Journal
INTERNATIONAL JOURNAL OF STROKE
Volume 13, Issue 5, Pages 530-538Publisher
SAGE PUBLICATIONS LTD
DOI: 10.1177/1747493017731947
Keywords
Lacunar stroke; small vessel disease; cilostazol; isosorbide mononitrate; endothelium; blood-brain barrier; white matter hyperintensities; cerebrovascular reactivity
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Funding
- Alzheimer's Society [252 (AS-PG-14-033)]
- European Union Horizon 2020 project, 'SVDs@Target' [666881]
- Stroke Association Princess Margaret Research Development Fellowship scheme
- Stroke Association Garfield Weston Foundation Senior Clinical Lectureship
- NHS Research Scotland
- China Scholarships Council/University of Edinburgh
- NHS Lothian Research and Development Office
- Scottish Funding Council through the Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) Collaboration
- Fondation Leducq [16 CVD 05]
- Edinburgh and Lothians Health Foundation
- National Institutes of Health Research (NIHR) HTA TARDIS trial
- National Institutes of Health Research (NIHR) BHF RIGHT-2 trial
- NIHR HTA TICH-2 trial
- HTA TARDIS trial
- NIHR Clinical Research network (CRN) East Midlands
- MRC [UKDRI-4002] Funding Source: UKRI
- Medical Research Council [UKDRI-4002, MR/K026992/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0515-10044] Funding Source: researchfish
- Stroke Association [TSA15LECT04, TSA2008/09] Funding Source: researchfish
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Rationale The pathophysiology of most lacunar stroke, a form of small vessel disease, is thought to differ from large artery atherothrombo- or cardio-embolic stroke. Licensed drugs, isosorbide mononitrate and cilostazol, have promising mechanisms of action to support their testing to prevent stroke recurrence, cognitive impairment, or radiological progression after lacunar stroke. Aim LACI-1 will assess the tolerability, safety, and efficacy, by dose, of isosorbide mononitrate and cilostazol, alone and in combination, in patients with ischemic lacunar stroke. Sample size A sample of 60 provides 80+% power (significance 0.05) to detect a difference of 35% (90% versus 55%) between those reaching target dose on one versus both drugs. Methods and design LACI-1 is a phase IIa partial factorial, dose-escalation, prospective, randomized, open label, blinded endpoint trial. Participants are randomized to isosorbide mononitrate and/or cilostazol for 11 weeks with dose escalation to target as tolerated in two centers (Edinburgh, Nottingham). At three visits, tolerability, safety, blood pressure, pulse wave velocity, and platelet function are assessed, plus magnetic resonance imaging to assess cerebrovascular reactivity in a subgroup. Study outcomes Primary: proportion of patients completing study achieving target maximum dose. Secondary symptoms whilst taking medications; safety (hemorrhage, recurrent vascular events, falls); blood pressure, platelet function, arterial stiffness, and cerebrovascular reactivity. Discussion This study will inform the design of a larger phase III trial of isosorbide mononitrate and cilostazol in lacunar stroke, whilst providing data on the drugs' effects on vascular and platelet function. Trial registration ISRCTN (ISRCTN12580546) and EudraCT (2015-001953-33).
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