LACI-3

Title	LACunar Intervention trial 3 (LACI-3)
Acronym	LACI-3
Chief investigator	Professor Joanna Wardlaw
Objectives	To determine if, in patients with symptomatic lacunar ischaemic stroke, the routine long-term administration of isosorbide mononitrate 50mg od or equivalent, and /or cilostazol 100mg bd, individually or together, in addition to continuing routine stroke prevention therapy, compared with continuing routine stroke prevention therapy alone, reduces cognitive impairment after lacunar ischaemic stroke, a marker of cerebral small vessel disease.
Trial design	An investigator-led, multicentre, prospective, randomised, controlled, open label, 2x2 factorial, blinded endpoint (PROBE) confirmatory trial.
Setting	At least 60 hospitals in the UK (Scotland, England, Wales, Northern Ireland)
Sample size estimate	The primary outcome, cognitive impairment assessed using the DSM-5 7-level ordinal score, will be compared between ISMN vs no ISMN, cilostazol vs no cilostazol, and ISMN+cilostazol vs no ISMN or cilostazol using ordinal logistic regression adjusted for stratification and minimisation variables. The null hypothesis is that ISMN, alone or with cilostazol, will not reduce long-term cognitive impairment in patients with lacunar ischaemic stroke. A sample of N=1300 is needed (650 ISMN, 650 no ISMN) assuming alpha 5%, power 90%; distribution of DSM-5 7-level ordinal score in the control (standard of care) group is: level 1 (normal): 35%, 2: 24%, 3: 12%, 4: 20%, 5: 3%, 6: 3%, 7 (dead):3% (as in LACI-2); DSM-5 7-level unadjusted odds ratio 0.70 (the risk reduction exceeds the minimal clinically important difference [MCID] of 0.27), standard deviation 1.33; losses/cross-overs 15%; no covariate adjustment; sample rounded up.
Number of participants	1,300
Eligibility criteria	Inclusions Aged 30 years old and above Clinical stroke syndrome compatible with a lacunar stroke and brain imaging (MRI preferred but CT allowed) at the time of the stroke shows a relevant recent small subcortical infarct, or if no relevant infarct then no other explanation for symptoms is seen Genetic forms of SVD (e.g. CADASIL) may be included if they present with a lacunar stroke Capacity to give consent in the opinion of the PI or any delegated member of the research team Exclusions Less than 24 hours since onset of the lacunar stroke Patient on dual antiplatelet drugs (see additional exclusion, below) Stroke mechanism with definite treatment indication (e.g. cardioembolism, ipsilateral carotid stenosis) Other explanation for the lacunar stroke symptoms (i.e. recent cortical infarct, haemorrhage or tumour) Other active neurological disease (e.g. brain tumour, multiple sclerosis, recurrent seizures, neurodevelopmental disorder - well-controlled epilepsy present prior to the lacunar stroke, a single seizure at onset of the stroke, or provoked seizure, is not an exclusion) Contraindication to both trial drugs in section 4.3 of the SPCs (patients with a contraindication to one trial drug may still be randomised to the other trial drug) Indication for either trial drug (patient already prescribed one trial drug may still be randomised to the other trial drug) Dependent - mRS cannot be 3-5 Clinical diagnosis of dementia Planned surgery during the trial period including carotid endarterectomy. Note prior and apparently successful carotid endarterectomy (or other surgery) is not an exclusion criterion and patients who would otherwise be eligible but require endarterectomy first may be randomised after recovery from successful endarterectomy Unable to swallow Diagnosis of hypotension, defined as sitting systolic blood pressure less than 100 mmHg History of drug overdose or attempted suicide Unlikely to be available for follow-up at 18 months Unlikely to comply with study procedures and follow-up procedures for whatever reason (e.g. history of poor medication compliance) in the opinion of the randomising physician Pregnant, breast-feeding, or of child-bearing potential and not using highly effective contraception as stated in