Safety Study of Dabigatran in CADASIL - Full Text View

Purpose

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.

Condition	Intervention	Phase
CADASIL	Drug: Dabigatran Drug: Antiplatelets	Phase 2


Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety Study Intervention Model: Crossover Assignment Masking: Single Blind (Outcomes Assessor) Primary Purpose: Treatment
Official Title:	Phase II, Randomized, Crossover, Single Blind, Safety Trial of DABIGATRAN Versus ASA for Preventing Ischaemic Brain Lesions in Patients Affected by CADASIL

Resource links provided by NLM:

Genetics Home Reference related topics: cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy

Drug Information available for: Dabigatran Dabigatran etexilate Dabigatran etexilate mesylate

Genetic and Rare Diseases Information Center resources: CADASIL

U.S. FDA Resources

Further study details as provided by S. Andrea Hospital:

Primary Outcome Measures:

Number of microbleeds on MRI [ Time Frame: Six Months ] [ Designated as safety issue: Yes ]
Primary endpoint is defined as the difference in number of microbleeds on MRI images taken at the end of the 2 treatments (i.e, during W2 and W3). Secondary endpoint is major bleeding. The neuroradiologists (or trained neurologists) who will examine the images on MRI will be blind to treatment.

Secondary Outcome Measures:

Major bleeding [ Time Frame: Six Months ] [ Designated as safety issue: Yes ]
Severe haemorrhages are defined as a reduction of the haemoglobin level by at least 20g per litre, need of a transfusion of at least 2 units of blood, or symptomatic bleeding of an organ or critical area. Life threatening haemorrhages are a subcategory of severe hemorrhages defined as: fatal haemorrhages, symptomatic intracranial haemorrhages, haemorrhages with a diminution of haemoglobin level of at least 50g per litre or that require transfusion of at least 4 blood units, or surgery. All the other haemorrhages are considered minor.


Estimated Enrollment:	50
Study Start Date:	June 2011
Estimated Study Completion Date:	February 2015
Estimated Primary Completion Date:	January 2015 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Dabigatran	Drug: Dabigatran 110 mg twice daily
Active Comparator: Antiplatelets	Drug: Antiplatelets 100mg once a day

Detailed Description:

The primary endpoint is the number of microbleeds, as measured by MRI, at 90 days of follow up.

The study is based on the hypothesis that drugs inhibitor of the thrombin is more effective than ASA in preventing vessel obstruction. The rationale behind the study is based on the assumption that: a) the formation of microthrombi is relevant to the clinical expression of the CADASIL disease, and b) thrombin inhibitors are more effective than antiplatelet drugs in preventing lesions by microvessel obstruction.

Eligible patients will be randomized into one of the 2 treatment groups:

One week wash-out (W1), Dabigatran one tablet 100mg twice a day for 12 weeks, a second one week wash-out (W2), treatment with ASA one tablet of 100mg/day once a day for 12 weeks;
The same scheme repeated with reversed sequence No initial wash-out week will be required for patients in group 2 already treated with ASA.

Clinical and instrumental evaluations will be carried out during the first (W1) and second wash-out weeks (W2), and at the end of the study (during the week that follows the second treatment regimen (W3). Each evaluation will consist of physical examination, blood tests and MRI.

Safety is evaluated on the basis of brain microbleeds and severe haemorrhages.

Eligibility


Ages Eligible for Study:	18 Years and older (Adult, Senior)
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Patients aged 18 years or older diagnosed with CADASIL according genetic test will be eligible.

