Lacunar Intervention Trial 1 (LACI-1)

Study Overview
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Brief Summary
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Phase II pilot randomised, factorial, short term dose escalation, open label, blinded intermediary endpoint trial, in two hospital centres in the UK, of tolerability and safety of cilostazol, isosorbide mononitrate, both or neither in patients with small vessel disease manifest as symptomatic small subcortical stroke.

Detailed Description
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A quarter of all ischaemic strokes are lacunar (small vessel) in type, about 35000 per annum in the United Kingdom, and due to an intrinsic, non-atheromatous, non-cardioembolic perforating cerebral arteriolar disease. 'Small vessel disease' also affects the brain diffusely, causing up to 40% of dementias, alone or mixed with Alzheimer's disease, 350,000+ patients estimated currently in the United Kingdom. There is no proven treatment: conventional antiplatelet drugs may be ineffective or even hazardous, antihypertensive treatment and statins have been disappointing. The disease mechanism is poorly understood but endothelial dysfunction, blood-brain barrier failure and vessel stiffness appear to contribute to the pathogenesis. Promising data available for licensed drugs with relevant modes of action, cilostazol (>6000 stroke patients in the Asia Pacific region) and isosorbide mononitrate (ISMN, widely used in cardiac disease) support their testing in small vessel disease. This trial will be a phase 2, randomised, dose-escalation, factorial trial to test short-term administration of cilostazol, Isosorbide Mononitrate, both, or neither, to provide data on patient tolerability of dose (including headache, dizziness), safety (including blood pressure, platelet function), provide mechanistic evidence of efficacy (cerebrovascular reactivity, arterial compliance), and to inform the design of a larger phase 2-3 trial. The trial will recruit 60 patients with small vessel disease, in two expert stroke centres (Edinburgh and Nottingham) where there are suitable patients, expert stroke centres, established trials infrastructures and neuroimaging and platelet testing expertise. The trial will also advance methods to stratify patients by small vessel disease burden in routine practise and data on intermediary mechanistic outcomes to assist in planning future trials testing novel agents for either stroke or dementia.

Official Title
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Preventing Cognitive Decline and Dementia From Cerebral Small Vessel Disease

Conditions
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Cerebral Small Vessel Diseases, Cognitive Impairment, Stroke

Intervention / Treatment
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* Drug: isosorbide mononitrate
* Drug: cilostazol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Mild symptomatic ischaemic stroke in the past four years compatible with a clinical lacunar stroke syndrome, with brain magnetic resonance imaging or computed tomography scanning that is compatible with a symptomatic small subcortical (lacunar) infarct, or if no recent relevant infarct is visible, that excluded other cause for symptoms Age > 35 years Independent in activities of daily living (modified Rankin ≤2) Able to give consent themselves Exclusion Criteria: Other significant active neurological illness present since suffering stroke (eg seizures, multiple sclerosis, brain tumour) Age < 35 Montreal Cognitive Assessment score <26 Requiring assistance with activities of daily living (Modified Rankin ≥3) Active cardiac disease (atrial fibrillation, myocardial infarction in past 6 months, active angina, symptomatic cardiac failure) Carotid stenosis > 50% in the symptomatic artery territory requiring carotid endarterectomy (prior and apparently successful carotid endarterectomy is not an exclusion criterion) Definite indication for, or definite contraindication to either trial drug Unable to swallow Bleeding tendency (platelets<100, taking anticoagulant medication) Unlikely to comply with trial medication Planned surgery during the trial period History of intracranial haemorrhage (subdural haematoma, subarachnoid haemorrhage, intracerebral haemorrhage, but not asymptomatic haemorrhagic transformation of infarction) Other life threatening illness History of drug overdose or attempted suicide or significant active mental illness Pregnancy If recruited in Edinburgh and participating in cerebrovascular reactivity arm of trial: active respiratory illness (such as moderate to severe asthma or chronic obstructive airways disease), unable to tolerate magnetic resonance imaging or unable to lie flat

Ages Eligible for Study
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Minimum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1<br>Isosorbide mononitrate 25mg bd | Drug: isosorbide mononitrate<br>* slow release nitric oxide donor that enhances vasodilation and widely used in angina prophyaxis<br>* Other names: Isotard;|
| Active Comparator: Group 2<br>Cilostazol 100mg bd | Drug: cilostazol<br>* phosphodiesterase 3-inhibitor that enhances vessel wall function with weak antiplatelet effects<br>* Other names: pletal;|
| Active Comparator: Group 3<br>Isosorbide mononitrate 25mg bd and cilostazol 100mg bd start immediately | Drug: isosorbide mononitrate<br>* slow release nitric oxide donor that enhances vasodilation and widely used in angina prophyaxis<br>* Other names: Isotard;Drug: cilostazol<br>* phosphodiesterase 3-inhibitor that enhances vessel wall function with weak antiplatelet effects<br>* Other names: pletal;|
| Other: Group 4<br>Isosorbide mononitrate 25mg bd and cilostazol 100mg bd delayed start | Drug: isosorbide mononitrate<br>* slow release nitric oxide donor that enhances vasodilation and widely used in angina prophyaxis<br>* Other names: Isotard;Drug: cilostazol<br>* phosphodiesterase 3-inhibitor that enhances vessel wall function with weak antiplatelet effects<br>* Other names: pletal;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerability proportion of patients able to tolerate the target dose | proportion of patients able to tolerate the target dose | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety - bleeding | systemic or intracranial bleeding | 12 weeks | 
| Safety - recurrent stroke | recurrent vascular events, | 12 weeks | 
| Safety - death | death | 12 weeks | 
| Safety - blood pressure | reduction in blood pressure | 8 weeks | 
| Safety - bleeding | effect on platelet function assessed using p-selectin | 8 weeks | 
| Efficacy - cerebrovascular function | effect on cerebrovascular reactivity assessed using carbon dioxide challenge in magnetic resonance imaging | 8 weeks | 
| Efficacy - systemic arterial stiffness | effect on systemic large artery stiffness assessed with pulse wave velocity measurement | 8 weeks | 
| Tolerability Proportion of patients with headache that interferes with daily activities | Proportion of patients with headache that interferes with daily activities | 8 weeks | 
| Tolerability Proportion of patients with dizziness that interferes with daily activities | Proportion of patients with dizziness that interferes with daily activities | 8 weeks | 
| Tolerability Proportion of patients with nausea that interferes with daily activities | Proportion of patients with nausea that interferes with daily activities | 8 weeks | 
| Tolerability Proportion of patients with palpitations | Proportion of patients with palpitations | 8 weeks | 
| Tolerability Proportion of patients with loose stools | Proportion of patients with loose stools | 8 weeks | 
| Tolerability Tablet count | Tablet count | 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cerebral small vessel disease, cerebrovascular reactivity, cilostazol, isosorbide mononitrate