Safety Study of Dabigatran in CADASIL

Summary

This study is a Phase II, randomized, crossover trial designed to compare one fixed dose of dabigatran with open-label use of ASA in patients affected by CADASIL; the study is a safety trial, and the primary objective is to assess that dabigatran is not less safe than ASA in subjects with CADASIL.

Timeline

Start

2011-06

Primary completion

2015-01

Completion

2015-02

Publications

• Background Bailey EL, McCulloch J, Sudlow C, Wardlaw JM. Potential animal models of lacunar stroke: a systematic review. Stroke. 2009 Jun;40(6):e451-8. doi: 10.1161/STROKEAHA.108.528430. Epub 2009 Apr 23.
• Background Chen B, Cheng Q, Yang K, Lyden PD. Thrombin mediates severe neurovascular injury during ischemia. Stroke. 2010 Oct;41(10):2348-52. doi: 10.1161/STROKEAHA.110.584920. Epub 2010 Aug 12.
• Background Chabriat H, Joutel A, Dichgans M, Tournier-Lasserve E, Bousser MG. Cadasil. Lancet Neurol. 2009 Jul;8(7):643-53. doi: 10.1016/S1474-4422(09)70127-9.
• Background Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009 Sep 17;361(12):1139-51. doi: 10.1056/NEJMoa0905561. Epub 2009 Aug 30.
• Background Cumurciuc R, Guichard JP, Reizine D, Gray F, Bousser MG, Chabriat H. Dilation of Virchow-Robin spaces in CADASIL. Eur J Neurol. 2006 Feb;13(2):187-90. doi: 10.1111/j.1468-1331.2006.01113.x.
• Background Dichgans M, Holtmannspotter M, Herzog J, Peters N, Bergmann M, Yousry TA. Cerebral microbleeds in CADASIL: a gradient-echo magnetic resonance imaging and autopsy study. Stroke. 2002 Jan;33(1):67-71. doi: 10.1161/hs0102.100885.
• Background Heye N, Paetzold C, Steinberg R, Cervos-Navarro J. The topography of microthrombi in ischemic brain infarct. Acta Neurol Scand. 1992 Nov;86(5):450-4. doi: 10.1111/j.1600-0404.1992.tb05122.x.
• Background Hills M, Armitage P. The two-period cross-over clinical trial. Br J Clin Pharmacol. 1979 Jul;8(1):7-20. doi: 10.1111/j.1365-2125.1979.tb05903.x. No abstract available.
• Background Bokura H, Kobayashi S, Yamaguchi S. Distinguishing silent lacunar infarction from enlarged Virchow-Robin spaces: a magnetic resonance imaging and pathological study. J Neurol. 1998 Feb;245(2):116-22. doi: 10.1007/s004150050189.
• Background Oh JH, Lee JS, Kang SY, Kang JH, Choi JC. Aspirin-associated intracerebral hemorrhage in a patient with CADASIL. Clin Neurol Neurosurg. 2008 Apr;110(4):384-6. doi: 10.1016/j.clineuro.2007.12.001. Epub 2008 Jan 22.
• Background Kario K, Matsuo T, Hoshide S, Umeda Y, Shimada K. Effect of thrombin inhibition in vascular dementia and silent cerebrovascular disease. An MR spectroscopy study. Stroke. 1999 May;30(5):1033-7. doi: 10.1161/01.str.30.5.1033.
• Background Lesnik Oberstein SA, van den Boom R, van Buchem MA, van Houwelingen HC, Bakker E, Vollebregt E, Ferrari MD, Breuning MH, Haan J; Dutch CADASIL Research Group. Cerebral microbleeds in CADASIL. Neurology. 2001 Sep 25;57(6):1066-70. doi: 10.1212/wnl.57.6.1066.
• Background Pfefferkorn T, von Stuckrad-Barre S, Herzog J, Gasser T, Hamann GF, Dichgans M. Reduced cerebrovascular CO(2) reactivity in CADASIL: A transcranial Doppler sonography study. Stroke. 2001 Jan;32(1):17-21. doi: 10.1161/01.str.32.1.17.
• Background Rouhl RP, van Oostenbrugge RJ, Knottnerus IL, Staals JE, Lodder J. Virchow-Robin spaces relate to cerebral small vessel disease severity. J Neurol. 2008 May;255(5):692-6. doi: 10.1007/s00415-008-0777-y. Epub 2008 Feb 21.
• Background Stenborg A, Kalimo H, Viitanen M, Terent A, Lind L. Impaired endothelial function of forearm resistance arteries in CADASIL patients. Stroke. 2007 Oct;38(10):2692-7. doi: 10.1161/STROKEAHA.107.490029. Epub 2007 Aug 30.
• Background Turturro F, Rocca B, Gumina S, De Cristofaro R, Mangiola F, Maggiano N, Evangelista A, Salsano V, Montanaro A. Impaired primary hemostasis with normal platelet function in Duchenne muscular dystrophy during highly-invasive spinal surgery. Neuromuscul Disord. 2005 Aug;15(8):532-40. doi: 10.1016/j.nmd.2005.05.005.
• Background van Den Boom R, Lesnik Oberstein SA, van Duinen SG, Bornebroek M, Ferrari MD, Haan J, van Buchem MA. Subcortical lacunar lesions: an MR imaging finding in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Radiology. 2002 Sep;224(3):791-6. doi: 10.1148/radiol.2243011123.
• Background Wang CX, Ding X, Shuaib A. Treatment with melagatran alone or in combination with thrombolytic therapy reduced ischemic brain injury. Exp Neurol. 2008 Sep;213(1):171-5. doi: 10.1016/j.expneurol.2008.05.020. Epub 2008 Jun 7.
• Background Yin X, Wright J, Wall T, Grammas P. Brain endothelial cells synthesize neurotoxic thrombin in Alzheimer's disease. Am J Pathol. 2010 Apr;176(4):1600-6. doi: 10.2353/ajpath.2010.090406. Epub 2010 Feb 11.
• Background Mastroiacovo F, Busceti CL, Biagioni F, Moyanova SG, Meisler MH, Battaglia G, Caricasole A, Bruno V, Nicoletti F. Induction of the Wnt antagonist, Dickkopf-1, contributes to the development of neuronal death in models of brain focal ischemia. J Cereb Blood Flow Metab. 2009 Feb;29(2):264-76. doi: 10.1038/jcbfm.2008.111. Epub 2008 Oct 1.
• Background Zhang QG, Wang R, Khan M, Mahesh V, Brann DW. Role of Dickkopf-1, an antagonist of the Wnt/beta-catenin signaling pathway, in estrogen-induced neuroprotection and attenuation of tau phosphorylation. J Neurosci. 2008 Aug 20;28(34):8430-41. doi: 10.1523/JNEUROSCI.2752-08.2008.
• Background Rosi MC, Luccarini I, Grossi C, Fiorentini A, Spillantini MG, Prisco A, Scali C, Gianfriddo M, Caricasole A, Terstappen GC, Casamenti F. Increased Dickkopf-1 expression in transgenic mouse models of neurodegenerative disease. J Neurochem. 2010 Mar;112(6):1539-51. doi: 10.1111/j.1471-4159.2009.06566.x. Epub 2009 Dec 29.
• Background De Ferrari GV, Moon RT. The ups and downs of Wnt signaling in prevalent neurological disorders. Oncogene. 2006 Dec 4;25(57):7545-53. doi: 10.1038/sj.onc.1210064.

Drugs

Indications