Oxford Haemodynamic Adaptation to Reduce Pulsatility: Randomised, Placebo-controlled, Double-blind Crossover Trial of Effects of Sildenafil on Cerebral Arterial Pulsatility in Patients With Cryptogenic or Lacunar Stroke and Small Vessel Disease
Phase: PHASE2
Conditions: Small Vessel Cerebrovascular Disease
Sponsor: University of Oxford

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Oxford Haemodynamic Adaptation to Reduce Pulsatility Trial: 
Randomised, placebo controlled, double-blind crossover study of effects of sildenafil on cerebral 
arterial pulsatility in patients with cryptogenic or lacunar stroke and small vessel disease 
(OxHARP) 
Ethics Ref: 19/SC/0022 
Date and Version No: 8th February 2021, Version 3.0 
Chief Investigator: 
Dr Alastair Webb 
Wellcome Trust Clinical Research Career Development Fellow / NHS 
Honorary Consultant Neurologist, Wolfson Centre for Prevention of 
Stroke and Dementia, Department of Clinical Neurosciences, John 
Radcliffe Hospital, Oxford, OX39DU 
Tel: 01865231601 
 
Fax: 01865234629 
alastair.webb@ndcn.ox.ac.uk 
Investigators: 
  
Professor Peter Rothwell, Wolfson Centre for Prevention of Stroke and 
Dementia 
Prof Peter Jezzard, Professor of Neuroimaging, Centre for Functional 
Magnetic Resonance of the Brain, University of Oxford 
Amy Lawson, Clinical Research Assistant, CPSD 
Dr Karolina Wartolowska, Postdoctoral Fellow, CPSD 
Dr Louise Silver, Study Coordinator, CPSD 
 
Sponsor:  
University of Oxford   
Clinical Trials and Research Governance  
Research Services 
University of Oxford 
Joint Research Office 
Boundary Brook House 
Churchill Drive 
OXON, OX3 7GB  
Funder:  
Wellcome Trust 
Chief Investigator Signature:  
Statistician Signature: 
 
 
Dr Joanna Moschandreas, Centre for Prevention of Stroke and Dementia 
I declare that the Chief Investigator or other investigators have no conflict of interest 
Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other than the 
Sponsor, the Investigator Team, HRA, host organisation, and members of the Research Ethics Committee, 
unless authorised to do so. 

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TABLE OF CONTENTS 
1. 
KEY STUDY CONTACTS ........................................................................................................................... 3 
2. 
SYNOPSIS ............................................................................................................................................... 4 
3. 
ABBREVIATIONS ..................................................................................................................................... 6 
4. 
BACKGROUND AND RATIONALE ............................................................................................................ 8 
5. 
OBJECTIVES AND OUTCOME MEASURES ............................................................................................. 10 
6. 
STUDY DESIGN ..................................................................................................................................... 10 
7. 
PARTICIPANT IDENTIFICATION ............................................................................................................ 13 
7.1. 
Study Participants ........................................................................................................................ 13 
7.2. 
Inclusion Criteria .......................................................................................................................... 13 
7.3. 
Exclusion Criteria ......................................................................................................................... 13 
8. 
STUDY PROCEDURES ........................................................................................................................... 15 
8.1. 
Recruitment ................................................................................................................................. 16 
8.1. 
Screening and Eligibility Assessment ........................................................................................... 17 
8.2. 
Informed Consent ........................................................................................................................ 17 
8.3. 
Randomisation, blinding and code-breaking ............................................................................... 17 
8.4. 
Baseline Assessments .................................................................................................................. 18 
8.5. 
Subsequent Visits ........................................................................................................................ 21 
8.6. 
Sample Handling .......................................................................................................................... 22 
8.7. 
Discontinuation/Withdrawal of Participants from Study Treatment .......................................... 22 
8.8. 
Definition of End of Study ........................................................................................................... 23 
9. 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) ................................................................................. 23 
9.1. 
IMP Description ........................................................................................................................... 23 
9.2. 
Storage of IMP ............................................................................................................................. 24 
9.3. 
Compliance with Study Treatment .............................................................................................. 24 
9.4. 
Accountability of the Study Treatment ....................................................................................... 24 
9.5. 
Concomitant Medication ............................................................................................................. 24 
9.6. 
Post-study Treatment .................................................................................................................. 24 
10. 
SAFETY REPORTING ......................................................................................................................... 24 
10.1. 
Definitions ............................................................................................................................... 24 
10.2. 
Causality .................................................................................................................................. 26 
10.3. 
Procedures for Recording Adverse Events .............................................................................. 26 
10.4. 
Reporting Procedures for Serious Adverse Events .................................................................. 26 
10.5. 
Expectedness ........................................................................................................................... 27 
10.6. 
SUSAR Reporting ..................................................................................................................... 27 

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10.7. 
Safety Monitoring Committee ................................................................................................. 27 
10.8. 
Development Safety Update Reports .......................................... Error! Bookmark not defined. 
11. 
STATISTICS ....................................................................................................................................... 27 
11.1. 
Description of Statistical Methods .......................................................................................... 27 
11.2. 
The Number of Participants .................................................................................................... 28 
11.3. 
The Level of Statistical Significance ......................................................................................... 29 
11.4. 
Criteria for the Termination of the Study .................................... Error! Bookmark not defined. 
11.5. 
Procedure for Accounting for Missing, Unused, and Spurious Data. ...................................... 29 
11.6. 
Inclusion in Analysis ................................................................................................................. 29 
11.7. 
Procedures for Reporting any Deviation(s) from the Original Statistical Plan ........................ 29 
12. 
DATA MANAGEMENT ...................................................................................................................... 30 
12.1. 
Source Data ............................................................................................................................. 30 
12.2. 
Access to Data ......................................................................................................................... 30 
12.3. 
Data Recording and Record Keeping ....................................................................................... 30 
13. 
QUALITY ASSURANCE PROCEDURES ............................................................................................... 30 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ............................................................................... 30 
14.1. 
Declaration of Helsinki............................................................................................................. 30 
14.2. 
Guidelines for Good Clinical Practice ...................................................................................... 30 
14.3. 
Approvals ................................................................................................................................. 31 
14.4. 
Reporting ................................................................................................................................. 31 
14.5. 
Participant Confidentiality ....................................................................................................... 31 
14.6. 
Expenses and Benefits ............................................................................................................. 31 
14.7. 
Other Ethical Considerations ................................................................................................... 27 
15. 
FINANCE AND INSURANCE .............................................................................................................. 32 
15.1. 
Funding .................................................................................................................................... 32 
15.2. 
Insurance ................................................................................................................................. 32 
16. 
PUBLICATION POLICY ....................................................................................................................... 32 
17. 
REFERENCES .................................................................................................................................... 32 
18. 
APPENDIX A:  STUDY FLOW CHART ................................................................................................. 27 
19. 
APPENDIX B:  SCHEDULE OF PROCEDURES ..................................................................................... 27 
20. 
APPENDIX D:  AMENDMENT HISTORY ............................................................................................. 33 
 
1. KEY STUDY CONTACTS 
 

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Chief Investigator 
Dr Alastair Webb 
Wellcome Trust Clinical Research Career Development Fellow  
NHS Honorary Consultant Neurologist,  
Wolfson Centre for Prevention of Stroke and Dementia, Department of 
Clinical Neurosciences, John Radcliffe Hospital, Oxford, OX39DU Tel: 
01865231601  
Fax: 01865234629 
alastair.webb@ndcn.ox.ac.uk 
Sponsor 
University of Oxford 
Clinical Studies and Research Governance  
Research Services 
University of Oxford 
Joint Research Office 
Boundary Brook House 
Churchill Drive 
Headington 
OXON, OX3 7GB 
Clinical Trials Unit 
Study management supported by Dendron, Thames Valley Clinical 
Research Network 
Statistician 
Dr Joanna Moschandreas 
Wolfson Centre for Prevention of Stroke and Dementia, Department of 
Clinical Neurosciences, John Radcliffe Hospital, Oxford, OX39DU 
Tel: 01865231601 
 
Fax: 01865234629 
Committees 
Data and Safety Monitoring Committee: 
Prof David Werring, Professor of Neurology, University College London, 
London (Chair) 
Prof Jesse Dawson, Professor of Stroke Medicine, Institute of 
Cardiovascular and Medical Sciences, University of Glasgow 
Dr Alex Rothman, Wellcome Trust Clinical Research Career 
Development Fellow and NIHR Clinical Lecturer in Cardiology, 
Department of Cardiology and Pulmonary Hypertension Unit, Sheffield 
Teaching Hospitals NHS Trust / University of Sheffield 
 
2. SYNOPSIS 
 
Study Title 
Oxford Haemodynamic Adaptation to Reduce Pulsatility: 
Randomised, placebo controlled, crossover study of effects of sildenafil on 
cerebral arterial pulsatility in patients with cryptogenic or lacunar stroke and 
small vessel disease 
Internal ref. no. (or 
short title) 
OxHARP 
Study Design 
Randomised, placebo-controlled, double-blind, crossover study 

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Study Participants 
Cryptogenic or lacunar stroke or TIA, with mild to moderate small vessel 
disease changes on MRI or CT 
Planned Sample Size 
75 
Treatment duration 
3 weeks per treatment (12-14 weeks in total) 
Follow up duration 
11 to 15 weeks 
Planned Study Period 
36 months 
 
Objectives 
Outcome Measures 
Primary 
 
Assess whether 3 weeks of 
treatment with sildenafil (a PDE5 
inhibitor) reduces cerebral 
arterial pulsatility on transcranial 
ultrasound, compared to placebo 
in patients with chronic vascular 
injury to the brain (small vessel 
disease) 
 
Gosling’s MCA pulsatility index on  
Transcranial ultrasound (MCA-PI) 
Secondary 
 
1) Assess whether 3 weeks of 
treatment with sildenafil (a PDE5 
inhibitor) alters cerebral arterial 
reactivity to carbon dioxide on 
transcranial ultrasound, 
compared to placebo 
 
2) Assess whether 3 weeks of 
treatment with sildenafil (a PDE5 
inhibitor) has non-inferior effects 
on cerebral arterial pulsatility and 
reactivity to carbon dioxide on 
transcranial ultrasound, 
compared to cilostazol (a PDE 3 
inhibitor 
 
1) and 2) Change in mean flow 
velocity on TCD before vs during 
CO2 challenge 
 
 
Tertiary Objectives 
1) Assess whether 3 
weeks of treatment 
with sildenafil or 
cilostazol increases 
cerebral arterial 
reactivity to carbon 
dioxide on MRI, 
compared to placebo  
 
2) Biochemical / genetic 
predictors of response 
to treatment 
 
Reactivity of BOLD signal on MRI 
to CO2 challenge 
 
 
 
 
 
 
 
Markers of endothelial function 
(e.g. ICAM, VEGF, vWF) and 
genetic targets of the 
medications in the trial 
After 3 weeks of treatment with 
sildenafil and cilostazol versus 
placebo 
 
 
 
 
 
 
 
Analysed in the 2 years after the 
last visit of the last participant. 

