Clinical trial NCT02481323: Lacunar Intervention Trial 1 (LACI-1)
Official title: Preventing Cognitive Decline and Dementia From Cerebral Small Vessel Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cerebral Small Vessel Diseases
Cognitive Impairment
Stroke
Keywords: cerebral small vessel disease
cerebrovascular reactivity
cilostazol
isosorbide mononitrate
Lead sponsor: University of Edinburgh
Sponsor class: OTHER
Collaborators: name: University of Nottingham
First posted: 2015-06-25
Enrollment: 57
Sex: ALL
Minimum age (years): 35
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Tolerability proportion of patients able to tolerate the target dose
timeFrame: 8 weeks
Secondary outcomes:
measure: Safety - bleeding
timeFrame: 12 weeks
measure: Safety - recurrent stroke
timeFrame: 12 weeks
measure: Safety - death
timeFrame: 12 weeks
measure: Safety - blood pressure
timeFrame: 8 weeks
measure: Safety - bleeding
timeFrame: 8 weeks
measure: Efficacy - cerebrovascular function
timeFrame: 8 weeks
measure: Efficacy - systemic arterial stiffness
timeFrame: 8 weeks
measure: Tolerability Proportion of patients with headache that interferes with daily activities
timeFrame: 8 weeks
measure: Tolerability Proportion of patients with dizziness that interferes with daily activities
timeFrame: 8 weeks
measure: Tolerability Proportion of patients with nausea that interferes with daily activities
timeFrame: 8 weeks
measure: Tolerability Proportion of patients with palpitations
timeFrame: 8 weeks
measure: Tolerability Proportion of patients with loose stools
timeFrame: 8 weeks
measure: Tolerability Tablet count
timeFrame: 8 weeks
Other outcomes:
Locations:
city: Edinburgh
country: United Kingdom
facility: University of Edinburgh
city: Nottingham
country: United Kingdom
facility: University of Nottingham
Study officials:
affiliation: University of Edinburgh
name: Joanna M Wardlaw, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Blair GW, Janssen E, Stringer MS, Thrippleton MJ, Chappell F, Shi Y, Hamilton I, Flaherty K, Appleton JP, Doubal FN, Bath PM, Wardlaw JM. Effects of Cilostazol and Isosorbide Mononitrate on Cerebral Hemodynamics in the LACI-1 Randomized Controlled Trial. Stroke. 2022 Jan;53(1):29-33. doi: 10.1161/STROKEAHA.121.034866. Epub 2021 Dec 1.