Skip to main content

Research Repository

Advanced Search

Preventing cognitive decline and dementia from cerebral small vessel disease: The LACI-1 Trial. Protocol and statistical analysis plan of a phase IIa dose escalation trial testing tolerability, safety and effect on intermediary endpoints of isosorbide mononitrate and cilostazol, separately and in combination

Blair, Gordon W.; Appleton, Jason P.; Law, Zhe Kang; Doubal, Fergus; Flaherty, Katie; Dooley, Richard; Shuler, Kirsten; Richardson, Carla; Hamilton, Iona; Shi, Yulu; Stringer, Michael; Boyd, Julia; Thrippleton, Michael J.; Sprigg, Nikola; Bath, Philip M.W.; Wardlaw, Joanna M.

Preventing cognitive decline and dementia from cerebral small vessel disease: The LACI-1 Trial. Protocol and statistical analysis plan of a phase IIa dose escalation trial testing tolerability, safety and effect on intermediary endpoints of isosorbide mononitrate and cilostazol, separately and in combination Thumbnail


Authors

Gordon W. Blair

Jason P. Appleton

Zhe Kang Law

Fergus Doubal

Katie Flaherty

Richard Dooley

Kirsten Shuler

Carla Richardson

Iona Hamilton

Yulu Shi

Michael Stringer

Julia Boyd

Michael J. Thrippleton

NIKOLA SPRIGG nikola.sprigg@nottingham.ac.uk
Professor of Stroke Medicine

PHILIP BATH philip.bath@nottingham.ac.uk
Stroke Association Professor of Stroke Medicine

Joanna M. Wardlaw



Abstract

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.

Citation

Blair, G. W., Appleton, J. P., Law, Z. K., Doubal, F., Flaherty, K., Dooley, R., …Wardlaw, J. M. (2018). Preventing cognitive decline and dementia from cerebral small vessel disease: The LACI-1 Trial. Protocol and statistical analysis plan of a phase IIa dose escalation trial testing tolerability, safety and effect on intermediary endpoints of isosorbide mononitrate and cilostazol, separately and in combination. International Journal of Stroke, 13(5), 530-538. https://doi.org/10.1177/1747493017731947

Journal Article Type Article
Acceptance Date Aug 14, 2017
Online Publication Date Sep 14, 2017
Publication Date Jul 1, 2018
Deposit Date Oct 6, 2017
Publicly Available Date Oct 6, 2017
Journal International Journal of Stroke
Print ISSN 1747-4930
Electronic ISSN 1747-4949
Publisher SAGE Publications
Peer Reviewed Peer Reviewed
Volume 13
Issue 5
Pages 530-538
DOI https://doi.org/10.1177/1747493017731947
Keywords Lacunar stroke, Small vessel disease, Cilostazol, Isosorbide mononitrate, Endothelium, Blood–brain barrier, White matter hyperintensities, Cerebrovascular reactivity
Public URL https://nottingham-repository.worktribe.com/output/943177
Publisher URL https://doi.org/10.1177/1747493017731947
Additional Information Copyright © 2017 by World Stroke Organization
Contract Date Oct 6, 2017

Files





Downloadable Citations