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Investigational 
Medicinal Product(s) 
Sildenafil 
Cilostazol 
Formulation, Dose, 
Route of Administration 
Sildenafil: Oral 25 - 50mg tds, tablet 
Cilostazol: Oral, 50 - 100mg, BD, tablet (with mid-day placebo) 
Placebo: Oral, TDS 
 
3. ABBREVIATIONS 
 
AE 
Adverse event 
AR  
Adverse reaction 
CI 
Chief Investigator 
CO2 
Carbon dioxide 
CRA 
Clinical Research Associate (Monitor) 
CRF 
Case Report Form 
CRO  
Contract Research Organisation 
CT 
Computed Tomography (brain scan) 
CTA 
Clinical Trials Authorisation 
CTRG 
Clinical Trials and Research Governance 
DMC/DMSC 
Data Monitoring Committee / Data Monitoring and Safety Committee 
DSUR 
Development Safety Update Report 
etCO2 
End-tidal carbon dioxide 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
HRA 
Health Research Authority 
IB 
Investigators Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IMP 
Investigational Medicinal Product 
IRB 
Independent Review Board 
MCA-PI 
Middle cerebral artery pulsatility index 
MHRA 
Medicines and Healthcare products Regulatory Agency 
N2 
Nitrogen 
NHS 
National Health Service 
NRES 
National Research Ethics Service  

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PDE5 
Phosphodiesterase 5 inhibitor 
PI 
Principal Investigator 
MCA-PI 
Middle cerebral artery pulsatility index (Gosling’s) 
PIL 
Participant/ Patient Information Leaflet 
R&D 
NHS Trust R&D Department 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SDV 
Source Data Verification 
SMPC 
Summary of Medicinal Product Characteristics 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TMF 
Study Master File 
TSG 
Oxford University Hospitals NHS Foundation Trust / University of Oxford Trials Safety 
Group 
 
 
 

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4. BACKGROUND AND RATIONALE 
 
Chronic injury to the small vessels of the brain (‘small vessel disease’) is associated with acute 
stroke,1 progressive cognitive decline,2 late-onset refractory depression,3 functional impairment in 
daily living4 and increased mortality.5 Originally defined on pathological grounds, it is now 
recognised primarily on brain imaging by a pattern of white matter hyperintensiities on T2-based 
imaging in the periventricular and deep white matter, or acute lacunar strokes, cerebral 
microbleeds and dilated perivascular spaces.6 Despite accounting for more than 30% of strokes 
and 40% of dementia,7 the underlying mechanism of small vessel injury is unclear and may reflect 
systemic haemodynamic influences on the cerebral vasculature, such as increased transmission 
of pulsatile blood pressure to the brain8 or inherent dysfunction of the small vessels and their 
endothelium.9 However, white matter hyperintensities are highly prevalent in the population, 
affecting the majority of patients over the age of 65 and many patients with advanced imaging 
changes of SVD remain functionally independent.10 As such, it is important to target novel 
treatments at those patients with SVD who are at an increased risk of morbidity. 
The underlying cause of many strokes remains undefined despite intensive investigation 
(‘cryptogenic’ stroke), indicative of a major gap in our understanding of the pathophysiology of 
stroke and resulting in significant excess morbidity.11 In patients with small vessel disease, acute 
stroke due to small vessel occlusion (lacunar stroke) is commonly recognised as the principle type 
of stroke, but cryptogenic stroke remains common. Furthermore, classification of lacunar stroke 
relies upon clinical and imaging criteria rather than demonstration of an in situ occlusion of a 
perforating small vessel. This can therefore result from multiple aetiologies and rates of 
misclassification of lacunar events are high. Given this aetiological uncertainty, the diffuse cerebral 
arteriopathy of small vessel disease is likely to contribute to both lacunar stroke and cryptogenic 
strokes.12 Lacunar and cryptogenic strokes are therefore a marker of an increased risk of morbidity 
in the context of chronic SVDs, and identification of an effective treatment for the associated 
arteriopathy may also offer a novel intervention for a large number of cryptogenic strokes that 
currently have no specific treatment option.12 
Hypertension is the strongest modifiable risk factor for small vessel disease, but there is only 
limited evidence that reduction of blood pressure alone significantly reduces progression of 
development of SVD.13 However, pulsatility of blood flow in the brain is associated with small 
vessel disease,8 resulting from increased transmission of the pulsatile aortic waveform to the brain 
through stiff conduit vessels. Secondly, there is significant endothelial dysfunction in SVDs, with 
increased breakdown of the blood-brain barrier detected by increased extravasation of contrast 
material on MRI in both white matter hyperintensities and normal appearing white matter.14 This 

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may be secondary to factors such as hypertension or arterial pulsatility, or it may reflect an 
underlying, primary endotheliopathy. 
Aortic pulsatility, aortic stiffness and transmission of the aortic waveform are increased by 
reflection of the outgoing aortic pressure wave from the distal small vessels back towards the 
aorta, increasing aortic pulsatility. The resulting enhanced pulsatility of blood reaching the low 
resistance small vessels in the brain causes increased shear stress during systole and potential 
hypoperfusion of tissues during diastole.15 This is potentially modifiable by vasodilating 
medications that delay the site and severity of wave reflection, reducing aortic pulsatility. Such 
medications may also act upon muscular conduit vessels (distal ICA / MCA) to increase elasticity, 
improve dampening of the aortic waveform and reducing pulsatility at distal vessels.  
Endothelial dysfunction is associated with abnormalities of vasodilation and vasoconstriction, 
controlled through the endothelial nitric oxide – cGMP pathway.16 This can be tested by measuring 
the cerebral blood flow response to carbon dioxide,17 with either transcranial ultrasound or MRI 
imaging. A number of agents have the potential to effect the endothelium. Phosphodiesterase 
inhibitors reduce breakdown of cGMP, potentiating the nitric oxide driven vasodilation of small 
arterioles. Phosphodiesterase 5 inhibitors (sildenafil, tadalafil) have been widely used in erectile 
dysfunction and in another occlusive vasculopathy (pulmonary arterial hypertension), with an 
established safety profile and tolerability. A number of studies have demonstrated a potential 
benefit of sildenafil on endothelial function,18 but this has not been assessed specifically in cerebral 
small vessel disease. Cilostazol is a phosphodiesterase 3 inhibitor that has been tested in clinical 
trials of patients with stroke with a reduction in recurrent events during follow up,19 potentially 
explained by a reduction in cerebral arterial pulsatility.20 Polymorphisms in the PDE3 gene have 
also been shown to be associated with stroke risk in genome-wide association studies.21 However, 
it has an additional antiplatelet effect, complicating understanding of how it’s pharmacological 
effects translates into clinical outcomes, and complicating its use in clinical practice.  
This study therefore aims to test the physiological effect of sildenafil, a phosphodiesterase 5 
inhibitor, on cerebral arterial pulsatility, with secondary assessment of effects on cerebrovascular 
endothelial function. This will be tested at doses consistent with those tolerated in pulmonary 
arterial hypertension. It will be tested in recovered patients with a previous cryptogenic or lacunar 
stroke or probable TIA requiring treatment, and mild-moderate small vessel disease. This will allow 
assessment of effects on cerebrovascular physiology in the presence of small vessel injury, but 
prior to establishment of likely irreversible changes. Secondly, patients will then receive cilostazol, 
to compare the relative effect of PDE5 inhibition and PDE3 inhibition on cerebrovascular 
haemodynamics as a secondary outcome measure. 
 

