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| ID | Type | Description | Link |
|---|---|---|---|
| CS/15/5/31475 | Other Grant/Funding Number | British Heart Foundation | |
| 2016-002277-35 | EudraCT Number | ||
| 14911850 | Registry Identifier | ISRCTN |
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| Name | Class |
|---|---|
| British Heart Foundation | OTHER |
| University of Nottingham | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| 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. |
|
| 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 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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) |
| Measure | Description | Time Frame |
|---|---|---|
| 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). | 12 months |
Not provided
Inclusion Criteria:
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 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.
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Joanna M Wardlaw, MB ChB | University of Edinburgh | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Royal Infirmary | Edinburgh | Lothian | EH16 4SA | United Kingdom |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37222252 | Derived | 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. | |
| 35833913 |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. Isosorbide Mononitrate 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. |
| FG001 | Cilostazol | 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. 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. |
| FG002 | ISMN XL and Cilostazol | 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 ISMN 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. |
| FG003 | Neither ISMN Nor Cilostazol | Neither isosorbide mononitrate nor Cilostazol is administered for the entire duration of the study. Neither ISMN nor cilostazol: Neither isosorbide mononitrate nor Cilostazol administered for the entire duration of the study. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Randomisation |
| |||||||||||||
| SAE Reporting - Exposure to IMP |
| |||||||||||||
| Randomisation to 12 Month Follow Up |
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | 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. Isosorbide Mononitrate 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Number of participants at 12 months who did not complete follow up - because they refused, were lost to follow up or withdrawn | Posted | Count of Participants | Participants | 36 months (24 Months Recruitment + 12 months Follow Up) |
|
From randomisation to 12 months.
Other [Not Including Serious] Adverse Events were not monitored/assessed. These are reported as 0 in the table below.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. Isosorbide Mononitrate 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Respiratory | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
Not provided
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.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Prof Joanna Wardlaw | University of Edinburgh | 0131 465 9599 | joanna.wardlaw@ed.ac.uk |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Nov 6, 2020 | Nov 16, 2022 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jun 6, 2022 | Nov 16, 2022 | SAP_001.pdf |
Not provided
| ID | Term |
|---|---|
| D059345 | Cerebral Small Vessel Diseases |
| D059409 | Stroke, Lacunar |
| D003704 | Dementia |
| D000544 | Alzheimer Disease |
| ID | Term |
|---|---|
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
Not provided
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| ID | Term |
|---|---|
| D000077407 | Cilostazol |
| ID | Term |
|---|---|
| D013777 | Tetrazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
Not provided
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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.
Not provided
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| Neither ISMN nor cilostazol |
| Placebo Comparator |
Neither isosorbide mononitrate nor Cilostazol is administered for the entire duration of the study. |
|
|
| 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. |
|
| 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. |
|
|
| Neither ISMN nor cilostazol | Other | Neither isosorbide mononitrate nor Cilostazol administered for the entire duration of the study. |
|
| 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. | 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 | 12 months |
| 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. |
| COMPLETED |
|
| NOT COMPLETED |
|
| COMPLETED |
|
| NOT COMPLETED |
|
| BG001 | Cilostazol | 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. 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. |
| BG002 | ISMN XL and Cilostazol | 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 ISMN 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. |
| BG003 | Neither ISMN Nor Cilostazol | Neither isosorbide mononitrate nor Cilostazol is administered for the entire duration of the study. Neither ISMN nor cilostazol: Neither isosorbide mononitrate nor Cilostazol administered for the entire duration of the study. |
| BG004 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Stroke onset to randomisation, days | Mean | Standard Deviation | days |
|
| Stroke onset to randomisation <=100 days | Count of Participants | Participants |
|
| Highest education level - postgraduate | Count of Participants | Participants |
|
| Highest education level - undergraduate | Count of Participants | Participants |
|
| Highest education level - A Level or Equivalent | Count of Participants | Participants |
|
| Highest education level - O-level/GCSE or equivalent | Count of Participants | Participants |
|
| Highest education level - Secondary School | Count of Participants | Participants |
|
| Highest education level - Primary School | Count of Participants | Participants |
|
| Systolic Blood Pressure | Mean | Standard Deviation | mmHg |
|
| OG001 | Cilostazol | 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. 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. |
| OG002 | ISMN XL and Cilostazol | 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 ISMN 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. |
| OG003 | Neither ISMN Nor Cilostazol | Neither isosorbide mononitrate nor Cilostazol is administered for the entire duration of the study. Neither ISMN nor cilostazol: Neither isosorbide mononitrate nor Cilostazol administered for the entire duration of the study. |
|
|
| Secondary | 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). | Adherence to medication at half dose or more at 1 year | Posted | Count of Participants | Participants | 12 months |
|
|
|
| Secondary | 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. | Posted | Count of Participants | Participants | 12 months |
|
|
|
| Secondary | 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 | Clinical, functional, QoL and global outcomes at 12 months- Stroke/TIA, MI, Cognitive impairment, Dependency, Death. Data are number (%) | Posted | Count of Participants | Participants | 12 months |
|
|
|
| 1 |
| 181 |
| 21 |
| 181 |
| 0 |
| 0 |
| EG001 | Cilostazol | 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. 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. | 1 | 182 | 29 | 182 | 0 | 0 |
| EG002 | ISMN XL and Cilostazol | 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 ISMN 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. | 0 | 91 | 15 | 91 | 0 | 0 |
| EG003 | Neither ISMN Nor Cilostazol | Neither isosorbide mononitrate nor Cilostazol is administered for the entire duration of the study. Neither ISMN nor cilostazol: Neither isosorbide mononitrate nor Cilostazol administered for the entire duration of the study. | 1 | 91 | 12 | 91 | 0 | 0 |
| Gastrointestinal | Gastrointestinal disorders | Systematic Assessment |
|
| Genitourinary | Renal and urinary disorders | Systematic Assessment |
|
| Haematological | Blood and lymphatic system disorders | Systematic Assessment |
|
| Metabolic/Endocrine | Metabolism and nutrition disorders | Systematic Assessment |
|
| Musculoskeletal | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Infection/sepsis | Infections and infestations | Systematic Assessment |
|
| Tumour/ malignancy | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Systematic Assessment |
|
| Other | General disorders | Systematic Assessment |
|
| Cardiovascular | Cardiac disorders | Systematic Assessment |
|
Not provided
Not provided
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D000083244 | Thrombotic Stroke |
| D000083242 | Ischemic Stroke |
| D020521 | Stroke |
| D020520 | Brain Infarction |
| D007238 | Infarction |
| D007511 | Ischemia |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D009336 | Necrosis |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D024801 | Tauopathies |
| D019636 | Neurodegenerative Diseases |
| D011804 |
| Quinolines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| Male |
|