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

Primary Purpose

Cerebral Small Vessel Diseases, Cognitive Impairment, Stroke

Status
Completed
Phase
Phase 2
Locations
United Kingdom
Study Type
Interventional
Intervention
isosorbide mononitrate
cilostazol
Sponsored by
University of Edinburgh
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Cerebral Small Vessel Diseases focused on measuring cerebral small vessel disease, cerebrovascular reactivity, cilostazol, isosorbide mononitrate

Eligibility Criteria

35 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • University of Edinburgh
  • University of Nottingham

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Active Comparator

Active Comparator

Other

Arm Label

Group 1

Group 2

Group 3

Group 4

Arm Description

Isosorbide mononitrate 25mg bd

Cilostazol 100mg bd

Isosorbide mononitrate 25mg bd and cilostazol 100mg bd start immediately

Isosorbide mononitrate 25mg bd and cilostazol 100mg bd delayed start

Outcomes

Primary Outcome Measures

Tolerability proportion of patients able to tolerate the target dose
proportion of patients able to tolerate the target dose

Secondary Outcome Measures

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

Full Information

First Posted
June 19, 2015
Last Updated
January 18, 2018
Sponsor
University of Edinburgh
Collaborators
University of Nottingham
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1. Study Identification

Unique Protocol Identification Number
NCT02481323
Brief Title
Lacunar Intervention Trial 1 (LACI-1)
Acronym
Prevent-SVD
Official Title
Preventing Cognitive Decline and Dementia From Cerebral Small Vessel Disease
Study Type
Interventional

2. Study Status

Record Verification Date
January 2018
Overall Recruitment Status
Completed
Study Start Date
March 2016 (Actual)
Primary Completion Date
August 2017 (Actual)
Study Completion Date
November 30, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Edinburgh
Collaborators
University of Nottingham

4. Oversight

Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cerebral Small Vessel Diseases, Cognitive Impairment, Stroke
Keywords
cerebral small vessel disease, cerebrovascular reactivity, cilostazol, isosorbide mononitrate

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Factorial Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
57 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Group 1
Arm Type
Active Comparator
Arm Description
Isosorbide mononitrate 25mg bd
Arm Title
Group 2
Arm Type
Active Comparator
Arm Description
Cilostazol 100mg bd
Arm Title
Group 3
Arm Type
Active Comparator
Arm Description
Isosorbide mononitrate 25mg bd and cilostazol 100mg bd start immediately
Arm Title
Group 4
Arm Type
Other
Arm Description
Isosorbide mononitrate 25mg bd and cilostazol 100mg bd delayed start
Intervention Type
Drug
Intervention Name(s)
isosorbide mononitrate
Other Intervention Name(s)
Isotard
Intervention Description
slow release nitric oxide donor that enhances vasodilation and widely used in angina prophyaxis
Intervention Type
Drug
Intervention Name(s)
cilostazol
Other Intervention Name(s)
pletal
Intervention Description
phosphodiesterase 3-inhibitor that enhances vessel wall function with weak antiplatelet effects
Primary Outcome Measure Information:
Title
Tolerability proportion of patients able to tolerate the target dose
Description
proportion of patients able to tolerate the target dose
Time Frame
8 weeks
Secondary Outcome Measure Information:
Title
Safety - bleeding
Description
systemic or intracranial bleeding
Time Frame
12 weeks
Title
Safety - recurrent stroke
Description
recurrent vascular events,
Time Frame
12 weeks
Title
Safety - death
Description
death
Time Frame
12 weeks
Title
Safety - blood pressure
Description
reduction in blood pressure
Time Frame
8 weeks
Title
Safety - bleeding
Description
effect on platelet function assessed using p-selectin
Time Frame
8 weeks
Title
Efficacy - cerebrovascular function
Description
effect on cerebrovascular reactivity assessed using carbon dioxide challenge in magnetic resonance imaging
Time Frame
8 weeks
Title
Efficacy - systemic arterial stiffness
Description
effect on systemic large artery stiffness assessed with pulse wave velocity measurement
Time Frame
8 weeks
Title
Tolerability Proportion of patients with headache that interferes with daily activities
Description
Proportion of patients with headache that interferes with daily activities
Time Frame
8 weeks
Title
Tolerability Proportion of patients with dizziness that interferes with daily activities
Description
Proportion of patients with dizziness that interferes with daily activities
Time Frame
8 weeks
Title
Tolerability Proportion of patients with nausea that interferes with daily activities
Description
Proportion of patients with nausea that interferes with daily activities
Time Frame
8 weeks
Title
Tolerability Proportion of patients with palpitations
Description
Proportion of patients with palpitations
Time Frame
8 weeks
Title
Tolerability Proportion of patients with loose stools
Description
Proportion of patients with loose stools
Time Frame
8 weeks
Title
Tolerability Tablet count
Description
Tablet count
Time Frame
8 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
35 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Joanna M Wardlaw, MD
Organizational Affiliation
University of Edinburgh
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Edinburgh
City
Edinburgh
ZIP/Postal Code
EH4 2XU
Country
United Kingdom
Facility Name
University of Nottingham
City
Nottingham
ZIP/Postal Code
NG7 2RD
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
34847709
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.
Results Reference
derived

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Lacunar Intervention Trial 1 (LACI-1)

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