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.
Phase: PHASE2
Conditions: Cerebral Small Vessel Diseases, Stroke, Lacunar
Sponsor: University of Edinburgh

 
 
 
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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.
Version 7.0, 06Nov2020 
 
 
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. 
 
Co-sponsors 
University of Edinburgh & NHS Lothian 
ACCORD 
 
47 Little France Crescent 
Edinburgh 
EH16 4TJ 
Funder 
British Heart Foundation 
Funding Reference Number 
CS/15/5/31475 
Chief Investigator 
Professor Joanna M Wardlaw  
EudraCT Number 
2016-002277-35 
REC Number 
17/EM/0077 
ISRCTN Number 
14911850 
Version Number and Date 
 Version 7.0           14Oct2020 
COORDINATING CENTRE 
Chief Investigator 
Professor Joanna M Wardlaw  
Neuroimaging Sciences 
University of Edinburgh 
Centre for Clinical Brain Sciences (CCBS) 
Chancellor's Building 
49 Little France Crescent 
Edinburgh EH16 4SB  
Tel: +44 (0)131 465 9599  
Fax: Not available  
Email: Joanna.Wardlaw@ed.ac.uk  
Co-sponsor Representative 
 
Clinical Research Facilitator 
Research Governance & QA Office 
University of Edinburgh 
The Queen's Medical Research Institute 
47 Little France Crescent 
Edinburgh, EH16 4TJ 
  
Tel: +44 (0)131 242 9418  
Fax: 0131 242 9447 
Email: f
@ed.ac.uk 
 
Co-sponsor Representative 
Heather Charles  
Office E1.13 
Research & Development Management 
Suite 
The Queen's Medical Research Institute 
47 Little France Crescent 
Edinburgh EH16 4TJ  
Tel: 0131 242 3359  
Principal Investigator 
Dr Fergus Doubal 
Neuroimaging Sciences 
University of Edinburgh 
Centre for Clinical Brain Sciences (CCBS) 
Chancellor's Building 
49 Little France Crescent 
Edinburgh EH16 4SB  
Tel: +44 (0)131 465 9599  

 
 
 
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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.
Version 7.0, 06Nov2020 
Fax: 0131 242 3343  
Email: 
heather.charles@nhslothian.scot.nhs.uk 
Fax: Not available  
Email: Fergus.Doubal@ed.ac.uk 
Trial Manager 
Anna Heye 
Edinburgh Clinical Trials Unit 
University of Edinburgh 
Western General Hospital 
Crewe Road 
Edinburgh EH4 2XU  
Tel:  0131 651 9917 
Fax: Not available 
Email: anna.heye@ed.ac.uk 
Trial Statistician 
Lisa Woodhouse (a member of Prof A. 
 team) 
Room B48 Clinical Sciences Building 
Nottingham City Hospital 
Hucknall Road 
Nottingham 
NG5 1PB  
 
Tel:  0115 82 31670 
Fax: Not available 
Email: l.woodhouse@nottingham.ac.uk 
 
 
PARTICIPATING SITES 
The up to date list of participating sites is maintained on the LACI-2 trial website 
 
 

 
 
 
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LACunar Intervention (LACI-2) Trial 2: Assessment of 
safety and efficacy of cilostazol and isosorbide 
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progression of cerebral small vessel disease.
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PROTOCOL APPROVAL ................................................................................... 6 
1 
INTRODUCTION ...................................................................................... 10 
1.1 
BACKGROUND ............................................................................... 10 
1.2 
RATIONALE FOR STUDY ............................................................... 12 
2 
STUDY OBJECTIVES .............................................................................. 14 
2.1 
OBJECTIVES .................................................................................. 14 
2.1.1 
Primary Objective .......................................................................... 14 
2.1.2 
Secondary Objectives ................................................................... 14 
2.2 
ENDPOINTS .................................................................................... 14 
2.2.1 
Primary Endpoint .......................................................................... 14 
2.2.2 
Secondary Endpoints .................................................................... 14 
3 
STUDY DESIGN ....................................................................................... 15 
4 
STUDY POPULATION ............................................................................. 17 
4.1 
NUMBER OF PARTICIPANTS ......................................................... 17 
4.2 
INCLUSION CRITERIA .................................................................... 17 
4.3 
EXCLUSION CRITERIA ................................................................... 18 
4.3.1 
General exclusion criteria .............................................................. 18 
4.3.2 
Cilostazol exclusion criteria (still allows randomisation to ISMN) ... 18 
4.3.3 
ISMN exclusion criteria (still allows randomisation to Cilostazol) ... 18 
4.4 
CO-ENROLMENT ............................................................................ 19 
5 
PARTICIPANT SELECTION AND ENROLMENT .................................... 19 
5.1 
IDENTIFYING PARTICIPANTS ....................................................... 19 
5.2 
CONSENTING PARTICIPANTS ...................................................... 19 
5.3 
SCREENING FOR ELIGIBILITY ...................................................... 20 
5.4 
INELIGIBLE AND NON-RECRUITED PARTICIPANTS .................... 21 
5.5 
RANDOMISATION ........................................................................... 21 
5.5.1 
Randomisation Procedures ........................................................... 21 
5.5.2 
Emergency Unblinding Procedures ............................................... 22 
5.5.3 
Withdrawal of Study Participants ................................................... 22 
6 
INVESTIGATIONAL MEDICINAL PRODUCTS ........................................ 23 
6.1 
STUDY DRUGS ............................................................................... 23 
6.1.1 
Study Drug Identification ............................................................... 23 
6.1.2 
Study Drug Manufacturer .............................................................. 23 
6.1.3 
Marketing Authorisation Holder ..................................................... 24 
6.1.4 
Labelling and Packaging ............................................................... 24 
6.1.5 
Storage ......................................................................................... 24 
6.2 
DOSING REGIME ............................................................................ 24 
6.3 
DOSE CHANGES ............................................................................ 26 
6.4 
PARTICIPANT COMPLIANCE ......................................................... 26 
6.5 
OVERDOSE .................................................................................... 27 
6.6 
OTHER MEDICATIONS ................................................................... 27 
6.6.1 
Non-Investigational Medicinal Products ......................................... 27 
6.6.2 
Permitted Medications ................................................................... 27 
6.6.3 
Prohibited Medications .................................................................. 27 

 
 
 
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7 
STUDY ASSESSMENTS ......................................................................... 27 
7.1 
SAFETY ASSESSMENTS ............................................................... 27 
7.2 
STUDY ASSESSMENTS ................................................................. 27 
8 
DATA COLLECTION ............................................................................... 30 
9 
STATISTICS AND DATA ANALYSIS ...................................................... 30 
9.1 
SAMPLE SIZE CALCULATION ........................................................ 30 
9.2 
PROPOSED ANALYSES ................................................................. 31 
10 
ADVERSE EVENTS ................................................................................. 31 
10.1 
DEFINITIONS .................................................................................. 32 
10.2 
IDENTIFYING AEs AND SAEs ........................................................ 32 
10.3 
RECORDING AEs AND SAEs ......................................................... 32 
10.3.1 Pre-existing Medical Conditions .................................................... 33 
10.3.2 Outcome Events ........................................................................... 33 
10.3.3 Events That Are Common in the Trial Population .......................... 33 
10.3.4 All Other Events Not Covered Above ............................................ 35 
10.4 
ASSESSMENT OF AEs AND SAEs ................................................. 37 
10.4.1 Assessment of Seriousness .......................................................... 37 
10.4.2 Assessment of Causality ............................................................... 37 
10.4.3 Assessment of Expectedness ....................................................... 37 
10.4.4 Assessment of Severity ................................................................. 37 
10.5 
REPORTING OF AEs TO THE SPONSOR ...................................... 38 
10.6 
REPORTING OF SAEs/SARs/SUSARs ........................................... 38 
10.7 
REGULATORY REPORTING REQUIREMENTS ............................. 38 
10.8 
CENTRAL BLINDED REVIEW OF SAEs ......................................... 38 
10.9 
FOLLOW UP PROCEDURES .......................................................... 39 
11 
PREGNANCY........................................................................................... 39 
12 
TRIAL MANAGEMENT AND OVERSIGHT ARRANGEMENTS............... 39 
12.1 
TRIAL MANAGEMENT GROUP ...................................................... 39 
12.2 
TRIAL STEERING COMMITTEE ..................................................... 39 
12.3 
DATA MONITORING COMMITTEE ................................................. 40 
12.4 
INSPECTION OF RECORDS .......................................................... 40 
12.5 
RISK ASSESSMENT ....................................................................... 40 
12.6 
STUDY MONITORING AND AUDIT ................................................. 40 
13 
GOOD CLINICAL PRACTICE .................................................................. 40 
13.1 
ETHICAL CONDUCT ....................................................................... 40 
13.2 
REGULATORY COMPLIANCE ........................................................ 40 
13.3 
INVESTIGATOR RESPONSIBILITIES ............................................. 41 
13.3.1 Informed Consent ......................................................................... 41 
13.3.2 Study Site Staff ............................................................................. 41 
13.3.3 Data Recording ............................................................................. 41 
13.3.4 Investigator Documentation ........................................................... 41 
13.3.5 GCP Training ................................................................................ 41 
13.3.6 Confidentiality ............................................................................... 42 
13.3.7 Data Protection ............................................................................. 42 
14 
STUDY CONDUCT RESPONSIBILITIES ................................................. 42 

 
 
 
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14.1 
PROTOCOL AMENDMENTS ........................................................... 42 
14.2 
PROTOCOL VIOLATIONS AND DEVIATIONS ................................ 42 
14.3 
SERIOUS BREACH REQUIREMENTS ........................................... 43 
14.4 
STUDY RECORD RETENTION ....................................................... 43 
14.5 
END OF STUDY .............................................................................. 43 
14.6 
CONTINUATION OF DRUG FOLLOWING THE END OF STUDY ... 43 
14.7 
INSURANCE AND INDEMNITY ....................................................... 43 
15 
REPORTING, PUBLICATIONS AND NOTIFICATION OF RESULTS ...... 44 
15.1 
AUTHORSHIP POLICY ................................................................... 44 
15.2 
PUBLICATION ................................................................................. 44 
15.3 
PEER REVIEW ................................................................................ 44 
16 
REFERENCES ......................................................................................... 45 
 
 

 
 
 
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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.
Version 7.0, 06Nov2020 
 
 
PROTOCOL APPROVAL 
 
 
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. 
EudraCT number: 2016-002277-35 
 
Professor Joanna Wardlaw 
 
 
 
Chief Investigator 
Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
Lisa Woodhouse 
 
 
 
Trial Statistician 
Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor(s) Representative 
Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
Anna Heye 
 
 
 
Trial Manager 
Signature 
 
Date 
 
 
 
 
 
 
 
 
TO BE COMPLETED 
 
 
 
 
 
 

 
 
 
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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.
Version 7.0, 06Nov2020 
 
 
ACCORD 
Academic and Clinical Central Office for Research & Development 
AE 
Adverse Event 
AMP 
Adenosine Monophosphate 
AR 
Adverse Reactions 
BBB 
Blood-Brain Barrier 
BP 
Blood Pressure 
BHF 
British Heart Foundation 
CA 
Competent Authority 
CI 
Chief Investigator 
CO2 
Carbon Dioxide 
CRF 
Case Report Form 
CSPS trial 
Clinical Stroke Prevention Study 
CSPS2 trial 
Clinical Stroke Prevention Study 2 
CSPS3 trial 
Clinical Stroke Prevention Study 3 
CT 
Computed Tomography 
CVR 
Cerebrovascular Reactivity 
eCRF 
Electronic Case Report Form 
ENOS 
Efficacy of Nitric Oxide in Stroke 
GMP 
Guanosine Monophosphate 
GTN 
Glyceryl Trinitrate 
ICF 
Informed Consent Form 
ICH GCP 
International Conference on Harmonisation Tripartite Guideline for 
Good Clinical Practice 
ISF 
Investigator Site File 
ISMN 
Isosorbide Mononitrate 
IQCODE 
Informant questionnaire on cognitive decline in the elderly 
LACI-2 
LACunar Intervention Trial 2 
MMSE 
Mini-Mental State Examination 
MOCA 
Montreal Cognitive Assessment 
MRI 
Magnetic Resonance Imaging 
NO 
Nitric Oxide 
O2 
Oxygen 
PDE3 
Phosphodiesterase 3 
PGI2 
Prostaglandin Inhibitor 2 
PI 
Principal Investigator 
PIS 
Patient Information Sheet 

 
 
 
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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.
Version 7.0, 06Nov2020 
REC 
Research Ethics Committee 
RCT 
Randomised Controlled Trial 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SPC 
Summary of Product Characteristics 
SPS3 
Secondary Prevention of Small Subcortical Strokes Trial 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SVD 
Small Vessel Disease 
TICS 
Telephone Interview for Cognitive Status 
TMOCA 
Telephone Montreal Cognitive Assessment 
UK 
United Kingdom 
USA 
United States of America 
WMH 
White Matter Hyperintensities 

 
 
 
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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.
Version 7.0, 06Nov2020 
 
Professional Summary 
 
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 
. 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.  
 
Lay Summary  
 
stroke, which is different to other common types of stroke and for which there is no proven 
treatment. We think 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 
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. We 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. 
 

