title: Results of a preclinical randomized controlled multicenter trial (pRCT): Anti-CD49d treatment for acute brain ischemia.
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.
authors.affiliation: 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.
authors.forename: Gemma
authors.initials: G
authors.lastname: Llovera
authors.affiliation: 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.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Hofmann
authors.affiliation: 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.
authors.forename: Stefan
authors.initials: S
authors.lastname: Roth
authors.affiliation: 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.
authors.forename: Angelica
authors.initials: A
authors.lastname: Salas-Pérdomo
authors.affiliation: 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.
authors.forename: Maura
authors.initials: M
authors.lastname: Ferrer-Ferrer
authors.affiliation: Neuroscience Department, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Perego
authors.affiliation: Neuroscience Department, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy.
authors.forename: Elisa R
authors.initials: ER
authors.lastname: Zanier
authors.affiliation: 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.
authors.forename: Uta
authors.initials: U
authors.lastname: Mamrak
authors.affiliation: 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.
authors.forename: Andre
authors.initials: A
authors.lastname: Rex
authors.affiliation: 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.
authors.forename: Hélène
authors.initials: H
authors.lastname: Party
authors.affiliation: 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.
authors.forename: Véronique
authors.initials: V
authors.lastname: Agin
authors.affiliation: Experimental Stroke Research Platform (ESRP), IBiSA platform, Centre Universitaire de Ressources Biologiques (CURB), Université de Caen Basse-Normandie, F-14074 Caen Cedex, France.
authors.forename: Claudine
authors.initials: C
authors.lastname: Fauchon
authors.affiliation: 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.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Orset
authors.affiliation: 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.
authors.forename: Benoît
authors.initials: B
authors.lastname: Haelewyn
authors.affiliation: Neuroscience Department, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, 20156 Milan, Italy.
authors.forename: Maria-Grazia
authors.initials: MG
authors.lastname: De Simoni
authors.affiliation: 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.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dirnagl
authors.affiliation: Department of Biostatistics and Clinical Epidemiology, Charité-Universitätsmedizin Berlin, 12203 Berlin, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Grittner
authors.affiliation: 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.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Planas
authors.affiliation: 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.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Plesnila
authors.affiliation: 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.
authors.forename: Denis
authors.initials: D
authors.lastname: Vivien
authors.affiliation: 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.
authors.forename: Arthur
authors.initials: A
authors.lastname: Liesz
mesh_terms: D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000276:immunology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006801:Humans; D039441:Integrin alpha4 / Q000276:immunology*; D051379:Mice; D011897:Random Allocation; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D039441:Integrin alpha4