Information for Researchers

Trial Title

LACunar Intervention (LACI) Trial-3: Assessment of efficacy and safety of cilostazol and isosorbide mononitrate to prevent adverse outcomes in patients with cerebral small vessel disease(lacunar) ischaemic stroke

Study Acronym

LACI-3

Clinical Phase

3

Trial Design

An investigator led, multicentre, prospective, randomised, controlled, open label, 2x2 factorial, blinded endpoint (PROBE) confirmatory trial. MHRA Scientific Advice has been incorporated into the trial design. 

Trial Participants

LACI-3 will include independent adults (mRS ≤2), age ≥30 years with a clinical lacunar stroke diagnosed by brain imaging (CT or MRI), who can be recruited at least 24 hours after lacunar stroke symptom onset with no latest time limit after the stroke, who have capacity to give consent and no exclusion criteria.

Randomisation cannot occur ≤24 hours after lacunar symptom onset, and in most cases ≤1 month, to avoid the period when guideline stroke secondary prevention advises prescription of dual antiplatelet drugs (aspirin, clopidogrel) for 28 days followed thereafter by single antiplatelet, usually clopidogrel in the UK. Once the dual antiplatelet phase is over, then participants meeting the criteria can be randomised

Planned Number of Participants

1300

Planned Number of Sites

≥ 60

Countries Anticipated to be Involved in Trial

UK (Scotland, England, Wales, Northern Ireland)

LACI-3 is open to support international collaboration.

Treatment Duration

From within one day of randomisation until the end of trial follow-up.

Follow up Duration

18 months

Total Planned Trial Duration

52 months

Primary Objective

To determine if, in patients with symptomatic lacunar ischaemic stroke, the routine long-term administration of isosorbide mononitrate 50mg od or equivalent, and /or cilostazol 100mg bd, individually or together, in addition to continuing routine stroke prevention therapy, compared with continuing routine stroke prevention therapy alone, reduces cognitive impairment after lacunar ischaemic stroke, a marker of cerebral small vessel disease.

Secondary Objectives

To determine if the long-term administration of isosorbide mononitrate 50mg od or equivalent and/or cilostazol 100mg bd individually or together, in addition to continuing routine stroke prevention therapy, compared with continuing routine stroke prevention therapy alone, reduces dependency, recurrent stroke or TIA, MI, death, and improves mood, quality of life, and health economic resource usage and is safe and well tolerated in long term use in patients with lacunar ischaemic stroke, a marker of cerebral small vessel disease.

Tertiary Objective

To collect data on the antihypertensive drug prescriptions and blood pressure measurements made by participants or available from GP or hospital medical records as a part of the routine stroke prevention therapy.

Primary Endpoint

At 18 months:

• 7-level ordinal cognitive impairment based on operationalisation of DSM-V criteria of cognitive impairment or dementia derived using subscores of the tMOCA, TICS, animal naming, clinical dementia diagnosis, as in LACI-2 and R4VaD.

Secondary Endpoint

At 18 months:

• dependency (mRS>2)
• tMOCA
• TICS
• Concentration (from MMSE)
• Animal naming
• Recurrent ischaemic stroke or TIA or haemorrhagic stroke
• Fatal or non-fatal MI
• Stroke Impact Scale (individual domains and global)
• EQ5D-5L, EQ-VAS
• Death, due to vascular and any cause;
• Safety SAEs;
• IMP Symptoms (headache; palpitations; loose stools; falls; etc);
• Composite of recurrent stroke or TIA, MI, death, dependency (mRS>2), cognitive impairment.
• Global Clinical Outcome of recurrent stroke or TIA, MI, death, mRS>2, cognitive impairment, QoL, mood (ZUNG)
• Health economic usage

Tertiary Endpoint

• BP measures

IMP(s)

Any brand of isosorbide Mononitrate (ISMN) and cilostazol that is available in the hospital pharmacy can be used as IMP is defined by the active substance only.

Participants will be randomised to start one of four treatments:

• Isosorbide mononitrate slow release 50mg oral once daily
• Cilostazol 100mg oral twice daily
• Both ISMN and cilostazol
• Neither ISMN nor cilostazol

A target dose of ISMN is 40-60mg daily. If a slow release ISMN is not available, the non-slow release tablets may be used.

All patients will continue their prescribed medications including guideline stroke prevention treatment (antiplatelet, antihypertensive, lipid lowering, lifestyle advice).

Patients with contraindications to one drug can be randomised to the other drug; patients who develop a contraindication to one of the drugs during the trial can continue in the trial taking the other drug. 

Trial drug will be dispensed in original manufacturer’s packaging from participating hospital pharmacies.

Drug will be supplied in a treatment pack marked with the participant ID and including instructions on how to take the tablets including the dose initiation and escalation phase.

A maximum of six months supply will be dispensed at a time.

Patients will be phoned by the local centre at one and three weeks after starting medication to check and advise on dose escalation.

IMP Route of Administration

Oral

NIMP(s)

Not applicable

Title

LACunar Intervention (LACI) Trial-3: Assessment of efficacy and safety of cilostazol and isosorbide mononitrate to prevent adverse outcomes in patients with cerebral small vessel disease (lacunar) ischaemic stroke

Co-Sponsors

The University of Edinburgh & Lothian Health Board ACCORD The Queen’s Medical Research Institute 47 Little France Crescent Edinburgh EH16 4TJ

Funder

National Institute for Health and Care Research (NIHR) Health Technology Assessment (UK)

Chief investigator

Prof Joanna Wardlaw

ISRCTN

ISRCTN44436843

IRAS number

1008629

Sponsor number

AC24127

REC number

24/SS/0095

Protocol

Version 3.0, 30 Janauary 2025

Role

Name 

Chairman

Prof John O’Brien

Academic 

Prof Christine Roffe

Academic

Dr Sharon McCann

Academic

Prof Edo Richard 

Lay representative

Ms Donna Cullinane

Statistician

Dr Gordon Prescott

Role

Name 

Chief Investigator

Prof Joanna M Wardlaw

Co-Chair

Dr John Bamford

Role

Name 

Non-independent Members

Prof Philip Bath - Co-Chief Investigator

Dr Fergus Doubal

Prof David Werring

Prof Timothy England

Dr Vera Cvoro

Dr Ahamad Hassan

Prof Alan Montgomery

Dr Lisa Woodhouse

Mr Andrew Stoddart

Mr Alexander Kilpatrick

Mr Robert Barnham

Funder Representative

Mr Alan Marshall

Sponsor Representative

Dr Fiach O’Mahony

Trial Manager/Facilitator

Kasia Adamczuk

Role

Name 

Chairman

Professor Gary A Ford

Member 

Professor A Ross Naylor

Member

Professor Charlotte Cordonnier

Member

Professor Jonathan Emberson

Chief Investigator:

Professor Joanna M Wardlaw