 
 
 
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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.
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1 
INTRODUCTION 
1.1 BACKGROUND 
Burden of disease: Stroke and dementia rank among the most pressing health issues, show 
substantial co-morbidity and share many risk factors. Cerebral small vessel disease (SVD) has 
emerged as a central link between the two disease states.1, 2 SVD accounts for up to 45% of all 
1, 3 SVD also causes 20-25% of 
clinical strokes (lacunar stroke)4, about 35,000 per year in the UK, and leaves at least a third of 
these patients with cognitive impairment or dementia after the stroke.5, 6 Patients with lacunar 
stroke are often younger than for other stroke subtypes7 and cognitive impairment restricts their 
return to work not just independence. In addition, about 50% of 65 year olds and almost all 90 
year olds, have imaging manifestations of SVD,8 which build up insidiously and diffusely in the 
brain until of sufficient severity to cause symptoms. Both stroke and vascular dementia are 
major Government targets, are increasing in prevalence,9 and have enormous economic and 
societal costs. 
 
SVD is easily detected on magnetic resonance brain imaging (MRI) as white matter 
hyperintensities (WMH), lacunes, microbleeds, prominence of perivascular spaces and brain 
atrophy.10 Individually, and when mild, these imaging features are often clinically silent. 
However, when more severe, they cause cognitive impairment, physical disability and 
depression. They are associated with worse outcomes after acute stroke,11 increase the risk of 
developing dementia (2-fold) and of having a stroke (3-fold).12, 13 A simple visual sum score 
may capture the overall burden of total SVD brain damage better than the individual separate 
features, and highlights that the importance of some risk factors for SVD, like smoking, may 
have been under-recognised.14, 15 
 
Pathology of lacunar stroke: Despite this profound impact on human health, there are no 
treatments with proven efficacy that prevent progression of SVD and its clinical or imaging 
manifestations.16 In part this reflects our limited understanding of the cause of SVD, and how it 
affects the brain. Less than 11% of clinically-evident lacunar ischaemic strokes are 
atherothromboembolic.17 Lacunar stroke patients have less large artery atheroma (less 
ischaemic heart disease, carotid stenosis, peripheral vascular disease (PVD)), despite similar 
rates of hypertension and diabetes, to those with atheromatous stroke.7 Risk factors for SVD in 
general include hypertension, smoking, diabetes,4 but all common vascular risk factors 
combined explain less than 2% of variance in SVD features.18  
 
Instead, most lacunar stroke is due to an intrinsic deep perforating arteriolar disease with 
arteriolar wall thickening, mural and perivascular inflammation, segmental arteriolar wall 
disintegration,19 and perivascular brain damage.2 The arteriolar damage is linked with cerebral 
endothelial dysfunction, impaired vasoreactivity,20, 21 and increased blood-brain barrier (BBB) 
permeability,2, 22, 23 all of which increase secondary ischaemic brain damage. Additionally, the 
damaged endothelium may precipitate local thrombosis, further worsening ischaemic damage.2 
Subtle BBB failure is a key component of the pathology,3, 24-26 which could explain the thickening 
and stiffening of arteriole walls, and subsequent increase in WMH.21, 27, 28 Systemic arteriolar 
stiffness may also account, at least partly, for the link between hypertension and WMH.29 Stiff 
arterioles do not vasodilate well to increase blood supply in response to increased brain activity, 
thus potentially increasing secondary ischaemic damage and dementia.30 Impaired 
cerebrovascular reactivity (CVR) 
31 and amyloid 
angiopathy 32 making endothelial dysfunction an important potential SVD therapeutic target. 
 
Prevention of lacunar stroke is suboptimal: Although many patients with lacunar stroke and 
other SVD features must have been included in many previous stroke prevention randomised 
clinical trials (RCTs), few reported their results by stroke subtype. Where subtyping was 
reported, it was often suboptimal, mixing lacunar and athero-thrombo-embolic or cardio-embolic 
strokes. There have been few RCTs specifically in lacunar stroke. The largest of these, the 
Secondary Prevention of Small Subcortical Stroke (SPS3) trial (3000+ lacunar stroke patients), 
tested aspirin+clopidogrel vs aspirin and target vs guideline BP reduction to prevent recurrent 
stroke and cognitive decline. The aspirin+clopidogrel vs aspirin arm stopped early as 

 
 
 
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LACunar Intervention (LACI-2) Trial 2: Assessment of 
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progression of cerebral small vessel disease.
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aspirin+clopidogrel increased bleeding and death33 without reducing recurrent stroke33 or MI,34 
more evidence of the non-atheromatous nature of SVD. Target (vs guideline) BP lowering was 
consistent with a small reduction in recurrent stroke,35 but neither it nor aspirin+clopidogrel vs 
aspirin reduced cognitive decline.36 There are few data on statins16 but statins did not prevent 
WMH progression in PROSPER.37 However, statins are guideline therapy after stroke and their 
anti-inflammatory effects may benefit SVD.  
 
Implications of current management: Current guideline-based secondary prevention of lacunar 
stroke with antiplatelet, antihypertensive drugs and statins has a limited evidence base, may 
be ineffective, or even hazardous. The burden of SVD, in particular its stroke and dementia 
consequences, is increasing with longevity. Brain haemorrhage also increases with age,38 SVD 
features and antiplatelet drugs.34 Other approaches are therefore needed to reduce the clinical 
impact of SVD. 
 
Therapeutic targets: In light of the SVD mechanisms outlined above, we (and others39) reviewed 
all potential drugs tested in RCTs that included lacunar stroke and found many relevant drugs.16 
In a systematic review of experimental models of SVD,40, 41 we also found promising data on 
several drugs available for human use. We particularly looked for available licensed drugs with 
relevant effects: to stimulate the nitric oxide (NO)-cyclic GMP or Prostacyclin (PGI2)-cyclic AMP 
systems thereby improving vasodilatation, reducing inflammation and smooth muscle 
hypertrophy (to reduce stiffness) and improving cerebral endothelial integrity (prevent extra-
vascular leakage) and neuroprotective effects.2 Two drugs, both licensed in Europe for 
treatment of vascular diseases, show promise.  
 
Cilostazol is a phosphodiesterase 3-inhibitor (PDE3-inhibitor) that enhances the PGI2-cAMP 
system. It has weak antiplatelet effects (so low bleeding risk),42 reduces infarct size41 and 
reduces ageing-related decline in myelin repair43 in experimental models, has a UK license for 
treatment of peripheral vascular disease, and has data from trials including more than 6400 
patients with stroke (Figure 1).44-47 Amongst those, the trials where >50% of participants had 
lacunar stroke (n=4780) found long-term cilostazol (vs placebo or aspirin) reduced recurrent 
stroke (OR 0.62, 95%CI 0.49-0.77) without increasing haemorrhage (OR 0.52, 95%CI 0.36-
0.75), or death (OR 0.90 95%CI 0.53-1.52) over median 1 year treatment (Figure 1). However, 
there are no data on the effects of cilostazol on cognition, or on imaging features of SVD, and 
all data are from Asia-Pacific region countries where the epidemiology, range of risk factors, 
stroke subtype profiles, and other vascular characteristics differ from those commonly seen in 
the West. 
Figure 1. Meta-analysis of trials of cilostazol for stroke prevention. % indicates proportion of 
patients recruited with lacunar stroke. 
 
Isosorbide mononitrate (ISMN), is an NO donating organic nitrate that enhances vasodilation, 
is widely used in ischaemic heart disease, and has no antiplatelet activity.48 NO is an important 
regulator of cerebral haemodynamic function which is impaired in patients with lacunar stroke 
and WMH.21 Replacing NO might improve vasoreactivity,49 but drugs that increase NO 
availability are rarely used in stroke, particularly lacunar stroke (e.g. pre-stroke nitrates were 
used in <2% in patients randomised in the Efficacy of Nitric Oxide in Stroke (ENOS) trial 
including those randomised into the trial with lacunar syndromes50 or in our lacunar stroke 
cohort studies14). This is surprising since ISMN is well established in the UK for cardiac disease 
with a known safety profile, endogenous NO is reduced in patients with SVD,21 so replacing NO 

 
 
 
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LACunar Intervention (LACI-2) Trial 2: Assessment of 
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progression of cerebral small vessel disease.
Version 7.0, 06Nov2020 
might improve vessel function.49 The related drug, transdermal GTN, another organic nitrate, 
administered short term after acute stroke, improved cerebral perfusion,51 vascular reactivity 
and functional outcome, including cognition, at three months after stroke in ENOS, when started 
within three hours of acute stroke and given for up to seven days after stroke.50 These data 
were sufficiently promising for the BHF to fund a new trial of GTN in hyperacute stroke, RIGHT-
2 (ongoing). 
 
Use of two drugs with complementary actions that affect different parts of the pathological 
pathway could increase benefit over one drug alone. The importance of vascular disease in 
neurodegeneration is now being recognised,10, 52 together with the importance of SVD as a 
bridge between stroke and dementia.1 The contributing mechanisms to target are clearer2 and 
licensed drugs are available.16, 39    
1.2 RATIONALE FOR STUDY 
The need for a trial in lacunar stroke: There is no established treatment to prevent recurrent 
lacunar stroke or other features of SVD. The disparity between the apparent benefits of 
cilostazol in stroke prevention in the Asia-Pacific region and its lack of use in the UK is striking 
and supports evaluation. Cilostazol is available worldwide and generics are now available in 
the UK. Similarly, ISMN is widely used in cardiology, is available as a generic, but its potential 
benefits in stroke have received little attention despite relevant NO actions, an oversight that 
also needs to be addressed. As well as effective treatments, we need more data for designing 
trials in lacunar stroke: on recruitment and assessment methods; long term event rates; on 
safety and tolerance of promising drugs to undertake large Phase III trials. 
 
Mechanisms by which Cilostazol and/or ISMN might work: Cerebral haemodynamic function is 
impaired in lacunar stroke and SVD.21 Cilostazol is a PDE3-inhibitor that preserves cAMP and 
should reduce cerebral microvessel vasoconstriction, smooth muscle proliferation and 
inflammation, secondary brain damage, protect the endothelium,53 and may enhance myelin 
repair.43 Importantly, in SVD where there may be increased bleeding risk, cilostazol has low 
bleeding risk.42 Cilostazol was trialled in Japan, China and Korea, with more trials ongoing in 
Japan (CSPS3, Toyoda, collaborator), China and Taiwan.54 Promising data on reduction in 
recurrent stroke (Figure 1) and improving cerebral arterial stiffness in human55 and 
experimental53, 56 SVD, support testing in Europeans. Effects of Cilostazol on cognitive and 
physical function in SVD are unknown.  
 
ISMN replaces NO, which is low in acute lacunar stroke,57 so should also enhance cerebral 
endothelial function and vasodilatation.49 ISMN has no antiplatelet effects. Endothelial 
dysfunction is well documented in SVD.1, 2, 39 There is little experience with nitrates in patients 
with lacunar stroke,14, 50 because conventional large artery atheromatous indications such as 
angina are infrequent.7, 34 
 
Combined stimulation of the NO-cGMP and PGI2-cAMP systems potentially maximises the 
above benefits, if it does not increase adverse effects, so cilostazol and ISMN together may be 
more effective than either drug alone. Both may improve BP control, lower BP modestly, reduce 
BP variability, further reducing stroke and SVD risk. Combining ISMN (no antiplatelet effects) 
and cilostazol (weak antiplatelet) should avoid excess bleeding when given with guideline 
clopidogrel or aspirin (both moderate-strong antiplatelet agents).33  
 
Rationale for the approach: The trial was designed as part of an NIHR SRN-Portfolio 
Development Expert Writing Group using experience from the USA NIH-funded SPS3 trial 
(3000+ lacunar stroke patients, CI Benavente; SRN Writing Group, LACI-2 International Advisor 
to TSC),33, 35, 36 the CSPS and CSPS2 trials (3740 patients44, 46) and ongoing CSPS3 trial testing 
cilostazol to prevent stroke in Japan (PI Toyoda, International Advisor to TSC), the PRESERVE 
trial (CI Markus, SRN Writing Group), and in monogenic SVD (Chabriat, SRN Writing Group, 
International Advisor to TSC). UKSRN Prevention CSG strongly supported a trial testing 
cilostazol and ISMN in SVD prevention: many (>80) UK Stroke Research Network Centres 
expressed interest in joining the trial. 
 

 
 
 
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Relevant drugs are available: Although many experts are uncertain of what agents to test in 
lacunar stroke,33, 35 we identified targets with available drugs.10, 16, 41 Other trials are testing BP-
lowering on cognition in patients with combined lacunar stroke and severe WMH (BHF 
PRESERVE, CI Markus, UK). However, other approaches are clearly needed since 
hypertension explains <1.5% of variance in WMH,18 target BP reduction did not prevent stroke 
or cognitive decline in SPS3,35 may increase stroke58 and SVD worsening at older ages.59 There 
is increasing uncertainty about antiplatelet drugs: in SPS3, they increased hazard without 
benefit.33, 37 SVD is now recognised as a major cause of haemorrhagic stroke60 especially at 
older ages.  
 
Experience with cilostazol and ISMN are lacking in Europe: Despite the large amount of 
promising data from the Asia-Pacific region for cilostazol (Figure 1) and in European cardiology 
for ISMN, and both drugs being licensed in Europe for vascular indications with available 
generic forms, there is little experience with cilostazol for vascular disease in Europe or North 
America and little experience of long term administration of ISMN or related nitrate donors in 
any type of stroke. Therefore, information on patient tolerability (e.g. cilostazol and ISMN cause 
headache), safety (e.g. platelet function, postural hypotension, bleeding), markers of efficacy 
(reduction in stroke recurrence), or on whether both drugs can be taken together in full dose, is 
lacking. Information on safety is important given that a) cilostazol will need to be given in 
addition to guideline secondary antiplatelet stroke prevention which might increase bleeding 
(despite little evidence of antiplatelet effects of cilostazol combined with other antiplatelet 
drugs42,33), and b) ISMN may reduce BP leading to postural hypotension and falls or accelerate 
brain white matter damage in older patients, which may concern physicians. Thus information 
on these points is necessary in order to justify a large Phase III trial of cilostazol and/or ISMN 
to prevent stroke and dementia manifestations of SVD and justify further testing of cilostazol 
and/or ISMN.  
 
