Characterisation of a Novel Regimen of Very Low-dose Aspirin Combined With Rivaroxaban in Patients With Chronic Coronary Syndromes: WILL lOWer Dose Aspirin be Better With Rivaroxaban in Patients With Chronic Coronary Syndromes?
Phase: PHASE4
Conditions: Coronary Syndrome
Sponsor: Sheffield Teaching Hospitals NHS Foundation Trust

 
 
 
STH20412 WILLOW CCS Clinical Study Protocol v2 03 Mar 2020, IRAS 273020    
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Characterisation of a novel regimen of very 
low-dose aspirin combined with rivaroxaban 
in patients with chronic coronary syndromes: 
 
WILL lOWer dose aspirin be better with 
rivaroxaban in patients with Chronic Coronary 
Syndromes? ² (WILLOW CCS) 
 
Clinical Study Protocol 

 
 
 
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RESEARCH REFERENCE NUMBERS 
 
STH20412 
 
 
TRIAL REGISTRY NUMBER 
 
Clinicaltrials.gov: NCT04990791  
 
 
 
OTHER RESEARCH REFERENCE NUMBERS  
 
EudraCT: 2019-000267-25 
MHRA CTA: 21304/0272/001-0001 
REC Ref: 20/LO/0147 
IRAS ID: 273020 
 
SPONSOR  
Sheffield Teaching Hospitals NHS Foundation Trust 
 
 
 
This protocol has regard for the NHS Health Research Authority guidance and order of content 
 
 

STH20412 WILLOW CCS Clinical Study Protocol v2 03 Mar 2020, IRAS 273020   
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SIGNATURE PAGE 
The undersigned confirm that the following protocol has been agreed and accepted and that the Chief 
Investigator agrees to conduct the trial in compliance with the approved protocol and will adhere to the 
principles outlined in the Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031), 
amended regulations (SI 2006/1928) and any subsequent amendments of the clinical trial regulations, 
GCP JXLGHOLQHV, WKH SSRQVRU·V (and any other relevant) SOPs, and other regulatory requirements as 
amended. 
I agree to ensure that the confidential information contained in this document will not be used for any other 
purpose other than the evaluation or conduct of the clinical investigation without the prior written consent 
of the Sponsor 
I also confirm that I will make the findings of the trial publicly available through publication or other 
dissemination tools without any unnecessary delay and that an honest accurate and transparent account of 
the trial will be given; and that any discrepancies and serious breaches of GCP from the trial as planned in 
this protocol will be explained. 
For and on behalf of the Trial Sponsor: 
Signature:  
...................................................................................................... 
Date: 
....../....../...... 
Name (please print): 
...................................................................................................... 
Position: 
...................................................................................................... 
Chief Investigator: 
Signature: 
..................................................................................................... 
Date: 
....../....../...... 
Name: (please print): Professor Robert Storey 
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STH20412 WILLOW CCS Clinical Study Protocol v2 03 Mar 2020, IRAS 273020    
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SIGNATURE PAGE 
The undersigned confirm that the following protocol has been agreed and accepted and that the Chief 
Investigator agrees to conduct the trial in compliance with the approved protocol and will adhere to the 
principles outlined in the Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031), 
amended regulations (SI 2006/1928) and any subsequent amendments of the clinical trial regulations, 
GCP JXLGHOLQHV, WKH SSRQVRU·V (and any other relevant) SOPs, and other regulatory requirements as 
amended. 
I agree to ensure that the confidential information contained in this document will not be used for any other 
purpose other than the evaluation or conduct of the clinical investigation without the prior written consent 
of the Sponsor 
I also confirm that I will make the findings of the trial publicly available through publication or other 
dissemination tools without any unnecessary delay and that an honest accurate and transparent account of 
the trial will be given; and that any discrepancies and serious breaches of GCP from the trial as planned in 
this protocol will be explained. 
 
For and on behalf of the Trial Sponsor: 
Signature:  
...................................................................................................... 
 
Date: 
....../....../...... 
Name (please print): 
 
...................................................................................................... 
 
 
 
Position:  
...................................................................................................... 
 
 
 
Chief Investigator: 
 
Signature:  
 
..................................................................................................... 
 
Date: 
....../....../...... 
Name: (please print): Professor Robert Storey 
 
 
 
 
17  08  2021

 
 
 
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KEY TRIAL CONTACTS 
 
Chief Investigator/Principal 
Investigator (Single site) 
Professor Robert F. Storey 
Professor and Honorary Consultant in Cardiology 
Department of Infection, Immunity and Cardiovascular Disease 
University of Sheffield 
Beech Hill Road, Sheffield 
S10 2RX 
Telephone 0114 2261124 
Fax 0114 3052008 Email r.f.storey@sheffield.ac.uk 
Co-Investigator 
Dr William Parker 
Clinical Research Fellow in Cardiology 
Cardiovascular Research Unit 
Northern General Hospital 
Barnsley Road Drive, Sheffield 
S5 7AU 
Telephone 0114 2266159 
Fax 0114 3052008 Email w.parker@sheffield.ac.uk 
Trial Co-ordinator 
Miss Jessica Hanson  
Clinical Research Co-Ordinator 
Cardiovascular Research Unit 
Centre for Biomedical Research 
Northern General Hospital 
Barnsley Road Drive, Sheffield 
S5 7AU 
Telephone 0114 2266159 
Fax 0114 3052008 Email j.hanson@sheffield.ac.uk 
Sponsor 
Sheffield Teaching Hospitals NHS Foundation Trust 
Clinical Research & Innovation Office 
D Floor, Royal Hallamshire Hospital 
Glossop Road, Sheffield 
S10 2JF 
Tel. 0114 2712763 
Funder 
Medical Research Council (MRC) Confidence in Concept Scheme 
 
Clinical Research Facility 
Sheffield Clinical Research Facility 
Centre for Biomedical Research 
Northern General Hospital 
Barnsley Road Drive, Sheffield 
S5 7AU 
Pharmacy Co-ordinator 
Mrs Kim Ryalls 
Pharmacy Department 
Northern General Hospital 
Herries Road, Sheffield 
S5 7AU 
 
 

 
 
 
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i. LIST of CONTENTS 
GENERAL INFORMATION 
Page No. 
TITLE PAGE 
 
1 
RESEARCH REFERENCE NUMBERS 
 
2 
SIGNATURE PAGE 
3 
KEY TRIAL CONTACTS  
4 
i. LIST of CONTENTS 
5 
ii. LIST OF ABBREVIATIONS 
6 
iii. TRIAL SUMMARY 
 
8 
iv. FUNDING 
 
9 
v. ROLE OF SPONSOR AND FUNDER 
9 
vi. ROLES & RESPONSIBILITIES OF TRIAL MANAGEMENT COMMITTEES, GROUPS AND 
INDIVIDUALS   
9 
vii, PROTOCOL CONTRIBUTORS 
9 
viii. KEYWORDS 
10 
ix. TRIAL FLOW CHART  
10 
SECTION  
1. BACKGROUND 
 
11 
2. RATIONALE  
11 
3. OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS  
16 
4. TRIAL DESIGN 
17 
5. TRIAL SETTING 
18 
6. PARTICIPANT ELIGIBILITY CRITERIA 
18 
7. TRIAL PROCEDURES 
20 
8. STUDY MEDICATIONS 
20 
9. PHARMACOVIGILANCE 
34 
10. STATISTICS AND DATA ANALYSIS 
38 
11. DATA MANAGEMENT  
43 
12. MONITORING, AUDIT & INSPECTION 
44 
13  ETHICAL AND REGULATORY CONSIDERATIONS 
44 
14. DISSEMINATION POLICY 
47 
15. REFERENCES 
47 
 
 

 
 
 
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ii. LIST OF ABBREVATIONS 
AA 
Arachidonic Acid 
ACE 
Angiotensin Converting Enzyme 
ACS 
Acute Coronary Syndrome 
ADP 
Adenosine Diphosphate 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
APR 
Annual Progress Report 
AR 
Adverse Reaction 
AUC 
Area Under the Curve 
BD 
Twice-daily 
BHF 
British Heart Foundation 
BLT1 
Leukotriene B receptor 
BMI 
Body Mass Index 
CAD 
Coronary artery disease 
CCS 
Chronic coronary syndromes 
CI 
Chief Investigator 
COMPASS 
Cardiovascular OutcoMes for People using Anticoagulation StrategieS 
COX 
Cyclo-oxygenase 
CRF 
Case Report Form 
CRP 
C-reactive Protein 
CTA 
Clinical Trial Authorisation 
CYP 
Cytochrome P450 
DAPT 
Dual Antiplatelet Therapy 
DATT 
Dual Antithrombotic Therapy 
DSUR 
Development safety update report 
EP 
Prostaglandin E receptor 
EU 
European Union 
EudraCT 
European Clinical Trials Database 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
HRA 
Health Research Authority 
ICF 
Informed Consent Form 
IHD 
Ischaemic heart disease 
IL-1 
Interleukin 1 
IL-6 
Interleukin 6 
IMP 
Investigational Medicinal Product 
IV 
Intravenous 
kg 
Kilograms 
L  
Litres 
LTB4 
Leukotriene B4 
m2 
Metres Squared 

 
 
 
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MACE 
Major Adverse Cardiovascular Events 
mg 
Milligrams 
MHRA 
Medicines and Healthcare products Regulatory Authority 
MI 
Myocardial Infarction 
ml 
Millilitres 
mmHg 
Millimetres of Mercury 
ng 
Nanograms 
NGH-CRF 
Northern General Hospital Clinical Research Facility 
NHS 
National Health Service 
NIHR 
National Institute for Healthcare Research 
NIMP 
Non-investigational medicinal product 
NOAC 
Non-vitamin K antagonist oral anticoagulant  
NR 
Not Recorded 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
OD 
Once-daily 
P2Y12 
Platelet adenosine diphosphate receptor 
PAD 
Peripheral arterial disease 
PCI 
Percutaneous Coronary Intervention 
PGI2 
Prostacyclin 
PGI-M 
Prostacyclin Metabolite 
PI  
Principal Investigator 
PIS 
Patient Information Sheet 
PLATO 
PLATelet inhibition and patient Outcomes 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
STH 
Sheffield Teaching Hospitals 
SUSAR 
Suspected unexpected serious adverse reaction 
TLR4 
Toll-like Receptor 4 
TMF 
Trial Master File 
TMG 
Trial Management Group 
TNF-α 
Tumour Necrosis Factor α 
TXA2 
Thromboxane A2 
TxM 
Thromboxane metabolite 
µg 
Micrograms 
UK 
United Kingdom 
µL 
Microlitres 
µmol 
Micromoles 
USA 
United States of America 

 
 
 
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iii. TRIAL SUMMARY 
Trial Title 
WILL lOWer dose aspirin be better with rivaroxaban in patients with Chronic Coronary 
Syndromes? ² (WILLOW CCS) 
Internal ref. no. 
STH20412 
Clinical Phase  
Phase IV 
Trial Design 
Randomised controlled open-label crossover study 
Trial Participants 
Men or women aged 18+ with a history of chronic coronary syndromes and high risk 
for atherothrombotic events, receiving antiplatelet monotherapy with aspirin 75 mg 
once daily 
Planned Sample Size 
48 
Treatment duration 
3 x 14 (-2) day periods 
Follow up duration 
Until 14 (-2) days after last IMP dose 
Planned Trial Period 
January 2020 ² December 2020 
 
