N Wahlgren1,2, M Thorén1,2, B Höjeberg3, T-B Käll4, A-C Laska5, C Sjöstrand1,2, J Höijer6, H Almqvist2,7, S Holmin2,7, A Lilja2,7, L Fredriksson8, D Lawrence9, U Eriksson8, N Ahmed1,2. 1. Department of Neurology, Karolinska University Hospital, Stockholm, Sweden. 2. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. 3. Department of Neurology, Capio St Göran Hospital, Stockholm, Sweden. 4. Department of Internal Medicine, Södersjukhuset, Stockholm, Sweden. 5. Department of Internal Medicine, Danderyd Hospital, Stockholm, Sweden. 6. Unit of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. 7. Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden. 8. Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. 9. Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
Abstract
BACKGROUND:Imatinib, a tyrosine kinase inhibitor, has been shown to restore blood-brain barrier integrity and reduce infarct size, haemorrhagic transformation and cerebral oedema in stroke models treated with tissue plasminogen activator. We evaluated the safety of imatinib, based on clinical and neuroradiological data, and its potential influence on neurological and functional outcomes. METHODS: A phase II randomized trial was performed in patients with acute ischaemic stroke treated withintravenous thrombolysis. A total of 60 patients were randomly assigned to four groups [3 (active): 1 (control)]; the active treatment groups received oral imatinib for 6 days at three dose levels (400, 600 and 800 mg). Primary outcome was any adverse event; secondary outcomes were haemorrhagic transformation, cerebral oedema, neurological severity on the National Institutes of Health Stroke Scale (NIHSS) at 7 days and at 3 months and functional outcomes on the modified Rankin scale (mRS). RESULTS: Four serious adverse events were reported, which resulted in three deaths (one in the control group and two in the 400-mg dose group; one patient in the latter group did not receive active treatment and the other received two doses). Nonserious adverse events were mostly mild, resulting in full recovery. Imatinib ameliorated neurological outcomes with an improvement of 0.6 NIHSS points per 100 mg imatinib (P = 0.02). For the 800-mg group, the mean unadjusted and adjusted NIHSS improvements were 4 (P = 0.037) and 5 points (P = 0.012), respectively, versus controls. Functional independence (mRS 0-2) increased by 18% versus controls (61 vs. 79; P = 0.296). CONCLUSION: This phase II study showed that imatinib is safe and tolerable and may reduce neurological disability in patients treated with intravenous thrombolysis after ischaemic stroke. A confirmatory randomized trial is currently underway.
RCT Entities:
BACKGROUND:Imatinib, a tyrosine kinase inhibitor, has been shown to restore blood-brain barrier integrity and reduce infarct size, haemorrhagic transformation and cerebral oedema in stroke models treated with tissue plasminogen activator. We evaluated the safety of imatinib, based on clinical and neuroradiological data, and its potential influence on neurological and functional outcomes. METHODS: A phase II randomized trial was performed in patients with acute ischaemic stroke treated with intravenous thrombolysis. A total of 60 patients were randomly assigned to four groups [3 (active): 1 (control)]; the active treatment groups received oral imatinib for 6 days at three dose levels (400, 600 and 800 mg). Primary outcome was any adverse event; secondary outcomes were haemorrhagic transformation, cerebral oedema, neurological severity on the National Institutes of Health Stroke Scale (NIHSS) at 7 days and at 3 months and functional outcomes on the modified Rankin scale (mRS). RESULTS: Four serious adverse events were reported, which resulted in three deaths (one in the control group and two in the 400-mg dose group; one patient in the latter group did not receive active treatment and the other received two doses). Nonserious adverse events were mostly mild, resulting in full recovery. Imatinib ameliorated neurological outcomes with an improvement of 0.6 NIHSS points per 100 mg imatinib (P = 0.02). For the 800-mg group, the mean unadjusted and adjusted NIHSS improvements were 4 (P = 0.037) and 5 points (P = 0.012), respectively, versus controls. Functional independence (mRS 0-2) increased by 18% versus controls (61 vs. 79; P = 0.296). CONCLUSION: This phase II study showed that imatinib is safe and tolerable and may reduce neurological disability in patients treated with intravenous thrombolysis after ischaemic stroke. A confirmatory randomized trial is currently underway.