LACI-1 Pilot trial: The LACI-2 trial design is based on experience gained by the LACI-2 
investigators with cilostazol and ISMN in patients with lacunar ischaemic stroke in a pilot trial 
-1 started recruitment March 2016, is recruiting 60 
patients in two UK centres (Nottingham, Edinburgh), and testing short-term dose escalation 
protocols for cilostazol and ISMN, individually and together, to the dose planned for LACI-2, 
and records tolerability, safety and early markers of efficacy. 
 
Many patients may benefit: If cilostazol and/or ISMN can be administered safely to patients with 
clinical evidence of SVD, and if large scale trials demonstrate that they are effective in 
preventing clinical progression of SVD, then large proportions of patients with stroke and 
dementia will benefit as SVD is such a common cause of these conditions. Up to 35,000 new 
patients per annum with stroke and several million patients with cognitive decline or incipient 
dementia in the UK will benefit each year. Both drugs are licensed in Europe and available in 
generic form, therefore both interventions will be inexpensive to the NHS. Both drugs are taken 
orally, once or twice daily, so are easy to administer. The long-term impact of successful 
treatment is difficult to quantify but potentially, a reduction of 10-20% in the combined stroke, 
cognitive or physical consequences of SVD would benefit several tens of thousands of patients 
per year in the UK.  
 
The present trial aims to determine if either or both cilostazol and ISMN are tolerated at the 
target dose for at least a year, gather data on outcome event rates and provide safety and 
efficacy data. Both drugs cause headache, a marker of vasoreactivity61 that could limit 
tolerance, but as with other side effects (palpitations, nausea), our international advisor 
indicates that these can minimised by starting at half dose, at night, escalating slowly to full 
dose over several weeks. LACI-2 will proceed seamlessly to a larger phase III trial, with 
additional funding, once there is sufficient confidence in trial procedures, event rates and 
recruitment. LACI-2 will also provide methods for balancing randomisation, streamlining of 
follow-up and reliable data on key event rates for lacunar stroke/SVD trials, promoting more 
personalised approaches to brain vascular disease required by the key differences between 
stroke subtypes and their mechanisms. 

 
 
 
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2 
STUDY OBJECTIVES 
2.1 OBJECTIVES 
Our ultimate goal is to prevent progression of cerebral small vessel disease (SVD) and its 
clinical consequences of stroke, dementia and physical disability. We have identified that two 
drugs, licensed for other vascular disease indications, cilostazol and isosorbide mononitrate 
(ISMN), have relevant mechanisms and some promising data that supports testing in an early 
Phase III trial, prior to a large definitive Phase III trial. 
 
The LACunar Intervention Trial-2 (LACI-2) will assess feasibility of recruitment, drug 
tolerability, trial procedures, safety and event rates in at least 400 patients recruited in UK stroke 
centres and followed up for one year. Safety will be assessed in an MR follow-up study as well 
as with clinical outcomes in all patients. Funding to continue LACI-2 into a phase III trial will be 
sought once the initial phases of LACI-2 have provided confidence about estimated event rates 
and hence sample size, recruitment and trial procedures. 
 
Cilostazol and ISMN will need to be administered in addition to guideline therapies (usually 
clopidogrel; antihypertensives; statins). Data on effects on safety outcomes, WMH progression 
and new infarcts on brain MRI, and on recurrent clinical vascular events, cognition, and on trial 
procedures, will help provide confidence that the drugs are safe and testable in this population 
in a large-scale RCT with clinical only endpoints and that such a trial is likely to achieve the 
sample size likely to be required to demonstrate definitively clinically-meaningful reductions in 
SVD progression. 
2.1.1 Primary Objective 
To determine whether a prospective, randomised trial of cilostazol and ISMN in lacunar stroke 
is feasible in the UK, thence proceeding seamlessly to a large phase III trial. 
2.1.2 
Secondary Objectives 
To assess drug tolerability, safety, event and recruitment rates preparatory to a large Phase III 
partial factorial randomised controlled trial to prevent recurrent lacunar stroke, physical and 
cognitive impairment. 
2.2 ENDPOINTS 
2.2.1 Primary Endpoint 
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.  
2.2.2 Secondary Endpoints 
Tolerability - 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). 
Safety - symptoms of systemic or intracranial bleeding, recurrent cerebral and 
systemic vascular events, and vascular and non-vascular causes of death will be 
collected. 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.  
Efficacy  individual event-rate data (stroke, TIA, myocardial ischaemia, cognitive 
impairment and dementia, will be collected. 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. 

 
 
 
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Health Economics  data to assess health economic impact will be gathered. 
3 
STUDY DESIGN 
LACI-2 will be an investigator-led, Phase IIb preparatory to Phase III, prospective, randomised, 
2x2 partial factorial, open label, blinded outcome trial performed in multiple hospital-based 
centres. The schematic in Figure 2 describes the study design. This Phase will test trial 
procedures and feasibility, tolerability of drug, provide safety and intermediary outcome 
endpoints and clinical and cognitive endpoints to power a main Phase III trial which will follow 
seamlessly from LACI-2 with additional funding. Brain imaging with MRI is to be used in 
preference to CT for diagnosis of the index stroke wherever possible, but CT is allowed. 
 
Patients who have all of the following:  
1) suffered a minor stroke with clinical features compatible with a lacunar stroke syndrome 
 
2) on contemporaneous brain imaging have either  
a) on MR imaging, a recent, relevant (in time and location) acute lacunar infarct on 
diffusion MR imaging, or  
b) if no visible acute lacunar infarct on diffusion MR imaging then there may be a 
recent-appearing relevant (in time and location) acute lacunar infarct on FLAIR, T2, 
or T1, and  
c) there will be no competing pathology as a cause for stroke (e.g. no acute cortical 
infarct on diffusion MR imaging or recent-appearing cortical infarct on FLAIR, T2, T1), 
no intra-cerebral haemorrhage, no stroke mimic such as tumour, or subdural 
haematoma); 
d) where CT brain imaging is used soon after stroke instead of MR, a recent relevant 
(in time and location) small subcortical infarct (e.g. that was not present on CT prior 
to the stroke, or that becomes visible on a follow-up scan, if available) and no 
evidence of alternative causes of the stroke symptoms as in 2c above.   
3) capacity to give consent; and  
4) meet inclusion/exclusion criteria below (4.2),  
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.  
 
Patients with contraindications to cilostazol can be randomised to isosorbide mononitrate 
versus no isosorbide mononitrate arms only; patients with contraindications to isosorbide 
mononitrate can be randomised to cilostazol versus no cilostazol arms only. The partial factorial 
design allows testing of both drugs when given alone and together.  
 
The doses will be escalated until participants are on their full dose by 1 month. If a patient 
encounters intolerable side effects at full dose, then they will be able to remain on the highest 
dose regime that they can tolerate and this dose will be recorded. The total duration of the trial 
drug administration will be 1 year.  
 
Note that no maximum time since the index lacunar ischaemic stroke will be set  patients will 
be eligible for the trial for several years after their lacunar stroke at the discretion of the local 
medical staff, as long as the index stroke was compatible with lacunar ischaemic stroke and 
competing pathologies as a cause of the stroke were excluded using contemporaneous MR 
imaging, or CT, as above. That is, that the index stroke was not a non-lacunar stroke, that it 
was ischaemic and not haemorrhagic, and that it was not a non-stroke based on clinical and 
MR imaging, or CT, acquired at the time of the stroke.  
 
Note also that no minimum cut off cognitive score is set. The Montreal Cognitive Assessment 
(MOCA) will be collected at baseline but will not be an inclusion/exclusion criterion. The 
important point is that the patient has capacity to consent, in the opinion of the randomising 
doctor. 
 

 
 
 
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Throughout the trial, patients will continue to take their normal prescribed medication which will 
include stroke secondary prevention prescribed since their event as per national 
guidelines/usual post-stroke care in participating centres.  
 
Four hundred patients will be recruited from UK stroke research network centres. The most 
active of these sites see 10-15 patients per month with suspected lacunar stroke, of whom 25-
33% would be eligible. Some interested sites have indicated that they could randomise 1-2 per 
month. Patients will be recruited from hospital-based stroke services, including patients who 
have participated in previous completed studies and indicated that they would like to be 
informed of future stroke studies.  
 
On entry to the study, participants will be assessed by the study researcher, including 
presenting history, past medical history, medication history, neurological examination, check of 
brain MR or CT scan, blood pressure measurement and cognitive testing. They will then be 
randomised. 
 
Patients will receive a telephone call at 1-2 weeks post randomisation into the study and again 
after 3-4 weeks, with intermediary phone calls as necessary, to ascertain that they have 
escalated the dose and have achieved the full dose or are established on a tolerated dose if 
not the full dose. Further follow up by site or central Trial staff will occur at six months 
(phone/post) and 12 months (obtain MRI, phone/post/in person).  
 
Figure 2. Study flow diagram 
 
 
*Diagnostic MR or CT brain scan assessment 
(Baseline) refers to a visual assessment of the 
scan that has already been performed as part of 
and diagnosis. Features present on the scan are 
scored for their presence and severity to create 
a total sum of small vessel disease score. This is 
used in the minimisation algorithm.  
Dispensing may be at 3-monthly intervals if 
preferred in particular centres. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The patient will return to hospital to collect their next prescription every three or six months and 
for an MRI at 12 months.  
Visit 1 Baseline
Check eligibility
Medical history
Blood pressure    
MR or CT brain assessment*
Cognitive testing
check haematology and biochemistry
End of Week 1 to 2 follow up by phone (site)
Questionnaire about symptoms and tablet compliance
End of Week 3 to 4 follow up by phone (site)
Questionnaire about symptoms and tablet compliance
Consent
Isosorbide 
mononitrate alone
Neither Isosorbide 
mononitrate or 
cilostazol
Randomisation
Cilostazol alone
Isosorbide 
mononitrate and 
cilostazol
Identify eligible patients
12 month postal or phone follow up (ECTU)
Questionnaire about symptoms, tablet compliance, recurrent vascular 
events, modified Rankin Scale, cognition, mood, HRQoL IQCODE
6 month postal or phone follow up (ECTU)
Questionnaire about symptoms, tablet compliance, recurrent vascular 
events, modified Rankin Scale, cognition, mood
Brain MRI 
all 
participants
Issue 6 month trial 
drug supply
Reduce and stop drug and return unused drug to local hospital 
pharmacy
Issue drug 

 
 
 
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After the end of 52 weeks, the patients will reduce the tablets over about two weeks and then 
stop the medication (section 6.2). They will return any unused drug to their local hospital 
pharmacy for tablet counting and then destruction. They will complete participation in the study 
after a final phone call when they are off the medication.  
 
Participants who stop IMP (e.g. through tolerability issues or for medical reasons) will remain 
in the trial in follow-up unless they withdraw consent for further participation in the trial. Patients 
may withdraw consent at any time, in the event of which the trial will not collect further data on 
that patient. Data already collected will be kept and included in the analysis unless participants 
specifically ask for their data not to be included. Study medication maybe withdrawn in line with 
SPC guidelines at any time by the investigator or treating physician if deemed advisable for 
medical reasons, but the patient will remain in follow-up unless they withdraw consent.  
4 
STUDY POPULATION 
4.1 NUMBER OF PARTICIPANTS 
About 400 participants will be recruited from multiple UK sites.  
4.2 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:  
o 
a recent, relevant (in time and location) acute lacunar infarct on diffusion MR 
imaging1,  
o 
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); 
o 
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). 
1Note 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. 
2Note 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 
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 R
) 
 
Capacity to give consent themselves 
 

 
 
 
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4.3 EXCLUSION CRITERIA 
 
4.3.1 General 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.  
 
 
 
Has been diagnosed as having dementia on formal clinical assessment 
 
Diagnosis of hypotension, defined as sitting systolic blood pressure less than 
100mmHg 
 
Unable to swallow tablets  
 
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 
 
(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. 
 
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 
-2. 
 
Unable to tolerate MRI or contraindication to MRI (Claustrophobia, Pacemaker) 
 
4.3.2 Cilostazol exclusion criteria (still allows randomisation to ISMN) 
 
Definite indication for (i.e. already prescribed) Cilostazol, or definite contraindication to 
Cilostazol as per SPCs. 
 
Prohibited medications to Cilostazol (see sections 4.5 of the appended SPCs and 
protocol section 6.6.3, plus no anticoagulant drugs). 
 
Active cardiac disease (atrial fibrillation, myocardial infarction in past 6 months, active 
angina, symptomatic cardiac failure). 
 
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). 
 
4.3.3 ISMN exclusion criteria (still allows randomisation to Cilostazol) 
 
Definite indication for (i.e. already prescribed) ISMN, or definite contraindication to 
ISMN as per SPCs. 
 
Prohibited medications to ISMN (see sections 4.5 of the appended SPCs and protocol 
section 6.6.3). 
 

