Title
LACunar Intervention trial 3 (LACI-3)
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Acronym
LACI-3
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Chief investigator
Professor Joanna Wardlaw
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Objectives
To determine if, in patients with symptomatic lacunar ischaemic stroke,
the routine long-term administration of isosorbide mononitrate 50mg od or
equivalent, and /or cilostazol 100mg bd, individually or together, in
addition to continuing routine stroke prevention therapy, compared with
continuing routine stroke prevention therapy alone, reduces cognitive
impairment after lacunar ischaemic stroke, a marker of cerebral small
vessel disease.
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Trial design
An investigator-led, multicentre, prospective, randomised, controlled,
open label, 2x2 factorial, blinded endpoint (PROBE) confirmatory trial.
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Setting
At least 60 hospitals in the UK (Scotland, England, Wales, Northern
Ireland)
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Sample size estimate
The primary outcome, cognitive impairment assessed using the DSM-5
7-level ordinal score, will be compared between ISMN vs no ISMN,
cilostazol vs no cilostazol, and ISMN+cilostazol vs no ISMN or cilostazol
using ordinal logistic regression adjusted for stratification and
minimisation variables. The null hypothesis is that ISMN, alone or
with cilostazol, will not reduce long-term cognitive impairment in
patients with lacunar ischaemic stroke. A sample of N=1300 is
needed (650 ISMN, 650 no ISMN) assuming alpha 5%, power 90%; distribution
of DSM-5 7-level ordinal score in the control (standard of care) group
is: level 1 (normal): 35%, 2: 24%, 3: 12%, 4: 20%, 5: 3%, 6: 3%, 7
(dead):3% (as in LACI-2); DSM-5 7-level unadjusted odds ratio 0.70 (the
risk reduction exceeds the minimal clinically important difference [MCID]
of 0.27), standard deviation 1.33; losses/cross-overs 15%; no covariate
adjustment; sample rounded up.
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Number of participants
1,300
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Eligibility criteria
Inclusions
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Aged 30 years old and above
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Clinical stroke syndrome compatible with a lacunar stroke and brain
imaging (MRI preferred but CT allowed) at the time of the stroke
shows a relevant recent small subcortical infarct, or if no relevant
infarct then no other explanation for symptoms is seen
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Genetic forms of SVD (e.g. CADASIL) may be included if they present
with a lacunar stroke
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Capacity to give consent in the opinion of the PI or any delegated
member of the research team
Exclusions
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Less than 24 hours since onset of the lacunar stroke
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Patient on dual antiplatelet drugs (see additional exclusion, below)
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Stroke mechanism with definite treatment indication (e.g.
cardioembolism, ipsilateral carotid stenosis)
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Other explanation for the lacunar stroke symptoms (i.e. recent
cortical infarct, haemorrhage or tumour)
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Other active neurological disease (e.g. brain tumour, multiple
sclerosis, recurrent seizures, neurodevelopmental
disorder - well-controlled epilepsy present prior to the lacunar
stroke, a single seizure at onset of the stroke, or provoked
seizure, is not an exclusion)
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Contraindication to both trial drugs in section 4.3 of the SPCs
(patients with a contraindication to one trial drug may still be
randomised to the other trial drug)
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Indication for either trial drug (patient already prescribed one
trial drug may still be randomised to the other trial drug)
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Dependent - mRS cannot be 3-5
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Clinical diagnosis of dementia
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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
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Unable to swallow
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Diagnosis of hypotension, defined as sitting systolic blood
pressure less than 100 mmHg
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History of drug overdose or attempted suicide
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Unlikely to be available for follow-up at 18 months
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Unlikely to comply with study procedures and follow-up procedures