protocol (see Pregnancy section) Renal impairment (creatinine clearance under 25 ml/min) Hepatic impairment Currently prescribed dual antiplatelet treatment (single antiplatelet is not an exclusion); patients can be randomised into the trial once the 28-day period of dual antiplatelet for guideline secondary prevention following the acute lacunar ischaemic stroke has completed Previously enrolled in LACI-3 Enrolled in a study that precludes co-enrolment with LACI-3 Exclusions for Cilostazol only Allergy to Cilostazol Already prescribed Cilostazol Any contraindication to Cilostazol Patient is on a prohibited medication: Warfarin Acenocoumarol (Sinthrome®) Phenindione Dabigatran (Pradaxa ®) Apixaban (Eliquis®) Rivaroxaban (Xarelto®) Edoxaban Heparin Dalteparin (Fragmin®) Enoxaparin (Clexane®) Tinzaparin (Innohep®) Omeprazole – can be switched to Lansoprazole or other Proton Pump Inhibitor Anagrelide Clarithromycin Erythromycin Diltiazem (Tildiem®) Itraconazole (Sporanox®) Boceprevir (Victrelis®) Ritonavir (Norvir®) Telaprevir (Incivo®) Ketoconazole (Nizoral®) Active cardiac disease (atrial fibrillation, myocardial infarction in past 6 months, active angina, symptomatic cardiac failure) Bleeding tendency (platelets under 100 ×10⁹/L, active peptic ulcer, taking anticoagulant medication) Exclusions for ISMN only Allergy to ISMN Already prescribed ISMN Any contraindication to ISMN (e.g. lactose intolerance) or other regular nitrate Patient is on a prohibited medication: Avanafil (Spedra®) Sildenafil (Nipatra®, Viagra®, Revatio®) Tadalafil (Cialis®) Vardenafil (Levitra®)
Description of interventions	Cilostazol only Cilostazol 100mg oral twice daily ISMN only Isosorbide mononitrate slow release 50mg oral once daily Both Cilostazol and ISMN Cilostazol 100mg oral twice daily and Isosorbide mononitrate slow release 50mg oral once daily None (neither Cilostazol nor ISMN)
Duration of study	Treatment duration: from within one day of randomisation until the end of trial follow-up Follow-up duration: 18 months Total planned trial duration: 52 months
Randomisation and blinding	The study will be performed open label. Placebo tablets are not available and masking by encapsulation is too complicated and expensive. However, blinding of outcomes is important to obtain unbiased information about tolerability, safety, and efficacy. As such, IMP adherence structured questionnaire and prescribed medications will be taken by site staff who are already unblinded to trial allocation, while ascertainment of the main cognitive and clinical outcomes will be collected by central follow-up co-ordinators who are masked to treatment allocation.
Outcome measures	Primary objective: To determine if, in patients with symptomatic lacunar ischaemic stroke, the routine long-term administration of isosorbide mononitrate 50mg od or equivalent, and /or cilostazol 100mg bd, individually or together, in addition to continuing routine stroke prevention therapy, compared with continuing routine stroke prevention therapy alone, reduces cognitive impairment after lacunar ischaemic stroke, a marker of cerebral small vessel disease. Secondary objectives: To determine if the long-term administration of isosorbide mononitrate 50mg od or equivalent and/or cilostazol 100mg bd individually or together, in addition to continuing routine stroke prevention therapy, compared with continuing routine stroke prevention therapy alone, reduces dependency, recurrent stroke or TIA, MI, death, and improves mood, quality of life, and health economic resource usage and is safe and well tolerated in long term use in patients with lacunar ischaemic stroke, a marker of cerebral small vessel disease.
Statistical methods	A full statistical analysis plan (SAP) will be finalised prior to database lock.

Contact details
Address:	Centre for Clinical Brain Sciences Chancellor's Building University of Edinburgh 49 Little France Crescent Edinburgh EH16 4SB, United Kingdom Tel: 0131 465 9592
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LACI-3 trial

LACunar Intervention trial 3