 
 
 
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4.4 CO-ENROLMENT 
If a participant has already been enrolled into another CTIMP, they cannot be enrolled 
into this trial. If a patient is enrolled into LACI-2, they may not subsequently be enrolled 
into another CTIMP whilst they are randomised and participating in LACI-2.  
Inclusion in another non-CTIMP research study is permissible as long as the Chief Investigators 
of both studies and the Sponsor have agreed to co-enrolment  (see ACCORD guideline: 
http://www.accord.scot/sites/default/files/GL001%20Guidelines%20for%20Co-
Enrolment%20v2.0.pdf). 
5 
PARTICIPANT SELECTION AND ENROLMENT 
5.1 IDENTIFYING PARTICIPANTS 
Participants will be recruited from stroke services in participating NIHR Clinical Research 
Network sites. This will include patients presenting for the first time with a new stroke or 
recurrent stroke and patients who presented to the stroke services of participating sites in the 
past. Furthermore, participants will be recruited from existing registries, studies and trials where 
participants remain in long term contact, meet eligibility criteria, and have indicated that they 
are willing to be contacted about new studies.  
 
Patients under the care of the stroke services will initially be approached by a member of the 
-lead clinical care team (which includes the researcher teams at 
some locations). This initial contact will take place in person, by phone or by post following local 
clinical practice. The member of the clinical care team will inform the patient about the trial and 
provide them with the Information Sheet. If, after reviewing the Information sheet, the patient 
expresses an interest and requests further information, s/he will then be contacted directly by 
a member of the research team. Patients from existing registries (including National Databases 
such as SHARE), studies and trials will only be contacted by researchers if they previously 
indicated that they were happy to receive information about new studies, via approved SHARE 
or relevant procedures. 
 
The investigator or their nominee will inform the patient of all aspects pertaining to participation 
in the trial. It will be explained to the potential participant that entry into the trial is entirely 
voluntary and that their treatment and care will not be affected by their decision. It will also be 
explained that they can withdraw at any time. In the event of their withdrawal it will be 
determined if the patient agrees that the data collected so far can be retained in the trial 
analyses where appropriate so as not to jeopardise the scientific credibility of the trial. The 
discussion of the trial and preferred method of co
Patients will be given as much time as they require (at least 24 hours) to consider the trial 
information before deciding whether to join the trial or not. After allowing time for consideration, 
patients will be contacted by a member of the research team (clinical research fellow or 
research nurse) using their preferred contact method to find out if they are interested or not. 
Patients who are interested will be invited to attend for the first assessment visit and an 
appointment arranged. 
 
5.2 CONSENTING PARTICIPANTS 
Patients will give informed written consent upon entry to the trial (baseline), prior to any trial 
related procedures taking place. The decision to participate in clinical research is voluntary and 
should only be based on a clear understanding of what is involved.  
 
Consent will only be taken from the patient. Patients unable to give consent for any reason will 
be excluded, including those considered to lack capacity by medical staff. Patients who are 
found to have an exclusion criterion after consent but before randomisation, will be recorded as 
population, will be excluded from the primary analysis and will not be followed for AEs. 
 

 
 
 
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Consent will be obtained by Good Clinical Practice trained staff who are members of the clinical 
research team after full discussion of the trial procedures and requirements with the patient. 
The Investigator or designated person is responsible for ensuring that the consent form is 
completed, signed and dated by all parties prior to any protocol specific procedures being 
carried out. Participants must receive adequate oral and written information 
 appropriate 
Participant Information Sheet (PIS) and Informed Consent Form (ICF) will be provided. The oral 
explanation to the participant should be performed by the Investigator or designated person, 
and must cover all elements specified in the PIS/ICF. The participant must be given every 
opportunity to clarify any points that they do not understand and, if necessary, ask for more 
information. It should be emphasised that the participant may withdraw their consent to 
participate at any time without loss of clinical care benefits to which he/she would be entitled.  
 
The participant will be asked for their permission to contact a relative/partner/carer in case of 
difficulty in contacting themselves during follow-up and who could and would be willing to 
provide information about the participant during follow-up in the event that the participant 
themselves becomes incapacitated and unable to provide the information during the course of 
the trial. If there is no suitable relative/partner/carer, or the participant is not willing to have such 
a person approached, then they can still participate in the trial and their wishes will be noted in 
the site file, hospital notes and eCRF. An information sheet and consent form about the trial for 
relatives/partners/carers will be given to the participant, or posted or given directly to the 
relative/partner/carer if accompanying the participant, at the start of the trial. At this point 
relatives/partners/carers contact details will be stored in the site files only. Consent from the 
relative/partner/carer for central storage of their contact details and their involvement in the trial 
will be sought. If consent is given the 
secure, encrypted, password-protected database linked to the participant number, enabling the 
follow-up to be done centrally. The absence of a nominated informant will not be counted as a 
protocol deviation or violation. A 12 month follow-up pack will be posted to the 
relative/partner/carer. This will contain a covering letter, the Informant Questionnaire on 
Cognitive Decline in the Elderly, IQCODE and a prepaid envelope for return. The 
relative/partner/carer will be asked to complete and return the questionnaire. It is their decision 
as to whether they complete the form or not. Data may be collected by phone from the relative 
if the questionnaire is not returned, unless the relative/partner/carer has not agreed to this.   
 
The participant should be informed and agree to their medical records being inspected by 
regulatory authorities and representatives of the sponsor. They should also be informed about 
and agree to the possibility of further analyses of the trial data (anonymised) as new relevant 
questions arise,  the contribution of the data to individual  patient data meta-analyses and the 
need to make the trial dataset publicly available as per research funder requirements.  
 
records. The Investigator or delegated member of the trial team and the participant should sign 
and date the ICF(s) to confirm that consent has been obtained. The participant should receive 
(a PDF will be 
uploaded to the medical record on sites where medical records are only held electronically) and 
the original filed in the Investigator Site File (ISF). Full details of the consent process should 
completed consent form.  
5.3 SCREENING FOR ELIGIBILITY 
Following consent, the research doctor will confirm that the patient is eligible to participate in 
the trial as per the inclusion/exclusion criteria.  Eligibility will be documented by the PI (or a 
medically qualified doctor who has been delegated this role) 
The baseline information required for randomisation will be recorded in the eCRF. 

 
 
 
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5.4 INELIGIBLE AND NON-RECRUITED PARTICIPANTS 
Participants who have been approached for the study and subsequently found to be ineligible 
will be informed of the reasons why and continue under the care of their stroke physician. 
Screening logs will not be used as part of the data collection for this study.  
5.5 RANDOMISATION 
5.5.1 Randomisation Procedures 
The electronic randomisation system and trial database are hosted by the University of 
Nottingham. Randomisation involves minimisation on key prognostic factors including: age, 
sex, stroke severity (NIHSS), dependency resulting from the stroke, systolic blood pressure 
smoker status, time after stroke, years of education. Years of education give an 
estimate of pre-morbid cognitive ability and predicts post-stroke cognitive impairment; BP and 
smoking predict recurrent stroke; delay since stroke reflects disease activity; age, sex and 
stroke severity are standard minimisation variables. This approach ensures concealment of 
allocation (note allocation concealment means that it is not possible to guess which treatment 
the next patient will be randomised to), minimises differences in key baseline prognostic 
variables, and improves statistical power. Randomisation will not be minimised by Centre 
because this may result in high rates of allocation prediction, but a pre-specified post-hoc 
analysis by centre will be performed to investigate and adjust for heterogeneity of treatment 
effect by centre. 
 
Randomisation will allocate a trial treatment, which will be prepared by the local participating 
Pharmacy. 
 
Note that randomisation will be performed during normal office hours (09.00  17.00) and the 
trial allows for randomisation to occur months or years after the stroke. Therefore, in the event 
of computer failure (for example: server failure), the investigator will wait until the computer 
system is re-established to perform the randomisation. Normally, this would only be a few 
minutes to two hours. However, if this delay requires the patient to return on a separate 
occasion to collect the drugs, then a separate appoint
expenses covered as per other trial visits.   
 
Patients will be randomised to one of the following at a 1:1 ratio as per Section 6.2: 
 
 
cilostazol versus no cilostazol 
 
isosorbide mononitrate versus no isosorbide mononitrate 
resulting in a partial factorial comparison of cilostazol versus isosorbide mononitrate versus 
both drugs versus neither drug. 
 
The randomisation algorithm will allocate a unique identifier which will be used to label the 
treatment pack containing the appropriate drug made up for the patient and dispensed by the 
local Pharmacy.  
 
Participants with an indication for or contraindication to one of the trial drugs may still be 
randomised to the other trial drug. If a participant allocated to both trial drugs develops a 
contraindication to one of the trial drugs after randomisation into the trial, then they should 
discontinue that drug but continue to take the other trial drug. If a patient has to discontinue 
either or both drugs, they should continue to be followed up in the trial as planned (unless they 
withdraw from the trial). Patients should remain in follow up until the end of the trial follow up 
period, even if they discontinue trial drug, unless they withdraw from the trial. 
 
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, structured 
symptom questionnaires, ascertainment of clinical outcomes and MRI analysis will be collected 
by individuals blinded to treatment allocation.  
 

 
 
 
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Treatment Allocation: Participants randomised to start drug will be provided with their allocated 
drug/s after randomisation at the baseline visit, which they will start on the next day (i.e. day 1, 
week 1). In the event that there is any delay between receiving the trial tablets and starting the 
treatment, then the patient will receive a reminder telephone call shortly before the day that the 
medication should be commenced. The first day of treatment defines day 1, week 1.  
 
Participants will be supplied with trial tablets from the hospital pharmacy to cover a maximum 
period of six months. Detailed dated instructions on dosing will be provided in the patient pack. 
The participant will be telephoned between the end of weeks 1 and 2 and between the end of 
weeks 3 and 4, and other times during drug introduction as necessary, as well as follow-up time 
points, to ensure they are taking the medication correctly.  
 
Drugs will be provided in their packs as marketed and licensed (i.e unaltered) and dispensed 
by the participating hospital pharmacy under research protocols.  
 
5.5.2 Emergency Unblinding Procedures 
If the patient develops a contraindication to the trial medications, the medication should be 
stopped in line with SPC guidance. Similarly if the patient develops a definite indication for the 
trial medications the study medications should be stopped as per the SPC. 
 
As this is an open label trial, there should be no need to unblind the allocated treatment. If some 
contraindication to cilostazol or ISMN develops after randomisation, the trial treatment should 
simply be stopped as per SPC guidance. If identification of the trial drug is considered 
necessary, the tablets can simply be examined and identified as cilostazol or ISMN as they will 
be dispensed in their licensed packaging.  
5.5.3 Withdrawal of Study Participants 
Participants may withdraw consent at any point. Where participants agree, we will retain the 
data collected up to the point of withdrawal for analysis. If the participant is willing, we will record 
the reason for withdrawal. Trial medication may be stopped at any time by the investigator or 
treating physician if deemed advisable. Stopping trial medication on its own does not 
necessarily equate with withdrawal from the trial, and follow-up procedures will continue unless 
the participant withdraws consent. If after randomisation into LACI-2, a participant subsequently 
is found to have a condition which would have made them ineligible for recruitment, these 
participants will be retained in the trial, at least for the purposes of follow-up, to protect the 
e of analysis, and a decision for the continuation of the IMP will be 
made by the Principal Investigator with the participant or their relatives in the event of loss of 
capacity on the basis of safety. A recurrent event, such as stroke or other outcome, is not of 
itself a reason for withdrawal 
trial medication and participation in the event that they lose capacity during the trial will be 
documented in the trial consent form. 
 
 

 
 
 
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6 
INVESTIGATIONAL MEDICINAL PRODUCTS  
6.1 STUDY DRUGS 
 
The IMP is defined by the active substance only, therefore all authorised brands may be used. 
Oral cilostazol or isosorbide mononitrate slow release will be prescribed as per the brand 
available in the participating hospital pharmacy. Most isosorbide mononitrate preparations are 
slow release in the UK however, in pharmacies where slow release preparations of isosorbide 
mononitrate are not available, then non-slow release preparations may be used. 
Several doses and brands of these drugs are marketed in the UK, examples are given below. 
Oral Cilostazol 100mg tables, Generics [UK] Ltd t/a Mylan, Station Close, Potters Bar, 
Hertfordshire, EN6 1TL, United Kingdom. (http://www.mylan.co.uk)  
 
Oral Isotard® 25 mg XL (Isosorbide Mononitrate) tablets, Kyowa Kirin Limited, 3 Galabank 
Business Park, Queen Street, Galashiels, TD1 1QH, United Kingdom. (http://www.kyowa-
kirin.com/kkr/) 
 
Isosorbide mononitrate (ISMN) 20mg, Pharmavit Ltd, 177 Bilton Road, Perivale, Greenford, 
Middlesex, UB6 7HQ (http://www.pharmavit.eu)  
 
Cilostazol and ISMN are both licensed products for treatment of vascular diseases in Europe 
and the example summaries of the product characteristics are appended to this trial protocol. 
 
6.1.1 Study Drug Identification 
The IMP is defined by the active substance only, therefore all authorised brands may be used. 
 
Cilostazol, generic, as 50mg or 100mg tablets. 
 
Isosorbide mononitrate slow release, generic, for example as 25mg XL or 50mg XL tablets to 
the suggested target dose of 40-60mg daily.  
 
Isosorbide mononitrate, generic, as 20mg tablets to the suggested target dose of 40-60mg 
daily.  
 