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5. OBJECTIVES AND OUTCOME MEASURES 
Objectives 
Outcome Measures  
Timepoint(s) 
Primary Objective 
Assess whether 3 weeks of 
treatment with sildenafil (a PDE5 
inhibitor) reduces cerebral arterial 
pulsatility on transcranial 
ultrasound, compared to placebo in 
patients with chronic vascular 
injury to the brain (small vessel 
disease) 
Middle cerebral arterial pulsatility index 
((Gosling’s PI = peak systolic velocity – 
end diastolic velocity)/(mean flow 
velocity)) on transcranial ultrasound 
Baseline, after 3 
weeks of treatment 
with placebo 
versus 3 weeks of 
sildenafil 
Secondary Objectives 
1) Assess whether 3 weeks of 
treatment with sildenafil (a PDE5 
inhibitor) alters cerebral arterial 
reactivity to carbon dioxide on 
transcranial ultrasound, compared 
to placebo 
2) Assess whether 3 weeks of 
treatment with sildenafil (a PDE5 
inhibitor) has non-inferior effects on 
cerebral arterial pulsatility and 
reactivity to carbon dioxide on 
transcranial ultrasound, compared 
to cilostazol (a PDE 3 inhibitor) 
 
Percentage increase in MCA velocity on 
6% CO2 vs medical air 
 
As above 
 
 
 
 
As above 
Tertiary Objectives 
1) Assess whether 3 weeks of 
treatment with sildenafil (a PDE5 
inhibitor) or cilostazol increases 
cerebral arterial reactivity to 
carbon dioxide on MRI, compared 
to placebo  
 
2) Determine biochemical / genetic 
predictors of response to treatment 
 
Reactivity of BOLD signal on MRI to CO2 
challenge 
 
 
 
Markers of endothelial function (e.g. 
ICAM, VEGF, vWF) and genetic targets of 
the medications in the trial 
After 3 weeks of 
treatment with 
sildenafil or 
cilostazol versus 
placebo 
 
 
Analysed in the 2 
years after the last 
visit of the last 
participant. 
6. STUDY DESIGN 
This is an investigator-led, randomised, placebo and actively controlled, double-blind (patient and 
clinician), assessor-blinded, crossover design study. 75 participants will be consented and assessed at a 
baseline visit, undergo a clinical assessment, followed by a research assessment including transcranial 
ultrasound to determine cerebral arterial pulsatility and reactivity. They receive three treatments in 

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randomised sequence: placebo (one tablet TDS, titrated to 2 tablets after 1 week), cilostazol (50mg bd, 
titrated to 100mg bd, with midday placebo) or sildenafil (25mg tds, titrated to 50mg tds)- NB titration up 
only happens if the participant is not on omeprazole. After each treatment, the will undergo a repeat 
clinical and physiological assessment, followed by at least 1 week washout before starting the next 
treatment. However, the washout may be prolonged if unavoidable (ie due to the COVID-19 pandemic). A 
subgroup of 60 participants will undergo MRI imaging when on sildenafil and placebo to assess arterial 
pulsatility on MRI and cerebrovascular reactivity, whilst 30 will undergo MRI on all three treatments. 
FLOWCHART 
 
 
 
 
 
 
 
     Included 
 
      Screening 
 
 
 
 
 
 
      
 
Sequence 
Drug 1 
Drug 2 
Drug 3 
1 
Sildenafil 
Placebo 
Cilostazol 
Identify Eligible Participants:  
1. Previous research participants providing 
consent for contact for future studies 
2. Direct referrals from clinicians 
3. Research database for consent to be 
contacted 
Baseline Visit (can be combined with screening) 
History & Examination                         Blood tests  
Cognitive Assessment         Physiological Assessment 
 
Randomisation 

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` 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 
Sildenafil 
Cilostazol 
Placebo 
3 
Cilostazol 
Sildenafil 
Placebo 
4 
Cilostazol 
Placebo 
Sildenafil 
5 
Placebo 
Sildenafil 
Cilostazol 
6 
Placebo 
Cilostazol 
Sildenafil 
Screening Visit: 
Review eligibility 
Detailed explanation of trial 
 
 
 
 
Medical History & Examination                
  Blood tests / Pregnancy Test / ECG 
Review medical records (if necessary) 
Screening phone-call ,patient invited and PIS 
sent in advance 
2 weeks Drug 1 – full dose 
Visit 2: 
History and examination 
Drug accountability 
Blood tests  
 
    Physiological Assessment 
MRI scan (60 patient subgroup) 
7 day BP 
Monitor 
Visit 3: 
History and examination 
Drug accountability 
Blood tests  
 
    Physiological Assessment 
MRI scan (60 patient subgroup) 
Visit 4: 
History and examination 
Drug accountability 
Blood tests  
 
    Physiological Assessment 
MRI scan (60 patient subgroup) 
CONSENT 
1 weeks Drug 1 – low dose 
2 weeks Drug 2 – full dose 
7 day BP 
Monitor 
1 weeks Drug 2 – low dose 
Washout (Minimum 1 week) 
2 weeks Drug 3 – full dose 
7 day BP 
Monitor 
1 weeks Drug 3 – low dose 
Washout (Minimum 1 week) 
Drug Allocation 
Drug free period (ideally 0-2 weeks) 
*Note that participants will only go up to the full dose if they are not on omeprazole.  

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7. PARTICIPANT IDENTIFICATION 
7.1. Study Participants 
75 patients with a history of a cryptogenic or lacunar stroke or probable TIA requiring treatment more 
than 1 month previously and mild-moderate small vessel disease. 
7.2. Inclusion Criteria 
 
• 
Participant is willing and able to give informed consent for participation in the study. 
• 
Male or Female, aged 18 years or above. 
• 
Can record MCA waveform on at least one side (‘useable TCD window’) 
• 
Non-disabling, ischaemic stroke or probable TIA requiring treatment, >1 month prior to 
randomisation, of either cryptogenic or lacunar aetiology, confirmed clinically or on brain imaging  
• 
White matter hyperintensities on MRI (Fazekas scale) or CT (Blennow scale) consistent with 
cerebral small vessel disease: 
o Age <60:  
MRI - Fazekas score   1 – 3  (max 2 points in periventricular or deep score) 
CT –   Blennow score 1 – 3  (max 2 points in periventricular or deep score) 
o Age >60: 
MRI - Fazekas score   1 – 4  (max 2 points in periventricular or deep score)  
CT – Blennow score   1 – 4  (max 2 points in periventricular or deep score) 
7.3. Exclusion Criteria 
 
• 
Pregnant or breastfeeding women, women of childbearing age not taking contraception.  
o Acceptable contraception in women of childbearing age is a “highly effective” 
contraceptive measure as defined by the Clinical Trials Facilitation Group 
(http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf) 
and 
includes combined (oestrogen and progesterone containing) or progesterone-only 
contraception associated with inhibition of ovulation, or intrauterine device or bilateral 
tubal occlusion 
• 
Other major neurological or psychiatric conditions affecting the brain and interfering with the 
study design (e.g. multiple sclerosis) 
• 
Other causes of stroke such as 
o 
≥50% luminal stenosis (NASCET) in large arteries supplying the infarct area 

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o 
major-risk cardioembolic source of embolism (permanent or paroxysmal atrial fibrillation, 
sustained atrial flutter, intracardiac thrombus, prosthetic cardiac valve, atrial myxoma or 
other cardiac tumours, mitral stenosis, recent (<4 weeks) myocardial infarction, left 
ventricular ejection fraction less than 30%, valvular vegetations, or infective endocarditis) 
o 
other specific causes of stroke (e.g. arteritis, dissection, drug misuse) 
• 
Large vessel occlusion on MRA or CTA (carotid, basilar or MCA) 
• 
Modified Rankin Score >3 (requires assistance to walk) 
• 
Unable to swallow 
• 
Renal impairment (eGFR <35ml/min)  
• 
Significant biochemical abnormalities (sodium <130, K+ <2.5 or >5.5, LFTs >3 x upper limit of 
normal range) 
• 
Life expectancy <2 years 
• 
Contraindication to active agents 
o 
Concurrent use of alphablocker 
o 
Regular use of nitrate (ISMN, GTN, other) 
o 
Heart failure (NYHA 2-4) 
o 
Severe aortic stenosis 
o 
Bilateral renal artery stenosis 
o 
Uncontrolled arrhythmias 
o 
Previous priapism 
o 
Anatomical deformation of the penis 
o 
Recent myocardial infarction (within 6 months) 
o 
Unstable angina 
o 
History of non-arteritic ischaemic optic neuropathy 
o 
Hypotension: BP <90/60 
o 
Haemodynamically significant aortic / mitral valve disease 
o 
Sickle cell disease, myeloma, leukaemia 
o 
Uncontrolled hypertension (BP >180/110 despite treatment with 3 antihypertensives) 
• 
Scheduled elective surgery or other procedures requiring general anaesthesia during the study. 
• 
Any other significant disease or disorder which, in the opinion of the Investigator, may either put 
the participants at risk because of participation in the study or the participant’s ability to 
participate in the study. 

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• 
Participants who have participated in another research study involving an investigational product 
in the past 12 weeks. 
• 
Use of an anticoagulant (warfarin, dabigatran, rivaroxaban etc) or more than one antiplatelet drug. 
• 
Predisposition to intracerebral haemorrhage (previous ICH, likely cerebral amyloid angiopathy) or 
intraocular haemorrhage (uncontrolled diabetic retinopathy or neovascularisation) 
• 
Allergy to constituents of medications or components of placebo / overencapsulation 
• 
Use of CYP induces that interact with study medications (ketoconazole, erythromycin). 
Exclusion criteria specific for MRI substudy: 
 
• 
Not able to transfer to MRI scanner 
• 
Active respiratory illness (such as moderate to severe asthma or COPD) such that they are unable 
to tolerate MRI or unable to lie flat 
• 
Claustrophobia 
• 
Contraindication to MRI scan (pacemaker, aneurysm clip etc) 
• 
Other significant brain disorder that may confound interpretation of MRI imaging (multiple 
sclerosis, brain tumour) 
8. STUDY PROCEDURES 
 
Participants will be recruited from multiple sites within travel distance of the John Radcliffe 
Hospital in Oxford, but the study visits will take place in Oxford (see below). 
Each participant will undergo a screening visit, a baseline visit (which can be combined with the 
screening visit if the test results required for determining eligibility are available) and 3 ‘on-medication’ 
visits. The screening visit will incorporate an assessment of eligibility and detailed trial explanation, 
followed by informed consent. They will then have a full medical history and examination, review of 
medical records, ECG (if one is not available from the previous year) and blood tests (if none available in 
the previous 3 months). They will then have a baseline study visit, either combined with the screening visit, 
if the availability of screening results permit, or within 1 month. At the baseline visit, they will undergo a 
repeat medical history for any events since the screening visit, repeat screening blood tests or ECG (if 
indicated), a formal cognitive assessment and a physiological assessment. If all eligibility criteria are 
fulfilled, they will be then assigned a study ID and associated randomisation schedule, followed by 
provision of allocated medication by the clinical trials pharmacy. Participants will then take each of 
placebo, sildenafil or cilostazol for 3 weeks each, in random order, at low dose for 1 week followed by 
titration to full dose for 2 weeks (minimum 11 days). Patients on omeprazole will not increase the dose 
after one week (due to an interaction with cilostazol). After visits 1 and 2, there will be a minimum of a 1 
week washout period prior to starting the new medication. On-treatment visits will include review for SAEs 
and a repeat core physiological assessment. All participants, up to a maximum of 60, will additionally be 
invited to undergo an MRI scan at follow ups on placebo and sildenafil (with up to thirty also being scanned 
on cilostazol). 
For participants who are unable to attend an on-treatment study visit once their medication has been 
started (for example due to the COVID-19 pandemic), then they will be able to restart treatment at the 

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point of stopping treatment, if still during the titration phase, but otherwise will restart three weeks of 
treatment from the beginning. The washout period can be prolonged as long as is necessary during the 
COVID-19 outbreak, before the next treatment phase is started. 
 
