Condition category
Nervous System Diseases
Date applied
02/10/2017
Date assigned
09/10/2017
Last edited
09/10/2017
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
About 35,000 people each year in the UK have a type of stroke, called ‘lacunar’ or ‘small vessel’ stroke, which is different to other common types of stroke and for which there is no proven treatment. Small vessel stroke may be caused by damage to the lining of the tiny blood vessels deep inside the brain that stops them functioning normally. This not only causes stroke but, perhaps more importantly, causes problems with thinking and walking, possibly causing up to 45% of all dementias either on its own, or mixed with Alzheimer’s disease (about 350,000 patients in the UK). Some drugs that are commonly used in other blood vessel diseases may help improve small vessel function and prevent worsening of brain damage. One drug (cilostazol) has been tested in patients with stroke in the Asia Pacific countries but not on dementia; the other drug (isosorbide mononitrate) is widely used in the UK for heart disease but not stroke. The aim of this study is to test if the study methods are practical so that patients and trial centres can follow the procedures, and to confirm how many patients have more stroke-like symptoms or experience worsening of their thinking skills. This information is needed to be sure that a very large clinical trial to find out if these drugs can prevent worsening of small vessel disease will be possible.

Who can participate?
Adults aged 30 and older who have had a small vessel stroke.

What does the study involve?
Participants are randomly allocated to one of four groups. Those in the first group receive cilostazol by mouth twice a day. Those in the second group receive the isosorbide mononitrate by mouth 20 mg twice a day or 50 mg once a day if the extended release formulation used. Those in the third group receive both medications in the same doses and ways above. Those in the last group do not receive any treatment. The treatment lasts one year. Participants are followed up around one to two weeks and three to four weeks by phone as well as six and 12 months by a phone or face to face meeting to assess the tolerability and safety of the medication. The last follow up visit includes a brain scan.

What are the possible benefits and risks of participating?
There are no direct benefits with participation, although some patients find the regular check-ups reassuring and the MRI Brain scan may give more details to your doctors about their stroke. There are no foreseeable risks however there is a chance that you may experience side effects from the Trial drugs. Both drugs have been used for many years to treat other conditions so the side effects are well known. If any of these occur, they are usually noticed when first starting the tablets.

Where is the study run from?
1. Royal Infirmary of Edinburgh (UK)
2. Nottingham City Hospital (UK)

When is the study starting and how long is it expected to run for?
May 2017 to November 2020

Who is funding the study?
British Heart Foundation (BHF) (UK)

Who is the main contact?
1. Dr Julia Boyd
julia.boyd@ed.ac.uk
2. Professor Joanna Wardlaw
Joanna.Wardlaw@ed.ac.uk

Trial website

Contact information

Type

Public

Primary contact

Dr Julia Boyd

ORCID ID

http://orcid.org/0000-0002-9872-3893

Contact details

Edinburgh Clinical Trials Unit
University of Edinburgh (Usher Institute)
Outpatients Building - 2nd Floor D35
Western General Hospital
Crewe Road
Edinburgh
EH4 2XU
United Kingdom
+44 131 537 3842
julia.boyd@ed.ac.uk

Type

Scientific

Additional contact

Prof Joanna Wardlaw

ORCID ID

http://orcid.org/0000-0002-9812-6642

Contact details

Neuroimaging Sciences
University of Edinburgh
Centre for Clinical Brain Sciences (CCBS)
Chancellor's Building
49 Little France Crescent
Edinburgh
EH16 4SB
United Kingdom
+44 131 465 9599
Joanna.Wardlaw@ed.ac.uk

Additional identifiers

EudraCT number

2016-002277-35

ClinicalTrials.gov number

Protocol/serial number

36168

Study information

Scientific title

LACunar Intervention (LACI-2) Trial-2: Assessment of safety and efficacy of cilostazol and isosorbide mononitrate to prevent recurrent lacunar stroke and progression of cerebral small vessel disease

Acronym

LACI-2

Study hypothesis

The trial hypothesis is to test whether a much larger scale study testing the effects of Cilostazol and ISMN on preventing brain damage from small vessel disease will be feasible. We will assess how easy is it to identify suitable patients, how many of them are willing to take part in the study and how many stay on the study for the full 12 months. Feedback from participants on study procedures/burden will also inform any future studies. We will also collect information on how many patients have another stroke, experience difficulties in independent daily living or in thinking skills, and on drug safety such as bleeding.