for whatever reason (e.g. history of poor medication compliance) in
the opinion of the randomising physician
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Pregnant, breast-feeding, or of child-bearing potential and not
using highly effective contraception as stated in protocol
(see Pregnancy section)
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Renal impairment (creatinine clearance under 25 ml/min)
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Hepatic impairment
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Currently prescribed dual antiplatelet treatment (single
antiplatelet is not an exclusion); patients can be randomised
into the trial once the 28-day period of dual antiplatelet for
guideline secondary prevention following the acute lacunar
ischaemic stroke has completed
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Previously enrolled in LACI-3
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Enrolled in a study that precludes co-enrolment with LACI-3
Exclusions for Cilostazol only
- Allergy to Cilostazol
- Already prescribed Cilostazol
- Any contraindication to Cilostazol
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Patient is on a prohibited medication:
- Warfarin
- Acenocoumarol (Sinthrome®)
- Phenindione
- Dabigatran (Pradaxa ®)
- Apixaban (Eliquis®)
- Rivaroxaban (Xarelto®)
- Edoxaban
- Heparin
- Dalteparin (Fragmin®)
- Enoxaparin (Clexane®)
- Tinzaparin (Innohep®)
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Omeprazole – can be switched to Lansoprazole or other
Proton Pump Inhibitor
- Anagrelide
- Clarithromycin
- Erythromycin
- Diltiazem (Tildiem®)
- Itraconazole (Sporanox®)
- Boceprevir (Victrelis®)
- Ritonavir (Norvir®)
- Telaprevir (Incivo®)
- Ketoconazole (Nizoral®)
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Active cardiac disease (atrial fibrillation, myocardial infarction
in past 6 months, active angina, symptomatic cardiac failure)
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Bleeding tendency (platelets under 100 ×109/L,
active peptic ulcer, taking anticoagulant medication)
Exclusions for ISMN only
- Allergy to ISMN
- Already prescribed ISMN
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Any contraindication to ISMN (e.g. lactose intolerance) or other
regular nitrate
- Patient is on a prohibited medication:
- Avanafil (Spedra®)
- Sildenafil (Nipatra®, Viagra®, Revatio®)
- Tadalafil (Cialis®)
- Vardenafil (Levitra®)
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Description of interventions
- Cilostazol only
Cilostazol 100mg oral twice
daily - ISMN only
Isosorbide mononitrate slow release
50mg oral once daily - Both Cilostazol and
ISMN
Cilostazol 100mg oral twice daily and Isosorbide
mononitrate slow release 50mg oral once daily - None (neither
Cilostazol nor ISMN)
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Duration of study
Treatment duration: from within one day of randomisation until the
end of trial follow-up
Follow-up duration: 18 months
Total planned trial duration: 52 months
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Randomisation and blinding
The study will be performed open label. Placebo tablets are not
available and masking by encapsulation is too complicated and
expensive. However, blinding of outcomes is important to obtain
unbiased information about tolerability, safety, and efficacy. As
such, IMP adherence structured questionnaire and prescribed medications
will be taken by site staff who are already unblinded to trial
allocation, while ascertainment of the main cognitive and clinical
outcomes will be collected by central follow-up co-ordinators who are
masked to treatment allocation.
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Outcome measures
Primary objective: To determine if, in patients with symptomatic
lacunar ischaemic stroke, the routine long-term administration of
isosorbide mononitrate 50mg od or equivalent, and /or cilostazol 100mg
bd, individually or together, in addition to continuing routine stroke
prevention therapy, compared with continuing routine stroke prevention
therapy alone, reduces cognitive impairment after lacunar ischaemic
stroke, a marker of cerebral small vessel disease.
Secondary objectives: To determine if the long-term administration
of isosorbide mononitrate 50mg od or equivalent and/or cilostazol 100mg
bd individually or together, in addition to continuing routine stroke
prevention therapy, compared with continuing routine stroke prevention
therapy alone, reduces dependency, recurrent stroke or TIA, MI, death,
and improves mood, quality of life, and health economic resource usage
and is safe and well tolerated in long term use in patients with lacunar
ischaemic stroke, a marker of cerebral small vessel disease.
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Statistical methods
A full statistical analysis plan (SAP) will be finalised prior to
database lock.
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