Activity / assessment  
Screening 
-21 to 0 
Baseline  
Day 0 
Visit 1 
Day 28 
   Visit 2  
Day 56 
Visit 3 
Day 84 
Informed Consent 
X 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical/ History 
X 
X 
 
 
 
Vital Signs 
X 
 
X 
X 
X 
Physical Exam 
X 
 
X 
X 
X 
Cognitive Assessment 
 
X 
 
 
 
Pregnancy Test*** 
(X) 
(X) 
(X) 
(X) 
(X) 
Laboratory Tests * 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
Randomisation 
 
X 
 
 
 
7 days home BP monitoring 
twice daily for 1 week 
 
X 
 
X 
 
X 
 
X 
 
Study drug dispensation 
 
X 
X 
X 
 
mRS (disability) 
 
X 
 
 
 
NIHSS (stroke severity) only for 
stroke patients 
 
X 
 
 
 
Drug accountability 
 
 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
Adverse Events (AE) 
 
X 
X 
X 
X 
Pulse wave velocity/ pulse wave 
analysis 
 
X 
X 
X 
X 
Transcranial (TCD)  ultrasound 
scan 
 
X 
X 
X 
X 
Beat-to-beat BP monitoring 
 
X 
X 
X 
X 
Peripheral Vascular Reactivity 
 
X 
X 
X 
X 
MRI assessment (60 patients) 
 
 
X 
X 
X 
* Laboratory Tests: FBC, U+Es, LFTs (screening and monitoring). Baseline tests will also include gamma-
GT, HbA1C, lipid profile, BNP or NT-proBNP. 
*** Pregnancy tests will only be applicable to women of child-bearing potential 
8.1. Recruitment 
Stroke clinicians and members of the clinical team at each Participation Identification Centre (including 
research staff associated with the clinical research network) will be asked to recommend potentially 
eligible patients, including patients who have previously been seen by the clinical service. Research nurses 
from the clinical research network will screen potential patients for eligibility, discuss the study with them 
face-to-face if attending for clinical follow-up or send a letter to patients at other times. Eligible patients 
will be provided invitation letters and the patient information sheet, including the contact details of the 
OxHARP core team at the Centre for Prevention of Stroke and Dementia, University of Oxford, and invited 
to contact the core team to discuss the study further. In all centres, patients who have provided specific 

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consent to be approached for further research studies, either as part of research databases or through 
previous clinical studies, will be contacted directly by managers of these research databases to invite them 
to participate in this study using their own materials.  
8.2. Screening and Eligibility Assessment 
Initial screening against eligibility criteria will be carried out against recorded demographic and clinical 
information, and then during the screening telephone call / visit. The patient information sheet will be 
sent to the potential participant prior to the baseline visit, with a minimum 1 week interval prior to the 
face-to-face assessment. At the screening visit, the study will be explained in detail, and the patient’s  
demographic details and clinical history reviewed, which may include review of the their medical notes (if 
necessary if the participant is unable to be detailed enough, done by secure correspondence with the 
clinical care team). After informed consent is provided, an ECG, physical exam and laboratory tests will be 
performed for screening purposes prior to randomisation, except where an ECG is available from the past 
year, or blood tests (U+Es, FBC) are available from the past 3 months, without a clinical event that would 
require repeat testing. 
8.3. Informed Consent 
Informed consent will be taken by the chief investigator, or a delegated study physician, compliant with 
GCP best practice. The participant must personally sign and date the latest approved version of the 
Informed Consent form before any study specific procedures are performed. Potential participants from 
Patient Identification Centres will be asked to contact the OxHARP clinical team and discuss the study first 
by telephone prior to arranging to visit the John Radcliffe for a formal screening visit.  
Written and verbal versions of the Participant Information Sheet and Informed Consent will be presented 
to the participants detailing no less than: the precise nature of the study; what it will involve for the 
participant; the implications and constraints of the protocol; the known side effects and any risks involved 
in taking part. It will be clearly stated that the participant is free to withdraw from the study at any time 
for any reason without prejudice to future care, without affecting their legal rights and with no obligation 
to give the reason for withdrawal. 
The participant will be allowed as much time as wished to consider the information, and the opportunity 
to question the Investigator, their GP or other independent parties to decide whether they will participate 
in the study. Written Informed Consent will then be obtained by means of participant dated signature and 
dated signature of the person who presented and obtained the Informed Consent. The person who 
obtained the consent must be suitably qualified and experienced, and have been authorised to do so by 
the Chief/Principal Investigator. A copy of the signed Informed Consent will be given to the participant. 
The original signed form will be retained at the study site in the study master file, with a copy in the 
patient’s medical notes. 
8.4. Randomisation, blinding and code-breaking 
Randomisation will be performed by the Huddersfield PMU at the point of overencapsulation of 
medication in advance of provision of treatments to the Oxford Clinical Trial pharmacy. Study numbers will 
then be provided in sequence to participants at the Oxford Clinical Trial pharmacy. Each sequential study 
ID will be randomly allocated to one of six different treatment schedules, as outlined in the drug allocation 

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table on page 11, to produce three groups of 12 and three groups of 13 patients. The randomisation 
schedule will be generated by Huddersfield PMU. 
The study will be blinded to the participant, blinded to the core study team (Dr Webb, Ms Amy Lawson, Dr 
Karolina Wartolowska) and blinded to the endpoint assessors (TCD measurement and MRI analysis). In 
patients consenting to the MRI substudy, the Trials pharmacy (or Dr Louise Silver, who is otherwise 
independent of the study), will identify the visit at which the participant will be taking cilostazol so that 
the MRI scans can be arranged, but will not inform the patient or core team when sildenafil or placebo are 
assigned. 
If clinical need requires unblinding of a specific patient, this will be done by the study pharmacist who will 
retain the randomisation schedule, following formal discussion with the Chief Investigator. Due to the low 
risk level associated with the study medication, and no specific medical intervention indicated for any 
potential complication that requires prior knowledge of current study treatment, emergency out of hours 
code-breaking is not required. 
8.5. Baseline Assessments 
 
Clinical Assessment 
Following assessment of eligibility and full informed consent at the screening visit, the participant will be 
interviewed for demographic details, medical history, a review of the their medical notes (if necessary if 
the participant is unable to be detailed enough) since screening and undergo a medical examination: 
• 
Vital signs (sitting blood pressure x2 with a BHS validated device, heart rate, oxygen 
saturations, temperature)  
• 
Cardiovascular examination (heart sounds, postural blood pressure) 
• 
Respiratory examination 
• 
Gastrointestinal examination 
• 
Neurological examination 
• 
National Institute of Health Stroke Scale (NIHSS) 
• 
Modified Rankin Score (mRS) 
• 
Montreal Cognitive Assessment (MoCA)  
• 
Fluid Intelligence and matching pairs cognitive assessments (Biobank protocol) 
Clinical Tests 
If an ECG within the previous year is not available, or the medical history indicates that a potential cardiac 
event has occurred since the last ECG, this will be performed prior to randomisation. In addition, if relevant 
blood tests are not available from the last 3 months, clinical blood tests (~10mls blood) will be performed 
for FBC, U+Es, LFTs, CRP, BNP or NT-proBNP, gamma-GT, lipid profile, HbA1C. In women of child-bearing 
potential, a pregnancy test will be performed. These initial clinical tests will be performed for screening 
according to the inclusion criteria (FBC, U+Es, LFTs), and used for demographic baseline data (CRP, BNP or 
NT-proBNP, gamma-GT, lipid profile, HbA1C). At each follow-up visit, we will repeat FBC, U+Es, LFTs for 
monitoring effects of initiating medications. 

