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

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ClinicalTrials.gov Identifier: NCT02481323
Recruitment Status : Completed
First Posted : June 25, 2015
Last Update Posted : January 19, 2018
Sponsor:
Collaborator:
University of Nottingham
Information provided by (Responsible Party):
University of Edinburgh

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 Type : Interventional  (Clinical Trial)
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 : March 2016
Actual Primary Completion Date : August 2017
Actual Study Completion Date : November 30, 2017

Resource links provided by the National Library of Medicine


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 Name: Isotard

Active Comparator: Group 2
Cilostazol 100mg bd
Drug: cilostazol
phosphodiesterase 3-inhibitor that enhances vessel wall function with weak antiplatelet effects
Other Name: 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 Name: Isotard

Drug: cilostazol
phosphodiesterase 3-inhibitor that enhances vessel wall function with weak antiplatelet effects
Other Name: pletal

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 Name: Isotard

Drug: cilostazol
phosphodiesterase 3-inhibitor that enhances vessel wall function with weak antiplatelet effects
Other Name: pletal




Primary Outcome Measures :
  1. Tolerability proportion of patients able to tolerate the target dose [ Time Frame: 8 weeks ]
    proportion of patients able to tolerate the target dose


Secondary Outcome Measures :
  1. Safety - bleeding [ Time Frame: 12 weeks ]
    systemic or intracranial bleeding

  2. Safety - recurrent stroke [ Time Frame: 12 weeks ]
    recurrent vascular events,

  3. Safety - death [ Time Frame: 12 weeks ]
    death

  4. Safety - blood pressure [ Time Frame: 8 weeks ]
    reduction in blood pressure

  5. Safety - bleeding [ Time Frame: 8 weeks ]
    effect on platelet function assessed using p-selectin

  6. Efficacy - cerebrovascular function [ Time Frame: 8 weeks ]
    effect on cerebrovascular reactivity assessed using carbon dioxide challenge in magnetic resonance imaging

  7. Efficacy - systemic arterial stiffness [ Time Frame: 8 weeks ]
    effect on systemic large artery stiffness assessed with pulse wave velocity measurement

  8. Tolerability Proportion of patients with headache that interferes with daily activities [ Time Frame: 8 weeks ]
    Proportion of patients with headache that interferes with daily activities

  9. Tolerability Proportion of patients with dizziness that interferes with daily activities [ Time Frame: 8 weeks ]
    Proportion of patients with dizziness that interferes with daily activities

  10. Tolerability Proportion of patients with nausea that interferes with daily activities [ Time Frame: 8 weeks ]
    Proportion of patients with nausea that interferes with daily activities

  11. Tolerability Proportion of patients with palpitations [ Time Frame: 8 weeks ]
    Proportion of patients with palpitations

  12. Tolerability Proportion of patients with loose stools [ Time Frame: 8 weeks ]
    Proportion of patients with loose stools

  13. Tolerability Tablet count [ Time Frame: 8 weeks ]
    Tablet count



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Ages Eligible for Study:   35 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02481323


Locations
United Kingdom
University of Edinburgh
Edinburgh, United Kingdom, EH4 2XU
University of Nottingham
Nottingham, United Kingdom, NG7 2RD
Sponsors and Collaborators
University of Edinburgh
University of Nottingham
Investigators
Principal Investigator: Joanna M Wardlaw, MD University of Edinburgh

Responsible Party: University of Edinburgh
ClinicalTrials.gov Identifier: NCT02481323     History of Changes
Other Study ID Numbers: PrevSVD-2015
2015‐001953‐33 ( EudraCT Number )
252 (AS-PG-14-033) ( Other Grant/Funding Number: Alzheimer's Society UK )
First Posted: June 25, 2015    Key Record Dates
Last Update Posted: January 19, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by University of Edinburgh:
cerebral small vessel disease
cerebrovascular reactivity
cilostazol
isosorbide mononitrate

Additional relevant MeSH terms:
Cognitive Dysfunction
Cerebral Small Vessel Diseases
Cognition Disorders
Neurocognitive Disorders
Mental Disorders
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Cilostazol
Isosorbide-5-mononitrate
Isosorbide Dinitrate
Isosorbide
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors
Vasodilator Agents
Neuroprotective Agents
Protective Agents
Phosphodiesterase 3 Inhibitors
Phosphodiesterase Inhibitors