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

January 18, 2018 updated by: University of Edinburgh

Preventing Cognitive Decline and Dementia From Cerebral Small Vessel Disease

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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

Enrollment (Actual)

57

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
      • Edinburgh, United Kingdom, EH4 2XU
        • University of Edinburgh
      • Nottingham, United Kingdom, NG7 2RD
        • University of Nottingham

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

35 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Edinburgh

Collaborators

University of Nottingham

Investigators

  • Principal Investigator: Joanna M Wardlaw, MD, University of Edinburgh

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 1, 2016

Primary Completion (Actual)

August 1, 2017

Study Completion (Actual)

November 30, 2017

Study Registration Dates

First Submitted

June 19, 2015

First Submitted That Met QC Criteria

June 24, 2015

First Posted (Estimate)

June 25, 2015

Study Record Updates

Last Update Posted (Actual)

January 19, 2018

Last Update Submitted That Met QC Criteria

January 18, 2018

Last Verified

January 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PrevSVD-2015
  • 2015-001953-33 (EudraCT Number)
  • 252 (AS-PG-14-033) (Other Grant/Funding Number: Alzheimer's Society UK)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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