. arthur.liesz@med.uni-muenchen.de.

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.

PMID:
26246166
DOI:
10.1126/scitranslmed.aaa9853
[Indexed for MEDLINE]

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