LACunar Intervention (LACI-2) Trial-2

NCT03451591 | Completed Phase 2 Results DMC

• 4 other identifiers: V6 06Feb2020CS/15/5/314752016-002277-3514911850
• Study Type: interventional
• Target: 363
• Locations: 1 country
• Sites: 1

Brief Summary

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. It is thought that small vessel stroke is 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 investigators want to set up a clinical trial 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.

Conditions

Cerebral Small Vessel Diseases; Stroke, Lacunar

Keywords

Cerebral Small Vessel Diseases; Stroke, Lacunar; Dementia; Alzheimer's disease

Outcome Measures

Primary Outcomes (1)

• Feasibility of Phase III Trial

  Feasibility of Phase III trial, i.e. that eligible patients can be identified correctly, in sufficient numbers, enrolled and \>95% retained in follow-up at one year, to achieve feasibility target sample size recruitment and randomisation of 400 patients in 24 months in the UK.

  36 months (24 Months Recruitment + 12 months Follow Up)

Secondary Outcomes (3)

• Trial Medication Tolerability Measured by Number of Participants With Adherence to Medication at Half Dose or More at 1 Year

  12 months

• Incidence of Treatment Emergent Adverse Effects [Safety]

  12 months

• Treatment Efficacy - Percentage of Participants Experiencing an Event (Stroke, TIA, Myocardial Ischaemia, Cognitive Impairment and Dementia)

  12 months

Study Arms (4)

Isosorbide Mononitrate XL (ISMN)

ACTIVE COMPARATOR

Oral Isotard® 25mg XL (Isosorbide Mononitrate) tablets. Oral Isotard® 25mg XL: Day 1-5 / 25mg daily morning dose. Day 6 to week 52 / 50mg daily morning dose. Week 53 / 25mg daily morning dose. Week 54 / NIL dose. Or Oral Isosorbide mononitrate (ISMN) non-XL 20mg tablets: Day 1-5 / 20mg daily evening dose. Day 6 to week 52 / 20mg twice daily morning \& evening. Week 53 / 20mg daily morning dose. Week 54 / NIL dose.

Drug: Isosorbide Mononitrate XL (ISMN)

Cilostazol

ACTIVE COMPARATOR

Oral Cilostazol 100mg tablets. Day 1-5 / 50mg daily evening dose. Day 6-10 / 50mg twice daily morning \& evening. Day 11-15 / 50mg daily morning dose \& 100mg daily evening dose. Day 16 to week 52 / 100mg twice daily morning \& evening. Week 53 / 50mg twice daily morning \& evening. Week 54 / NIL dose.

Drug: Cilostazol

ISMN XL and Cilostazol

ACTIVE COMPARATOR

Oral Isotard® 25 mg XL (ISMN) and oral Cilostazol 100mg tablets. Day 1-5 / ISMN - 25mg daily evening dose / Cilostazol - NIL. Day 6-10 / ISMN - 50mg daily morning dose and Cilostazol - NIL. Day 11-15 / ISMN - 50mg daily morning dose / Cilostazol - 50mg daily evening dose. Day 16-20 / ISMN - 50mg daily morning dose and Cilostazol - 50mg twice daily morning \& evening. Day 21-25 / ISMN - 50mg daily morning dose and Cilostazol - twice daily, 50mg morning \& 100mg evening dose. Day 26-30 ISMN - 50mg daily morning dose and Cilostazol 100mg - twice daily morning \& evening. Day 30 to week 52 / ISMN 50mg morning dose and Cilostazol 100mg - twice daily morning \& evening. Week 53 / ISMN 25mg daily morning dose and Cilostazol 50mg twice daily morning \& evening. Week 54 / NIL dose

Drug: ISMN XL and Cilostazol

Neither ISMN nor cilostazol

PLACEBO COMPARATOR

Neither isosorbide mononitrate nor Cilostazol is administered for the entire duration of the study.

Other: Neither ISMN nor cilostazol

Interventions

Isosorbide Mononitrate XL (ISMN) DRUG

Isosorbide mononitrate (ISMN), is an NO donating organic nitrate that enhances vasodilation, is widely used in ischaemic heart disease, and has no antiplatelet activity.

Also known as: Isosorbide mononitrate non-XL (ISMN)

Isosorbide Mononitrate XL (ISMN)

Cilostazol DRUG

Cilostazol is a phosphodiesterase 3-inhibitor (PDE3-inhibitor) that enhances the PGI2-cAMP system. It has weak antiplatelet effects (so low bleeding risk), reduces infarct size and reduces ageing-related decline in myelin repair in experimental models.

Cilostazol

ISMN XL and Cilostazol DRUG

Cilostazol is a phosphodiesterase 3-inhibitor (PDE3-inhibitor) that enhances the PGI2-cAMP system. It has weak antiplatelet effects (so low bleeding risk), reduces infarct size and reduces ageing-related decline in myelin repair in experimental models. Isosorbide mononitrate (ISMN), is an NO donating organic nitrate that enhances vasodilation, is widely used in ischaemic heart disease, and has no antiplatelet activity.