Objectives 
Outcome Measures 
Primary 
 
Assess effects on haemostasis 
Bleeding time 
 
Secondary 
 
Assess fibrin clot dynamics 
Lag time 
Lysis time 
Final clot turbidity 
 
Assess inflammatory parameters 
 
Plasma interleukin 6 
Plasma tumour necrosis factor D 
Serum C-reactive protein 
Circulating leukocyte count 
 
Assess effects on platelet function 
Platelet aggregation responses to 
arachidonic acid, collagen and adenosine 
diphosphate 
 
Assess effects on key arachidonic acid 
metabolites  
Serum thromboxane B2 
Urine prostacyclin metabolite 
Urine thromboxane metabolite 
Investigational 
Medicinal Product(s) 
1. Aspirin (aspirin lysine) 
2. Rivaroxaban 
Formulation, Dose, 
Route of 
1. 100 mg sachets for dissolution, administered orally as 20 mg twice-daily, or 
75 mg once-daily 

 
 
 
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Administration 
2. 2.5 mg tablets administered orally twice-daily 
 
iv. FUNDING AND SUPPORT IN KIND 
FUNDERS 
 
FINANCIAL AND NON FINANCIAL SUPPORT GIVEN 
Medical Research 
Council (MRC) 
Funding of the study (MRC Confidence in Concept Scheme) 
Sheffield Teaching 
Hospitals NHS 
Foundation Trust 
(STHNFT) 
Provision of space and services in kind to conduct the study 
 
v. ROLE OF TRIAL SPONSOR AND FUNDER 
The sponsor, STHNFT, will approve the protocol and associated study documents. The sponsor will 
contribute to site initiation, monitoring and close-out. They will also provide pharmacy support to the study. 
The funder, MRC Confidence in Concept scheme, reviewed and approved an application for this study, and 
will provide monetary resources to complete it. 
 
vi. ROLES AND RESPONSIBILITIES OF TRIAL MANAGEMENT COMMITTEES/GROUPS 
The trial management group, chaired by the CI and including the sub-investigators, co-ordinators and 
laboratory team, will meet regularly to discuss a documented agenda. Minutes will be kept and shared with 
the sponsor. A trial management plan, agreed with the sponsor, will be written and a copy kept in the trial 
master file (TMF). 
Given the small sample size, stable nature of the study population and exploratory nature of the study, in 
addition to the proven safety of the combination of aspirin and a low dose of factor-Xa inhibitor in the target 
population, there will not be a formal data monitoring committee. However, procedures defined in this 
protocol will be followed with regards to safety monitoring, including discussion with the sponsor in the 
event of any serious adverse event occurring. 
 
vii. PROTOCOL CONTRIBUTORS 
Dr William Parker led the writing of this protocol, under the supervision of the CI (Professor Rob Storey). 
Dr Heather Judge assisted with designing laboratory methods. 
Dr Erica Wallis critically reviewed the protocol on behalf of the sponsor. 
Kim Ryalls and Mark Davy provided input into the pharmacy arrangements detailed in the protocol 
 
 
viii. KEY WORDS: 
Aspirin, rivaroxaban, fibrin clot dynamics, inflammation, 
prostanoids, platelets, haemostasis 

 
 
 
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ix. TRIAL FLOW CHART 
 
 
 
 
 
 
 
 

 
 
 
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1 
BACKGROUND 
 
The current standard antiplatelet regimen for secondary prevention of cardiovascular events for most 
patients with chronic coronary syndromes (CCS), including those with a history of stable angina or acute 
coronary syndromes >1 year ago,  is aspirin 75 mg once-daily (OD) [1, 2]. The Cardiovascular OutcoMes for 
People using Anticoagulation StrategieS (COMPASS) study showed that, in high-risk individuals, adding  
rivaroxaban, a non-vitamin-K-antagonist oral anticoagulant (NOAC), at a dose of 2.5 mg twice-daily (BD) to 
standard aspirin treatment leads to a significantly lower risk of major adverse cardiovascular events (MACE) 
[3]. This may be because this combination, known as dual antithrombotic therapy (DATT), provides not only 
antiplatelet effects but also anticoagulation. Anticoagulation might affect parameters of fibrin clot dynamics 
that are an emerging risk factor for MACE [4, 5]. However, this approach also leads to increased bleeding 
[3], which dissuades clinicians and patients alike from long-term use. Whilst this may apply broadly across 
patient groups, there may be those in whom the risk-benefit profile is particularly difficult to balance, for 
example those over the age of 75 years or those with a history of CCS but at the lower end of the 
ischaemic-risk spectrum. Accordingly, those patients with CCS in whom DATT is currently not recommended 
may hypothetically derive benefit, over standard aspirin monotherapy, from a combination regimen with a 
better balance of anti-ischaemic benefit and harm from bleeding. Improving the safety profile of 
combination therapy with aspirin and a NOAC could lead to wider applicability of the approach and 
substantial improvement in clinical outcomes for patients at significant risk of ischaemic events. 
Aspirin is a non-selective, irreversible inhibitor of cyclooxygenase (COX) 1 and 2 enzymes, at lower doses 
exhibiting relative pharmacokinetic selectivity for platelet COX1 [6], which is responsible for the synthesis of 
thromboxane A2 (TXA2), a pro-aggregant and vasoconstrictive prostanoid. At doses >325 mg/daily, based 
on the higher systemic concentration, aspirin can also significantly inhibit endothelial-derived COX2, leading 
to reduced release of the antithrombotic and vasodilatory compound prostacyclin (PGI2). Aspirin is able to 
act as an antiplatelet drug by inhibiting TXA2-mediated platelet activation without concurrent inhibition of 
PGI2 synthesis entirely counteracting this [7]. Aspirin may also have beneficial effects on fibrin clot structure 
[8], although it is unclear if these translate into detectable differences in vivo. 
We previously showed that a novel regimen of aspirin, 20 mg twice-daily (BD), reduced steady-state peak 
effects of aspirin, resulting in improved haemostasis, measured as bleeding time, compared to standard 
doses, in patients also receiving a second antithrombotic drug, ticagrelor [9]. Trough steady-state effects 
were maintained with adequate antiplatelet effect over a 24-hour period. We also saw a biologically-
plausible reduction in pro-inflammatory cytokines with the novel regimen and, importantly, no differences in 
fibrin clot dynamics. 
 
2 
RATIONALE  
Any antithrombotic regimen that provides a degree of anticoagulation and maintains adequate antiplatelet 
effects but avoids excess bleeding risk is highly attractive. A novel regimen of very-low-dose twice-daily 
aspirin (20 mg) and low-dose (2.5 mg) twice-daily rivaroxaban may have a range of benefits over standard 
aspirin therapy. 

 
 
 
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First, when compared to the standard regimen of DATT, it may provide a smoother profile of antithrombotic 
effect, with reduced peak-trough variation and hence reduced effects on haemostasis, mitigating the 
addition of a second agent. Second, when compared to standard aspirin therapy alone, the novel regimen 
may provide a degree of anticoagulation, for example increasing lag time and reducing lysis time, an 
independent predictor of MACE in patients with ischaemic heart disease (IHD) [10]. Third, as chronic aspirin 
treatment can potentiate the intravascular inflammatory response [11], when compared to both standard 
aspirin alone and DATT, a lower total dose might reduce any harmful proinflammatory effects, which might 
also improve fibrin clot dynamics further [12]. Targeting inflammation is an emerging effective strategy for 
reducing cardiovascular risk [13]. Finally, using lower-dose aspirin might result in reduced harmful 
inhibition of COX2. 
A combination of standard dose aspirin (75 mg OD) and a NOAC, rivaroxaban 2.5 mg BD, is licensed for the 
secondary prevention of IHD in patients at high risk of recurrent thrombotic events, for example those with 
multi-vessel coronary artery disease (CAD), history of myocardial infarction (requiring additional risk factors 
if <65 years old) or symptomatic peripheral arterial disease (PAD). However, this combination leads to 
significantly increased bleeding when compared to aspirin alone, and is not recommended for long-term 
use in patient groups in whom the risk of ischaemia and bleeding are more finely balanced. For example, 
whilst patients >75 years old at high-risk of ischaemia were included in the COMPASS study, the benefit of 
DATT vs. aspirin alone appeared more modest than in other age groups, although there was not a 
statistically-significant interaction between age group and efficacy of DATT [3].  
However, if a combination of aspirin and a NOAC with a better safety profile were to be available, as well as 
offering potential benefits to those in whom DATT is already considered an option, this may expand the 
group that could benefit from DATT, including those patients who are not currently regarded as good 
candidates for DATT, maximising the benefits whilst minimising harm. 
 
2.1 
Assessment and management of risk 
Aspirin and rivaroxaban are both widely used as antithrombotic drugs for the treatment of cardiovascular 
disease. Combining aspirin and rivaroxaban increases the risk of bleeding over aspirin alone [3], but is 
licensed for use in patients at high ischaemic risk.  
Whilst we hypothesise there are advantages of the novel regimen over standard aspirin therapy and 
standard DATT, we will limit participants· exposure to the shortest time possible to maintain scientific 
integrity. Those receiving drugs that significantly interact with aspirin and/or rivaroxaban will not proceed to 
randomisation. 
Known side effect profiles 
Aspirin (Aspirin lysine) 
Reported side effects of aspirin (aspirin lysine), taken from the current SmPC, include: 
More common: 
x 
Increased bleeding tendency (e.g. nose bleed, bleeding gums, bruises, intestinal bleeds and 
bleeding due to trauma). It is normal to note increased bleeding with cuts or spontaneous bruising 
with any dose of aspirin. 

 
 
 
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x 
Stomach irritation. This is usually mild and, if necessary, can often be treated with acid-lowering 
medications. There is some evidence that lower doses of aspirin have a lower chance of causing 
irritation than high doses. 
 
Less common side effects of aspirin: 
x 
Rhinitis, shortness of breath and itching have been reported uncommonly (up to 1 in 100 patients). 
x 
Blood count abnormalities, allergic reactions, bleeding into the brain, inflammation of the blood 
vessels, asthma, heavy periods, nausea and vomiting have been reported rarely (up to 1 in 1000). 
x 
Other cases of renal failure, water retention, stomach or intestinal ulceration, headache, ringing in 
the ears, reduced hearing, vertigo and diarrhoea have been reported (exact chance not known). 
 