Exclusion Criteria:

Treatment with antiplatelet drugs for a condition different from CADASIL;
conditions associated with an increased risk of bleeding (major surgery within the previous month, planned surgery or intervention within the next 3 months;
history of intracranial, intraocular, spinal, retroperitoneal or atraumatic intra‐articular bleeding;
gastrointestinal hemorrhage within the past year;
symptomatic or endoscopically documented gastroduodenal ulcer disease in the previous 30 days; hemorrhagic disorder or bleeding diathesis;
need for anticoagulant treatment of disorders other than atrial fibrillation; fibrinolytic agents within 48 hours of study entry; uncontrolled hypertension (systolic blood pressure greater than 180 mm Hg and/or diastolic blood pressure greater than 100 mm Hg);
recent malignancy or radiation therapy (within 6 months) and not expected to survive 3 years; severe renal impairment (estimated creatinine clearance 30 mL/min or less);
active infective endocarditis;
active liver disease (including but not limited to persistent ALT, AST, Alk Phos greater than twice the upper limit of the normal range; active hepatitis C (positive HCV RNA);
active hepatitis B (HBs antigen +, anti HBc IgM +), active hepatitis A);
women who are pregnant or of childbearing potential who refuse to use a medically acceptable form of contraception throughout the study.

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01361763

Contacts


Contact: Francesco Orzi, MD	+3933775829	francesco.orzi@uniroma1.it
Contact: Giulio Caselli, MD	3478654946	giulio.caselli@gmail.com

Locations


Italy
Emergency Department Stroke Unit, Umberto I Hospital	Not yet recruiting
Rome, Italy, 00161
Contact: Danilo Toni, MD +39-06-49979595 danilo.toni@uniroma1.it
Contact: Agata Correnti, MD
Principal Investigator: Emanuele Puca, MD
NESMOS Department St. Andrea Hospital	Recruiting
Rome, Italy, 00189
Contact: Francesco Orzi, MD +39-06-33775829 francesco.orzi@uniroma1.it
Contact: Giulio Caselli, MD +39-347-8654946 giulio.caselli@gmail.com
Principal Investigator: Giulio Caselli, MD
Principal Investigator: Barbara Casolla, MD

Sponsors and Collaborators

S. Andrea Hospital

Investigators


Study Chair:	Francesco Orzi, MD	NESMOS Department, University of Rome "La Sapienza"; St. Andrea Hospital

More Information

Publications:

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. Review.

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.

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. Review.

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. Erratum in: N Engl J Med. 2010 Nov 4;363(19):1877.

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.

Dichgans M, Holtmannspötter 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.

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.

Hills M, Armitage P. The two-period cross-over clinical trial. Br J Clin Pharmacol. 1979 Jul;8(1):7-20.

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.

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.

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.

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.

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.

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.

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. Epub 2007 Aug 30.

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.

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.

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.

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.

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.

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.

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.

De Ferrari GV, Moon RT. The ups and downs of Wnt signaling in prevalent neurological disorders. Oncogene. 2006 Dec 4;25(57):7545-53. Review.


Responsible Party:	Francesco Orzi, Department of Neuroscience, Mental Healt and Sensory Organs (NESMOS); University of Rome "La Sapienza"
ClinicalTrials.gov Identifier:	NCT01361763 History of Changes
Other Study ID Numbers:	DABCAD2010
Study First Received:	May 16, 2011
Last Updated:	February 10, 2014
Health Authority:	Italy: Ministry of Health

Keywords provided by S. Andrea Hospital:


Dabigatran Microbleeds Microthrombi CADASIL Small Vessel Disease

Additional relevant MeSH terms:


CADASIL Dementia, Multi-Infarct Cerebral Small Vessel Diseases Cerebrovascular Disorders Brain Diseases Central Nervous System Diseases Nervous System Diseases Dementia, Vascular Cerebral Arterial Diseases Intracranial Arterial Diseases Dementia Vascular Diseases Cardiovascular Diseases Genetic Diseases, Inborn	Cerebral Infarction Brain Infarction Brain Ischemia Stroke Neurocognitive Disorders Mental Disorders Dabigatran Antithrombins Serine Proteinase Inhibitors Protease Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Anticoagulants

ClinicalTrials.gov processed this record on September 29, 2016

Safety Study of Dabigatran in CADASIL (SONICA)