Cerebral Small Vessel DiseasesPhase 2/3LACI-2NCT03451591
LACunar Intervention (LACI-2) Trial-2
A Phase 2/3 study testing Isosorbide Mononitrate XL (ISMN), Cilostazol and ISMN XL and Cilostazol in people with Cerebral Small Vessel Diseases and Stroke, Lacunar, run by University of Edinburgh at 1 site in United Kingdom.
Trial 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. Read more about this study
- Who is it for?
- Ages 30 years and older
- Conditions the study is for
- Cerebral Small Vessel Diseases, Stroke, Lacunar
- What is being tested?
- Isosorbide Mononitrate XL (ISMN), Cilostazol and ISMN XL and Cilostazol
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 363 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 8 Jan 2018to 11 Aug 2022
- Phase
- Phase 2/3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 30 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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
Who cannot join
- 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.
- 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)
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- 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)
- 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.
- 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
- 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.
- Unable to tolerate MRI or contraindication to MRI (Claustrophobia, Pacemaker)
Trial locations and contacts
1 site in 1 country.
About this study
Official 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.
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.
Read the detailed description
A quarter of all ischaemic strokes (about 35000 per annum in the UK) are lacunar (small vessel) in type, mainly caused by an intrinsic, non-atheromatous, non-cardioembolic disease of the small deep perforating cerebral arterioles. More diffuse cerebral small vessel disease also causes up to 45% of dementias (350,000+ patients estimated currently in the UK), either alone or in association with Alzheimer's disease. There is no proven treatment for cerebral small vessel disease: conventional antiplatelet drugs may be ineffective or even hazardous, whilst antihypertensive treatment and statins may not have an effect. 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 cerebral small vessel disease. This trial will be an Phase IIb preparatory to Phase III, randomised, partial factorial, open label, blinded end-point trial, testing cilostazol, ISMN, both, or neither, to assess the feasibility of recruitment, drug tolerability, trial procedures, safety and event rates in 400 patients recruited in UK stroke centres and followed-up to one year (primary endpoint). This trial is preparatory to a large, definitive, Phase III randomised controlled trial to prevent recurrent lacunar stroke and progressive small vessel disease-related physical and cognitive impairments after lacunar stroke.
- Conditions
- Cerebral Small Vessel Diseases, Stroke, Lacunar
- Being tested
- Isosorbide Mononitrate XL (ISMN), Cilostazol, ISMN XL and Cilostazol, Neither ISMN nor cilostazol
- Keywords
- Cerebral Small Vessel Diseases, Stroke, Lacunar, Dementia, Alzheimer's disease
- Medical subject headings
- Cerebral Small Vessel Diseases, Stroke, Lacunar, Dementia, Alzheimer Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Isosorbide Mononitrate XL (ISMN)Drug
Also called Isosorbide mononitrate non-XL (ISMN)
Isosorbide mononitrate (ISMN), is an NO donating organic nitrate that enhances vasodilation, is widely used in ischaemic heart disease, and has no antiplatelet activity.
CilostazolDrug
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.
ISMN XL and CilostazolDrug
Also called isosorbide mononitrate non-XL and cilostazol
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.
Neither ISMN nor cilostazolOther
Neither isosorbide mononitrate nor Cilostazol administered for the entire duration of the study.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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 Receives: 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. Receives: Other: Neither ISMN nor cilostazol |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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
It is estimated that in this trial 75% of patients will be able to tolerate trial medication, in at least half dose, up to one year after randomisation (i.e. less than 25% will stop trial medication completely through inability to tolerate the drugs).
Measured: 12 months
Incidence of Treatment Emergent Adverse Effects [Safety]
Safety - symptoms of systemic or intracranial bleeding, recurrent cerebral and systemic vascular events, and vascular and non-vascular causes of death will be collected. It is estimated that in this trial the absolute risk of death, including fatal haemorrhage, will not differ significantly (ie fall outside the upper 95% CI) from 2% per year on trial drugs versus no trial drugs, when given in addition to guideline drugs; and will not increase bleeding or ischaemic SVD lesions significantly (at the p<0.01 level) on MRI.
Measured: 12 months
Treatment Efficacy - Percentage of Participants Experiencing an Event (Stroke, TIA, Myocardial Ischaemia, Cognitive Impairment and Dementia)
It is estimated that in this trial the combined rate of recurrent stroke, MI, death, cognitive impairment and dependency will be 40-50% at one year after enrolment in order to detect modest but clinically-important reductions in poor outcomes.
The study has a 2x2 partial factorial design. This allows testing of both drugs when given alone and together. Participants were allocated into one of four treatment groups. However, as some participants were in a group which received both treatments simultaneously then the subgroups reported for IMP exposure include a count of both participants from the single and the combined treatment groups as the total number exposed to that IMP
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Mar 2018
- Study start8 Jan 2018
- Primary completion31 May 2022
- Study completion11 Aug 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Cerebral Small Vessel DiseasesStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Factorial
- Model description
- 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.