Rivaroxaban 
Reported side effects of rivaroxaban (at doses up to 20 mg once daily) include the following, reproduced 
from the current SmPC (DVT, deep vein thrombosis; NVAF, non-valvular atrial fibrillation; PE, pulmonary 
embolism; VTE, venous thromboembolism) [14]: 
 
Common 
Uncommon 
Rare 
Very rare 
Not known 
Blood and lymphatic system disorders 
Anaemia (incl. 
respective laboratory 
parameters) 
Thrombocytosis (incl. 
platelet count 
increased)A, 
Thrombocytopenia 
 
 
 
Immune system disorders 
 
Allergic reaction, 
dermatitis allergic, 
Angioedema and 
allergic oedema 
 
Anaphylactic reactions 
including anaphylactic 
shock  
 
Nervous system disorders 
Dizziness, headache 
Cerebral and 
intracranial 
haemorrhage, syncope 
 
 
 
Eye disorders 
Eye haemorrhage (incl. 
conjunctival 
haemorrhage) 
 
 
 
 
Cardiac disorders 
 
Tachycardia 
 
 
 

 
 
 
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Vascular disorders 
Hypotension, 
haematoma 
 
 
 
 
Respiratory, thoracic and mediastinal disorders 
Epistaxis, haemoptysis 
 
 
 
 
Gastrointestinal disorders 
Gingival bleeding, 
gastrointestinal tract 
haemorrhage (incl. 
rectal haemorrhage), 
gastrointestinal and 
abdominal pains, 
dyspepsia, nausea, 
constipationA, 
diarrhoea, vomitingA 
Dry mouth 
 
 
 
Hepatobiliary disorders 
Increase in 
transaminases 
Hepatic impairment, 
Increased bilirubin, 
increased blood 
alkaline phosphataseA, 
increased GGTA 
Jaundice, Bilirubin 
conjugated increased 
(with or without 
concomitant increase 
of ALT), Cholestasis, 
Hepatitis (incl. 
hepatocellular injury) 
 
 
Skin and subcutaneous tissue disorders 
Pruritus (incl. 
uncommon cases of 
generalised pruritus), 
rash, ecchymosis, 
cutaneous and 
subcutaneous 
haemorrhage 
Urticaria 
 
Stevens-Johnson 
syndrome/ Toxic 
Epidermal Necrolysis , 
DRESS syndrome  
 
Musculoskeletal and connective tissue disorders 
Pain in extremityA 
Haemarthrosis 
Muscle haemorrhage 
 
Compartment 
syndrome secondary to 
a bleeding 
Renal and urinary disorders 
Urogenital tract 
haemorrhage (incl. 
haematuria and 
 
 
 
Renal failure/acute 
renal failure secondary 
to a bleeding sufficient 

 
 
 
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menorrhagiaB), renal 
impairment (incl. blood 
creatinine increased, 
blood urea increased) 
to cause hypoperfusion 
General disorders and administration site conditions 
FeverA, peripheral 
oedema, decreased 
general strength and 
energy (incl. fatigue 
and asthenia) 
Feeling unwell (incl. 
malaise)  
Localised oedemaA 
 
 
Investigations 
 
Increased LDHA, 
increased lipaseA, 
increased amylaseA 
 
 
 
Injury, poisoning and procedural complications 
Postprocedural 
haemorrhage (incl. 
postoperative anaemia, 
and wound 
haemorrhage), 
contusion, wound 
secretionA 
 
Vascular 
pseudoaneurysmC 
 
 
A: observed in prevention of VTE in adult patients undergoing elective hip or knee replacement surgery 
B: observed in treatment of DVT, PE and prevention of recurrence as very common in women < 55 years 
C: observed as uncommon in prevention of atherothrombotic events in patients after an ACS (following percutaneous 
coronary intervention) 
 
Mitigation of risks 
Any risks in this study are mitigated by: 
x 
a robust informed consent procedure, followed before any study-related activities take place 
x 
ensuring at screening that potential participants do not have any medical or medication issues that 
would preclude safe involvement in the study 
x 
excluding those with co-morbidities or receiving concomitant medication likely to significantly 
increase the risk of taking part in the study 
x 
as short as feasible exposure to study drugs whilst maintaining scientific credibility  
x 
rigorous safety monitoring by the study team and sponsor 

 
 
 
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3 
OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS 
 
3.1 
Primary objective 
The primary objective of this study is to assess, in patients with a history of IHD currently receiving aspirin 
75 mg once daily as antithrombotic monotherapy, the effects of a novel regimen of very-low-dose twice-
daily aspirin (aspirin lysine) (20 mg BD) and rivaroxaban (2.5 mg BD), compared to a standard regimen of 
aspirin (aspirin lysine) monotherapy (75 mg OD), and a standard regimen of DATT (aspirin 75 mg OD plus 
rivaroxaban 2.5 mg BD) on post-dose bleeding time. 
It is hypothesised that the difference in bleeding time when receiving aspirin (aspirin lysine) 75 mg once-
daily alone vs. aspirin (aspirin lysine) 20 mg twice-daily plus rivaroxaban 2.5 mg twice-daily will be less than 
the difference in bleeding time between aspirin (aspirin lysine) 75 mg once-daily alone vs. aspirin (aspirin 
lysine) 75 mg once-daily plus rivaroxaban 2.5 mg twice-daily. 
 
3.2 
Secondary objectives 
The secondary objectives of this study are to assess, in patients with a history of CCS, the effects of a novel 
regimen of very-low-dose twice-daily aspirin (aspirin lysine)  (20 mg BD) and rivaroxaban (2.5 mg BD) 
compared to (i) a standard regimen of aspirin (aspirin lysine) monotherapy (75 mg OD) and (ii) a  standard 
regimen of DATT (aspirin 75 mg OD plus rivaroxaban 2.5 mg BD) on: 
1. Fibrin clot dynamics (lag time, lysis time, final clot turbidity) 
2. Inflammatory parameters (plasma IL-6, TNFD; serum CRP; circulating leukocyte count) 
3. Platelet function (platelet aggregation responses to arachidonic acid, collagen and adenosine 
diphosphate) 
4. Arachidonic acid metabolites (serum TXB2, urine PGI-M, urine TxM) 
3.3 
Outcome measures/endpoints 
Primary endpoint/outcome 
The primary endpoint will be difference in bleeding time, measured at 2 hours post-dose, assessed 
between aspirin (aspirin lysine) 75 mg once-daily alone vs. aspirin (aspirin lysine) 20 mg twice-daily plus 
rivaroxaban 2.5 mg twice-daily and aspirin (aspirin lysine) 75 mg once-daily alone vs. aspirin (aspirin lysine) 
75 mg once-daily plus rivaroxaban 2.5 mg twice-daily. 
 
Secondary endpoints/outcomes 
When receiving aspirin (aspirin lysine) 20 mg BD plus rivaroxaban, vs. aspirin (aspirin lysine) 75 mg OD, vs. 
aspirin (aspirin lysine) 75 mg OD plus rivaroxaban 2.5 mg BD: 
1. Bleeding time pre-dose 
2. Fibrin clot lag time pre-dose and 2 hours post-dose 
3. Fibrin clot lysis time pre-dose and 2 hours post-dose 
4. Plasma TNF-Ơ pre-dose and 2 hours post-dose 
5. Plasma IL-6 pre-dose and 2 hours post-dose 
6. Serum CRP 2 hours post-dose 
7. Leukocyte count pre-dose and 2 hours post-dose 
8. Serum TXB2 pre-dose and 2 hours post-dose 
9. Urine PGI-M pre-dose and 2 hours post-dose 
10. Urine TxM pre-dose and 2 hours post-dose 

 
 
 
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11. Mean platelet aggregation responses to arachidonic acid (AA), collagen and adenosine diphosphate 
(ADP), pre-dose and 2 hours post-dose 
12. Final clot turbidity pre-dose and 2 hours post-dose 
Secondary endpoints will be compared between the three groups by repeated-measures ANOVA (1,2) and 
paired t-tests (3-9), where appropriate, between: 
1. Post-dose (aspirin 20 mg BD plus rivaroxaban 2.5 mg BD) vs. post-dose (aspirin 75 mg OD) vs. post-
dose (aspirin 75 mg OD plus rivaroxaban 2.5 mg BD) 
2. Pre-dose (aspirin 20 mg BD plus rivaroxaban 2.5 mg BD) vs. pre-dose (aspirin 75 mg OD) vs. pre-
dose (aspirin 75 mg OD plus rivaroxaban 2.5 mg BD) 
3. Pre-dose (aspirin 20 mg BD plus rivaroxaban 2.5 mg BD) vs. post-dose (aspirin 20 mg BD plus 
rivaroxaban 2.5 mg BD) 
4. Pre-dose (aspirin 75 mg OD) vs. post-dose (aspirin 75 mg OD) 
5. Pre-dose (aspirin 75 mg OD plus rivaroxaban 2.5 mg BD) vs. post-dose (aspirin 75 mg OD plus 
rivaroxaban 2.5 mg BD) 
6. Post-dose (aspirin 20 mg BD plus rivaroxaban 2.5 mg BD) vs. post-dose (aspirin 75 mg OD) 
7. Post-dose (aspirin 20 mg BD plus rivaroxaban 2.5 mg BD) vs. post-dose (aspirin 75 mg OD plus 
rivaroxaban 2.5 mg BD) 
8. Pre-dose (aspirin 20 mg BD plus rivaroxaban 2.5 mg BD) vs. pre-dose (aspirin 75 mg OD) 
9. Pre-dose (aspirin 20 mg BD plus rivaroxaban 2.5 mg BD) vs. pre-dose (aspirin 75 mg OD plus 
rivaroxaban 2.5 mg BD) 
 
4 
TRIAL DESIGN 
The trial is a pharmacodynamic study to determine the effect of a novel regimen of aspirin 20 mg BD plus 
rivaroxaban 2.5 mg BD on haemostasis, fibrin clot dynamics, inflammatory markers, platelet function and 
arachidonic acid metabolites when compared to standard regimens of aspirin 75 mg OD and aspirin 75 mg 
OD plus rivaroxaban 2.5 mg BD. 
In a randomised open-label three-period crossover design, patient participants receiving aspirin 75 mg OD 
for secondary prevention of IHD will be randomised 1:1 to receive one of two sequences of aspirin: aspirin 
75 mg OD, then aspirin 20 mg BD plus rivaroxaban 2.5 mg BD, then aspirin 75 mg OD plus rivaroxaban 2.5 
mg BD; or aspirin 75 mg OD, then aspirin 75 mg OD plus rivaroxaban 2.5 mg BD, then aspirin 20 mg BD 
plus rivaroxaban 2.5 mg BD. 
This design allows comparison of the three regimens with a lead-in period on the baseline antiplatelet 
treatment participants are receiving at enrolment, but replaced with a soluble aspirin preparation to allow 
accurate comparisons with the other treatments. Having the two periods including rivaroxaban adjacent to 
each other, but in a randomised order, allows simplification of dispensing arrangements allowing us to 
maximise use of resources available to conduct the study, and removes any concern over carryover effects 
of rivaroxaban relevant to study measurements into a period of aspirin monotherapy. 
At the end of each 14(-2) day medication period, they will attend a study visit at which blood and urine 
samples will be obtained, and bleeding time measured, before and 2 hours after the last dose of IMP of the 
treatment period. The samples will be tested for fibrin clot dynamics; inflammatory markers and cytokines; 
prostanoids; and platelet function. 
Participants will be transitioned back to standard-of-care aspirin 75 mg OD at the end of the third treatment 
period and followed up by telephone call 14(-2) days later. 
 

 
 
 
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5 
TRIAL SETTING 
This will be a single-centre open-label study, conducted by the Cardiovascular Research Unit, University of 
Sheffield within the Clinical Research Facility at the Northern General Hospital, Sheffield. 
Participants will be outpatients with a history of ischaemic heart disease currently receiving aspirin 75 mg 
OD, recruited from the local area. 
There is anticipated to be a large population of eligible potential participants under the current or previous 
care of the Cardiology and Cardiothoracic Surgery Directorate of Sheffield Teaching Hospitals NHS 
Foundation Trust, meaning a single-centre design is appropriate without the need for any separate 
participant identification centres. 
 
6 
PARTICIPANT ELIGIBILITY CRITERIA 
 
6.1 
Inclusion criteria 
To participate in this trial, subjects must meet all of the following criteria: 
For inclusion in the study, subjects should fulfil the following criteria: 
1. 
Provision of informed consent prior to any study specific procedures 
2. 
Male or female aged greater than 18 years 
3. 
Existing diagnosis of a chronic coronary syndrome: 
(i) 
History of stable angina 
or 
(ii) 
History of an acute coronary syndrome event >1 year ago 
or 
(iii) 
Previous evidence on imaging of either at least one stenosis >50% in an epicardial 
coronary artery or a myocardial perfusion defect  
4. 
High-risk for atherothrombotic events, defined as: 
 
(i) aged 65 years or over 
 
or 
 
(ii) atherosclerosis in at least 2 vascular territories (such as coronary, cerebrovascular, or 
peripheral arteries) 
or 

 
 
 
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         19 
 
 
(iii)  Two or more of the following: current smoking, diabetes mellitus,  estimated glomerular 
filtration rate (eGFR) less than 60 ml/min, heart failure, previous non-lacunar ischaemic stroke. 
5. 
Receiving single antiplatelet therapy with aspirin 75 mg once daily 
 
6.2 
Exclusion criteria 
Subjects meeting any of the following criteria will be excluded from participation in the study: 
1. 
Any history of haemorrhagic stroke or lacunar stroke 
2. 
History of ischaemic stroke or transient ischaemic attack in the last year 
3. 
Heart failure associated with NYHA class III or IV symptoms 
4. 
Estimated glomerular filtration rate <30 ml/min 
5. 
Planned procedure for coronary revascularization 
6. 
Any planned surgery or other procedure that may require suspension or discontinuation of 
antiplatelet therapy expected to occur within 3 months of randomisation 
7. 
Prior intention by patient or physician to discontinue aspirin within the study period 
8. 
Receiving doses of aspirin other than 75 mg once daily 
9. 
Treatment or planned treatment with antiplatelet medication apart from aspirin (eg. clopidogrel, 
prasugrel, ticagrelor, dipyridamole, ticlopidine) 
10. 
Current use of a loop, thiazide or potassium sparing diuretic (affects prostanoid assays) 
11. 
Any acute coronary syndrome event, percutaneous coronary intervention or coronary artery 
bypass grafting within 1 year prior to randomisation 
12. 
Current or planned use of an oral anticoagulant (e.g. warfarin, dabigatran, rivaroxaban [including 
2.5 mg BD], apixaban, edoxaban) or parenteral anticoagulant (eg. unfractionated heparin, low 
molecular weight heparin, bivalirudin) 
13. 
Current or planned use of a GPIIb/IIIa inhibitor (eg. abciximab, tirofiban) 
14. 
Current or planned use of a fibrinolytic agent (eg. tissue plasminogen activator) 
15. 
Requiring or likely to require treatment with a non-steroidal anti-inflammatory drug (NSAID), 
including COX2 inhibitors, and including regular or intermittent/as required use 
16. 
Current or planned use of a strong CYP3A4 inhibitor (eg, ketoconazole, itraconazole, 
voriconazole, telithromycin, clarithromycin [but not erythromycin or azithromycin], nefazadone, 

 
 
 
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         20 
 
ritonavir, saquinavir, nelfinavir, indinavir, atanazavir, cobicistat or over 1 litre daily of grapefruit 
juice), strong inducer 
(e.g. rifampin/rifampicin, rifabutin, phenytoin, carbamazepine, 
phenobarbital), a selective serotonin reuptake inhibitor (SSRI) or selective noradrenergic 
reuptake inhibitor (SNRI). 
17. 
Current or planned use of the following: methotrexate at a dose >15 mg per week; tenofovir; or a 
uricosuric drug (e.g. probenecid, benzbromarone and sulfinpyrazone). 
18. 
Clinically significant liver disease, defined as known or suspected diagnosis of hepatic cirrhosis 
with current Child Pugh class B or C; or elevation of serum alanine transferase or aspartate 
transferase greater than 3 times the upper limit of the normal range for the processing 
laboratory. 
19. 
History of alcohol or drug abuse, defined as regular use of an illicit substance for recreational 
purposes or regular consumption of greater than 50 units (males) or 35 units (females) of 
alcohol per week, in the last year 
20. 
Co-morbidity associated with life expectancy less than 1 year 
21. 
Any other condition deemed by the investigator to significantly affect haemostasis, coagulation, 
bleeding risk or ability to comply with the study protocol. 
22. 
Women of child-bearing potential (WOCBP)A unless negative pregnancy test at screening and 
willing to use highly-effective contraceptionB for the duration of treatment with study medication. 
23. 
Pregnant or breast-feeding women. 
24. 
Any contraindication for aspirin (aspirin lysine) or rivaroxaban treatment as detailed in the 
respective SmPCs. 
NOTES 
A.  WOCBP are defined as women who are fertile, following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral 
oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. 
 
B. Highly-effective methods of contraception are defined as combined (oestrogen- and progestogen-containing) hormonal 
contraception associated with inhibition of ovulation (oral, intravaginal or transdermal), progestogen-only hormonal 
contraception associated with inhibition of ovulation (oral, injectable or implantable),  intrauterine device, intrauterine 
hormone-releasing system, bilateral tubal occlusion, vasectomised partner or sexual abstinence. Sexual abstinence is 
considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of 
risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject. 
 

 
 
 
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7 
TRIAL PROCEDURES  
Details of analysis of blood & urine samples 
The aim of the analysis of the study samples will be to: (i) show the effects of aspirin 20 mg BD plus 
rivaroxaban 2.5 mg BD on, haemostasis, fibrin clot dynamics, prostanoids, platelet function and 
inflammation, when compared to standard aspirin 75 mg OD and aspirin 75 mg OD plus rivaroxaban 2.5 
mg BD. 
Haemostasis will be assessed by measuring, in steady state, bleeding time pre- and 2 hours post-dose 
using a method shown to be sensitive to additive effects of antiplatelet agents [15]. The procedure for 
measuring bleeding time is described in the study-specific SOP relating to this. 
We will measure parameters of fibrin clot formation and lysis, specifically lag time, final clot turbidity and 
lysis time. 
To determine the detailed effects of the three regimens on prostanoid synthesis, we will measure the 
principal metabolites of TXA2 and PGI2 (serum TXB2 and urinary PGI-M respectively). 
Effects on the inflammatory state will be assessed by measurement of the inflammatory markers TNF-α, IL-
6 and CRP. 
Finally, in order to confirm the efficacy of the antiplatelet aspects of the drug regimens being studied, the 
activity of a broad range of pathways of platelet activation and aggregation will be assessed by light 
transmittance aggregometry, pre-medication and 2 hours post-medication, using arachidonic acid 0.3 and 
1 mmol/L, collagen 4 and 16 µg/mL, and ADP 20 µmol/L as agonists. 
Study samples will either be measured immediately after collection (e.g. light transmittance aggregometry) 
or stored for assays at a later time (other endpoints). 
We will also store acellular samples of serum, plasma, deoxyribonucleic acid (DNA), ribonucleic acid (RNA) 
and urine within the Cardiovascular Research Unit for future, as yet unplanned, studies. Consent will be 
sought for this at study enrolment. 
 
7.1 
Recruitment 
 
 
7.1.1 Participant identification 
Potential participants will be identified through review of the records of the South Yorkshire Cardiothoracic 
Centre and/or by referral by their clinical team. 
Specifically, participants may be approached in the following ways: 
1. An invitation letter sent by post in combination with a copy of the participant information sheet. 
There will be a reply slip which they can return by post, and there will be contact details (telephone 
and email) for the research team to allow them to respond by these methods too. 

 
 
 
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         22 
 
2. Directly by telephone. In this case, should they be happy to learn more, they will be sent a copy of 
the invitation letter, participant information sheet and reply slip by post or email, depending on their 
preference. If they agree to attend for study screening, they will communicate this to the research 
team by returning the reply slip by post or email, or by contacting the research team directly using 
the contact details provided to them. 
3. Directly in clinics within the Cardiology and Cardiothoracic Surgery Directorate at Sheffield Teaching 
Hospitals NHS Foundation Trust, upon referral from their clinical team. In this case they will be 
provided with a copy of the participant information sheet and, if unable to decide whether they wish 
to attend for screening or not during the clinic visit, will be signposted to the contact details of the 
research team to provide their response. 
Potential participants who are interested in taking part in the study will then be contacted by the research 
team to book a screening appointment. 
 
7.1.2 Screening 
Screening will occur at visit 1. The following study procedures will be performed, after obtaining written 
consent for the study: 
x 
Medical history 
x 
Physical examination 
x 
Collection of demographic data 
x 
Vital signs (pulse, blood pressure and temperature). 
x 
Height, weight and BMI 
x 
Recording of any concomitant medication 
x 
Safety blood tests (13.5 ml blood sample for haematology, clinical chemistry [including serum 
pregnancy test in WOCBP] and coagulation) 
x 
Urinalysis (dipstick) 
x 
Baseline electrocardiogram 
 
7.1.3  Payment  
Volunteers will receive no payment for taking part in the study, however travel costs to and from the Clinical 
Research Facility will be reimbursed or transportation by taxi arranged. 
 
7.2 Consent  
 
Written, informed consent, using the current version of the approved designated form for this study, will be 
obtained prior to any study procedures being carried out. This will be explained and obtained by a 
medically-qualified member of the research team, listed on the delegation log. Participants will have the 
chance to read the ICF/PIS for as long as they need, and will be able to ask any questions, prior to signing. 

 
 
 
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         23 
 
Minors and those judged to be without the mental capacity to provide informed consent will not be enrolled 
into the study. 
Participants will remain free to withdraw at any time from the trial, without giving reasons and without 
prejudicing his/her further treatment, and will be provided with a contact point where he/she may obtain 
further information about the trial. Samples collected up to the point of withdrawal will only be used after 
withdrawal if the participant consents for this, otherwise they will be destroyed. However, data collected up 
to that point will be used for analysis, and this will be explicitly stated in the participant information sheet 
and consent form. 
 
7.2.1 Additional consent provisions for collection and use of participant data and biological specimens in 
ancillary studies, if applicable 
As described above, we will also store acellular samples of serum, plasma, DNA, RNA and urine for future, 
as yet unplanned, studies. Explicit consent for this will be sought on the consent form at enrolment. Any 
cellular samples taken will be destroyed before the end of the study. 
 
7.3 The randomisation scheme 
Participants will be randomised to one of the following two treatment sequences, in a 1:1 fashion: 
 
(A) Aspirin 75 mg OD for 14(-2) days then aspirin 20 mg BD plus rivaroxaban 2.5 mg BD for 14(-2) days 
then aspirin 75 mg OD plus rivaroxaban 2.5 mg BD 
 
or 
 
(B) Aspirin 75 mg OD for 14(-2) days then aspirin 75 mg OD plus rivaroxaban 2.5 mg BD for 14(-2) days 
then aspirin 20 mg BD plus rivaroxaban 2.5 mg BD 
 
7.3.1 Method of implementing the randomisation/allocation sequence 
Randomisation 
will 
be 
handled 
by 
an 
online 
interactive 
web-based 
randomisation 
service, 
sealedenvelope.com. TKHLU ¶VLPSOH UaQGRPLVaWLRQ VHUYLcH· ZLOO bH XVHG aQG a VWXG\-specific SOP will be 
prepared and followed. 
Participants will be allocated a three-digit number at enrolment (starting at 001) SUHIL[HG ZLWK ¶E01· (H.J. 
E01001), then if they proceed to randomisation they will be allocated a separate three-digit randomisation 
number (starting at 001) SUHIL[HG ZLWK ¶R· (H.J. R001). 
The system will generate an immediate email to the investigators stating the treatment allocation and this will 
bH SULQWHG, RQH cRS\ bHLQJ SOacHG LQ WKH SaUWLcLSaQW·V VWXG\ ILOH aQG a IXUWKHU cRS\ VHQW WR WKH NRUWKHUQ GHQHUaO 
Hospital Pharmacy with a study-specific prescription for study medication during period 1. A separate 
prescription will be issued to cover periods 2 and 3 but using the same randomisation document as evidence 
of the allocation. 
 
7.4 
Blinding 
 

 
 
 
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         24 
 
This study will be open-label i.e. unblinded to participants and investigators throughout. However, those 
performing the laboratory assessments will be blinded to treatment allocation in order to reduce bias. 
 
7.5 
Emergency Unblinding 
Procedures for emergency unblinding are not relevant to this study. 
 
7.6 
Baseline data 
 
At visit 1 
x 
Medical history 
x 
Physical examination 
x 
Demographic data 
x 
Vital signs (pulse, blood pressure and temperature)  
x 
Weight and BMI 
x 
Concomitant medication 
x 
Lab safety parameters (full blood count, urea & electrolytes, liver function tests, clotting screen, 
dipstick urinalysis, urinary pregnancy test if female and of childbearing potential) 
x 
Electrocardiogram findings 
 
At visit 2 
x Vital signs: pulse, blood pressure and temperature 
x Physical examination 
 
 
 
7.7 
Trial assessments 
 
Visit 1 - Screening (Day -21 to 0) 
Screening of subjects and all study-related procedures will take place in the Sheffield Clinical Research 
Facility, a specialist environment for the conduct of clinical research. The following assessments and 
procedures will be performed: 
x 
Full informed consent, including completion of the informed consent form 

 
 
 
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         25 
 
x 
Inclusion/exclusion criteria (see section 6) 
x 
Medical history 
x 
Physical examination 
x 
Demographic data 
x 
Vital signs: pulse, blood pressure and temperature 
x 
Weight and BMI 
x 
Concomitant medication 
x 
Lab safety (13.5 ml blood sample for haematology; clinical chemistry & coagulation; urinalysis) 
x 
Electrocardiogram 
If eligible, subjects will be asked to return to the Clinical Research Facility, Northern General Hospital, on 
Day 0 for the experimental part of the study. They will be randomised to receive a three-period medication 
regimen as detailed in section 7.3 of this protocol. Providing results of all screening tests are available 
before visit 2 is commenced, visit 2 may occur on the same day as visit 1. 
A OHWWHU ZLOO bH VHQW WR WKH SaUWLcLSaQW·V GP WR LQIRUP WKHP RI HQUROPHQW LQ WKH VWXG\. TUaQVSRUWaWLRQ WR aQG 
from the Clinical Research Facility will be provided if necessary. Subjects who fail screening will be recorded 
on a screen failure log with the reason for failure. 
Visit 2 (Day 0) - Randomisation 
x 
Vital signs 
x 
Physical examination 
x 
Adverse event recording 
x 
Reconfirm eligibility criteria met (by a medically qualified member of the study team, see section 6) 
and no withdrawal criteria met (section 7.10) 
x 
Randomisation 
x 
Provided with supply of aspirin (aspirin lysine) for periods 1, 2 and 3 (2 boxes of 30 sachets) 
x 
Dose-preparation training for aspirin (aspirin lysine) 75 mg OD, including supply of written 
illustrated instructions 
x 
Issue with participant information card detailing treatment allocation, restrictions during the study 
and contact details for the research team 
Period 1: 14 (-2) days 
x 
Participants will receive aspirin (aspirin lysine) 75 mg OD, but should withhold their dose on the 
morning of visit 3 (during which the dose will be taken). 

 
 
 
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         26 
 
 
Visit 3  - Period 1: Day 14 (-2) 
 
x 
Vital signs 
x 
Physical examination 
x 
Adverse event recording 
x 
Concomitant medication recorded 
x 
Venous blood sample pre- and 2 hours post-dose for fibrin clot dynamics, inflammatory markers, 
prostanoids and platelet function 
x 
Bleeding time pre- and 2 hours post dose 
x 
Urine sample pre- and 2 hours post-dose for prostanoids 
x 
IMP compliance check for period 1 
x 
Dispensing of rivaroxaban 2.5 mg tablets for periods 2 and 3 (total 56 tablets) 
x 
Urine pregnancy test for women of childbearing potential (must not continue to period 2 if positive) 
x 
Dose-preparation training for aspirin (aspirin lysine) 20 mg BD if allocated to sequence A, including 
provision of written instructions 
 
Period 2: 14(-2) days 
Participants will receive their allocated regimen for period 2 for 14(-2) days: 
o If randomised to sequence A they will receive aspirin (aspirin lysine) 20 mg BD plus 
rivaroxaban 2.5 mg BD in period 2. 
o If randomised to sequence B they will receive aspirin (aspirin lysine) 75 mg BD plus 
rivaroxaban 2.5 mg BD in period 2. 
Participants should withhold their dose on the morning of visit 4 (during which the dose will be taken). 
 
Visit 4 : 14(-2) days into period 2 
 
x 
Vital signs 
x 
Physical examination 
x 
Adverse event recording 

 
 
 
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         27 
 
x 
Concomitant medication recorded 
x 
Venous blood sample pre- and 2 hours post-dose for fibrin clot dynamics, inflammatory markers, 
prostanoids and platelet function 
x 
Bleeding time pre- and 2 hours post dose 
x 
Urine sample pre- and 2 hours post-dose for prostanoids 
x 
Urine preganacy test for WOCBP 
x 
IMP compliance recorded for period 2 
x 
Dose-preparation training for aspirin (aspirin lysine) 75 mg OD if allocated to sequence A or 20 mg 
BD if sequence B, including provision of written instructions 
 
Period 3: 14(-2) days 
Participants will receive their allocated regimen for period 3 for 14(-2) days: 
o If randomised to sequence A they will receive aspirin (aspirin lysine) 75 mg OD plus 
rivaroxaban 2.5 mg BD in period 3. 
o If randomised to sequence B they will receive aspirin (aspirin lysine) 20 mg BD plus 
rivaroxaban 2.5 mg BD in period 3. 
 
Participants should withhold their dose on the morning of visit 5 (during which the dose will be taken). 
 
Visit 5  : 14(-2) days into period 3 
 
x 
Vital signs 
x 
Physical examination 
x 
Adverse event recording 
x 
Concomitant medication recorded 
x 
Venous blood sample pre- and 2 hours post-dose for fibrin clot dynamics, inflammatory markers, 
prostanoids and platelet function 
x 
Bleeding time pre- and 2 hours post dose 
x 
Urine sample pre- and 2 hours post-dose for prostanoids 
x 
Urine pregnancy test for WOCBP 
x 
IMP compliance recorded for period 3 

 
 
 
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         28 
 
x 
Collect and return unused medication to pharmacy 
x 
Transition to standard of care aspirin 75 mg OD, ensuring participant has a supply of this 
 
 
Visit 6 : 14(-2) days after visit 5 (Telephone call) 
 
x 
Telephone follow-up for adverse events and concomitant medication 
 
 
7.8 
Long term follow-up assessments 
Participants will be followed until 14(-2) days after visit 5 by telephone. Any new adverse events will be 
recorded. Participants will be thanked for their involvement in the study. In the event of a participant 
remaining uncontactable at the end of the follow-up window, we will interrogate the hospital records of the 
SaUWLcLSaQW WR cOaULI\ YLWaO VWaWXV aQG aQ\ HYLGHQcH RI XQWRZaUG HYHQWV. PaUWLcLSaQWV ZLOO bH GHcOaUHG ¶ORVW WR 
IROORZ XS· LI WKH\ aUe uncontactable 28 days after visit 5. A file note will be made in this instance. 
 
7.9 
Qualitative assessments  
Not applicable to this study 
 
7.10 
Withdrawal or postponement criteria  
Subjects may be withdrawn or may discontinue from the trial if the following occur: 
 
Inability to obtain venous blood samples 
 
Withdrawal of consent 
 
Development of an intolerable adverse event due to study participation as determined by the 
investigator and/or subject 
 
Development of a significant intercurrent illness, condition or procedural complication that would 
LQWHUIHUH ZLWK WKH VXbMHcW·V cRQWLQXHG SaUWLcLSaWLRQ, unless further study activities can be appropriately 
postponed (see section 7.10.1) 
 
Participant becomes aware of pregnancy or positive pregnancy test at visit 3 
 
 
At the time of planned study visit 3, 4 or 5, receipt of a non-study medication in the preceding 48 
hours that, in the opinion of the investigator, is likely to significantly affect thrombosis, haemostasis, 
inflammation or prostanoid synthesis, unless the visit can be appropriately postponed (see section 7.10.1 
and section 8.9) 
 
Violation of the protocol 

 
 
 
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         29 
 
 
TKH LQYHVWLJaWRU IHHOV LW LV PHGLcaOO\ LQ WKH bHVW LQWHUHVW RI WKH VXbMHcW WR GLVcRQWLQXH WKH VXbMHcW·V 
participation in the study 
 
Previously unknown data becoming available raising concern about the safety of the study drugs, so 
that continuation could cause potential risks to the subjects 
The reason for withdrawal/discontinuation will be documented in the Case Report Form (CRF). 
Withdrawn participants who receive at least one dose of IMP will be followed up by telephone at 14(-2) days 
after withdrawal, and additionally all who discontinue due to adverse events (AEs) will be followed up until 
resolution or stabilisation. All outcomes of AEs will be recorded in the CRF. 
Participants withdrawn before visit 5 is completed will be replaced in order to maintain statistical power. 
 
7.10.1  Provision for postponement of visit in the event of intercurrent illness 
 
In the event of the following occurring in relation to a study participant: 
 
- 
a significant intercurrent illness, for example a lower respiratory tract infection requiring antibiotic 
therapy; 
- 
requirement for medication that, in the opinion of the investigators, is likely to affect measures of 
inflammation, thrombosis, haemostasis or prostanoid synthesis (see section 8.9); 
 
then if the subsequent study visit 3 or 4 cannot be postponed to a time within the permitted window of 14(-
2) days into the medication period at which the illness or relevant effect of medication has deemed to have 
resolved, study medication may be stopped (and transitioned to standard of care aspirin 75 mg OD) and 
the medication period may be restarted once the intercurrent illness or requirement for medication is 
deemed to have resolved. In this instance, an unscheduled visit will be arranged, the existing supply of 
aspirin (aspirin lysine) +/- rivaroxaban will be counted and, if necessary, a further supply of aspirin (aspirin 
lysine) +/- rivaroxaban will be issued, dispensed after study-specific prescription request has been made to 
the pharmacy at the Northern General Hospital. A file note will be made in the TMF. 
 
 
7.11 
Storage and analysis of clinical samples  
The samples will be stored and analysed according to the study-specific laboratory manual. Samples are 
anticipated to be analysed by the following laboratories and methods: 
 
Cardiovascular Research Unit, University of Sheffield 
1. Fibrin clot lysis time by fibrin clot turbidimetry [10] 
2. Fibrin clot lag time by fibrin clot turbidimetry [10] 
3. Fibrin clot final turbidity by fibrin clot turbidimetry [10] 
4. Plasma TNF-D by enzyme-linked immunosorbent assay (ELISA)/multiplex bead assay (MBA) [16] 
[12] 
5. Plasma IL-6 by ELISA/MBA [16] [12] 
6. Leukocyte count (and subsets), by automated cell counting [17] 
7. Serum TXB2 by ELISA [18]  
8. Urine PGI-M by ELISA [19]  
9. Urine TxM by ELISA [20]  

 
 
 
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         30 
 
10. Platelet aggregation responses to AA, collagen and adenosine diphosphate ADP by light 
transmittance aggregometry [18] 
Department of Laboratory Medicine, Sheffield Teaching Hospitals NHS Foundation Trust 
1. Serum CRP (Roche Cobas assay) [21] 
2. Urinary creatinine (required as a denominator for the correct analysis of urinary PGI-M and TxM) 
(Roche Cobas assay) [18] 
 
7.12 
End of study 
The study will end when the last laboratory analyses are completed. The sponsor will notify the MHRA of the 
end of the study within 90 days of its completion. In the event of early termination, this will be reported within 
15 days.  
 
8 
STUDY MEDICATIONS 
 
8.1 
Name and description of investigational medicinal product(s) 
The following medications will be used for experimental purposes during the study: 
x 
Aspirin lysine (H.J. ¶Aspegic· [Sanofi-Aventis] ¶100 PJ· VacKHWV) 
o Each aspirin lysine ¶100 mg· sachet contains 180 mg aspirin lysine, equivalent to 100 mg 
acetylsalicylic acid (aspirin). In this protocol the stated dose refers to the aspirin content. 
o Participants will be asked to prepare oral doses of 20 mg twice daily, where directed by the 
protocol, by dissolving 100 mg (1 sachet) in 100 ml of drinking water and ingesting 20 ml of 
the solution using a graduated syringe, discarding the remainder. 
o Participants will be asked to prepare oral doses of 75 mg once daily, where directed by the 
protocol, by dissolving 100 mg (1 sachet) in 100 ml of drinking water, removing 25 ml of 
the solution using a graduated syringe, and ingesting the remainder. 
o A new sachet will be used for each dose of study medication 
x 
Rivaroxaban 2.5 mg tablets for oral ingestion (Bayer, 56 tablets per pack) 
o When specified by the randomisation allocation, participants will be asked to take one 2.5 
mg rivaroxaban tablet twice a day, in the morning and evening, commencing the morning 
after visits 3 and 4. 
 
8.2 
Regulatory status of the drug  
x 
Aspirin (aspirin lysine) 100 mg sachets are not licensed in the UK but are licensed in other EU 
countries (e.g. Belgium, Italy) for the purposes of analgesia and antipyresis. Other preparations of 
aspirin are licensed in the UK for similar indications, as well as an antithrombotic agent after ACS. 
x 
As there is no marketing authorisation in the UK for aspirin lysine, we will import this from another 
EU country facilitated by an existing relationship with Mawdsleys Ltd. 

 
 
 
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x 
Rivaroxaban at a dose of 2.5 mg BD is licensed, including in the UK, for the prevention of 
atherothrombotic events in adult patients with CAD or symptomatic PAD at high risk of ischaemic 
events, when taken in combination with aspirin 75-100 mg OD. 
x 
We will retain the original presentation of drugs as supplied without modification, but will be asking 
participants to vary the regimens of aspirin (aspirin lysine) and rivaroxaban as detailed elsewhere in 
this protocol. 
 
8.3 
Product Characteristics  
Aspirin (aspirin lysine) 100 mg sachets have a current summary of product characteristics (SmPC) that has 
been translated and notarised from the original French. A copy will be kept in the trial management file. 
The current version of the SmPC for rivaroxaban 2.5 mg tablets will also be available for reference in the 
trial management file. 
The study team will check for updates to these documents at regular intervals throughout the development 
and conduct of the study, and will review and file these as needed, if necessary obtaining further notarised 
translations. If an update to section 4.8 (the reference safety information) is involved, the revised SmPC will 
be submitted and approved as a substantial amendment before the revised SmPC is filed as the new 
reference safety information for the trial for the assessment of expectedness of adverse events. 
 
8.4 
Drug storage and supply  
Aspirin (aspirin lysine) 100 mg sachets will be sourced by the Northern General Hospital Pharmacy through 
a study-specific arrangement with Mawdsleys Ltd at market price. 
 
Rivaroxaban 2.5 mg tablets will be sourced by the Northern General Hospital Pharmacy locally at market 
price. 
The initial shipment will be requested on site initiation (manual ordering) and re-ordering will occur 
manually as necessary until the end of the study. 
Prior to study medication dispensing, all study medications will be kept in a secure location in the pharmacy 
at Northern General Hospital, Sheffield, under appropriate storage conditions with temperature excursions 
permitted between 15ºC and 30ºC.  Aspirin (aspirin lysine) will be segregated as clinical trial stock for the 
purposes of this study. Rivaroxaban will be dispensed from unsegregated clinical pharmacy stock unless 
practical reasons for segregation of stock arise. 
 
Aspirin (aspirin lysine) and rivaroxaban will be supplied to the investigators upon receipt of a suitable 
signed study-specific prescription at the start of periods 1 and 2 respectively. Only medically-qualified 
members of the study team will be able to complete the prescription. At the start of period 1, two boxes of 
30 sachets of aspirin (aspirin lysine) will be dispensed for each participant. At the start of period 2, one box 
of 56 rivaroxaban 2.5 mg tablets will be dispensed for each participant.  
There are no specific post-dispensing storage instructions. 
Unused medication and used packaging will be returned to pharmacy at the end of treatment period 3. 
Pharmacy will perform pill/sachet count for accountability and will supervise destruction. 
In the event of postponing visit 3, 4 or 5 because of intercurrent illness and restarting a medication period 
from the beginning, unused medication from the period prior to the postponement will be counted by the 
investigators and, if necessary to ensure adequate amounts to restart the period, a new study-specific 
prescription will be made by a medically-qualified investigator for aspirin (aspirin lysine) +/- rivaroxaban. 

 
 
 
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8.5  
Preparation and labelling of Investigational Medicinal Product 
Labels for aspirin (aspirin lysine) and rivaroxaban will be prepared in accordance with Good Manufacturing 
Practice and regulatory guidelines of the Medicines Healthcare and Regulatory Agency. The label will 
include the following information: drug, formulation, dose, and dosing frequency as well as other 
information to comply with annex 13. 
Participants will also be given written, illustrated dose-preparation instructions for aspirin (aspirin lysine). 
They will be trained to prepare the correct dose of aspirin for periods 1 to 3 at visits 2 to 4.   
 
8.6 
Dosage schedules 
The dosage schedules are described in section 7.3, 7.7 and the trial flow chart within this protocol. 
When taking once-daily doses of study medication, this will be on waking, with the exception of the days of 
visits 3, 4 and 5 when they will be asked to delay taking until the appropriate point within the study visit. 
When taking twice-daily, this should be on waking (with the exception of the days of visits 4 and 5 when 
they will be asked to delay taking until the appropriate point within the study visit) and then as close to 12 
hours later as possible. 
In the case of a missed dose, the participant will be advised to take the dose when they remember if within 
6 hours (twice-daily regimens) or 12 hours (once-daily regimens) of the intended time, otherwise to wait to 
take the next dose on time. In the event of vomiting after a dose, they should wait for the next dose before 
taking the study medication again in order avoid accidental overdose. 
The doses of aspirin (aspirin lysine) and rivaroxaban will not be adjusted for any parameter. The maximum 
duration that a participant will receive aspirin (aspirin lysine) will be 42 days and rivaroxaban 28 days. 
 
8.7 
Dosage modifications  
Discontinuation of aspirin (aspirin lysine) and/or rivaroxaban may be considered in the following 
circumstances: 
 Major bleeding, including life-threatening bleeding 
 Intolerable adverse reaction such as minor bleeding that cannot be controlled by local measures 
 Discovery of severe thrombocytopenia (platelet count < 50,000/PL) 
 
No dose adjustment beyond that specified by the randomisation schedule will be permitted. 
 
8.8 
Known drug reactions and interaction with other therapies 
Details are to be found in section 8.9 below, in the current SmPCs for aspirin (aspirin lysine) and 
rivaroxaban. 
  

 
 
 
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8.9 
Concomitant medication 
Recording of any prescribed or over-the-counter medication after randomisation will be made at each visit. 
If at visits 3 and 4, any of the criteria in section 7.10 are met, the participant will be withdrawn if the visit 
cannot be postponed. All individual medications, prescription and over-the-counter, will be recorded peri-
event for any SAE or discontinuation due to AE. The following should be observed if any participant receives 
concomitant medication after enrolment: 
 
Oral antiplatelet/anticoagulant therapies 
Aspirin (acetylsalicylic acid): Aspirin use, with the exception of the study medication as prescribed, is 
prohibited during the study period. At enrolment, patients will be asked to not use aspirin as an analgesic 
and they will be made aware of the range of over-the-counter products that contain it. If no contraindication 
exists, paracetamol will be recommended if the need for analgesia arises. Patients will be asked about 
extra aspirin use, including over the counter supplies, at all visits. If, during the course of study treatment, a 
participant develops a clinical indication for combination antithrombotic therapy, a clinically appropriate 
regimen will be prescribed and they will be followed up but withdrawn from the study. Participants who 
receive at least one dose of IMP will be followed up by telephone 14(-2) days after withdrawal. 
Other oral thrombotic therapies: Treatment with any other oral antithrombotic therapy apart from the study 
medication (e.g. clopidogrel, prasugrel, ticagrelor, dipyridamole, cilostazol, warfarin, dabigatran, edoxaban, 
apixaban) is prohibited during the course of study drugs. However, if during the course of study treatment, a 
participant develops a contraindication to aspirin or rivaroxaban, these will be discontinued/withheld and 
they will be withdrawn from the study. Participants who receive at least one dose of IMP will be followed up 
by telephone 14(-2) days after withdrawal. 
As all participants will be taking rivaroxaban at some stage during the study, drugs that interact with its 
metabolism should be avoided. Strong inhibitors of CYP3A4 substantially increase plasma rivaroxaban 
levels whereas strong inducers of CYP3A4 have the opposite effects. Consequently, strong CYP3A4 
inhibitors (eg, ketoconazole, itraconazole, voriconazole, telithromycin, clarithromycin [but not erythromycin 
or azithromycin], nefazadone, ritonavir, saquinavir, nelfinavir, indinavir, atanazavir, cobicistat or over 1 litre 
daily of grapefruit juice) should not be co-administered with rivaroxaban as plasma drug levels would be 
substantially increased. If regular treatment with such therapies is essential, then rivaroxaban should be 
withheld and they should be withdrawn from the study. Participants who receive at least one dose of IMP 
will be followed up by telephone 14(-2) days after withdrawal. 
Co-administration of rivaroxaban with strong inducers of CYP3A should also be avoided (e.g. 
rifampin/rifampicin, rifabutin, phenytoin, carbamazepine, phenobarbital). 
Similarly, co-administration of rivaroxaban with SSRIs or SNRIs has been associated with an elevation of 
bleeding risk so therapy with these agents should be avoided. 
If regular treatment with such therapies becomes essential during the study medication period then they 
will be withdrawn from the study. Participants who receive at least one dose of IMP will be followed up by 
telephone 14(-2) days after withdrawal. 
 