Ethics approval

East Midlands - Nottingham 2 REC, 10/05/2017, ref: 17/EM/0077 00:00:00

Study design

Randomised; Interventional; Design type: Treatment, Drug

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Specialty: Stroke, Primary sub-specialty: Rehabilitation; UKCRC code/ Disease: Stroke/ Cerebrovascular diseases

Intervention

Randomisation involves minimisation on a number of key prognostic factors. An electronic randomisation system is used to allocate participants to one of four groups as detailed below. All patients receive best medical therapy for stroke prevention in addition to their randomly allocated trial treatment. Trial treatment period is 54 weeks.
1. Cilostazol: oral, 100mg twice a day
2. Isosorbide mononitrate (ISMN): oral, 20mgs twice a day or 50mg once a day if extended release formulation used
3. Cilostazol + ISMN - same doses as above
4. No trial treatment

There are 4 follow-up time points:
1. One-two week follow-up by phone
2. Three-four week follow-up by phone
3. Six month follow-up by phone or face to face
4. 12 month follow-up by phone or face to face

At the end of the 12 months they will stop their allocated treatment, have their final visit which includes a brain scan.

Intervention type

Drug

Phase

Phase II

Drug names

cilostazol, Isosorbide mononitrate

Primary outcome measures

Feasibility of a future Phase III trial is the primary outcome and is measured at 36 months. This will be attained if the feasibility target sample size of 400 patients are recruited in 24 months in the UK and >95% retained in follow-up at one year.

Secondary outcome measures

1. Assessment of drug tolerability are measured using questionnaires and reviewing patient notes at one-two weeks, three-four weeks, six months and 12 months
2. Safety is measured using questionnaires and reviewing patient notes at one-two weeks, three-four weeks, six months and 12 months
3. Event is measured using questionnaires and reviewing patient notes at one-two weeks, three-four weeks, six months and 12 months
4. Recruitment rates are measured using questionnaires and reviewing patient notes at one-two weeks, three-four weeks, six months and 12 months. Questionnaires include a study specific structured questionnaire to record symptoms, medication history and IMP adherence and a vascular event questionnaire.

Overall trial start date

01/05/2017

Overall trial end date

01/11/2020

Reason abandoned

Eligibility

Participant inclusion criteria

1. Clinical lacunar stroke syndrome.
2. Brain scanning* with MR including diffusion imaging wherever possible, and obtained soon after the presentation with stroke, shows either:
2.1. A recent, relevant (in time and location) acute lacunar infarct on diffusion MR imaging1,
2.2. Or, if no visible acute lacunar infarct on diffusion MR imaging2 then there is no competing pathology as a cause for stroke (e.g. no acute cortical infarct, no acute intra-cerebral haemorrhage, no stroke mimic such as tumour, subdural haematoma);
2.3. If only a CT brain scan is available as in section 3 above, then there is a small relevant (in age and location) subcortical infarct, or if no infarct then there is no competing pathology as a cause for stroke (e.g. no acute cortical infarct, no acute intra-cerebral haemorrhage, no stroke mimic such as tumour, subdural haematoma). Note that if there is no acute lacunar infarct on MR diffusion imaging but there is a recent-appearing lacunar infarct on FLAIR, T2, or T1 (i.e. no cavitation or ex-vacuo effect; may be slightly swollen, ill-defined edges; or scan in the few weeks before the stroke does not show a lesion but there is an acute lacunar infarct on MR T2, FLAIR, T1 scanning after the stroke in an appropriate area of the brain for symptoms), then the T2, FLAIR, T1 lesion may be counted as the acute lacunar infarct in the absence of a diffusion lesion. Similarly, on CT2 a recent relevant small subcortical infarct would not show cavitation or shrinkage/ex vacuo effect. Note that about a third of patients with a clinically definite lacunar syndrome do not have a corresponding recent infarct visible on MRI but should still be classed as ‘lacunar stroke’ if no other explanation can be found for the symptoms. The presence of a recent cortical infarct on FLAIR, T2, T1, the recent timing being indicated by the characteristics above, would count as a competing pathology. Note that the complete absence of any abnormality on MR or CT brain imaging (no acute subcortical infarct or pre-existing SVD such as white matter hyperintensities, lacunes, etc.) while occasionally seen in lacunar stroke is unusual and should question the diagnosis of lacunar ischaemic stroke.
3. Age > 30 years
4. Independent in activities of daily living (modified Rankin ≤2)
5. Capacity to give consent themselves