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All patients that have consented to the study will also have twenty millilitres of blood taken at baseline for 
storage and later analysis. In patients this will be drawn, where possible, at the same time as the screening 
visit bloods. Serum, plasma, buffy coat and whole blood samples are prepared and transferred to 
cryotubes. Each cryotube is labelled with a unique identification number, recorded in the specimen 
logbook and frozen at –85 0C. All bloods samples are stored in freezers in laboratories in the Wolfson 
Centre for Prevention of Stroke and Dementia for up to 2 years after final recruitment to the study, to 
allow for analysis of the samples. Samples will be tested for biomarkers that predict response to the 
randomized treatment allocation in the study, and for correlation with severity of baseline white matter 
hyperintensities (to determine interaction with treatment effect). Blood will be stored and then analysed 
at completion of the study, as the extent of testing will depend upon the demonstrated effect of 
medications in the study, whilst allowing for assessment of new biochemical and genetic markers reported 
during the study, in this rapidly developing field. As a minimum, markers of endothelial function (ICAM, 
VEGF, vWF) and genetic targets of the medications in the trial, shown to be associated with small small 
vessel disease (ie PDE3 polymorphisms), will be measured. These will not specifically include tests of direct 
clinical relevance to the participant and are very unlikely to have clinical implications. In the unlikely 
circumstance that incidental biomarker or genetic results that could be relevant to the participant are 
identified, these will be assessed by an independent physician (Peter Rothwell), the participant informed 
and a referral made to an appropriate specialty, where clinically indicated. 
Physiological Assessment 
Central Aortic Blood Pressure / Aortic Pulse Wave Velocity (10 minutes) 
Radial artery pulse waveforms will be recorded using a pressure tonometer and designated software 
(SphygmoCor, At-Cor Medical, Sydney, Australia). Briefly, mean values of approximately 10 radial pulse 
waves will be used to generate a corresponding central aortic pressure waveform with a validated 
mathematical transfer function. A minimum of 10 radial artery pulse waveforms are required by the 
software to calculate the AIx and to also derive an operator index (indicating the quality and reproducibility 
of the arterial signal (SphygmoCor, At-Cor Medical, Sydney, Australia).  
Aortic arterial stiffness will be assessed by the gold standard technique of carotid-femoral pulse wave 
velocity. This requires recording of the pulse wave by applanation tonometry with the SphygmoCor device 
from both carotid and femoral arteries, and the speed of transmission between the two sites used to 
estimate the velocity of the pulse wave. This provides a measure of the stiffness of the central arteries. 
Transcranial Doppler Ultrasound (TCD) 
TCD will be performed with DiaMon 2MHz probes, firstly with a handheld probe to best identify the middle 
cerebral and basilar arteries, with application of ultrasound gel over the temporal (in front of the ear) and 
suboccipital windows (at the nape of the neck). The M1 segment will be identified between 45-55mm 
depth as the segment of the artery with blood flow towards the probe, slightly superficial to a site of 
bifurcation into another vessel with flow away from the probe (the anterior cerebral artery), with blood 
flow towards the probe ideally extending for at least 1cm within the skull. The basilar artery will be idenfied 
via the trans-foramen magnum bone window, identifying blood flowing away from the probe at >75mm. 
The maximal velocity in these segments will be identified and peak, trough and mean blood flow velocities 
will be derived from the wave form envelope, taking the average of at least 5 cardiac cycles. From these 
measures Gosling’s pulsatility index will be derived as the primary measure of cerebral pulsatility. Where 
bone windows are adequate (ie MCA blood flow can be insonated via the temporal bone), bilateral 

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monitoring insonation of the middle cerebral  artery will be established with 2 probes held to the head a 
with a comfortable headset, with spectra acquired by a DWL Doppler Box to a dedicated laptop. This 
waveform will be acquired over 10 minutes with concurrent heart rate and blood pressure monitoring (see 
below). End-tidal carbon dioxide monitoring will be performed with AD Instruments Gas Analyser ML206. 
All waveforms will be simultaneously acquired with a AD Instruments Powerlab 8/35. 
Continuous non-invasive blood pressure monitoring 
Continuous ECG and BP will be recorded using a Finometer (BP monitor which allows continuous non-
invasive assessment of finger arterial pressure). After a period of at least 5 minutes of rest and after 
achievement of a satisfactory BP signal from the monitor and the stabilization of BP at the same level, 
recordings will be performed for up to 10 minutes (minimum 5 minutes). The outputs from the Finometer 
and simultaneous surface ECG recordings will be analysed to estimate cerebral autoregulation and 
transmission of arterial pulsatility using in-house analysis programs written in Matlab, according to both 
sequential and spectral methods. The system will be allowed to establish a stable internal calibration 
before this function is turned off for the monitoring period. A standard brachial blood pressure will be 
obtained twice with a calibrated device (A&D UA-767 BT) from the contralateral arm twice, and the 
Finometer trace calibrated to this reading by 2 point calibration. 
Cerebral Autoregulation (10 minutes) 
 
Once established, bilateral TCD, blood pressure, ECG and end-tidal CO2 will be acquired simultaneously 
for 5 minutes after a minimum of 5 minutes of supine rest. Continuous systolic, diastolic and mean values 
will be derived and related to each other by transfer function analysis using in-house software written in 
Matlab. This allows estimation of baroreceptor sensitivity and cerebral autoregulation.  
 
CO2 reactivity (10 minutes) 
 
Following the period of monitoring, reactivity to CO2 will be assessed by 3 minutes of inhalation of 6% 
CO2, delivered via a respiratory circuit with a non-invasive ventilation mask and harness, supplied with 2 
alternating periods of medical air versus 6%CO2/21%O2/balance N2. The resulting increase in MCA mean 
flow velocity on TCD will be related to the change in end-tidal CO2 to determine the vasodilatory response, 
adjusted for any change in blood pressure. Secondly, the participant will be instructed to hyperventilate 
at 1 breath per second for 30 seconds to reduce etCO2 and estimate change in mean flow velocity per unit 
change in etCO2. 
 
Peripheral Vascular Reactivity (10 minutes) 
Effects of medication on peripheral endothelial function will be estimated by assessment of flow-mediated 
slowing (Vicorder, Skidmore Industries). This determines the change in speed of flow of the pressure 
waveform between two sites in the arm, before and after a short period of occlusion. This induces 
endothelium dependent vasodilatation, which results in slowing of the speed of blood flow. If the previous 
tests last >60 minutes to achieve accurate measurements, or if the participant finds this procedure too 
uncomfortable this element may be omitted at follow up visits. 
Blood pressure monitoring 
Patients will be provided with a home blood pressure monitor to record their blood pressure twice daily 
(on waking and evening), recorded three times at each sitting, for 7 days prior to their subsequent study 
visit (A&D UA-767 BT). Patients will be asked to record their blood pressure readings and return them for 

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assessment of how allocated treatment affects blood pressure, and how this may interact with the primary 
outcome measure. If potential symptoms of hypotension occur, patients may be requested to perform 
additional readings for clinical safety purposes. Participants will be asked to record any side-effects on the 
same diary card as used for blood pressure monitoring. 
Medication Dispensation 
Study medication / placebo will be dispensed by the Oxford University Clinical Trials Pharmacy after 
randomisation.  
8.6. Subsequent Visits 
 
Participants will be reviewed at visits 2, 3 and 4 (3, 6-7 and 11-13 weeks respectively) following sequential, 
blinded treatment in random order with the study drugs, sildenafil and cilostazol, and placebo for 3 weeks. 
At each follow up visit they will undergo assessment of potential side effects or unwanted effects 
(SAEs/SUSARS – see below), including repeat clinical examination and repeat blood tests, as at the baseline 
visit. Concomitant medications will be recorded, and compliance with study drugs will be assessed by 
questionnaire and by counting of returned study drug.  
Following clinical assessment, the physiological assessment will be repeated as the primary study outcome 
(pulsatility index). Then the next drug will be dispensed, and any residual drug will be returned. 
8.7. MRI Sub-Study 
In 60 consenting patients an additional MRI assessment will be performed at each of the follow-up visits 
on sildenafil and placebo, and up to 30 on cilostazol, to assess cerebrovascular haemodynamics in greater 
detail. This may involve the following sequences, with a minimum requirement to have FLAIR and SWI 
images at a minimum of one timepoint and T1, arterial spin labelling and CO2 reactivity scanning at both 
timepoints : 
At first MRI visit: 
• 
T1 structural image (volume 3D acquisition, 1mm isotropic) 
• 
FLAIR (for quantification of white matter hyperintensities) 
• 
Susceptibility weighted imaging 
• 
Arterial Spin Labelling : 4 vessel selective, non-contrast perfusion imaging (pcASL), to estimate 
baseline absolute cerebral blood flow 
• 
High frequency, multiband BOLD imaging, optimised for pulsatility of blood flow (pulse-MB, TR 
0.4) – 7 minutes monitoring. 
• 
Standard multiband BOLD imaging (according to BioBank imaging protocol) with 5 minutes of 
fixation on a blank screen, viewing intermittent blank screens then a radial flashing checkerboards. 
• 
Carbon dioxide challenge with inhalation of 6% CO2 in medical air in 3 minute blocks, interposed 
with 2 minute blocks of breathing medical air, delivered via an open respiratory circuit with one 
way valves. Throughout imaging, the participant will have physiological blood pressure, end-tidal 
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At second / third MRI visits: 
• 
T1 structural image (volume 3D acquisition, 1mm isotropic) 
• 
Diffusion tensor imaging (DTI – 64 directions, for estimation of mean diffusitivity and fractional 
anisotropy as sensitive measures of white matter injury) (only at second visit) 
• 
Arterial Spin Labelling : 4 vessel selective, non-contrast perfusion imaging (pcASL), to estimate 
baseline absolute cerebral blood flow 
• 
High frequency, multiband BOLD imaging, optimised for pulsatility of blood flow (pulse-MB, TR 
0.4) – 7 minutes monitoring. 
• 
Standard multiband BOLD imaging (according to BioBank imaging protocol) with 5 minutes of 
fixation on a blank screen, viewing intermittent blank screens then a radial flashing checkerboards. 
• 
Carbon dioxide challenge with inhalation of 6% CO2 in medical air in 3 minute blocks, interposed 
with 2 minute blocks of breathing medical air, delivered via an open respiratory circuit with one 
way valves. Throughout imaging, the participant will have physiological blood pressure, end-tidal 
CO2 and oxygen saturation monitoring. 
8.8. Sample Handling 
All clinical blood tests will be taken for clinical screening and safety purposes and processed via the Oxford 
University Hospitals NHS Trust laboratory, after which the samples will be disposed of according to local 
procedures. For research samples, serum, plasma, buffy coat and whole blood samples are prepared and 
transferred to cryotubes. Each cryotube is labelled with a unique identification number, recorded in the 
specimen logbook and frozen at –85 0C. All bloods samples are stored in freezers in laboratories in the 
Wolfson Centre for Prevention of Stroke and Dementia 
8.9. Discontinuation/Withdrawal of Participants from Study Treatment 
Each participant has the right to withdraw from the study at any time.  In addition, the Investigator may 
discontinue a participant from the study at any time if the Investigator considers it necessary for any 
reason including: 
• 
Pregnancy 
• 
Ineligibility (either arising during the study or retrospectively having been overlooked at screening) 
• 
Significant protocol deviation 
• 
Significant non-compliance with treatment regimen or study requirements 
• 
An adverse event which requires discontinuation of the study medication or results in inability to 
continue to comply with study procedures 
• 
Withdrawal of Consent 
• 
Loss to follow up 
Any data acquired up to the point of withdrawal from the study will be retained except in circumstances 
where the participant explicitly withdraws consent for this. Participants will not be replaced. 
The reason for withdrawal will be recorded in the CRF. 
If the participant is withdrawn due to an adverse event, the Investigator will arrange for follow-up visits or 
telephone calls until the adverse event has resolved or stabilised. 