Most isosorbide mononitrate preparations are slow release in the UK. However, where slow 
release preparations of isosorbide mononitrate are not available, then non-slow release 
preparations may be used, but the dose should be split half in the morning (e.g. 08.00 am) and 
half in the evening (e.g. 18.00hrs). Non-slow release preparations may only be available in 
20mg tablets in which case the 20mg should be substituted for the 25mg dose. A target dose 
of ISMN is 40-60mg daily. Detailed prescribing and administration instructions will be provided 
in the treatment pack. 
 
6.1.2 Study Drug Manufacturer 
Details of one manufacturer of each of the trial drugs are given below. All drugs are available 
from several providers in the UK. Pharmacies may provide the brand of each drug that is 
available to them, i.e. a specific brand is not required for the trial. Example manufacturers are: 

 
 
 
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Oral Cilostazol 100mg tables are manufactured by Generics [UK] Ltd t/a Mylan, Station Close, 
Potters Bar, Hertfordshire, EN6 1TL, United Kingdom. (http://www.mylan.co.uk). 
 
Oral Isotard® 25 mg XL (Isosorbide Mononitrate) tablets are manufactured by Kyona Kirin 
Limited, 3 Galabank Business Park, Queen Street, Galashiels, TD1 1QH, United Kingdom. 
(http://www.kyowa-kirin.com/kkr) 
 
Isosorbide mononitrate (ISMN) 20mg are manufactured by Pharmavit Ltd, 177 Bilton Road, 
Perivale, Greenford, Middlesex, UB6 7HQ (http://www.pharmavit.eu)  
 
6.1.3 Marketing Authorisation Holder 
Details of one marketing authorisation holder of each of the trial drugs are given below. 
 
Cilostazol 100mg tables - Generics [UK] Ltd t/a Mylan, Station Close, Potters Bar, Hertfordshire, 
EN6 1TL, United Kingdom, under marketing authorisation number PL 04569/1426. 
 
Isotard® 25 mg XL tablets  Kyowa Kirin Limited, 3 Galabank Business Park, Queen Street, 
Galashiels, TD1 1QH, United Kingdom, under marketing authorisation number PL 16508/0018. 
 
Isosorbide mononitrate (ISMN) 20mg tablets - Pharmavit Ltd, 177 Bilton Road, Perivale, 
Greenford, Middlesex, UB6 7HQ (http://www.pharmavit.eu) under marketing authorisation 
number PL 04556/0057.. 
 
6.1.4 Labelling and Packaging 
The IMP will be clearly labelled for clinical trial use only. 
be displayed on the treatment pack. 
 
Each pack will be labelled in accordance with Annex 13 of Volume 4 of The Rules Governing 
Medicinal Products in the EU: Good Manufacturing Practices, with the primary and secondary 
packaging remain together throughout the trial.  
 
Detailed prescribing and administration instructions will be provided with the treatment pack. 
Dose initiation in first 2-4 weeks will be guided by a regular phone calls and instructions. 
6.1.5 Storage 
The trial drugs will be stored in participating hospital pharmacies as per requirements for the 
branded products. They will be stored in a restricted access area where temperature is 
monitored and maintained below 25 C. Stability data exist which demonstrates that cilostazol 
is stable for 3 years without temperature restrictions. ISMN is stable for 3 years at temperatures 
below 25°C.  
6.2 DOSING REGIME 
Patients will be supplied with trial drug in its usual (marketing) packaging unaltered. Patients 
will be issued with instructions reflecting the allocated dosing schedule which will instruct them 
what tablets they have to take initially and how to increase the dose. They will receive a phone 
call after 1 to 2 and 3 to 4 weeks as per schedule below to guide dose escalation. If a patient 
encounters intolerable side effects they will be asked to return to the highest previously 
tolerated dose and this will be recorded in the eCRF and hospital notes. They will be given clear 
instructions by phone or in person (depending on the stage of the trial). Patients will also receive 
instruction on how they should decrease the dose of trial drug incrementally at the end of the 
study. 
 
 
 
 

 
 
 
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Table 1: Patients randomised to Isosorbide Mononitrate alone - either XL or non-XL preparations, example 
 
If a slow release preparation is not available, then a non-slow release preparation may be used, but the dose should 
be given half in the morning (eg 08.00 am) and half in the evening (eg 18.00hrs) 
 
 
ISMN non-XL Dosing Regime 
Day 
ISMN non-XL 20mg 
Morning 
Evening 
1-5 
nil 
20mg 
6-10 
20mg 
20mg 
11-15 
20mg 
20mg 
16-20 
20mg 
20mg 
At end of study 
Week 
Morning 
Evening 
53 
20mg 
Nil 
54 
Nil 
Nil 
 
Table 2: Patients randomised to cilostazol alone 
 
Cilostazol Dosing Regime 
Day 
Cilostazol 
Morning 
Evening 
1-5 
Nil 
50mg 
6-10 
50mg 
50mg 
11-15 
50mg 
100mg 
16-20 
100mg 
100mg 
At end of study 
Week 
Morning 
Evening 
53 
50mg 
50mg 
54 
Nil 
Nil 
 
Table 3: Patients randomised to both Isosorbide Mononitrate and Cilostazol 
 
 
ISMN XL/Cilostazol Dosing Regime 
Day 
Isosorbide Mononitrate XL 25mg 
Cilostazol 
Morning 
Evening 
Morning 
Evening 
1-5 
25mg 
nil 
Nil 
Nil 
6-10 
50mg 
nil 
Nil 
Nil 
11-15 
50mg 
nil 
Nil 
50mg 
16- 20 
50mg 
nil 
50mg 
50mg 
21-25 
50mg 
nil 
50mg 
100mg 
26-30 
50mg 
nil 
100mg 
100mg 
At end of study 
Week 
Morning 
Evening 
Morning 
Evening 
53 
25mg 
Nil 
50mg 
50mg 
54 
Nil 
Nil 
Nil 
Nil 
 ISMN XL Dosing Regime 
Day 
ISMN XL 25mg 
Morning 
Evening 
1-5 
25mg 
nil 
6-10 
50mg 
nil 
11-15 
50mg 
nil 
16-20 
50mg 
nil 
At end of study 
Week 
Morning 
Evening 
53 
25mg 
Nil 
54 
Nil 
Nil 

 
 
 
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ISMN non-XL/Cilostazol Dosing Regime 
Day 
Isosorbide Mononitrate 20mg 
Cilostazol 
Morning 
Evening 
Morning 
Evening 
1-5 
nil 
20mg 
Nil 
Nil 
6-10 
20mg 
20mg 
Nil 
Nil 
11-15 
20mg 
20mg 
Nil 
50mg 
16- 20 
20mg 
20mg 
50mg 
50mg 
21-25 
20mg 
20mg 
50mg 
100mg 
26-30 
20mg 
20mg 
100mg 
100mg 
At end of study 
Week 
Morning 
Evening 
Morning 
Evening 
53 
20mg 
Nil 
50mg 
50mg 
54 
Nil 
Nil 
Nil 
Nil 
 
Table 4: Patients randomised to neither Isosorbide Mononitrate or Cilostazol 
 
Neither ISMN/Cilostazol Dosing Regime 
Day 
Isosorbide Mononitrate 
Cilostazol 
Morning 
Evening 
Morning 
Evening 
1-4 
Nil 
Nil 
Nil 
Nil 
5-8 
Nil 
Nil 
Nil 
Nil 
9-12 
Nil 
Nil 
Nil 
Nil 
13, 14 
Nil 
Nil 
Nil 
Nil 
At end of study 
Week 
Morning 
Evening 
Morning 
Evening 
53 
Nil 
Nil 
Nil 
Nil 
54 
Nil 
Nil 
Nil 
Nil 
 
6.3 DOSE CHANGES 
Doses will be initiated as per the example regime in section 6.2. Patients will be allowed to 
increment the dose more slowly, or to stay at a previously tolerated dose where their symptoms 
preclude reaching the target dose stated in 6.2. Variation of dose like this will not count as a 
protocol deviation. Patients will be able to stay on the dose they can tolerate. If necessary, this 
will be done under close guidance of the researcher. There will be no other changes to the 
doses described in section 6.2. 
6.4 PARTICIPANT COMPLIANCE 
Adherence and the tolerability of these treatments is a key outcome measure as part of the trial 
feasibility assessment. Symptoms related to taking either drug will be assessed using a 
structured questionnaire given as per schedule and the patient will be asked if they are 
continuing to take the medication at each review of symptoms.  
As indicated in 7.1 below, during the start-up phase, patients will be asked to contact the local 
PI or delegated research nurse if they experience adverse symptoms, or trial help line should 
neither of the above be available. Once patients are established on their steady dose of tablets, 
they will be asked to inform the trial team via the help line or contact their local PI if they 
experience untoward symptoms (in addition to contacting their GP or other relevant hospital 
service). Such episodes of contact will be recorded in the eCRF or AE form or reported as SAEs 
as appropriate. 
 

 
 
 
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Patients will be asked to return any unused tablets to the hospital pharmacy that provided the 
tablets at six and 12 months. Pharmacy will submit a tablet count to the eCRF. 
6.5 OVERDOSE 
Cilostazol: The SPC for Cilostazol states that there is limited information on the effects of acute 
overdose in humans. It is anticipated to feature severe headache, diarrhoea, tachycardia and 
possibly cardiac arrhythmia. Management would be supportive care and gastric lavage as 
appropriate. 
 
Isosorbide Mononitrate: The SPC describes the expected effects of isosorbide mononitrate 
in overdose and details measures for management. 
 
The risk of overdose will be minimised by excluding patients with a history of overdose or 
suicide, or significant active mental health problems. 
6.6 OTHER MEDICATIONS 
6.6.1 Non-Investigational Medicinal Products 
Not applicable 
6.6.2 Permitted Medications 
Patients may continue to take all usual prescribed medication during the study except those 
listed in 6.6.3 and in the exclusion criteria. 
6.6.3 Prohibited Medications 
Isosorbide mononitrate:  
 
 
Cilostazol: 
 
Other strong inhibitors of metabolic enzymes CYP3A4 or CYP2C19 (e.g. diltiazem). 
 
Erythromycin, clarithromycin, ketoconazole, itraconazole, omeprazole  
 
Dual antiplatelet drugs (e.g. aspirin and clopidogrel simultaneously) 
 
Anticoagulants (warfarin, heparin, dabigatran, rivaroxaban, apixaban)  
 
Although not noted in the BNF, SPCs for cilostazol indicate caution is advised with other strong 
inhibitors of metabolic enzymes CYP3A4 or CYP2C19, such as simvastatin, atorvastatin, 
lovastatin, carbamazepine, phenytoin, rifampicin. BNF notes caution with isosorbide 
mononitrate and hypotensive agents such as diltiazem, hydralazine, etc. 
Please refer to the SPCs for full details. 
7 
STUDY ASSESSMENTS 
7.1 SAFETY ASSESSMENTS 
Patients will be encouraged to contact the Trial team if, after randomisation, they have any 
concerns at all about the study drugs, their stroke, if they develop symptoms suggestive of a 
recurrent vascular event, if they become cognitively impaired or have another medical problem. 
 
Patients will be assessed at 1-2-weekly intervals in the first month and six monthly intervals as 
per Study Flow diagram and Section 7.2 for the presence of any symptoms related to taking 
the trial drugs. This will include a structured questionnaire to assess for headache, dizziness, 
palpitations, bleeding, recurrent neurological or cardiac symptoms as outcome events that are 
also common after stroke, and adherence to medication. 
7.2 STUDY ASSESSMENTS 
Study assessments are shown in Table 5 below, and in Figure 2.  

 
 
 
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Table 5: Study Assessments 
Assessment 
Prior to 
Baseline
Visit 1 
Baseline
 Week 
1-2 FU
Week 
3-4 FU
 6 
month 
FU 
 12 
month 
FU 
Screening for eligibility and Consent1;  
XS 
 
 
 
 
 
Confirm and document ongoing consent  
 
XS 
 
 
 
 
Medical including drug history 
 
XS 
 
 
 
 
Assess MR or CT diagnostic scan and send a copy to 
Edinburgh 
 
XS 
 
 
 
 
Randomisation 
 
XS 
 
 
 
 
Haematology (full blood count) and Biochemistry 
(urea, electrolytes, creatinine)  most recent value 
obtained since time of index stroke is acceptable 
unless clinical reason to expect change  
 
XS 
 
 
 
 
Blood Pressure recorded 
 
XS 
 
 
 
XS,* 
Cognitive test: document years of education;  
Montreal Cognitive Assessment (MOCA) 
 
XS 
 
 
 
 
Timed Trail Making Test B 
 
XS 
 
 
 
XS,* 
Dispense trial medication2 
 
XS 
 
 
XS 
 
Structured questionnaire: symptoms; medication 
history and IMP tablet adherence 
 
 
XS 
XS 
XC 
XC 
Structured Q: recurrent vascular events, mRS, TICS, 
TMOCA, SIS, ZUNG 
 
 
 
 
XC 
XC 
Obtain IQCODE (post/phone) from relative 
 
 
 
 
 
XC 
Follow-up brain MRI 
 
 
 
 
 
XS 
Health Economics data: EQ-5D-5L, EQ-VAS 
 
 
 
 
 
XC 
Adverse event / con meds reporting as necessary 
 
 
XS 
XS 
XS,C 
XS,C 
1Consent will be obtained before the data collection procedures commence or randomisation is performed. 
Randomisation occurs at the end of the baseline visit. *at 12 months in some centres only. 2 Dispensing in 3-monthly 
intervals is allowed. SAssessment performed by local site team. CAssessment performed by blinded assessor who is 
part of the central trial team. 
SIS=Stroke Impact Scale, TICS= Telephone Interview for Cognitive Status, TMOCA= telephone MOCA.  
Medical history: Will be performed by the study researcher and will include details of incident 
stroke, past medical history, vascular risk factors, medication history and years of education. 
 