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 363 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Edinburgh
- Sponsor type
- University, hospital or other
- Collaborators
- British Heart Foundation, University of Nottingham
- Responsible party
- Sponsor
- Investigators
- Joanna M Wardlaw, MB ChB, Study director, University of Edinburgh
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03451591
- Sponsor's protocol ID
- V6 06Feb2020
- Other IDs
- CS/15/5/31475, 2016-002277-35, 14911850, 2016
- Acronym
- LACI-2
- Status last verified
- Aug 2022
- First submitted
- 14 Nov 2017
- Last updated
- 12 Nov 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 37222252Kwan 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.
PubMed 35833913
Study at a glance
From the registry record, last updated by the sponsor on 12 Nov 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official 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.
- ClinicalTrials.gov ID
- NCT03451591
- Acronym / sponsor ID
- LACI-2 / V6 06Feb2020
- Conditions
- Cerebral Small Vessel Diseases, Stroke, Lacunar
- Keywords
- Cerebral Small Vessel Diseases, Stroke, Lacunar, Dementia, Alzheimer's disease
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 363 participants (actual)
- Lead sponsor
- University of EdinburghUniversity, hospital or other
- Collaborators
- British Heart Foundation, University of Nottingham
- Study start
- 8 Jan 2018 (actual)
- Primary completion
- 31 May 2022 (actual)
- Study completion
- 11 Aug 2022 (actual)
- First posted
- 2 Mar 2018 (actual)
- Results
- Posted 12 Nov 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
A quarter of all ischaemic strokes (about 35000 per annum in the UK) are lacunar (small vessel) in type, mainly caused by an intrinsic, non-atheromatous, non-cardioembolic disease of the small deep perforating cerebral arterioles. More diffuse cerebral small vessel disease also causes up to 45% of dementias (350,000+ patients estimated currently in the UK), either alone or in association with Alzheimer's disease. There is no proven treatment for cerebral small vessel disease: conventional antiplatelet drugs may be ineffective or even hazardous, whilst antihypertensive treatment and statins may not have an effect. 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 cerebral small vessel disease. This trial will be an Phase IIb preparatory to Phase III, randomised, partial factorial, open label, blinded end-point trial, testing cilostazol, ISMN, both, or neither, to assess the feasibility of recruitment, drug tolerability, trial procedures, safety and event rates in 400 patients recruited in UK stroke centres and followed-up to one year (primary endpoint). This trial is preparatory to a large, definitive, Phase III randomised controlled trial to prevent recurrent lacunar stroke and progressive small vessel disease-related physical and cognitive impairments after lacunar stroke.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 4
- Model description
- 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.
| Arm | Type | Receives |
|---|---|---|
| Isosorbide Mononitrate XL (ISMN) | Active comparator | Drug: Isosorbide Mononitrate XL (ISMN)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. |
| Cilostazol | Active comparator | Drug: CilostazolOral 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. |
| ISMN XL and Cilostazol | Active comparator | Drug: ISMN XL and CilostazolOral 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 |
| Neither ISMN nor cilostazol | Placebo comparator | Other: Neither ISMN nor cilostazolNeither isosorbide mononitrate nor Cilostazol is administered for the entire duration of the study. |
Who may qualify
- Ages
- 30 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- Clinical lacunar stroke syndrome.
- Brain scanning* with MR including diffusion imaging wherever possible, and obtained soon after the presentation with stroke, shows either:
- 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)
Key exclusion criteria (18 listed)
- 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.
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Isosorbide Mononitrate XL (ISMN)Also: Isosorbide mononitrate non-XL (ISMN)Isosorbide mononitrate (ISMN), is an NO donating organic nitrate that enhances vasodilation, is widely used in ischaemic heart disease, and has no antiplatelet activity. | Drug | Isosorbide Mononitrate XL (ISMN) |
| CilostazolCilostazol 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. | Drug | Cilostazol |
| ISMN XL and CilostazolAlso: isosorbide mononitrate non-XL and cilostazolCilostazol 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. | Drug | ISMN XL and Cilostazol |
| Neither ISMN nor cilostazolNeither isosorbide mononitrate nor Cilostazol administered for the entire duration of the study. | Other | Neither ISMN nor cilostazol |
Primary outcome
Feasibility of Phase III Trial
Time frame: 36 months (24 Months Recruitment + 12 months Follow Up)
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.
3 secondary outcomes
Trial Medication Tolerability Measured by Number of Participants With Adherence to Medication at Half Dose or More at 1 Year
Time frame: 12 months
Incidence of Treatment Emergent Adverse Effects [Safety]
Time frame: 12 months
Treatment Efficacy - Percentage of Participants Experiencing an Event (Stroke, TIA, Myocardial Ischaemia, Cognitive Impairment and Dementia)
Time frame: 12 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Nov 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 37222252Wardlaw 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.
- Derived from this study: PubMed 35833913Kwan 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.
- Individual participant dataSharing planned: No
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Lupus Nephritis, Immunoglobulin A Nephropathy
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Joanna M Wardlaw, MB ChB study director
University of Edinburgh
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Isosorbide Mononitrate XL (ISMN), Cilostazol and ISMN XL and Cilostazol in people with Cerebral Small Vessel Diseases and Stroke, Lacunar, run by University of Edinburgh at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 12 Nov 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 12 Nov 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Feasibility of Phase III Trial (time frame: 36 months (24 Months Recruitment + 12 months Follow Up)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03451591, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Nov 2024.