Non-steroidal anti-inflammatory drugs (NSAIDs) 
NSAIDs may affect the antiplatelet and immunomodulatory effects of aspirin whilst increasing the risk of 
gastric irritation/ulceration and renal impairment. Levels of arachidonic acid metabolites may also be 
affected. Requirement for regular treatment with an NSAID at enrolment meets the exclusion criteria of the 
study. Treatment with NSAIDs during the study period is discouraged. COX2 inhibitors are prohibited in 
combination with study medication. Paracetamol is safe in combination with both aspirin and rivaroxaban 

 
 
 
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and therefore will be the recommended analgesic/antipyretic agent if required. In the case of a participant 
requiring treatment with an NSAID/paracetamol/COX2 inhibitor within 48 hours prior to visit 3, 4 or 5, they 
will be withdrawn if the visit cannot be postponed. Participants who receive at least one dose of IMP will be 
followed up by telephone 14(-2) days after withdrawal. 
 
Diuretics 
Diuretics, including loop (eg. furosemide, bumetanide), thiazide (eg. bendroflumethiazide, indapamide) and 
potassium-sparing agents (eg. spironolactone, eplerenone, amiloride), exert effects on renal prostaglandin 
synthesis and therefore may interfere with urinary prostaglandins. A participant who receives a diuretic 
within 48 hours prior to visit 3, 4 or 5 will be withdrawn if the visit cannot be postponed. Those who receive 
at least one dose of IMP will be followed up by telephone 14(-2) days after withdrawal. 
 
Angiotensin converting enzyme (ACE) inhibitors and Angiotensin receptor blockers (ARBs) 
ACE inhibitors (eg. ramipril, enalapril, lisinopril) and ARBs (eg. candesartan, losartan, irbesartan) can 
modestly affect renal prostaglandin production and hence urinary assays, however, a significant proportion 
of the patients in the target population group being studied in this trial are expected to be receiving these 
agents at enrolment. Therefore, receipt of an ACE inhibitor or ARB will not preclude randomisation or 
ongoing participation in the study. The crossover design and within-patient comparisons are anticipated to 
minimise any interfering effect. 
 
Parenteral anticoagulants 
In the event of an indication for parenteral anticoagulation developing, the participant will be withdrawn 
from the study but those who receive at least one dose of IMP will be followed up by telephone 14(-2) days 
after withdrawal. 
 
Glycoprotein IIb/IIIa antagonists 
In the event of an indication for an agent in this group developing, the participant will be withdrawn from 
the study. Participants who receive at least one dose of IMP will be followed up by telephone 14(-2) days 
after withdrawal. 
 
Fibrinolytic agents 
Treatment with fibrinolytic agents should be avoided whenever possible during treatment with study 
medication. If a participant is to receive a fibrinolytic agent the participant will be withdrawn from the study. 
Participants who receive at least one dose of IMP will be followed up by telephone 14(-2) days after 
withdrawal. 
 
Methotrexate 
Treatment with doses of methotrexate > 15 mg/week in combination with aspirin may increase the toxicity 
of methotrexate.  
 
Uricosurics 

 
 
 
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         35 
 
Aspirin may reduce the effect of uricosurics (e.g. benzbromarone, probenecid) and so are not 
recommended in combination. Allopurinol may be given with low-dose aspirin. 
 
Tenofovir 
Administration of tenofovir disproxil fumarate with NSAIDs, including aspirin, can lead to a greater risk of 
renal failure so combining the two is not recommended. 
 
Other medications to be used with caution 
In addition to those medications contraindicated or not recommended above, caution is advised in use of 
the following drugs in combination with aspirin (aspirin lysine), as detailed in the current SmPC. Given 
participants will already receiving aspirin at enrolment, and total daily dose in this study will not exceed 
their baseline of 75 mg once-daily, there are no study-specific restrictions on prescription of these, but 
usual clinical considerations should be made. 
 GOXcRcRUWLcRLGV (ZLWK WKH H[cHSWLRQ RI K\GURcRUWLVRQH UHSOacHPHQW WKHUaS\) ZLWK aQaOJHVLc aQG aQWLS\UHWLc 
doses of doses: increased risk of haemorrhage. 
 PHPHWUH[HG LQ SaWLHQWV ZLWK PLOG-to-moderate renal failure (creatinine clearance between 45 ml/min and 
80 ml/min): increased risk of pemetrexed toxicity (following a reduction in the renal clearance of 
pemetrexed by aspirin) in the case of concomitant administration of anti-inflammatory doses of yylic acid. 
 AQWLGLabHWLcV (LQVXOLQV, cKORUSURSaPLGH): Lncrease in the hypoglycemic effect of high doses of aspirin  
(hypoglycemic effect and sulfamic reinstatement of its plasma protein bond). 
 IQWHUIHURQ aOSKa: ULVN RI LQKLbLWLRQ RI WKH HIIHcW RI LQWHUIHURQ. 
 IQWUaXWHULQH GHYLcH: (cRQWURYHUVLaO) ULVN RI reduction in the efficacy of the device. 
 DLXUHWLcV, aQJLRWHQVLQ-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists with 
anti-inflammatory, analgesic or antipyretic doses of aspirin: acute renal failure may occur in dehydrated 
patients owing to a reduction in glomerular filtration secondary to a fall in renal prostaglandin production. In 
addition, a reduction in the antihypertensive effect may occur. Ensure that the patient is correctly hydrated 
and monitor renal function at the start of treatment. 
 MHWKRWUH[aWH LQ GRVHV < 15 PJ/ZHHN: IQ WKH caVH RI a GUXJ cRPbLQaWLRQ RI PHWKRWUH[aWH aQG 
acetylsalicylic acid, the haematological toxicity of methotrexate may rise owing to aspirin inducing a 
reduction in renal clearance of methotrexate. During the first weeks of concomitant administration, blood 
counts should be checked every week. Closer supervision is necessary in patients with even mild renal 
function impairment and in elderly patients. 
 GaVWURLQWHVWLQaO WRSLcaOV, aQWacLds and charcoal: increase in renal excretion of acetylsalicylic acid 
following urine alkalinisation. It is recommended to administer gastrointestinal topicals and antacids at 
least 2 hours before or after aspirin. 
 DLJR[LQ aQG OLWKLXP: aspirin disrupts renal excretion of digoxin and lithium, bringing about an increase in 
their plasma concentration. It is recommended to monitor the plasma concentration of digoxin and lithium 
at the beginning and end of aspirin treatment. Dose adjustment may be necessary. 
 Corticosteroids via the systemic route: the risk of gastrointestinal ulcers and bleeding may be increased 
in the case of concomitant administration of aspirin and corticosteroids. 
 IbXSURIHQ: H[SHULPHQWaO GaWa VXJJHVW WKaW LbXSURIHQ Pa\ LQKLbLW WKH HIIHcW of low doses of aspirin on 
platelet aggregation in the case of concomitant administration. Nevertheless, the limitations of these data 
and uncertainties about the extrapolation of the data ex vivo to the clinical situation mean that it is 

 
 
 
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         36 
 
impossible to draw definite conclusions about the regular use of ibubrofen. A clinically significant effect is 
considered unlikely where ibuprofen is used occasionally. 
 VaOSURLc acLG: CRQcRPLWaQW aGPLQLVWUaWLRQ RI VaOLc\OaWHV aQG YaOSURLc acLG Pa\ OHaG WR GHcUHaVHG SURWein 
binding and inhibition of the metabolism of valproic acid causing increased free and total serum levels of 
valproic acid. 
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chickenpox vaccine. CaVHV RI RH\H·V V\QGURPH KaYH RccXUUHG IROORZLQJ WKH aGPLQLVWUaWLRQ RI VaOLc\OaWHV 
during chickenpox infections. 
 PKHQ\WRLQ: WKH cRQcRPLWaQW XVH RI VaOLc\OaWHV aQG SKHQ\WRLQ Pa\ OHaG WR aQ LQcUHaVH LQ VHUXP 
concentrations of phenytoin. 
 MHWaPL]ROH Pa\ UHGXce the effects of aspirin on platelet aggregation in the case of simultaneous 
administration. This combination must therefore be used with caution in patients taking low-dose aspirin 
for cardiovascular prophylaxis. 
 AcHWa]ROaPLGH: caXWLRQ LV UHTXLUHG ZKHQ salicylates are administered concomitantly with acetazolamide 
owing to an increased risk of metabolic acidosis.  
 AOcRKRO Pa\ LQcUHaVH ULVN RI JaVWURLQWHVWLQaO LQMXU\ LI cRQVXPHG cRQcRPLWaQWO\ ZLWK aspirin. Caution 
should therefore be exercised in the event of alcohol consumption by patients taking aspirin. 
 NLcRUaQGLO: IQ SaWLHQWV WUHaWHG cRQcXUUHQWO\ ZLWK QLcRUaQGLO aQG NSAIDV, LQcOXGLQJ aspirin lysine and other 
aspirin, the risk of serious complications such as gastrointestinal ulcers, gastrointestinal perforation and 
haemorrhage is increased. 
 LHYRWK\UR[LQH: SaOLc\OaWHV, LQ SaUWLcXOaU aW UHSHaWHG RU cKURQLc GRVHV KLJKHU WKaQ 2 J / G, caQ LQKLbLW WKH 
binding of thyroid hormones to transporter proteins and therefore cause an initial transient increase in free 
thyroid hormones, followed by an overall decrease in thyroid hormone levels. Thyroid hormone levels should 
be checked. The dose of levothyroxine should be adapted if necessary. 
 
8.10 
Trial restrictions  
There will be no specific restrictions on diet, exercise or lifestyle during the trial. 
 
Surgery and other invasive procedures 
If surgery or another procedure becomes necessary during the study medication period, study medication 
should be stopped and the participant will be withdrawn from the study. Participants who receive at least 
one dose of IMP will be followed up by telephone 14(-2) days after withdrawal. 
The effects of aspirin, but not rivaroxaban, may be reversed by platelet transfusion, which might be 
considered in the event of life-threatening bleeding.  
Similarly the effects of rivaroxaban, but not aspirin, may be reversed by prothrombin complex concentrate 
or, if available, andexanet alfa, which might be considered in the event of life-threatening bleeding. 
 