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 400; UK Sample Size: 400

Participant exclusion criteria

1. Other significant active neurological illness present since suffering stroke (e.g. recurrent seizures, multiple sclerosis, brain tumour). Well-controlled epilepsy present prior to the stroke, a single seizure at onset of the stroke or provoked seizure is not an exclusion.
2. Requiring assistance with activities of daily living (Modified Rankin ≥3)
3. Has been diagnosed as having dementia on formal clinical assessment
4. Active cardiac disease (atrial fibrillation, myocardial infarction in past 6 months, active angina, symptomatic cardiac failure)
5. Diagnosis of hypotension, defined as sitting systolic blood pressure less than 100mmHg
6. Definite indication for (i.e. already prescribed) either trial medication, or definite contraindication to a trial drug as per SmPCSPCs - lactose intolerance is a contraindication to ISMN preparations which contain lactose monohydrate - (indication for or contraindication to one of the trial drugs still allows randomisation to the other trial drug)
7. Unable to swallow tablets
8. Bleeding tendency (e.g. known platelets<100, active peptic ulcer, history of intracranial haemorrhage such as subdural haematoma, subarachnoid haemorrhage, intracerebral haemorrhage, but not asymptomatic haemorrhagic transformation of infarction or a few microbleeds, taking anticoagulant medication)
9. Unlikely to comply with trial medication based on knowledge of past history, lifestyle
10. Planned surgery during the trial period including carotid endarterectomy. Note prior and apparently successful carotid endarterectomy (or other surgery) is not an exclusion criterion and patients who would otherwise be eligible but require endarterectomy first may be randomised after recovery from successful endarterectomy.
11. Other concurrent life threatening illness
12. Unlikely to be available for follow-up (eg moving outside or visitor to the area)
13. History of drug overdose or attempted suicide or significant active mental illness
14. Pregnant or breastfeeding women, women of childbearing age not taking contraception. Acceptable contraception in women of childbearing age is a “highly effective” contraceptive measure as defined by the Clinical Trials Facilitation Group (http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf) and includes combined (oestrogen and progesterone containing) or progesterone-only contraception associated with inhibition of ovulation, or intrauterine device or bilateral tubal occlusion. Contraception must be continued for up to 30 days after the end of the IMP dosing
schedule.
15. Prohibited medications to either trial drug (see sections 4.5 of the appended SmPCSPCs and protocol section 6.6.3, plus no anticoagulant drugs); (prohibited medications to one of the trial drugs still allows randomisation to the other trial drug)
16. Renal impairment (creatinine clearance <25 ml/min)
17. Hepatic impairment
18. Current enrolment in another Clinical Trial of Investigational Medicinal Product (CTIMP); still in extended follow-up beyond the CTIMP primary outcome and no longer taking that trial’s IMP is not an exclusion to enrolment in LACI-2
19. Unable to tolerate MRI or contraindication to MRI (Claustrophobia, Pacemaker)

Recruitment start date

01/11/2017

Recruitment end date

01/11/2019

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Royal Infirmary of Edinburgh (Lead centre)
Royal Infirmary of Edinburgh 51 Little France Drive
Edinburgh
EH16 4SA
United Kingdom

Trial participating centre

Nottingham City Hospital
Hucknall Road
Nottingham
NG5 1PB
United Kingdom

Sponsor information

Organisation

University of Edinburgh and NHS Lothian - co-sponsors (UK)

Sponsor details

ACCORD Office
The Queen's Medical Research Institute
47 Little France Crescent
Edinburgh
EH16 4TJ
United Kingdom

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Government

Funder name

British Heart Foundation (BHF)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

On completion of the study a clinical study report will be prepared for publication in a peer reviewed journal in accordance with ICH guidelines. A report will also be submitted to the funder (British Heart Foundation). Papers describing secondary analysis will also be published.
The clinical study report will be used for publication and presentation at scientific meetings on stroke and dementia such as UK Stroke Forum, European Stroke Organisation Conference, International Stroke Conference, the World Stroke Congress, and conferences on Alzheimer’s disease and dementia. Investigators have the right to publish orally or in writing the results of the study. Reporting will be in compliance with CONSORT.
Summaries of results will also be made available to all Investigators for dissemination within their clinics (where appropriate and according to their discretion).
A newsletter will be sent to the participants informing them of the results and of other information relevant to small vessel disease and general information about maintaining a healthy lifestyle.

IPD sharing statement:
The datasets generated during and/or analysed during the current study are/will be available upon request from Dr Julia Boyd julia.boyd@ed.ac.uk or Professor Joanna Wardlaw Joanna.Wardlaw@ed.ac.uk

Intention to publish date

01/11/2021

Participant level data

Available on request

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes