The LACunar Intervention Trial 3 (LACI-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.
Lacunar (small vessel) ischaemic stroke
The intervention involves random allocation to one of the four treatment groups, in addition to the guideline standard care after lacunar ischaemic stroke, using an electronic randomisation system: 1. Isosorbide mononitrate (ISMN) oral: 1.1. Slow release 50 mg once daily or 1.2. Non-slow-release 20 or 25 mg twice daily 2. Cilostazol 100 mg oral twice daily 3. Both ISMN and cilostazol - same doses as above 4. Neither ISMN nor cilostazol A target dose of isosorbide mononitrate is 40-60 mg daily. If a slow-release ISMN is not available, the non-slow-release tablets may be used. The IMP is defined by the active substance only, therefore all authorised brands may be used. There is no placebo. The comparator will be a standard care alone including guideline stroke secondary prevention prescribed post-stroke as per national guidelines. The trial treatment period is 18 months. There are five follow-up timepoints after randomisation: 1. 1–2-week follow-up by phone 2. 3–4-week follow-up by phone 3. 6-month follow-up by post and phone 4. 12-month follow-up by post and phone 5. 18-month follow-up by post and phone
1. Age ≥30 years 2. 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 3. Genetic forms of SVD (e.g. CADASIL) may be included if they present with a lacunar stroke 4. Capacity to give consent in the opinion of the PI or any delegated member of the research team
General Exclusion Criteria: 1. Less than 24 hours since onset of the lacunar stroke or patient on dual antiplatelet drugs 2. Stroke mechanism with definite treatment indication (e.g. cardioembolism, ipsilateral carotid stenosis) 3. Other explanation for the lacunar stroke symptoms (i.e., recent cortical infarct, haemorrhage or tumour) 4. 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) 5. 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) 6. Indication for either trial drug (patient already prescribed one trial drug may still be randomised to the other trial drug) 7. Dependent (mRS>2) 8. Clinical diagnosis of dementia 9. 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 10. Unable to swallow 11. Diagnosis of hypotension, defined as sitting systolic blood pressure less than 100mmHg 12. History of drug overdose or attempted suicide 13. Unlikely to be available for follow-up at 18 months 14. 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 15. Pregnant, breast-feeding, or of child-bearing potential and not using highly effective contraception 16. Renal impairment (creatinine clearance <25 ml/min) 17. Hepatic impairment 18. Currently prescribed dual antiplatelet treatment (single antiplatelet is not an exclusion); patients can be randomised into t