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If an individual experiences side-effects on the first treatment, such that they can not continue, they will 
still be eligible to proceed to the next stage. Similarly, if patients are unable to tolerate study procedures 
related to secondary study outcomes (ie CO2 reactivity testing or MRI imaging), they will be able to 
continue with the study for the purposes of the primary outcome measures (TCD pulsatility index) but not 
undergo the non-tolerated component. This option will only be provided when the participant expresses 
a desire to withdraw from the study due to intolerability of the test. If participants withdraw from the 
study due to clinically significant adverse events, then they will continue to be monitored by the study 
team until resolution of the adverse event. 
8.10. 
Definition of End of Study 
The end of active patient management is the date of the last visit of the last participant (LVLP), but blood 
will be stored for up to 2 years after LVLP for analysis, 
9. INVESTIGATIONAL MEDICINAL PRODUCT (IMP) 
9.1. IMP Description 
 
The principal IMP is oral sildenafil, given at 25mg TDS for one week, then automatically increased to 50mg 
TDS for a further 2 weeks, if tolerated, as determined by its provision in labelled dispensing packs. If side-
effects occur at the higher dose, the dose will be returned to the lower dose. Sildenafil is a 
phosphodiesterase 5 inhibitor, widely used for erectile dysfunction and used in selected patients with 
primary pulmonary hypertension.  
The comparator will be placebo, also taken three times daily. 
The secondary comparator IMP is cilostazol, as a positive control, provided at 50mg bd and titrated to 
100mg bd after one week, to continue for 2 further weeks. Cilostazol is a phosphodiesterase 3 inhibitor 
used at this dose in peripheral arterial disease, and used in large randomised controlled Trials of patients 
with previous stroke, with a beneficial effect compared to aspirin.19 It is expected to improve cerebral 
reactivity22 and pulsatility20 and is included as a positive control to assess whether sildenafil has a similar 
magnitude of physiological effect, to estimate if a sufficient magnitude of clinical effect would be expected, 
to justify larger clinical trials. In order to preserve the blinding of this study, whilst taking cilostazol twice 
a day participants will be given placebo to take at midday. This means that, from the participant’s 
perspective, they are always taking the study medication three times daily.  
Participants will start sildenafil and cilostazol at lower doses for a week before being titrated up to the high 
dose. The high dose is similar to the medication’s use in usual care, given more frequently in the case of 
sildenafil, but the titration is necessary to settle the participants on the new medication.  
Medications will be overencapsulated, overlabelled and blinded by the Huddersfield NHS Pharmacy 
Manufacturing Unit, and dispensed by the Oxford University Clinical Trials pharmacy. Medications will be 
provided in ‘dosette’ type packaging providing dosing times, such that throughout the study patients will 
take TDS medication (sildenafil TDS, placebo TDS, cilostazol – placebo – cilostazol). Code-break will be 

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provided to and retained by the Oxford University Clinical Trials Pharmacy, with individual code-breaking 
allowed on request of the CI (Dr Alastair Webb) when clinically indicated.  
For each treatment, medication will be provided as one tablet three times a day for one week, followed 
by 2 tablets 3 times per day. If side effects occur on the higher dose, the participant will decrease back to 
one tablet 3 times per day, on discussion with an OxHARP physician. Participants will not be moved on to 
the higher dose if they are also taking omeprazole due to an interaction with cilostazol.  
Labelling and quality control will be performed by Huddersfield PMU according to Volume 4. Good 
Manufacturing Practices, Annex 13. Manufacture of investigational medicinal products, July 2010. 
9.2. Storage of IMP 
Medication and placebo will be stored in the Oxford University Clinical Trials pharmacy in recommended 
conditions, according to pharmacy Standard Operating Procedures. All medications are stable at room 
temperature for ease of storage by participants. 
9.3. Compliance with Study Treatment 
Participants will be required to return any unused medications and associated packaging for drug 
reconciliation at visits 2 and 3. The packaging will incorporate a dosing schedule allowing accurate 
accounting of compliance. 
9.4. Accountability of the Study Treatment 
 
All study medications will be dispensed by the Oxford University Clinical Trials Pharmacy, who will take 
principal responsibility for drug accountability. Dispensed medications will be documented, and 
participants will return all study medications to the study pharmacy after each study visit. Number of 
returned medication will be recorded. 
9.5. Concomitant Medication 
All concomitant medications will be listed at each study visit. Concomitant use of other PDE5 inhibitors 
(sildenafil, vardenafil) or other PDE inhibitors (cilostazol) will not be allowed. Similarly, concomitant use of 
alpha-blockers, nitrates (GTN, ISMN, nicorandil) or direct vasodilators (hydralazine, naftidofuryl) will not 
be allowed. Use of anticoagulants or more than one antiplatelet agent will also be contraindicated. If a 
clinical need for these medications arises, the participant will be withdrawn from the study. 
9.6. Post-study Treatment 
The IMP will not be provided beyond the duration of the study. 
10. SAFETY REPORTING 
10.1. 
Definitions 

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Adverse Event (AE) 
Any untoward medical occurrence in a participant to whom a medicinal 
product has been administered, including occurrences which are not 
necessarily caused by or related to that product. 
Adverse Reaction (AR) 
 
An untoward and unintended response in a participant to an 
investigational medicinal product which is related to any dose 
administered to that participant. 
The phrase "response to an investigational medicinal product" means 
that a causal relationship between a study medication and an AE is at 
least a reasonable possibility, i.e. the relationship cannot be ruled out. 
All cases judged by either the reporting medically qualified professional 
or the Sponsor as having a reasonable suspected causal relationship to 
the study medication qualify as adverse reactions. 
Serious 
Adverse 
Event 
(SAE) 
A serious adverse event is any untoward medical occurrence that: 
• results in death 
• is life-threatening 
• requires inpatient hospitalisation or prolongation of existing 
hospitalisation 
• results in persistent or significant disability/incapacity 
• consists of a congenital anomaly or birth defect. 
Other ‘important medical events’ may also be considered serious if they 
jeopardise the participant or require an intervention to prevent one of 
the above consequences. 
NOTE: The term "life-threatening" in the definition of "serious" refers to 
an event in which 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. 
Serious Adverse Reaction 
(SAR) 
An adverse event that is both serious and, in the opinion of the reporting 
Investigator, believed with reasonable probability to be due to one of 
the study treatments, based on the information provided. 
Suspected 
Unexpected 
Serious Adverse Reaction 
(SUSAR) 
A serious adverse reaction, the nature and severity of which is not 
consistent with the information about the medicinal product in question 
set out: 
• in the case of a product with a marketing authorisation, in the 
summary of product characteristics (SmPC) for that product 
• in the case of any other investigational medicinal product, in the 
investigator’s brochure (IB) relating to the study in question. 
 

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NB: to avoid confusion or misunderstanding of the difference between the terms “serious” and “severe”, 
the following note of clarification is provided: “Severe” is often used to describe intensity of a specific 
event, which may be of relatively minor medical significance. “Seriousness” is the regulatory definition 
supplied above. 
Any pregnancy occurring during the clinical study and the outcome of the pregnancy should be recorded 
and followed up for congenital abnormality or birth defect, at which point it would fall within the definition 
of “serious”. 
Safety data will be routinely collected at each follow-up, including clinical history of side effects or adverse 
events, clinical examination and blood tests (FBC, U+Es, LFTs). Patients will also be provided a telephone 
number to contact in case of side effects, and if the side effects suggest possible hypotension, may be 
asked to perform additional BP monitoring. 
10.2. 
Causality 
The relationship of each adverse event to the study medication must be determined by a medically 
qualified individual according to the following definitions: 
Related: The adverse event follows a reasonable temporal sequence from study medication 
administration. It cannot reasonably be attributed to any other cause. 
Not Related: The adverse event is probably produced by the participant’s clinical state or by other modes 
of therapy administered to the participant. 
10.3. 
Procedures for Recording Adverse Events 
All AEs occurring during the study that are observed by the Investigator or reported by the participant, will 
be recorded on the CRF, whether or not attributed to study medication. 
The following information will be recorded: description, date of onset and end date, severity, assessment 
of relatedness to study medication, other suspect drug or device and action taken.  Follow-up information 
should be provided as necessary. 
The severity of events will be assessed on the following scale:  1 = mild, 2 = moderate, 3 = severe. 
AEs considered related to the study medication as judged by a medically qualified investigator or the 
Sponsor will be followed either until resolution, or the event is considered stable. 
It will be left to the Investigator’s clinical judgment to decide whether or not an AE is of sufficient severity 
to require the participant’s removal from treatment.  A participant may also voluntarily withdraw from 
treatment due to what he or she perceives as an intolerable AE.  If either of these occurs, the participant 
will undergo an end of study assessment and be given appropriate care under medical supervision until 
symptoms cease, or the condition becomes stable. 
10.4. 
Reporting Procedures for Serious Adverse Events 
SAEs will be recorded and deemed reportable for up to 30 days following last administration of a trial drug, 
whether occurring after the end of the trial or between trial phases following a prolonged washout period.  

