LACunar Intervention (LACI) Trial-3: Assessment of efficacy and safety of cilostazol and isosorbide mononitrate to prevent adverse outcomes in patients with cerebral small vessel disease (lacunar) ischaemic stroke

Research question: Do oral isosorbide mononitrate (ISMN) and/or cilostazol, prevent cognitive impairment, dependency, adverse vascular outcomes, death, and improve quality of life, after lacunar (small vessel) ischaemic stroke?

Background: Lacunar ischaemic stroke, a type of small vessel disease (SVD), accounts for 25% of ischaemic strokes. Typically these are neurologically ‘minor’ strokes, so usually not physically disabling, but cognitive impairment is common, a James Lind Alliance priority, and main concern of patients. Current secondary prevention treatments have little benefit on recurrent stroke, cognition or dependency.

LACI-1 (n=57, 8wks) and LACI-2 (n=363, 1yr) trials tested ISMN and cilostazol, alone and together, meeting feasible/tolerable targets, found no safety concerns and showed possible clinical efficacy: ISMN reduced recurrent stroke, cognitive decline and improved QoL; cilostazol reduced dependency; ISMN+cilostazol reduced cognitive decline, dependency, composite outcome including recurrent stroke, and improved QoL. Long term cilostazol reduced recurrent stroke in other trials.

Aims, objectives: To determine if long term ISMN and/or cilostazol improve outcomes after lacunar ischaemic stroke and should be used in clinical practice. 1ry objective: Does ISMN+/-cilostazol reduce cognitive impairment? 2ry objectives: Does ISMN+/-cilostazol reduce dependency, recurrent stroke, death, improve mood, QoL.

Methods: Pragmatic phase III, prospective, randomised, controlled, open label, 2x2 factorial, blinded outcome (PROBE) trial. Pragmatic design, modest data collection will optimise enrolment, blinding will minimise bias. Setting: 60 UK hospital stroke services.

Participants: Patients with clinical lacunar ischaemic stroke, compatible brain imaging, aged >30, with capacity to consent. Exclusion: mainly indications for/contraindications to, either drug.

Intervention: Daily oral ISMN 50mg, cilostazol 200mg, both, or neither, randomised 1:1:1:1, started 1 day post randomisation for 18 months. Patients with contra-indications/indications to one drug may be randomised to the other drug. All receive usual guideline stroke prevention (antiplatelet, antihypertensive, lipid lowering, lifestyle advice).

Outcomes: Central blinded follow-up (cognition, dependency, recurrent stroke, mood, QoL). Primary: DSM-5 7-level ordinal cognition at 18 months.

Secondary: Dependency (modified Rankin Scale), recurrent stroke, MI, death, composite, mood, QoL, safety, cost efficiency at 18 months.

Sample size: n=1300 is needed, 650 ISMN v 650 no ISMN, to detect a 30% reduction (OR 0.70) in cognitive impairment, MCID 0.27, at 90% power, alpha 5%, 15% data losses, rounded up.

Timelines: 52month study; Approvals M-1; Initiate sites M3; Recruitment start M3, 60 sites activated M18, Recruitment end date M30, Follow-up end date M48, Data analysis M50-52, Dissemination M53, Final report M53-58.

Impact and dissemination: Both drugs are inexpensive, widely available, licenced for other diseases. If LACI-3 confirms LACI-2's results, then NHS England Medicines Repurposing Programme will help extend ISMN's and/or cilostazol's UK licences, with potential global impact on vascular cognitive decline, the main concern of lacunar stroke patients. Oral presentation at a major conference with high impact journal publication will ensure rapid dissemination and guideline inclusion; PPI groups will inform dissemination to the public via multiple channels.