LACunar Intervention trial - Cognition 1

Eligibility criteria

Inclusion Criteria:
1.	Age ≥ 50 years.
2.	Cognitive impairment* – mild cognitive impairment (abnormal cognitive testing in the view of the study investigator, but no functional impairment) or mild dementia (abnormal cognitive testing and functional impairment due to the cognitive problem). These diagnoses will be recorded in the medical notes.
3.	A moderate to severe burden of cSVD on brain imaging (MRI or CT) within the last three years, defined as Fazekas score ≥2 in each of periventricular and deep regions (i.e., a total Fazekas score ≥4) or total Fazekas score ≥3 AND one or more lacunes. The brain imaging is performed as part of routine clinical care
4.	The cSVD is considered to be a major contributor to the cognitive impairment in the opinion of the study investigator, documented in the medical record.**
5.	Retained capacity to provide written consent themselves in the opinion of the study investigator.
6.	Have a study partner*** who knows the participant sufficiently well to provide information about their functional abilities, in the view of the study investigator, and who is willing to join the study in this role.
7. Proficiency in written and spoken English to understand study materials and processes, in the view of the investigator, documented in the medical record.
*We will not use upper or lower bound cut-offs on cognitive testing to determine eligibility, but participants must be able to provide consent themselves. For the mild cognitive impairment stage (cognitive decline but no resulting functional impairment), cognitive impairment will be deemed present if the most recent cognitive testing performed during clinical care (usually an Addenbrooke’s Cognitive Examination III) identifies lower than expected performance for that patient’s age and educational background.
**Participants will be eligible if they are thought to have mixed pathology (e.g. vascular and Alzheimer’s disease), providing the vascular changes are considered to be the major contributor. Patients with genetic SVD (e.g. CADASIL) will be eligible if presenting with cognitive impairment and meeting the other inclusion criteria.
Added 09/06/2026:
***A study partner is usually someone who lives with the participant (e.g., a spouse) or a close relative or friend who is in regular contact (at least weekly) and knows the participant well enough to comment on their day-to-day functioning. The study partner must have known the participant for a sufficient period and have regular contact to provide a meaningful assessment of cognitive change over time using the IQCODE. Suitability of the study partner will be determined by the Principal Investigator (or delegated qualified investigator) at screening. The study partner may, but is not required to be, the participant’s welfare guardian or Power of Attorney.
Exclusion Criteria:
Current exclusion criteria as of 09/06/2026:
1. Unlikely to be able to manage medications without a dosette, based on information provided by the patient and family or carer. If a patient would be unable to manage their medications alone, but has sufficient family or carer support to take the trial medications in the view of the Principal Investigator, they can be included.
2. The cognitive impairment is thought to be mostly due to a cortical or large subcortical ischaemic or haemorrhagic stroke, rather than due to cSVD. This information will be contained within the medical record.
3. Significant active neurological illness, such as intractable epilepsy, multiple sclerosis, Parkinson’s disease, a neurodevelopmental disorder, or brain tumour. Well‑controlled epilepsy (for example, seizure‑free for more than 6 months) is not an exclusion criterion.
4. Hypotension, defined as sitting systolic blood pressure less than 100 mmHg.
5. Definite indication for (that is, already prescribed) either trial medication, or definite contraindication to both trial drugs as per SPCs. Lactose intolerance is a contraindication to ISMN preparations which contain lactose monohydrate. Having an indication for or contraindication to one of the trial drugs still allows randomisation to the other trial drug.
6. Unable to swallow tablets, based on information provided by the patient and/or their family or carer.
7. Planned surgery during the trial period.
8. Other concurrent life‑threatening illness, with life expectancy expected to be less than 1 year in the view of the study investigator.