Baseline brain MR (preferred wherever possible) or CT: To identify the index stroke or 
exclude other causes of symptoms, and assess the burden of SVD  this is the clinical scan 
with T2, FLAIR, T1, T2* and diffusion imaging or CT obtained soon after the presentation with 
stroke that shows either:  
-  a recent, relevant (in time and location) acute lacunar infarct,  
- or, if no visible acute lacunar infarct, there is no competing pathology as a cause for stroke 
(e.g. no acute cortical infarct, no acute lacunar or cortical intra-cerebral haemorrhage, no stroke 
mimic such as tumour, subdural haematoma). Scans will be sent for central reading.  
 
Cognitive baseline testing: Patients will be assessed at baseline using the Montreal Cognitive 
Assessment (MoCA), the timed Trail Making Test B for processing speed/executive function, 
and ZUNG for mood. Their years in full time education will be recorded. 
 
Symptoms and adverse effects: Will be assessed using a structured validated questionnaire 
to assess for recurrent neurological symptoms and whether these meet clinical criteria for TIA 
or stroke,  angina or MI, peripheral vascular disease (and details thereof), headache, dizziness, 

 
 
 
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palpitations, altered bowel habit, and adherence to medication, and if any other symptoms have 
occurred. The patient will be asked whether were severe enough to interfere with normal daily 
activities. Patients will also be able to report any other symptoms and describe them in detail. 
Depending on the time point in the study this will either be completed face to face at a study 
visit or by telephone. 
 
Tablet adherence: Will be assessed by asking the patient about their medication usage and 
recording the details in the eCRF. In addition, patients will be asked to return any packs of 
unused tablets to the hospital pharmacy at the end of the trial. All returned tablets will be 
counted at Pharmacy and then be destroyed. 
 
Blood pressure: Will be assessed using a validated clinical instrument that meets British 
Hypertension Society standards. 
 
Haematology and biochemistry: Full blood count, urea and electrolytes and renal function 
will be obtained from the most recent sample obtained since the time of the index stroke. If 
there is a clinical reason to expect change in which case the full blood count and biochemistry 
should be repeated prior to randomisation. These samples will be analysed in the hospital 
haematology or biochemistry labs in the centre in which the patient has been recruited. 
 
Neurological outcomes: Information on recurrent stroke, TIA, angina, MI, PVD will be 
assessed by postal or phone questionnaire at 6 and 12 months. Patients will be encouraged to 
seek medical advice if they develop new neurological events during the trial. 
 
Functional outcome: modified Rankin Scale to assess dependency at 6 and 12 months. If 
participants are unable to be contacted, the central assessor will obtain the most recent 
modified Rankin Score from the local staff (if available).  
 
Cognitive outcomes: Telephone MOCA, Telephone Interview for Cognitive Status (TICS), 
mobility and physical functioning sections of the Stroke Impact Scale and the ZUNG will be 
collected remotely at six and 12 months by the central trial team. TRAILS B will be repeated 
when attending for 1 year MR in Centres that are able to do this. TICS will be collected for 
consistency with prior and ongoing trials (ENOS, TARDIS, RIGHT 2, TICH) and good 
comparability.62 TMOCA will be collected for comparison with TICS for potential use in future 
trials as it purports to assess executive function more than TICS. IQCODE will be collected from 
the relative/partner/carer by post or phone. 
 
Health economics: EQ-5D-5L, EQ-VAS, return to work, hospitalisation, need for long term 
supportive care will be collected at 12 months. 
 
Follow-up Brain MRI: all patients will have repeat brain MRI at 12 months to assess burden 
of WMH, microbleeds, lacunes, new infarcts or haemorrhage and atrophy and where feasible 
to assess diffusion tensor tissue parameters. These scans will be sent to Edinburgh for central 
blinded adjudication.  
 
Follow-up at 6 and 12 months will be by post and telephone, blinded to allocated treatment.A 
trained assessor who is part of the central trial team and based either at the University of 
Edinburgh or University of Nottingham and who is blinded to treatment and baseline clinical 
information, will first confirm with the GP that the participant is contactable. They will then 
contact the patient or carer by post and phone to administer the questionnaires following a 
standardised script.  
 
In addition to the assessments detailed above, participants will receive one to five informal 
contacts over the duration of their trial participation.  One will consist of a participant newsletter 
and any other informal contacts will be a brief phone call or additional participant newsletter. 
During those contacts, a member of the central or site teams will update participants on the trial 
status, thank them for their continued help with the study, and give them an opportunity to ask 
questions. 

 
 
 
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8 
DATA COLLECTION 
Please see section 7.2 above for measurements and time points.  
 
The medical history, cognitive assessment, and structured questionnaire for symptoms and 
adverse events will be obtained from the patient in person (and medical notes where necessary) 
and by telephone by the study researcher after appropriate training as required and entered 
into the electronic case record form. These researchers will also measure blood pressure, 
obtain blood samples for haematology and biochemistry as necessary (analysed in the hospital 
NHS haematology or biochemistry labs in the centre in which the patient has been recruited).  
 
The researcher at each site will co-ordinate the appointment for one year MRI. A reminder that 
the MRI appointment is due will be sent by the Trial Co-ordinating Centre. The MRI will be 
performed in approved radiology departments using sequences specified for the trial.  
 
All baseline medical, cognitive, scanning and laboratory data will be entered into a secure 
password protected electronic case record form (eCRF) run from the University of Nottingham, 
accessible to approved research staff for data entry. The data from central reading of MRI will 
be added to the eCRF data for statistical analysis. Participant and relative/carer contact details, 
required to perform Trial follow-up, will be stored in an encrypted secure password-protected 
database also provided by the University of Nottingham, separate to the Trial eCRF database, 
and only accessible to selected researchers in the Trials Unit, University of Edinburgh and the 
University of Nottingham. 
 
Paper versions of the CRF (i.e. source data sheet) will be available to assist with data collection 
when interviewing patients at baseline and during follow-up visits in phone or in person. Paper 
-based folder and held in a secure locked filing cabinet 
at site. 
 
The MR or CT brain images obtained at diagnosis of the stroke and 1 year follow-up MRI will 
be anonymised and sent to Edinburgh where they will be assessed and quantified for the index 
stroke, features of small vessel disease and other features, using validated scores and volume 
measurements by an experienced rater. Images will only be identified by study ID.  
 
Questionnaires will be checked for completeness and any queries resolved by phone. 
Telephone follow-up will be used to minimise missing data. All paper forms will be stored in a 
secure locked facility after data have been entered onto the eCRF. 
 
9 
STATISTICS AND DATA ANALYSIS 
9.1 SAMPLE SIZE CALCULATION 
There are few data on which to base sample size. There is little experience with cilostazol in 
Europe or North America, and little experience with ISMN in this group of patients in the UK (or 
in any patients with stroke). We have been guided by colleagues in Japan where cilostazol is 
in common use and there is experience with it in stroke. The main purposes of the trial are to 
assess tolerability and safety. 
 
Table 6 Annual absolute risks (%) of outcome events after lacunar stroke 
Vascular 
death 
Non-vasc 
death 
Non-fatal 
isch stroke 
or TIA 
Non-fatal 
ICH 
MI 
MACE
Dependent 
(mRS 3-5) 
Any cogn
impt. 
Dementia
 
1.8 
0.5 
2.5 
0.5 
0.6 
3 
15 
30 
15 
 
We calculated mean annual event rates (Table 6) from trials (SPS3,33 lacunar patients in 
ENOS50 IST-3,63 of cilostazol, Figure 1) and observational data (LADIS;64 our4, 65 and other66 

 
 
 
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studies). We expect deaths including vascular deaths of median 2.0% p.a., with 4% being the 
upper 95% CI of 2% in 400 patients.33 LACI-2 therefore has a sample size of 400.  
 
For a main Phase III trial, recurrent stroke 2.5%pa, MI 0.6%pa and vascular death 1.8%pa,4, 33 
(MACE) are infrequent; new cognitive impairment c16% at one year,6, 66 dependency 15%, are 
frequent and important to patients, justifying their inclusion in a composite primary outcome. 
However, these event rates are imprecise with wide ranges; more precise estimates are 
needed. We estimate main Phase III trial sample size at 1100 (Table 7), assuming 80% power, 
alpha 5%, 10% loss to follow-up, composite event rate (45%) and conservative estimate of 
cilostazol effect (20% RRR is the lower 95% CI of effect, Figure 1). A primary outcome including 
MRI SVD progression (A, below) was considered but at least 15% of patients miss repeat MRI, 
sample sizes were similar (or larger, due to variance in WMH change65 short term), the cost is 
much higher and the WMH intermediary measure is less relevant to patients.  
 
Table 7. Sample size for composite outcome in main trial, estimated event rates. 
Composite model 
A 
B 
Ci 
Cii 
D 
Composite outcome 
for Phase III 
includes: 
MACE, 
dementia, non-
vasc death, new 
MR signs 
MACE, 
dementia, 
death 
MACE, cog , 
dependency , 
death 
 
MACE, cog 
imp, depend, 
all death 
1-beta (power) 
80% 
80% 
80% 
80% 
80% 
Event rate, control, 
pa 
50% 
10% 
30% 
30% 
45% 
Relative risk 
reduction 
20% 
20% 
20% 
30% 
20% 
Event rate, active, pa
40% 
8% 
24% 
21% 
36% 
Total sample size 
950 
6626 
1784 
778 
976 
Total trial size, inc 
losses 
1250 
7400 
2000 
900 
1100 
Assume: 1:1 randomisation and Fleiss adjustment; alpha 5%; primary outcome incomplete in 10% 
 
9.2 PROPOSED ANALYSES 
We will compare cilostazol v no cilostazol, ISMN v no ISMN, cilostazol and ISMN v neither. The 
proportion completing to target dose and any adverse events will be assessed using odds 
ratios. The LACI-2 will focus on numbers recruited, retained, tolerance and safety outcomes, 
blinded for TSC and unblinded intention to treat (ITT) for DMC. Safety analysis will use: Kaplan-
Meier and Cox proportional regression for analysis of time-to-event outcomes of death; binary 
logistic regression for SAEs, recurrent stroke, MI, and in those completing 12 month MRI, the 
amount of microbleeds, siderosis, new infarcts, WMH burden; all adjusted for minimisation 
variables to maximise power.67 We will collect data for future health economics analysis (EQ-
5D-5L, EQ-VAS). 
 
A secondary ITT analysis will be performed using logistic regression adjusted for minimisation 
variables of cilostazol+/-ISMN versus control on efficacy and safety outcomes, with secondary 
tests of subgroup interactions. Ordinal logistic regression will be used for ordinal categorical 
outcomes (e.g. mRS) to increase power.68  
 
A Statistical Analysis Plan (SAP) will be published prior to database lock and will describe 
analysis procedures and procedures for missing, unused or spurious data, and definitions of 
populations analysed. 
10  ADVERSE EVENTS 
Safety monitoring will only commence after the patient has been randomised into the trial.  
The Investigator is responsible for the detection and documentation of events meeting the 
criteria and definitions detailed below. Full details of contraindications and side effects that have 

 
 
 
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been reported following administration of the IMP can be found in the relevant Summary of 
Product Characteristics (SPC
 
10.1 DEFINITIONS 
Adverse events will only be recorded/reported after the participant has been randomised into 
the trial.  
An adverse event (AE) is any untoward medical occurrence in a clinical trial participant which 
does not necessarily have a causal relationship with an investigational medicinal product (IMP).  
An adverse reaction (AR) is any untoward and unintended response to an IMP which is related 
to any dose administered to that participant.  
A serious adverse event (SAE), serious adverse reaction (SAR). Any AE or AR that at any 
dose: 
 
results in death of the clinical trial participant; 
 
is life threatening*; 
 
requires in-patient hospitalisation^ or prolongation of existing hospitalisation; 
 
results in persistent or significant disability or incapacity; 
 
consists of a congenital anomaly or birth defect; 
 
results in any other significant medical event not meeting the criteria above. 
 
*Life-threatening in the definition of an SAE or SAR refers to an event where the participant 
was at risk of death at the time of the event. It does not refer to an event which hypothetically 
might have caused death if it were more severe. 
 
^Any hospitalisation that was planned prior to enrolment will not meet SAE criteria. Any 
hospitalisation that is planned post enrolment will not meet the SAE criteria unless it constitutes 
an untoward medical occurrence (e.g. cosmetic elective surgery, social and/or convenience 
admission, etc., will not count as SAEs). 
 
