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.

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