Also known as: isosorbide mononitrate non-XL and cilostazol

ISMN XL and Cilostazol

Neither ISMN nor cilostazol OTHER

Neither isosorbide mononitrate nor Cilostazol administered for the entire duration of the study.

Neither ISMN nor cilostazol

Eligibility Criteria

• Age: 30 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Clinical lacunar stroke syndrome.
• Brain scanning\* with MR including diffusion imaging wherever possible, and obtained soon after the presentation with stroke, shows either:
• a recent, relevant (in time and location) acute lacunar infarct on diffusion MR imaging1,
• 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);
• or, if only a CT brain scan is available2 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.
• Age \> 30 years
• Independent in activities of daily living (modified Rankin ≤2)
• Capacity to give consent themselves

You may not qualify if:

• Requiring assistance with activities of daily living (Modified Rankin ≥3)
• Has been diagnosed as having dementia on formal clinical assessment
• Active cardiac disease (atrial fibrillation, myocardial infarction in past 6 months, active angina, symptomatic cardiac failure)
• Diagnosis of hypotension, defined as sitting systolic blood pressure less than 100mmHg
• Definite indication for (i.e. already prescribed) either trial medication, or definite contraindication to a trial drug as per SPCs - 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)
• Unable to swallow tablets
• 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)
• Other concurrent life threatening illness
• Unlikely to be available for follow-up (e.g. moving outside or visitor to the area)
• History of drug overdose or attempted suicide or significant active mental illness
• 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.
• Prohibited medications to either trial drug (see sections 4.5 of the appended SPCs 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).
• Renal impairment (creatinine clearance \<25 ml/min)
• Hepatic impairment
• Unable to tolerate MRI or contraindication to MRI (Claustrophobia, Pacemaker)

Sponsors & Collaborators

• University of Edinburgh: lead
• British Heart Foundation: collaborator
• University of Nottingham: collaborator

Study Sites (1)

Royal Infirmary

Edinburgh, Lothian, EH16 4SA, United Kingdom

Location

Related Publications (2)

• Wardlaw JM, Woodhouse LJ, Mhlanga II, Oatey K, Heye AK, Bamford J, Cvoro V, Doubal FN, England T, Hassan A, Montgomery A, O'Brien JT, Roffe C, Sprigg N, Werring DJ, Bath PM; Lacunar Intervention Trial-2 (LACI-2) Investigator Group. Isosorbide Mononitrate and Cilostazol Treatment in Patients With Symptomatic Cerebral Small Vessel Disease: The Lacunar Intervention Trial-2 (LACI-2) Randomized Clinical Trial. JAMA Neurol. 2023 Jul 1;80(7):682-692. doi: 10.1001/jamaneurol.2023.1526.

  PMID: 37222252 DERIVED

• Kwan J, Hafdi M, Chiang LLW, Myint PK, Wong LS, Quinn TJ. Antithrombotic therapy to prevent cognitive decline in people with small vessel disease on neuroimaging but without dementia. Cochrane Database Syst Rev. 2022 Jul 14;7(7):CD012269. doi: 10.1002/14651858.CD012269.pub2.

  PMID: 35833913 DERIVED

MeSH Terms

Conditions

Cerebral Small Vessel Diseases; Stroke, Lacunar; Dementia; Alzheimer Disease

Interventions

Cilostazol

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Thrombotic Stroke; Ischemic Stroke; Stroke; Brain Infarction; Infarction; Ischemia; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Necrosis; Neurocognitive Disorders; Mental Disorders; Tauopathies; Neurodegenerative Diseases

Intervention Hierarchy (Ancestors)

Tetrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Limitations and Caveats

The open label design may have facilitated bias, though there is no evidence for this. The follow-up co-ordinators were masked to allocated drug whilst recording outcome data. Recruitment and one year follow-up at sites in LACI2 was affected by the SARS-Cov-19 pandemic. Some patients were unable to return for MRI or in person assessments at sites (Trails, BP) or return postal follow-up forms. As a factorial trial, comparison of the combination of drugs versus no drugs was underpowered.

Results Point of Contact

• Title: Prof Joanna Wardlaw
• Organization: University of Edinburgh

joanna.wardlaw@ed.ac.uk

0131 465 9599

Study Officials

• Joanna M Wardlaw, MB ChB

  University of Edinburgh

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Patients will be randomised to start one of four treatments; isosorbide mononitrate only; cilostazol only; both isosorbide mononitrate and cilostazol or neither isosorbide mononitrate nor cilostazol.

Study Record Dates

• First Submitted: November 14, 2017
• First Posted: March 2, 2018
• Study Start: January 8, 2018
• Primary Completion: May 31, 2022
• Study Completion: August 11, 2022
• Last Updated: November 12, 2024
• Results First Posted: November 12, 2024

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)