9. Unlikely to be available for follow‑up (for example, moving outside of the area).
10. History of drug overdose, attempted suicide, or significant active mental illness documented in the medical notes.
11. Women of childbearing potential. Women of childbearing potential (WOCBP), defined in line with the Clinical Trials Coordination Group (CTCG; March 2024) guidance as fertile following menarche (and having not been free from menses for >1 year), and until becoming post-menopausal (no menses for 12 months without an alternative medical cause) unless permanently sterilised by hysterectomy, bilateral salpingectomy, and bilateral oophorectomy) will not be eligible for this single-centre short-term IMP administration pilot trial. Firstly, women of childbearing potential with VCI due to cSVD are extremely rare, and secondly, LACI-Cog-1 is a small, single-centre, short-term administration trial focused on the feasibility of recruitment and tolerance of IMP in a population that is more typical of patients attending memory clinics.
12. Prohibited medications to either trial drug. Prohibited medications to one of the trial drugs still allow randomisation to the other trial drug.
13. Renal impairment, defined as creatinine clearance less than 25 ml/min.
14. Moderate to severe hepatic impairment.
15. No renal or hepatic function tests within the last 12 months.
16. Previous participation in previous LACI trials (LACI‑1, LACI‑2, and LACI‑3).
17. Participation in another Clinical Trial of an Investigational Medicinal Product, up to and including at least five half-lives after the last dose of that Investigational Medicinal Product.
Cilostazol exclusion criteria (still allows randomisation to ISMN):
1. Definite indication for (that is, already prescribed) Cilostazol, or definite contraindication to cilostazol as per SPC section 4.3.
2. Prohibited medications to cilostazol (see appended SPCs and protocol section 6.7.3).
3. Active cardiac disease, including myocardial infarction within the last six months, uncontrolled atrial fibrillation, active angina, or symptomatic cardiac failure. Controlled atrial fibrillation alone is not an exclusion criterion; however, anticoagulant medication is an exclusion for cilostazol.
4. Bleeding tendency, for example, platelets less than 100, active peptic ulcer, previous intracranial haemorrhage (subdural haematoma, subarachnoid haemorrhage, intracerebral haemorrhage, but not asymptomatic haemorrhagic transformation from infarct or a few microbleeds on neuroimaging according to medical records), or prescribed anticoagulant medication. Participants on anticoagulant medication cannot receive cilostazol, but they can be randomised to ISMN versus no ISMN.
5. Prescribed dual antiplatelet therapy (aspirin and clopidogrel) or dual antiplatelets taken within the last week. Taking monotherapy antiplatelet treatment (aspirin or clopidogrel) is not a contraindication. Participants taking dual antiplatelets can be randomised to ISMN versus no ISMN.
ISMN exclusion criteria (still allows randomisation to Cilostazol)
1. Definite indication for (i.e., already prescribed) ISMN, or definite contraindication to ISMN as per SPCs section 4.3.
2. Prohibited medications to cilostazol (see appended SPCs and protocol section 6.7.3).
3. ISMN is contraindicated for patients with the rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency. The medical notes will be reviewed to apply this criterion.
For the MRI CVR imaging (tertiary endpoint 2), additional exclusion criteria are:
1. Unable to tolerate MRI or contraindication to MRI, such as claustrophobia, pacemaker, or cochlear implant.
2. Active respiratory illness, such as moderate to severe asthma or chronic obstructive pulmonary disease.
3. Unable to lie flat.
For the retinal/RVR imaging (tertiary endpoint 3), additional exclusion criteria are:
1. Active respiratory illness, such as moderate to severe asthma or chronic obstructive pulmonary disease.
2. History of photosensitive epilepsy.
3. Shallow anterior chambers, as assessed by torch test.
4. No view of the fundus in either eye.
MRI CVR and retinal imaging assessments are optional.
Previous exclusion criteria:
1. Unlikely to be able to manage medications without a dosette, based on information provided by the patient and family or carer. If a patient would be unable to manage their medications alone, but has sufficient family or carer support to take the trial medications in the view of the Principal Investigator, they can be included.
2. The cognitive impairment is thought to be mostly due to a cortical or large subcortical ischaemic or haemorrhagic stroke, rather than due to cSVD. This information will be contained within the medical record.