A suspected unexpected serious adverse reaction (SUSAR) is any AR that is classified as 
serious and is suspected to be caused by the IMP, that it is not consistent with the information 
about the IMP in the Summary of Product Characteristics (SPC) or Investigators Brochure. 
10.2 IDENTIFYING AEs AND SAEs 
Participants will be asked about the occurrence of AEs/SAEs at each visit during the study.  
Participants will also be encouraged to contact the local PI or Central Trial Office (ECTU) via 
the Trial Helpline if they experience a potential adverse event. Open-ended and non-leading 
verbal questioning of the participant will be used to enquire about AE/SAE occurrence.  
Participants will also be asked if they have been admitted to hospital, had any accidents, used 
any new medicines or changed concomitant medication regimens.  If there is any doubt as to 
whether a clinical observation is an AE, the event will be recorded. 
AEs and SAEs may also be identified via information from GPs, other hospital specialties, and 
support departments e.g. laboratories, using usual procedures  
10.3 RECORDING AEs AND SAEs 
When an AE/SAE occurs, it is the responsibility of the Investigator, or another suitably qualified 
physician in the research team who is delegated to record and report AEs/SAEs, to review all 
documentation (e.g. hospital notes, laboratory and diagnostic reports) related to the event.  The 
Investigator will then record all relevant information in the 
edical records. 
Information to be collected includes type of event, onset date, dose at the time, Investigator 
assessment of severity and causality, date of resolution as well as treatment required, 
investigations needed and outcome as per ACCORD requirements.   
Depending on the type of the event and the seriousness and causality assessment, all relevant 
information will also be recorded on the eCRF, AE log, SAE form and/or eCRF as detailed 

 
 
 
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below and summarised in Table 8. The flow chart in Figure 3 can be used by investigators to 
aid recording and reporting of safety events. 
10.3.1 Pre-existing Medical Conditions 
Pre-existing medical conditions (i.e. existed prior to informed consent) should be recorded as 
medical history and only recorded as AEs if medically judged to have unexpectedly worsened 
during the study.  
10.3.2 Outcome Events 
The following events are outcome events and will be recorded as such in the eCRF. All 
outcome events must be assessed for seriousness and causality by the PI or a delegated trial 
physician. Outcome measures are not recorded as AEs or further reported to the Sponsor, 
unless they fulfil the criteria of seriousness as defined in section 10.1 and are deemed possibly 
related to the IMP. The TSC will review all outcome events six monthly blinded to treatment 
allocation; the DMC will review all outcomes unblinded to treatment allocation annually and on 
special request. These events are not of themselves reasons to automatically discontinue the 
trial treatment, the need for which should be assessed by the PI and attending medical staff 
capacity are collected on the Trial Participant Consent Form which should also be consulted. 
 
 
Bleeding 
 
Bruising 
 
Chest pain, non-specific 
 
Diarrhoea 
 
Dizziness or light headedness 
 
Falls 
 
Headache 
 
Heart attack 
 
Heartburn 
 
Hypotension 
 
Loss of mental capacity 
 
Nausea 
 
Palpitations 
 
Recurrent stroke or TIA 
 
10.3.3 Events That Are Common in the Trial Population 
The primary event of stroke is classified as a pre-existing condition. As such, the occurrence or 
expected progression of stroke related events are common. In addition, participants are likely 
to have many minor adverse events during the course of the study. These events will be 
recorded in the medical records and assessed as per section 10.4. However, they are not 
usually recorded as AEs/SAEs, unless they are thought to be caused by the 
involvement in the trial. 
 
 
 
Accidents (domestic, traffic, occupational) 
 
Agitation 
 
Anxiety 
 
Asthma 
 
Atrial fibrillation or other cardiac dysrhythmia 
 
Bacteraemia 
 
Blepharospasm 
 
Breathlessness 

 
 
 
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Bronchitis 
 
Bronchospasm 
 
Candida 
 
Carotid endarterectomy 
 
Chelitis 
 
Chest infection 
 
Cholecystitis, gall stones 
 
Chronic Obstructive Lung Disease or exacerbation thereof 
 
Common cold 
 
Constipation 
 
Deep vein thrombosis 
 
Dysphagia 
 
Eczema 
 
Electrolyte imbalance 
 
Embolism 
 
Fatigue 
 
Flu 
 
Gastrointestinal disturbance, non-specific 
 
Heart failure 
 
Heart valve or septal disorder 
 
Hernia 
 
Hypercalcaemia 
 
Hyperglycaemia 
 
Hypertension 
 
Hyperuricaemia 
 
Hypoxia 
 
Impetigo 
 
Incontinence, urinary or faecal 
 
Leucopenia 
 
Lymphadenopathy 
 
Malignancy, new diagnosis or new treatment for existing diagnosis 
 
Mild ankle swelling 
 
Mood disorders 
 
Muscle twitching, 
 
Oesophagitis 
 
Operations or medical procedures (endoscopy, pacemaker insertion) 
 
Oral ulceration  
 
Osteoarthritis 
 
Osteoporosis 
 
Other infections including soft tissue or skin infections and generalised sepsis 
 
Painful shoulder syndromes 
 
Pancreatitis, 
 
Periodontal disease 
 
Peripheral vascular disease 
 
Pleural effusions 
 
Pneumonia 
 
Pneumothorax 
 
Pressure sores 
 
Renal dysfunction 
 
Renal stones 
 
Sedation 
 
Seizure 
 
Sexual dysfunction 
 
Shingles 
 
Spasticity or contractures 
 
Spinal disc problem including spinal stenosis 

 
 
 
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Thrombophlebitis 
 
Urinary catheterisation 
 
Urinary infections 
 
Varicose ulcers 
 
Vasculitis 
 
Venous thromboembolism 
 
Vertigo 
 
Visual Loss e.g. cataract or macular degeneration or retinal detachment 
 
Vomiting 
 
Weight loss 
 
Any other known complications of or symptoms suggestive of worsening stroke 
 
10.3.4 All Other Events Not Covered Above 
All events not covered by sections 10.3.2 or 10.3.3, including known IMP side effects, should 
be recorded as AEs/SAEs and assessed and reported as per sections 10.4 to 10.6. 
 
 
Table 8: Summary of safety recording requirements. 
Outcome event 
(listed in section 
10.3.2) 
Event common in stroke 
patients (listed in 
section 10.3.3) 
All other events 
Event not related to IMP(s), 
non-serious 
eCRF 
Medical notes only 
AE log 
Event not related to IMP(s), 
serious 
eCRF 
Medical notes only 
SAE report form 
Event potentially related to 
IMP(s), non-serious 
eCRF 
AE log 
AE log 
Event potentially related to 
IMP(s), serious 
SAE report form 
SAE report form 
SAE report form 
 

 
 
 
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Figure 3: Flow diagram showing the process for recording and reporting of safety information. 
 

 
 
 
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10.4 ASSESSMENT OF AEs AND SAEs 
Each AE must be assessed for seriousness, causality, severity and ARs must be assessed for 
expectedness by the Principal Investigator or another suitably qualified physician in the 
research team who has been delegated this role.  
For randomised studies, AEs will be assessed as though the participant is taking active IMP. 
SUSARs will be unblinded by ACCORD before they are reported to the Research Ethics 
Committee (REC) and the Competent Authority (CA) (by ACCORD). 
The Chief Investigator (CI) may not downgrade an event that has been assessed by an 
Investigator as an SAE or SUSAR, but can upgrade an AE to an SAE, SAR or SUSAR if 
appropriate. 
10.4.1 Assessment of Seriousness 
The Investigator will make an assessment of seriousness as defined in Section 10.1. 
10.4.2 Assessment of Causality 
The Investigator will make an assessment of whether the AE/SAE is likely to be related to the 
IMP according to the definitions below.   
 
Unrelated: where an event is not considered to be related to the IMP. 
 
 
Possibly Related: The nature of the event, the underlying medical condition, 
concomitant medication or temporal relationship make it possible that the AE has a 
causal relationship to the study drug. The assessment of causality will be made against 
the reference safety information found in the Summary of Product Characteristics. 
Where non Investigational Medicinal Products (NIMPs) e.g. rescue/escape drugs are given:  if 
the AE is considered to be related to an interaction between the IMP and the NIMP, or where 
the AE might be linked to either the IMP or the NIMP but cannot be clearly attributed to either 
one of these, the event will be considered as an AR. Alternative causes such as natural history 
of the underlying disease, other risk factors and the temporal relationship of the event to the 
treatment should be considered and investigated. The blind should not be broken for the 
purpose of making this assessment.  
10.4.3 Assessment of Expectedness 
If the event is an AR, the evaluation of expectedness will be made based on knowledge of the 
reaction and the relevant product information documented in the SPC/IB. 
The event may be classed as either: 
Expected: the AR is consistent with the toxicity of the IMP listed in the SPC/IB. 
Unexpected: the AR is not consistent with the toxicity in the SPC/IB. 
10.4.4 Assessment of Severity 
The Investigator will make an assessment of severity for each AE/SAE and record this on the 
CRF or SAE form according to one of the following categories: 
Mild: an event that is easily tolerated by the participant, causing minimal discomfort and not 
interfering with every day activities. 
Moderate: an event that is sufficiently discomforting to interfere with normal everyday activities. 
Severe: an event that prevents normal everyday activities. 
which is a regulatory definition based on participant/event outcome or action criteria.  For 

 
 
 
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example, a headache may be severe but not serious, while a minor stroke is serious but may 
not be severe. 
10.5 REPORTING OF AEs TO THE SPONSOR 
Adverse events occurring during the trial that are observed by the investigator or reported by 
the par
 
 
Only SAEs/SARs/SUSARs will be documented in the eCRF and reported expeditiously to the 
Sponsor as below.  
10.6 REPORTING OF SAEs/SARs/SUSARs 
Once the Investigator becomes aware that an SAE has occurred in a study participant, the 
information will be reported to the ACCORD Research Governance & QA Office immediately 
or within 24 hours. If the Investigator does not have all information regarding an SAE, they 
should not wait for this additional information before notifying ACCORD.  The SAE report form 
can be updated when the additional information is received. The SAE report will be submitted 
simultaneously to the CI. 
The SAE report will provide an assessment of causality and expectedness at the time of the 
initial report to ACCORD according to Sections 10.4.2, Assessment of Causality and 10.4.3, 
Assessment of Expectedness. 
The SAE report will be submitted electronically to the ACCORD Research Governance & QA 
Office and the CI directly from the study database. If the database is inaccessible then a paper 
copy of the SAE form should be completed and be transmitted by fax to ACCORD on +44 
(0)131 242 9447 or may be transmitted by hand to the office or submitted via email to 
safety@accord.scot. Only forms in a pdf format will be accepted by ACCORD via email.  
Where missing information has not been sent to ACCORD after an initial report, ACCORD will 
contact the Investigator and request the missing information. The Investigator must respond to 
these requests in a timely manner.   
All reports will be retained by the Investigator in the Investigator Site File (ISF). 
10.7 REGULATORY REPORTING REQUIREMENTS 
The ACCORD Research Governance & QA Office is responsible for Pharmacovigilance 
reporting on behalf of the co-sponsors (The University of Edinburgh and Lothian Health Board). 
The ACCORD Research Governance & QA Office has a legal responsibility to notify the 
regulatory competent authority and relevant ethics committee (REC that approved the trial). 
Fatal or life threatening SUSARs will be reported no later than 7 calendar days and all other 
SUSARs will be reported no later than 15 calendar days after ACCORD is first aware of the 
reaction.   
ACCORD, unless otherwise delegated, will inform Investigators at participating sites of all 
SUSARs and any other arising safety information. 
ACCORD will be responsible for providing safety line listings and assistance; however, it is the 
responsibility of the Investigator to prepare the Development Safety Update Report. This annual 
report lists all SARs and SUSARs reported during that time period. The responsibility of 
submitting the Development Safety Update Report to the regulatory authority and RECs, lies 
with ACCORD.  
 
10.8 CENTRAL BLINDED REVIEW OF SAEs 
To ensure that collected safety data is reliable and robust, a central blinded assessor will 
evaluate all investigator-reported SAEs. This reviewer will have access to the web-based SAE 
form once this has been reported by the local investigator and submitted to ACCORD. The 
independent reviewer will assess the event diagnosis, expectedness of event and likely 

 
 
 
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causality, blinded to treatment allocation. If required, the reviewer will be able to request further 
information from the specific trial sites. The outcome of the central blinded review will be made 
available to local investigators for information. 
assessment as reported to ACCORD will comprise the definitive safety data for this trial and 
will be used for all analyses. Should an investigator change their assessment based on the 
outcome of the central blinded review, they will update the SAE record and submit a follow-up 
report to ACCORD. 
10.9 FOLLOW UP PROCEDURES 
After initially recording an AE or recording and reporting an SAE, the Investigator should make 
every effort to follow each event until a final outcome can be recorded or reported as necessary. 
Follow up information on an SAE will be reported to the ACCORD office. 
 
If, after follow up, resolution of an event cannot be established, an explanation should be 
recorded on the CRF or AE log or additional information section of the SAE form. Adverse 
events will continue to be recorded for 1 month after the last dose of IMP. 
11 PREGNANCY 
Although pregnancy is not considered an AE or SAE, as a matter of safety, the Investigator will 
of a male participant, who became pregnant while participating in the study. The Investigator 
will need to record the information on a Pregnancy Notification Form and submit this to the 
ACCORD office within 14 days of being made aware of the pregnancy. 
All pregnant female participants and pregnant partners of male participants will be followed up 
until the outcome of the pregnancy. 
12 TRIAL MANAGEMENT AND OVERSIGHT 
ARRANGEMENTS 
12.1 TRIAL MANAGEMENT GROUP 
 
The trial will be coordinated by a Trial Management Group, consisting of the grant holders 
Professor Joanna Wardlaw (Chief Investigator), Professor Philip Bath (Deputy Chief 
Investigator, Principal Investigator in Nottingham), Dr Fergus Doubal (Principal Investigator, 
Edinburgh), Dr Niki Sprigg (Co-Investigator, Nottingham), Anna Heye, Trial Manager 
(Edinburgh), clinical research fellow (Edinburgh and Nottingham where relevant), trial co-
ordinator (Nottingham and Edinburgh), trial statistician (Nottingham), Trial programmer 
(Nottingham), the Trial Image Data Manager (Edinburgh) and other Trial administrative and 
data management staff as appropriate. 
 