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All SAEs (other than those defined in the protocol as not requiring reporting) must be reported on the SAE 
reporting form to the DSMB within 24 hours of the Site Study Team becoming aware of the event. It will 
also be reviewed at the next DSMB meeting.  Additional and further requested information (follow-up or 
corrections to the original case) will be detailed on a new SAE Report Form and emailed to the DSMB as 
requested. The DSMB will review all AEs and SAEs on a yearly basis. 
10.5. 
Expectedness 
Expectedness will be determined according to the Summary of Product Characteristics by the study 
principal investigator. 
10.6. 
SUSAR Reporting 
All SUSARs will be reported by the CI to the sponsor and the REC and other parties as applicable. For fatal 
and life-threatening SUSARS, this will be done no later than 7 calendar days after the Sponsor or delegate 
is first aware of the reaction. Any additional relevant information will be reported within 8 calendar days 
of the initial report. All other SUSARs will be reported within 15 calendar days. Events reported to the REC 
will use the HRA report of serious adverse event form (see HRA website).  
Treatment codes will be un-blinded for specific participants.  
Principal Investigators will be informed of all SUSARs for the relevant IMP for all studies with the same 
Sponsor, whether or not the event occurred in the current study. 
10.7. 
Safety Monitoring Committee 
 
A Data Safety and Monitoring Board will conduct a review of all SAEs for the study reported during the 
quarter and cumulatively. The aims of this committee include: 
• 
To pick up any trends, such as increases in un/expected events, and take appropriate action 
• 
To seek additional advice or information from investigators where required 
• 
To evaluate the risk of the study continuing and take appropriate action where necessary 
The Data and Safety Monitoring Board have reviewed the study protocol, will be informed of SAEs yearly, 
and will perform an interim safety assessment after 30 patients have been recruited (or 12 months have 
elapsed). If recruitment is excessively slow, the DSMB may recommend either that the study is stopped, 
or that the cilostazol phase of the study is removed and subsequent patients are only randomised to 
sildenafil vs placebo in random order. With removal of the third arm of the study, the overall population 
size would also be reduced to 50 patients. 
11. STATISTICS 
11.1. 
Description of Statistical Methods 
 
A statistical analysis plan will be signed off prior to analysis.  

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Primary outcome : 
Change in Gosling’s Pulsatility Index from baseline to follow up, utilising the visually-assessed, better 
quality TCD recording (defined by blinded assessor) will be compared between sildenafil and placebo 
phases by paired T-test, comparing change in MCA-PI from baseline to after 3 weeks of treatment.   
Secondary outcome:  
The non-inferiority analysis will be based on the 95% CI for the mean change difference between sildenafil 
and cilostazol. If the upper 97.5% confidence limit is less than 0.08 units (2/3 of the clinically estimated 
overall cilostazol effect), non-inferiority will be declared. 
Differences in reactivity to CO2 from baseline in each of three states (sildenafil, cilostazol, placebo) will be 
compared by mixed-effect general linear models, with post-hoc pairwise comparison. 
Tertiary outcomes 
Equivalent statistical techniques will be used to determine responses to each of the further physiological 
measures for sildenafil versus placebo  as the primary comparison (paired t-test for continuous outcomes), 
and mixed-effect linear models across the three groups. MRI imaging outcomes will be compared by 
analysis tools within the FSL software library, utilising linear models for interaction between drug 
allocation and BOLD-response to carbon dioxide. Secondly, the relevance of derived physiological indices 
including  home blood pressure, arterial stiffness, cerebral autoregulation, peripheral vascular reactivity 
and beat-to-beat blood pressure variability will be determined both as predictors of cerebral pulsatility 
and autoregulation in linear models, and for the interaction between drug class and these indices on 
cerebral pulsatility and reactivity. 
Individuals missing either sildenafil or placebo interventions will be excluded from the analysis 
corresponding to the primary objective but included in the safety analysis. Participants without cilostazol 
exposure will be included in the sildenafil-placebo comparison, but not in the - secondary and tertiary 
analyses.  
Safety data will be presented for all patients who are randomised and receive at least one dose of one 
treatment. Safety data will be summarised descriptively. 
Genetic / biochemical predictors of response to treatment will be assessed by mixed linear models for 
continuous outcomes, and paired t-test for binary measures. 
 
11.2. 
The Number of Participants 
75 patients will be recruited to the study. All participants will be invited to optionally participate in the 
MRI substudy of  whom at least 30 will be imaged on sildenafil and placebo alone, and up to 30 on all three 
treatments. Participants who leave the study before taking any trial medication will be replaced. 
Participants unable to tolerate the MRI scan will continue in the main study, but will be replaced by new 
recruitment to the substudy, where necessary. 
 
 

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11.3. 
The Level of Statistical Significance 
 
At a power level of 0.9, with a 2-sided significance of 5%, a clinically relevant 0.12 unit change in pulsatility 
index (equivalent to a ~20% difference in risk of recurrent stroke), and conservatively allowing for a 
standard deviation of differences in PI between repeated measures of 0.2, gives an estimated minimum 
sample size of 32 patients (paired t-test). Allowing for a 15% drop-out rate, 38 patients would be required. 
A sample size of 66 achieves 90% power to detect the non-inferiority of sildenafil c.f. cilostazol using a non-
inferiority margin of 0.08 (and mean of paired differences 0) at α=0.025 (for a 95% CI) with a within-subject 
variance of 0.02 (equivalent to a SD of differences 0..23,24 This equates to 75 patients in total with a 12% 
drop out rate. 
A two-sided 5% significance level will be used for all hypothesis tests. 
 
11.4. 
Criteria for the Termination of the Study 
A Data and Safety Monitoring Board will be established. They will review the data after 30 patients have 
been recruited to the study, or 12 months after the first visit of the first patient (whichever is sooner), or 
at the request of the sponsor or CI. If a decision to terminate the study is contemplated, this will be 
discussed with the CI and the sponsor prior to a final decision being made. 
The advisory recruitment threshold is set at projected recruitment of <35 patients in 2 years, allowing 
for any delays resulting from the COVID-19 pandemic. No threshold is defined for efficacy for study 
cessation. Any statistically significant excess of SAEs in the treatment arm, or occurrence of unexpected 
treatment-related SAEs of sufficient severity (in the view of the DSMB), may also result in early cessation 
of the study. If after 12 months the recruitment falls below the rate expected to complete the study in 3 
years, allowing for delays due to the COVID-19 outbreak, the overall study size can be reduced to 50 
participants. Any data collected to that date, including on cilostazol, will be retained and analysed 
according to the original study plan. An interim statistical analysis plan will be signed off prior to the interim 
analyses. 
11.5. 
Procedure for Accounting for Missing, Unused, and Spurious Data. 
All physiological data will reviewed and cleaned by automated and manual processes to reduce artefactual 
data. Data will be defined as artefactual or missing. The statistical analysis plan will describe the procedure 
for accounting for missing or spurious data. The completeness and correctness of the data will be 
monitored as per the monitoring plan 
11.6. 
Inclusion in Analysis 
All possible data will be used on an intention-to-treat basis, but where patient withdrawal results in missing 
data, the final primary analysis will only include patients where primary outcome data is available 
(Gosling’s MCA-PI). 
11.7. 
Procedures for Reporting any Deviation(s) from the Original Statistical Plan 
All deviations from the statistical analysis plan for the study will be reported in the final report of the study. 

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12. DATA MANAGEMENT 
12.1. 
Source Data 
 
Source documents are where data are first recorded, and from which participants’ CRF data are obtained. 
These include, but are not limited to, hospital records (from which medical history and previous and 
concurrent medication may be summarised into the CRF), clinical and office charts, laboratory and 
pharmacy records, diaries, microfiches, radiographs, and correspondence. 
CRF entries will be considered source data if the CRF is the site of the original recording (e.g. there is no 
other written or electronic record of data).  All documents will be stored safely in confidential conditions. 
On all study-specific documents, other than the signed consent, the participant will be referred to by the 
study participant number/code, not by name. 
12.2. 
Access to Data 
Direct access will be granted to authorised representatives from the Sponsor, host institution and the 
regulatory authorities to permit study-related monitoring, audits and inspections. 
12.3. 
Data Recording and Record Keeping 
All study data will be entered and stored on paper CRFs. The participants will be identified by a unique 
study specific number and/or code in any database. The name and any other identifying detail will NOT be 
included in any study data electronic file.  
13. QUALITY ASSURANCE PROCEDURES 
The study will be conducted in accordance with the current approved protocol, GCP, relevant regulations 
and standard operating procedures. 
Regular monitoring will be performed according to GCP. Data will be evaluated for compliance with the 
protocol and accuracy in relation to source documents. Following written standard operating procedures, 
the monitors will verify that the clinical study is conducted and data are generated, documented and 
reported in compliance with the protocol, GCP and the applicable regulatory requirements. 
14. ETHICAL AND REGULATORY CONSIDERATIONS 
14.1. 
Declaration of Helsinki 
The Investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki.  
14.2. 
Guidelines for Good Clinical Practice 
The Investigator will ensure that this study is conducted in accordance with relevant regulations and with 
Good Clinical Practice. 