3. Significant active neurological illness, such as intractable epilepsy, multiple sclerosis, Parkinson’s disease, a neurodevelopmental disorder, or brain tumour. Well‑controlled epilepsy (for example, seizure‑free for more than 6 months) is not an exclusion criterion.
4. Hypotension, defined as sitting systolic blood pressure less than 100 mmHg.
5. Definite indication for (that is, already prescribed) either trial medication, or definite contraindication to both trial drugs as per SPCs. Lactose intolerance is a contraindication to ISMN preparations which contain lactose monohydrate. Having an indication for or contraindication to one of the trial drugs still allows randomisation to the other trial drug.
6. Unable to swallow tablets, based on information provided by the patient and/or their family or carer.
7. Planned surgery during the trial period.
8. Other concurrent life‑threatening illness, with life expectancy expected to be less than 1 year in the view of the study investigator.
9. Unlikely to be available for follow‑up (for example, moving outside of the area).
10. History of drug overdose, attempted suicide, or significant active mental illness documented in the medical notes.
11. Pregnancy or breastfeeding, or 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 and includes combined (oestrogen and progesterone containing) or progesterone‑only contraception associated with inhibition of ovulation, intrauterine device, or bilateral tubal occlusion. Contraception must be continued for up to 30 days after the end of the IMP dosing schedule.
12. Prohibited medications to either trial drug. Prohibited medications to one of the trial drugs still allow randomisation to the other trial drug.
13. Renal impairment, defined as creatinine clearance less than 25 ml/min.
14. Moderate to severe hepatic impairment.
15. Previous participation in previous LACI trials (LACI‑1, LACI‑2, and LACI‑3).
16. Cilostazol exclusion criteria (still allows randomisation to ISMN):
17. Definite indication for (that is, already prescribed) Cilostazol, or definite contraindication to Cilostazol as per SPC section 4.3.
18. Prohibited medications to Cilostazol (see appended SPCs and protocol section 6.7.3).
19. Active cardiac disease, including myocardial infarction within the last six months, uncontrolled atrial fibrillation, active angina, or symptomatic cardiac failure. Controlled atrial fibrillation alone is not an exclusion criterion; however, anticoagulant medication is an exclusion for cilostazol.
20. Bleeding tendency, for example platelets less than 100, active peptic ulcer, previous intracranial haemorrhage (subdural haematoma, subarachnoid haemorrhage, intracerebral haemorrhage, but not asymptomatic haemorrhagic transformation from infarct or a few microbleeds on neuroimaging according to medical records), or prescribed anticoagulant medication. Participants on anticoagulant medication cannot receive cilostazol, but they can be randomised to ISMN versus no ISMN.
21. Prescribed dual antiplatelet therapy (aspirin and clopidogrel) or dual antiplatelets taken within the last week. Taking monotherapy antiplatelet treatment (aspirin or clopidogrel) is not a contraindication. Participants taking dual antiplatelets can be randomised to ISMN versus no ISMN.
ISMN exclusion criteria (still allows randomisation to Cilostazol)
1.	Definite indication for (i.e. already prescribed) ISMN, or definite contraindication to ISMN as per SPCs section 4.3.
2.	Prohibited medications to Cilostazol (see appended SPCs and protocol section 6.7.3).
For the MRI CVR imaging (tertiary endpoint 2), additional exclusion criteria are:
1.	Unable to tolerate MRI or contraindication to MRI, such as claustrophobia, pacemaker, or cochlear implant.
2.	Active respiratory illness, such as moderate to severe asthma or chronic obstructive pulmonary disease.
3.	Unable to lie flat.
For the retinal/RVR imaging (tertiary endpoint 3), additional exclusion criteria are:
1.	Active respiratory illness, such as moderate to severe asthma or chronic obstructive pulmonary disease.
2.	History of photosensitive epilepsy.
3.	Shallow anterior chambers, as assessed by torch test.
4.	No view of the fundus in either eye.
MRI CVR and retinal imaging assessments are optional.

The sponsor's own eligibility wording, lightly reformatted. The study team makes the final eligibility decision — worth discussing with your doctor.

Eligibility criteria as of 2026-06-09