Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Multicenter, Randomized, Double Blind Study to Compare the Efficacy Between Cilostazol and Aspirin on White Matter Changes by Cerebral Small Vessel Disease
Brief Summary: There may be a difference in efficacy of cilostazol and aspirin on progression of white matter changes in cerebral small vessel disease.


Options:
A: Inclusion Criteria:

* diagnosis of ischemic stroke/TIA
* \< 90 days from onset of symptoms
* initial MRI available,
* not receiving antiplatelet therapy at the time of admission
* medical decision by the treating physician that antiplatelet therapy is indicated for secondary prevention (decision independent of the study and based on individual clinical decision for each patient).
* baseline coated-platelet levels at 40%,
* willingness to participate in the study for 24 months

Exclusion Criteria:

* dementia (based on chart review or self/proxy report)
* \> 90 days from onset of symptoms
* initiation of anticoagulation or thrombolytics prior to phlebotomy
* intracranial hemorrhage or bleeding diatheses
* end-stage renal disease (ESRD)
* inability to tolerate consenting or phlebotomy
* prior adverse/allergic reactions to clopidogrel
* treating physician deemed a different antiplatelet dose or dual antiplatelet therapy as the only treatment choice
B: Inclusion Criteria:

* Men and women
* African American and Hispanic persons age 65 or older
* Any person from another ethnic minority group and Caucasian persons age 70 or older
* Willing and able to provide informed consent, and willing to accept the study requirements

Exclusion Criteria:

* A history of a diagnosed cardiovascular event
* A serious intercurrent illness likely to cause death within the next 5 years, such as terminal cancer or obstructive airways disease
* A current or recurrent condition with a high risk of major bleeding, ex: cerebral aneurysm
* Anemia
* Absolute contraindication or allergy to aspirin
* Current participation in a clinical trial
* Current continuous use of aspirin or other anti-platelet drug or anticoagulant for secondary prevention. People with previous use of aspirin for primary prevention may enter the trial, provided they agree to cease existing use of aspirin and understand that they may be subsequently randomly allocated to low dose aspirin or placebo.
* A systolic blood pressure ≥180 mmHg and / or a diastolic blood pressure ≥105 mmHg
* A history of dementia
* Severe difficulty or an inability to perform any one of the 6 Katz ADLs
* Non-compliance to taking pill
C: Inclusion Criteria:

* 50 to 85 years of age
* He/She can walk to the hospital (walker or cane is permissible).
* Cerebral small vessel disease is observed on brain MRI.

  1) presence of one or more lacunar infarction and 2) moderate or severe confluent leukoaraiosis (defined as grade 2 or 3 on a modified Fazekas scale): periventricular WMCs with cap or rims lager than 5mm and deep subcortical WMCs \>10 mm in maximum diameter
* written informed consent

Exclusion Criteria:

* Any patient with contraindication of antiplatelets
* Any patient with cardioembolic source
* Carotid bruit or large cerebral artery stenosis \>50%
* Cortical infarction or subcortical infarction lager than 1.5 cm
* bleeding tendency
* chronic liver disease (AST or ALT \>100 IL/L)
* chronic renal disease (Creatinine \>3.0mg/dL)
* active gastrointestinal ulcer
* any patients with any severe or unstable medical disease that may prevent them from completing study requirements (i.e., unstable or severe asthma)
* Anemia (Hb \<10g/dL) or thrombocytopenia
* Cardiac pacemaker or contraindication to MRI
* Pregnancy or breast-feeding
* drug or alcohol addiction
* Any other white matte disease (i.e., Multiple sclerosis, sarcoidosis, or brain irradiation, etc) or brain tumor
* Parkinson's disease, Alzheimer's disease or any other neurodegenerative disease
* any hearing or visual impairment that can disturb the efficient evaluation of the patient
* recent cerebral infarction with 3 months
D: 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).

    1. 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.
    2. 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

Exclusion Criteria:

* 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)
* 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)

Answer: C