Authors: Jeffrey L Saver; Mayank Goyal; Alain Bonafe; Hans-Christoph Diener; Elad I Levy; Vitor M Pereira; Gregory W Albers; Christophe Cognard; David J Cohen; Werner Hacke; Olav Jansen; Tudor G Jovin; Heinrich P Mattle; Raul G Nogueira; Adnan H Siddiqui; Dileep R Yavagal; Blaise W Baxter; Thomas G Devlin; Demetrius K Lopes; Vivek K Reddy; Richard du Mesnil de Rochemont; Oliver C Singer; Reza Jahan Journal: N Engl J Med Date: 2015-04-17 Impact factor: 91.245
Authors: Bruce C V Campbell; Peter J Mitchell; Timothy J Kleinig; Helen M Dewey; Leonid Churilov; Nawaf Yassi; Bernard Yan; Richard J Dowling; Mark W Parsons; Thomas J Oxley; Teddy Y Wu; Mark Brooks; Marion A Simpson; Ferdinand Miteff; Christopher R Levi; Martin Krause; Timothy J Harrington; Kenneth C Faulder; Brendan S Steinfort; Miriam Priglinger; Timothy Ang; Rebecca Scroop; P Alan Barber; Ben McGuinness; Tissa Wijeratne; Thanh G Phan; Winston Chong; Ronil V Chandra; Christopher F Bladin; Monica Badve; Henry Rice; Laetitia de Villiers; Henry Ma; Patricia M Desmond; Geoffrey A Donnan; Stephen M Davis Journal: N Engl J Med Date: 2015-02-11 Impact factor: 91.245
Authors: Werner Hacke; Markku Kaste; Erich Bluhmki; Miroslav Brozman; Antoni Dávalos; Donata Guidetti; Vincent Larrue; Kennedy R Lees; Zakaria Medeghri; Thomas Machnig; Dietmar Schneider; Rüdiger von Kummer; Nils Wahlgren; Danilo Toni Journal: N Engl J Med Date: 2008-09-25 Impact factor: 91.245
Authors: Lawrence L Latour; Dong-Wha Kang; Mustapha A Ezzeddine; Julio A Chalela; Steven Warach Journal: Ann Neurol Date: 2004-10 Impact factor: 10.422
Authors: Melissa A Lopes Pinheiro; Gijs Kooij; Mark R Mizee; Alwin Kamermans; Gaby Enzmann; Ruth Lyck; Markus Schwaninger; Britta Engelhardt; Helga E de Vries Journal: Biochim Biophys Acta Date: 2015-10-23
Authors: Anuska V Andjelkovic; Jianming Xiang; Svetlana M Stamatovic; Ya Hua; Guohua Xi; Michael M Wang; Richard F Keep Journal: Arterioscler Thromb Vasc Biol Date: 2019-09-12 Impact factor: 8.311
Authors: Daniel Torrente; Enming Joseph Su; Linda Fredriksson; Mark Warnock; David Bushart; Kris M Mann; Cory D Emal; Daniel A Lawrence Journal: Transl Stroke Res Date: 2022-02-04 Impact factor: 6.800
Authors: Manuel Zeitelhofer; Hong Li; Milena Z Adzemovic; Ingrid Nilsson; Lars Muhl; Andrew M Scott; Ulf Eriksson Journal: PLoS One Date: 2018-07-18 Impact factor: 3.240
Authors: Enming Joseph Su; Chunzhang Cao; Linda Fredriksson; Ingrid Nilsson; Christina Stefanitsch; Tamara K Stevenson; Juanjuan Zhao; Margret Ragsdale; Yu-Yo Sun; Manuel Yepes; Chia-Yi Kuan; Ulf Eriksson; Dudley K Strickland; Daniel A Lawrence; Li Zhang Journal: Acta Neuropathol Date: 2017-07-19 Impact factor: 17.088