TY - JOUR
T1 - Results of a preclinical randomized controlled multicenter trial (pRCT)
T2 - Anti-CD49d treatment for acute brain ischemia
AU - Llovera, Gemma
AU - Hofmann, Kerstin
AU - Roth, Stefan
AU - Salas-Pérdomo, Angelica
AU - Ferrer-Ferrer, Maura
AU - Perego, Carlo
AU - Zanier, Elisa R.
AU - Mamrak, Uta
AU - Rex, Andre
AU - Party, Hélène
AU - Agin, Véronique
AU - Fauchon, Claudine
AU - Orset, Cyrille
AU - Haelewyn, Benoît
AU - De Simoni, Maria Grazia
AU - Dirnagl, Ulrich
AU - Grittner, Ulrike
AU - Planas, Anna M.
AU - Plesnila, Nikolaus
AU - Vivien, Denis
AU - Liesz, Arthur
PY - 2015/8/5
Y1 - 2015/8/5
N2 - 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 strokemodels 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 approachesmay depend on infarct severity and localization. This study supports the feasibility of performing pRCTs.
AB - 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 strokemodels 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 approachesmay depend on infarct severity and localization. This study supports the feasibility of performing pRCTs.
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U2 - 10.1126/scitranslmed.aaa9853
DO - 10.1126/scitranslmed.aaa9853
M3 - Article
C2 - 26246166
AN - SCOPUS:84938704875
VL - 7
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 299
M1 - 299ra121
ER -