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14.3. 
Approvals 
The protocol, informed consent form, participant information sheet and any proposed advertising material 
will be submitted to an appropriate Research Ethics Committee (REC), HRA (where required), and host 
institution(s) for written approval. 
The Investigator will submit and, where necessary, obtain approval from the above parties for all 
substantial amendments to the original approved documents. 
14.4. 
Reporting 
The CI shall submit once a year throughout the clinical study, or on request, an Annual Progress Report to 
the REC, HRA (where required), host organisation and Sponsor.  In addition, an End of Study notification 
and final report will be submitted to the MHRA, the REC, host organisation and Sponsor. 
14.5. 
Participant Confidentiality 
The study staff will ensure that the participants’ anonymity is maintained.  The participants will be 
identified only by a participant ID number on all study documents and any electronic database, with the 
exception of the CRF, where participant initials may be added.  All documents will be stored securely and 
only accessible by study staff and authorised personnel. The study will comply with the Data Protection 
Act, which requires data to be anonymised as soon as it is practical to do so, and the General Data 
Protection Regulation to ensure transparency and confidentiality of data use. 
14.6. 
Expenses and Benefits 
Reasonable travel expenses for any visits additional to normal care will be reimbursed on production of 
receipts, or a mileage allowance provided as appropriate. 
14.7. 
Other Ethical Considerations 
 
Potential incidental findings detected on brain imaging will be reviewed by the study Chief Investigator 
(Dr Alastair Webb). If deemed to be potentially clinically significant, this will be they will then be reviewed 
under the fMRIB SOP for incidental findings, including referral to an independent neurologist (Prof Martin 
Turner), review by a neuroradiologist if indicated and an independent clinical appointment arranged for 
the patient with the independent neurologist to discuss the findings and any implications. If this process 
is required, the chief investigator will inform the participant that an incidental finding has been identified 
on their brain scan and that they will have the opportunity to discuss this with an independent neurologist 
if they wish. 
Incidental findings identified on physiological testing or clinical examination will be reviewed by the 
study chief investigator. If any clinical action needs to be taken, the chief investigator will discuss this with 
the participant and contact the participants GP to initiate an appropriate clinical response. 
If patients lose capacity during the study, they will be withdrawn from the study and their GP will be 
informed. If this occurs as a result of study procedures or treatments, they will be followed up by the study 

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team until resolution of the adverse event or until they are clinically stable. Data collected up to the point 
of their withdrawal from the study will be retained. 
Finally, male participants will be asked if they have a deformity of the penis which is a contraindication 
to use of sildenafil due to an increased risk of priapism. This is a personal question but will be asked 
sensitively by an experienced physician. 
15. FINANCE AND INSURANCE 
15.1. 
Funding 
The study is funded through a Wellcome Trust Clinical Research Career Development Fellowship, held by 
the Chief Investigator (AW). 
15.2. 
Insurance 
The University has a specialist insurance policy in place which would operate in the event of any participant 
suffering harm as a result of their involvement in the research (Newline Underwriting Management Ltd, at 
Lloyd’s of London).  NHS indemnity operates in respect of the clinical treatment that is provided. 
16. PUBLICATION POLICY 
Any publications resulting from this study will be authored by the chief investigator and any additional 
study physicians recruited to the study in the future. In addition, any substantive contribution in recruiting 
and monitoring patients at non-core sites (Reading, High Wycombe, Swindon) will be recognised by 
authorship / acknowledgement, depending upon the level of involvement. There is no expectation that 
this study will generate intellectual property. 
17. REFERENCES 
1. 
Lau KK, Li L, Schulz U, et al. Total small vessel disease score and risk of recurrent stroke: Validation 
in 2 large cohorts. Neurology. 2017;88(24):2260-2267. 
2. 
Smith EE, Egorova S, Blacker D, et al. Magnetic resonance imaging white matter hyperintensities 
and brain volume in the prediction of mild cognitive impairment and dementia. Arch Neurol. 
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3. 
Teodorczuk A, Firbank MJ, Pantoni L, et al. Relationship between baseline white-matter changes 
and development of late-life depressive symptoms: 3-year results from the LADIS study. Psychol 
Med. 2010;40(4):603-610. 
4. 
Inzitari D, Pracucci G, Poggesi A, et al. Changes in white matter as determinant of global functional 
decline in older independent outpatients: three year follow-up of LADIS (leukoaraiosis and 
disability) study cohort. BMJ. 2009;339:b2477. 
5. 
Rensma SP, van Sloten TT, Launer LJ, Stehouwer CDA. Cerebral small vessel disease and risk of 
incident stroke, dementia and depression, and all-cause mortality: A systematic review and meta-
analysis. Neurosci Biobehav Rev. 2018;90:164-173. 
6. 
Wardlaw JM, Smith EE, Biessels GJ, et al. Neuroimaging standards for research into small vessel 
disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013;12(8):822-838. 
7. 
Gardener H, Wright CB, Rundek T, Sacco RL. Brain health and shared risk factors for dementia and 
stroke. Nature Reviews Neurology. 2015;11(11):651-657. 

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8. 
Webb AJ, Simoni M, Mazzucco S, Kuker W, Schulz U, Rothwell PM. Increased cerebral arterial 
pulsatility in patients with leukoaraiosis: arterial stiffness enhances transmission of aortic 
pulsatility. Stroke. 2012;43(10):2631-2636. 
9. 
Molina C, Sabin JA, Montaner J, Rovira A, Abilleira S, Codina A. Impaired cerebrovascular reactivity 
as a risk marker for first-ever lacunar infarction: A case-control study. Stroke. 1999;30(11):2296-
2301. 
10. 
Simoni M, Li L, Paul NL, et al. Age- and sex-specific rates of leukoaraiosis in TIA and stroke patients: 
population-based study. Neurology. 2012;79(12):1215-1222. 
11. 
Li L, Schulz UG, Kuker W, Rothwell PM, Oxford Vascular S. Age-specific association of migraine with 
cryptogenic TIA and stroke: Population-based study. Neurology. 2015;85(17):1444-1451. 
12. 
Li L, Yiin GS, Geraghty OC, et al. Incidence, outcome, risk factors, and long-term prognosis of 
cryptogenic transient ischaemic attack and ischaemic stroke: a population-based study. Lancet 
Neurol. 2015;14(9):903-913. 
13. 
van Middelaar T, Argillander TE, Schreuder F, Deinum J, Richard E, Klijn CJM. Effect of 
Antihypertensive Medication on Cerebral Small Vessel Disease: A Systematic Review and Meta-
Analysis. Stroke. 2018;49(6):1531-1533. 
14. 
Topakian R, Barrick TR, Howe FA, Markus HS. Blood-brain barrier permeability is increased in 
normal-appearing white matter in patients with lacunar stroke and leucoaraiosis. J Neurol 
Neurosurg Psychiatry. 2010;81(2):192-197. 
15. 
Markus HS, Lythgoe DJ, Ostegaard L, O'Sullivan M, Williams SC. Reduced cerebral blood flow in 
white matter in ischaemic leukoaraiosis demonstrated using quantitative exogenous contrast 
based perfusion MRI. J Neurol Neurosurg Psychiatry. 2000;69(1):48-53. 
16. 
Gomez-Vallejo V, Ugarte A, Garcia-Barroso C, et al. Pharmacokinetic investigation of sildenafil 
using positron emission tomography and determination of its effect on cerebrospinal fluid cGMP 
levels. J Neurochem. 2016;136(2):403-415. 
17. 
Blair GW, Doubal FN, Thrippleton MJ, Marshall I, Wardlaw JM. Magnetic resonance imaging for 
assessment of cerebrovascular reactivity in cerebral small vessel disease: A systematic review. J 
Cereb Blood Flow Metab. 2016;36(5):833-841. 
18. 
Olmestig JNE, Marlet IR, Hainsworth AH, Kruuse C. Phosphodiesterase 5 inhibition as a therapeutic 
target for ischemic stroke: A systematic review of preclinical studies. Cell Signal. 2017;38:39-48. 
19. 
Shinohara Y, Katayama Y, Uchiyama S, et al. Cilostazol for prevention of secondary stroke (CSPS 2): 
an 
aspirin-controlled, 
double-blind, 
randomised 
non-inferiority 
trial. 
Lancet 
Neurol. 
2010;9(10):959-968. 
20. 
Han SW, Lee SS, Kim SH, et al. Effect of cilostazol in acute lacunar infarction based on pulsatility 
index of transcranial Doppler (ECLIPse): a multicenter, randomized, double-blind, placebo-
controlled trial. Eur Neurol. 2013;69(1):33-40. 
21. 
Malik R, Chauhan G, Traylor M, et al. Multiancestry genome-wide association study of 520,000 
subjects identifies 32 loci associated with stroke and stroke subtypes. Nat Genet. 2018;50(4):524-
537. 
22. 
Blair GW, Appleton JP, Flaherty K, et al. Tolerability, safety and intermediary pharmacological 
effects of cilostazol and isosorbide mononitrate, alone and combined, in patients with lacunar 
ischaemic stroke: The LACunar Intervention-1 (LACI-1) trial, a randomised clinical trial. 
EClinicalMedicine. 2019;11:34-43. 
23. 
Julious SA, Campbell MJ, Altman DG. Estimating sample sizes for continuous, binary, and ordinal 
outcomes in paired comparisons: practical hints. J Biopharm Stat. 1999;9(2):241-251. 
24. 
Julious SA. Sample sizes for clinical trials with normal data. Stat Med. 2004;23(12):1921-1986. 
18. APPENDIX D:  AMENDMENT HISTORY 
 

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Amendment 
No. 
Protocol 
Version No. 
Date issued 
Author(s) of 
changes 
Details of Changes made 
1 
2.0 
14th 
April 
2020 
A.Webb 
See document ‘OxHARP Amendment 
1_14_4_20.docx’ 
 
 
 
 
 
 
Protocol amendments must be submitted to the Sponsor for approval prior to submission to the REC 
committee or MHRA.