Prevent-SVD: Lacunar Intervention Trial 1 (LACI-1)

Sponsor

University of Edinburgh (Other)

Overall Status

Completed

CT.gov ID

NCT02481323

Collaborator

University of Nottingham (Other)

Enrollment

Locations

Arms

Actual Duration (Months)

28.5

Patients Per Site

1.4

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Cerebral Small Vessel Diseases Cognitive Impairment Stroke	Drug: isosorbide mononitrate Drug: cilostazol	Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

57 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Masking:

None (Open Label)

Primary Purpose:

Prevention

Official Title:

Preventing Cognitive Decline and Dementia From Cerebral Small Vessel Disease

Actual Study Start Date :

Mar 1, 2016

Actual Primary Completion Date :

Aug 1, 2017

Actual Study Completion Date :

Nov 30, 2017

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

Tolerability proportion of patients able to tolerate the target dose [8 weeks]
proportion of patients able to tolerate the target dose

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

35 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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