The Trial Co-ordinator/Manager will oversee the day-to-day running of the study and will be 
accountable to the Chief Investigator. The Trial Manager will be responsible for checking the 
CRFs for completeness, plausibility and consistency. Any queries will be resolved by the 
Investigator or delegated member of the trial team. The Trial Co-ordinator in Edinburgh will 
cross check a sample of eCRFs of patients recruited in Nottingham and the trial coordinator in 
Nottingham will cross check a sample of eCRFs of patients recruited in Edinburgh. 
A Delegation Log will be prepared for each site, detailing the responsibilities of each member 
of staff working on the trial. 
12.2 TRIAL STEERING COMMITTEE 
 

 
 
 
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A Trial Steering Committee (TSC) has been established to oversee the conduct and progress 
of the trial. The current members may change as the study progresses: changes necessitated 
by illness or death or relocation of TSC members will not constitute a Protocol Deviation or 
Violation and will be addressed as a minor amendment. The roles and responsibilities of the 
TSC will be defined in the TSC Charter. 
12.3 DATA MONITORING COMMITTEE 
 
An independent Data Monitoring Committee (DMC), consisting of a Chair, two senior academic 
clinicians familiar with stroke and imaging and a statistician has been established to oversee 
the safety of participants in the trial. The current members may change as the study progresses: 
changes necessitated by illness or death or relocation of TSC members will not constitute a 
Protocol Deviation or Violation and will be addressed as a minor amendment. The roles and 
responsibilities of the DMC will be defined in the DMC Charter. 
12.4 INSPECTION OF RECORDS 
Investigators and institutions involved in the study will permit trial related monitoring and audits 
on behalf of the sponsor, REC review, and regulatory inspection(s). In the event of an audit or 
monitoring, the Investigator agrees to allow the representatives of the sponsor direct access to 
all study records and source documentation. In the event of regulatory inspection, the 
Investigator agrees to allow inspectors direct access to all study records and source 
documentation. 
12.5 RISK ASSESSMENT 
An independent risk assessment will be performed by an ACCORD Clinical Trials Monitor to 
determine if monitoring is required and if so, at what level. An independent risk assessment will 
also be carried out by the ACCORD Quality Assurance Group to determine if an audit should 
be performed before/during/after the study and if so, at what locations and at what frequency. 
12.6 STUDY MONITORING AND AUDIT 
An ACCORD Clinical Trials Monitor or an appointed monitor will contact the Investigator site 
prior to the start of the study and during the course of the study if required, in accordance with 
the monitoring plan, if required. Risk assessment will determine if audit, by the ACCORD QA 
group, is required. Details will be captured in an audit plan. Audit of Investigator sites, study 
management activities and study collaborative units, facilities and 3rd parties may be performed. 
13 GOOD CLINICAL PRACTICE 
13.1 ETHICAL CONDUCT 
The study will be conducted in accordance with the principles of the International Conference 
on Harmonisation Tripartite Guideline for Good Clinical Practice (ICH GCP). 
 
A favorable ethical opinion will be obtained from the HRA REC and local R&D approval will be 
obtained prior to commencement of the study. 
13.2 REGULATORY COMPLIANCE 
The study will not commence until a Clinical Trial Authorisation (CTA) is obtained from the 
appropriate Regulatory Authority. The protocol and study conduct will comply with the 
Medicines for Human Use (Clinical Trials) Regulations 2004, as amended. 

 
 
 
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13.3 INVESTIGATOR RESPONSIBILITIES 
The Investigator is responsible for the overall conduct of the study at the site and compliance 
with the protocol and any protocol amendments. In accordance with the principles of ICH GCP, 
the following areas listed in this section are also the responsibility of the Investigator.  
Responsibilities may be delegated to an appropriate member of study site staff.   
13.3.1 Informed Consent 
The Investigator is responsible for ensuring informed consent is obtained before any protocol 
specific procedures are carried out. The decision of a participant to participate in clinical 
research is voluntary and should be based on a clear understanding of what is involved. 
 
Participants must receive adequate oral and written information using the approved Participant 
Information and Informed Consent Forms. The oral explanation to the participant will be 
performed by the Investigator or qualified delegated person, and will cover all the elements 
specified in the Participant Information Sheet and Consent Form. 
 
The participant must be given every opportunity to clarify any points they do not understand 
and, if necessary, ask for more information. The participant must be given sufficient time to 
consider the information provided. It should be emphasised that the participant may withdraw 
their consent to participate at any time without loss of benefits to which they otherwise would 
be entitled. 
 
The participant will be informed and agree to their medical records being inspected by 
regulatory authorities and representatives of the sponsor(s) but understand that their name will 
not be disclosed outside the hospital. 
 
The Investigator or delegated member of the trial team and the participant will sign and date 
the Informed Consent Form(s) to confirm that consent has been obtained. The participant will 
receive a copy of this document and a copy filed in the Investigator Site File (ISF) and 
 (a PDF version will be uploaded to the participant medical record at 
sites where records are all electronic). 
13.3.2 Study Site Staff 
The Investigator must be familiar with the IMP, protocol and the study requirements. It is the 
informed about the IMP, protocol and their trial related duties. 
13.3.3 Data Recording 
The Principal Investigator is responsible for the quality of the data recorded in the eCRF at each 
Investigator Site. The source data plan identifies which source data correspond to eCRF data 
and states which data are recorded directly into the eCRF. 
13.3.4 Investigator Documentation 
Prior to beginning the study, each Investigator will be asked to provide particular essential 
documents to the ACCORD Research Governance & QA Office, including but not limited to: 
 
 
An original 
documents); 
 
Curriculum vitae (CV) signed and dated by the Investigator indicating that it is accurate 
and current. 
 
The ACCORD Research Governance & QA Office will ensure all other documents required by 
ICH GCP are retained in a Trial Master File (TMF), where required, and that appropriate 
documentation is available in local ISFs. 
13.3.5 GCP Training 
All study staff must hold evidence of appropriate GCP training.  

 
 
 
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13.3.6 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records must be identified in a 
manner designed to maintain participant confidentiality. All records must be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the participant. The Investigator and study site staff involved with this study may 
not disclose or use for any purpose other than performance of the study, any data, record, or 
other unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
13.3.7 Data Protection 
All Investigators and study site staff involved with this study must comply with the requirements 
of the appropriate data protection legislation (including the General Data Protection Regulation 
and Data Protection Act) with regard to the collection, storage, processing and disclosure of 
personal information. Access to collated identifiable participant data will be restricted to 
individuals from the research team treating the participants, representatives of the sponsor(s) 
and representatives of regulatory authorities. 
 
Computers used to collate the data will have limited access measures via user names and 
passwords. 
 
Published results will not contain any personal data that could allow identification of individual 
participants. 
14 STUDY CONDUCT RESPONSIBILITIES 
14.1 PROTOCOL AMENDMENTS 
Any changes in research activity, except those necessary to remove an apparent, immediate 
hazard to the participant in the case of an urgent safety measure, must be reviewed and 
approved by the Chief Investigator. 
 
Amendments to the protocol must be submitted in writing to the appropriate REC, Regulatory 
Authority and local R&D for approval prior to participants being enrolled into an amended 
protocol. 
14.2 PROTOCOL VIOLATIONS AND DEVIATIONS 
Prospective protocol deviations, i.e. protocol waivers, will not be approved by the sponsors and 
therefore will not be implemented, except where necessary to eliminate an immediate hazard 
to study participants. If this necessitates a subsequent protocol amendment, this should be 
submitted to the REC, Regulatory Authority and local R&D for review and approval if 
appropriate. 
 
Protocol deviations will be recorded in a protocol deviation log and logs will be submitted to the 
sponsors every 3 months. Each protocol violation will be reported to the sponsor within 24 hours 
of becoming aware of the violation. 
 
Protocol violation: A protocol violation is a deviation that may potentially significantly impact the 
completeness, accuracy, and/or reliability of the study data or that may significantly affect a 
-being.  
 
As tolerability of trial IMP is an outcome and will be recorded in the eCRF at each study visit, 
even any of the dose) will not constitute a protocol deviation or violation.  
 

 
 
 
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14.3 SERIOUS BREACH REQUIREMENTS 
A serious breach is a breach which is likely to effect to a significant degree: 
 
(a) the safety or physical or mental integrity of the participants of the trial; or 
(b) the scientific value of the trial. 
 
If a potential serious breach is identified by the Chief investigator, Principal Investigator or 
delegates, the co-sponsors (QA@accord.scot) must be notified within 24 hours. It is the 
responsibility of the co-sponsors to assess the impact of the breach on the scientific value of 
the trial, to determine whether the incident constitutes a serious breach and report to regulatory 
authorities and research ethics committees as necessary.  
14.4 STUDY RECORD RETENTION 
As there is limited data on the use of isosorbide mononitrate and cilostazol in UK stroke patients 
all study documentation including personal linked data will be kept for a minimum of 5 years 
from the protocol defined end of study point. This is in case of any later events and also because 
of sponsor guidelines. Study documentation will not be destroyed without permission from the 
sponsor. 
 
14.5 END OF STUDY 
The end of study is defined as the completion of analysis of the study data.  
 
The TSC and/or the co-sponsor(s) have the right at any time to terminate the study for clinical 
or administrative reasons, e.g. on recommendation of the DMC.  
 
The end of the study will be reported to the Sponsor, REC and Regulatory Authority within 90 
days, or 15 days if the study is terminated prematurely. The Investigators will inform participants 
of the premature study closure and ensure that the appropriate follow up is arranged for all 
participants involved. 
 
 A final clinical study report of the study will be provided to the REC and Sponsor within 1 year 
of the end of the study. The trial summary results will be uploaded to the European EudraCT 
trial entry and notified to MHRA as per ACCORD SOP CR009.  
 
14.6 CONTINUATION OF DRUG FOLLOWING THE END OF STUDY 
This is an early phase III trial to assess tolerability and safety of the trial medications in stroke 
patients taking routine post stroke secondary prevention medications. As such the trial drugs 
will not be continued beyond the study period as, at present, there is no evidence of efficacy in 
addition to standard post stroke care.  
 
14.7 INSURANCE AND INDEMNITY 
The co-sponsors are responsible for ensuring proper provision has been made for insurance or 
indemnity to cover their liability and the liability of the Chief Investigator and staff. 
The following arrangements are in place to fulfil the co-sponsors' responsibilities: 
 
 
The Protocol has been designed by the Chief Investigator and researchers employed 
by the University and collaborators. The University has insurance in place (which 
includes no-fault compensation) for negligent harm caused by poor protocol design by 
the Chief Investigator and researchers employed by the University. 
 
Sites participating in the study will be liable for clinical negligence and other negligent 
harm to individuals taking part in the study and covered by the duty of care owed to 
them by the sites concerned. The co-sponsors require individual sites participating in 
the study to arrange for their own insurance or indemnity in respect of these liabilities. 

 
 
 
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Sites which are part of the United Kingdom's Nation Health Service will have the benefit 
of NHS Indemnity. 
 
The manufacturer supplying IMP has accepted limited liability related to the 
manufacturing and original packaging of the study drug and to the losses, damages, 
claims or liabilities incurred by study participants based on known or unknown Adverse 
Events which arise out of the manufacturing and original packaging of the study drug, 
but not where there is any modification to the study drug (including without limitation 
re-packaging and blinding). 
15 REPORTING, PUBLICATIONS AND NOTIFICATION OF 
RESULTS 
15.1 AUTHORSHIP POLICY 
 
Ownership of the data arising from this study resides with the study team. On completion of the 
study, the study data will be analysed and tabulated, and a clinical study report will be prepared 
for publication in a peer reviewed journal in accordance with ICH guidelines. The paper will be 
published by named members of the trial team on behalf of the Lacunar Intervention (LACI) 2 
Trial (LACI-2). Members of the collaborative group will be listed in the publication. A report will 
be submitted to the funder (BHF UK). Papers describing secondary analyses will also be 
published and the data will be contributed to a systematic review where relevant. Any secondary 
publication may be published by named individuals, but with appropriate acknowledgement of 
the collaborative group. 
15.2 PUBLICATION 
 
The clinical study report will be used for publication and presentation at scientific meetings on 
stroke and dementia such as UK Stroke Forum, European Stroke Organisation Conference, 
International Stroke Conference, the World Stroke Congress
disease and dementia. Investigators have the right to publish orally or in writing the results of 
the study. Reporting will be in compliance with CONSORT. 
 
Summaries of results will also be made available to all Investigators for dissemination within 
their clinics (where appropriate and according to their discretion). 
 
A newsletter will be sent to the participants informing them of the results and of other information 
relevant to small vessel disease and general information about maintaining a healthy lifestyle. 
15.3 PEER REVIEW 
The trial design was informed by a Stroke Research Network-funded NIHR Stroke Research 
Network Writing Workshop, held in Nottingham, 31 March 2014 and attended by 20 experts on 
small vessel disease, stroke, dementia and imaging. The workshop proposal underwent peer 
review prior to securing funding. 
 
The trial underwent peer review during the funding application to the BHF.  
 
A paper describing potential drugs to prevent SVD progression was peer reviewed and is now 
published in the International Journal of Stroke.16  
 
The concepts described in this protocol have been presented at several Stroke and Dementia 
conferences and discussed.  
 
The Stroke Research Network Prevention Studies Group reviewed the proposal in 2014 and 
supported the work.  
 

 
 
 
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Many UK SRN Centers have expressed interest in joining the trial. 
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