8.11 
Assessment of compliance with treatment  
Compliance will be assessed at the end of each treatment period by counting the remaining drug sachets 
(aspirin lysine) and tablets (rivaroxaban) returned by the participant, and by direct observation of the 
participant taking last dose of aspirin (aspirin lysine) +/- rivaroxaban in each period. Sachet/tablet counts 

 
 
 
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will be carried out by the investigators and then cross-checked by the Pharmacy Department. Compliance 
will be recorded in the CRF. 
 
8.12 
Name and description of each Non-Investigational Medicinal Product (NIMP) 
There are no NIMPs included in this study. 
 
9 
PHARMACOVIGILANCE 
9.1 
Definitions 
Term 
Definition 
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 trial 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 trial medication qualify as adverse reactions. It is important to note 
that this is entirely separate to the known side effects listed in the SmPC. 
It is specifically a temporal relationship between taking the drug, the half-
life, and the time of the event or any valid alternative aetiology that would 
explain the event. 
Serious Adverse Event 
(SAE) 
A serious adverse event is any untoward medical occurrence that: 
x results in death 
x is life-threatening 
x requires inpatient hospitalisation or prolongation of existing hospitalisation 
x results in persistent or significant disability/incapacity 
x consists of a congenital anomaly or birth defect 
OWKHU ¶LPSRUWaQW PHGLcaO HYHQWV· Pa\ aOVR bH cRQVLGHUHG VHULRXV LI WKH\ 
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 
trial treatments, based on the information provided. 
Suspected Unexpected 
A serious adverse reaction, the nature and severity of which is not 

 
 
 
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Serious Adverse 
Reaction (SUSAR) 
consistent with the information about the medicinal product in question 
set out in the reference safety information: 
x SmPC for aspirin (aspirin lysine) 
x SmPC for rivaroxaban 
 
9.2 
Operational definitions for (S)AEs  
Adverse events and reactions will be recorded and reported from enrolment (visit 1) to visit 6 (14[-2] days 
after last dose of IMP). 
All SAEs will be reported to the sponsor within 24 hours of the research team becoming aware of them. This 
wiOO bH XVLQJ WKH VSRQVRU·V SURIRUPa ZKLcK ZLOO bH VHQW b\ HPaLO WR a GHGLcaWHG aGGUHVV SURYLGHG 
specifically for this purpose. A copy will be kept in the trial master file and the AE log will be completed. All 
SAEs will be reviewed at the regular trial management group meetings. 
All other AEs not meeting the criteria for reporting as serious will be recorded in the CRF. 
The investigators will assess the relatedness of adverse events to the IMPs (aspirin [aspirin lysine], rivaroxaban). 
 
 
9.3 
Recording and reporting of SAEs, SARs AND SUSARs  
SAEs/SUSARs will be recorded and reported from randomisation to visit 6 14(-2) days after last dose of IMP 
These must be recorded on the Sheffield Teaching Hospitals NHS Foundation Trust SAE reporting 
Form and emailed to the Sponsor·V GHGLcaWHG HPaLO aGGUHVV IRU WKLV SXUSRVH within 24 hours of the 
research staff becoming aware of the event. 
For each SAE or SUSAR the following information will be collected: 
x 
full details in medical terms and case description 
x 
event duration (start and end dates, if applicable) 
x 
action taken 
x 
outcome 
x 
seriousness criteria 
x 
causality (i.e. relatedness to trial drug / investigation), in the opinion of the investigator 
x 
whether the event would be considered anticipated. 
Any change of condition or other follow-up information should be emailed to the Sponsor as soon as 
it is available or at least within 24 hours of the information becoming available. Events will be 
followed up until the event has resolved or a final outcome has been reached. 
All SAEs assigned by the PI or delegate as both suspected to be related to IMP-treatment and 
unexpected will be classified as SUSARs and will be subject to expedited reporting to the Medicines 
and Healthcare Products Regulatory Agency (MHRA). The sponsor will inform the MHRA, the REC and 
the relevant Marketing Authorisation Holder(s) of SUSARs within the required expedited reporting 
timescales. 
 
9.4 
Responsibilities 

 
 
 
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Principal Investigator (PI) or delegate:  
1. Checking for AEs and ARs when participants attend for treatment / follow-up. 
2. Using medical judgement in assigning seriousness, causality and whether the event/reaction 
was anticipated using the Reference Safety Information approved for the trial. 
3. Ensuring that all SAEs are recorded and reported to the sponsor within 24 hours of becoming 
aware of the event and provide further follow-up information as soon as available. Ensuring 
that SAEs are chased with Sponsor if a record of receipt is not received within 2 working days 
of initial reporting.  
4. Ensuring that AEs and ARs are recorded and reported to the sponsor in line with the 
requirements of the protocol.  
 
Chief Investigator (CI, in this single-site study the same individual as the PI) or delegate: 
1. Clinical oversight of the safety of patients participating in the trial, including an ongoing 
review of the risk / benefit. 
2. Using medical judgement in assigning whether and event/reaction was anticipated or 
expected in line with the Reference Safety Information. 
3. Immediate review of all SUSARs.  
4. Assigning Medical Dictionary for Regulatory Activities (MedDRA) or Body System coding to all 
SAEs and SARs. 
5. Preparing the clinical sections and final sign off of the Development Safety Update Report 
(DSUR). 
6. Collection and verification of AEs, ARs, SAEs, SARs and SUSARs according to the trial 
protocol. 
Sponsor: (NB where relevant these can be delegated to CI) 
1. Expedited reporting of SUSARs to the Competent Authority (MHRA) and REC within required 
timelines. 
2. Checking for (annually) updates to the Reference Safety Information for the trial. 
3. Preparing standard tables and other relevant information for the DSUR in collaboration with 
the CI and ensuring timely submission to the MHRA and REC. 
 
9.5 
Notification of deaths  
o Any deaths will be treated as an SAE and reported accordingly to the sponsor using the SAE 
reporting procedures within 24 hours of becoming aware, irrespective of whether the death is 
related to the IMP or an unrelated event. 
 
9.6 
Pregnancy reporting  
x 
Pregnancy is not expected to occur as women of childbearing potential who are pregnant or 
unwilling to use reliable contraception will be excluded from study involvement. Nevertheless, any 
pregnancy occurring in a study participant should be reported to the Chief Investigator and the 
Sponsor using the relevant sponsor-provided Pregnancy Reporting Form within 24 hours of 
notification. Any pregnant participant will be withdrawn from the study. Follow-up of the pregnant 
participant and child born to a pregnant trial participant, if this becomes necessary, will be 
discussed with the sponsor in this unlikely event.  

 
 
 
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x 
There are no restrictions nor requirements for follow up of the children of male participants in the 
study. 
 
9.7 
Overdose  
An overdose will be defined as any amount taken, above that prescribed, that in the opinion of a medically-
qualified investigator has the potential to cause significant harm. If an overdose of a study drug occurs, 
then investigators or other site personnel will inform the Sponsor immediately that they become aware of it, 
and in any case within 24 hours. Overdoses may be observed from sachet/tablet counts or patient 
comment. 
In case of overdose of aspirin (aspirin lysine), this will be considered equivalent to standard preparations of 
aspirin.  Aspirin is an established agent and standard guidelines for the assessment and management of 
overdose should be followed. 
Similarly, rivaroxaban is an established drug and usual clinical procedures will be followed in the event of 
overdose. 
Participants who receive an overdose of medication may be withdrawn from the study at the discretion of 
the investigators. 
If an SAE is associated with the overdose, the investigators will ensure the overdose is fully described in the 
SAE report form. 
 
9.8 
Reporting urgent safety measures  
If any urgent safety measures are taken, the CI/Sponsor shall immediately and, in any event, no later than 
3 days from the date the measures are taken, give written notice to the MHRA and the relevant REC of the 
measures taken and the circumstances giving rise to those measures. 
 
9.9 
The type and duration of the follow-up of participants after adverse reactions. 
Adverse drug reactions will be followed up by telephone or in person, as necessary, until resolved or stable. 
Follow up of existing SUSARs (i.e. those which start within the reporting period) will need to be reported to 
the sponsor indefinitely until resolved. 
 
9.10 
Development safety update reports 
The CI will provide (in addition to the expedited reporting above) DSURs once a year throughout the clinical 
trial, or as necessary, to the Competent Authority (MHRA), where relevant the Research Ethics Committee 
and the sponsor.   
The report will be submitted within 60 days of the Developmental International Birth Date (DIBD) of the trial 
each year until the trial is declared ended. 
 
10 
STATISTICS AND DATA ANALYSIS 
 
10.1 
Sample size calculation 

 
 
 
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         41 
 
 
The primary hypothesis of this study is that the difference in post-dose bleeding time between aspirin (aspirin 
lysine) 75 mg once-daily and aspirin (aspirin lysine) 20 mg twice-daily plus rivaroxaban 2.5 mg twice-daily will 
be less than the difference in bleeding time between aspirin (aspirin lysine) 75 mg once-daily and aspirin 
(aspirin lysine) 75 mg once-daily plus rivaroxaban 2.5 mg twice-daily. 
 
Statistical power can be estimated based on previous data from our group showing a mean difference in peak 
effect bleeding time of 154.5 seconds (18%) between aspirin (aspirin lysine) 20 mg BD (plus ticagrelor 90 mg 
twice-daily, another antithrombotic drug) and 75 mg OD (also plus ticagrelor 90 mg twice-daily), with an inter-
individual standard deviation of 316 seconds. 
 
Assuming a similar proportionate difference in bleeding time between the aspirin (aspirin lysine) 20 mg BD- 
and aspirin (aspirin lysine) 75 mg OD-based combination regimens  seen in our previous study, and a worst-
case scenario where the intra-individual standard deviation of the difference is 316 secs (likely to be less 
because of effective pairing of bleeding time data seen in our previous data), we would have 80% power to 
detect a difference in the change in bleeding time from aspirin (aspirin lysine) 75 mg OD to aspirin (aspirin 
lysine) 20 mg BD + rivaroxaban 2.5 mg BD vs. aspirin (aspirin lysine) 75 mg OD to aspirin (aspirin lysine) 75 mg 
OD plus rivaroxaban 2.5 mg BD, of 115 seconds (one-tailed paired-t test), and 90% power to detect a 
difference of 135 secs.  
 
Based on our previous data for aspirin (aspirin lysine) 75 mg OD + ticagrelor as a baseline,  proportionally this 
would represent a difference of 14% (power 0.8) or 16% (power 0.9), which we would class as meaningful 
differences with the potential to reduce the incidence or severity of clinical bleeding events. 
 
Sample size calculations have not been prepared for the secondary endpoints as these are exploratory. 
 
 
10.2 
Planned recruitment rate 
It is aimed to recruit participants at the minimum UaWH RI RQH SHU ZHHN. BaVHG RQ RXU JURXS·V SUHYLRXV 
experience of similar studies, this is sensibly feasible. 
 
10.3 
Statistical analysis plan 
 
10.3.1 Summary of baseline data and flow of patients 
 
The following baseline data will be collected and reported: 
From visit 1 
x 
Demographic data (age, sex, ethnicity) 
x 
Vital signs: pulse, blood pressure and temperature 
x 
Weight and BMI 
x 
Full blood count, urea & electrolytes, liver function tests 

 
 
 
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         42 
 
Categorical data will be reported as proportions and percentages. Continuous data will be reported as 
mean and standard deviation if normally distributed otherwise median and interquartile range. Logarithmic 
transformation will be considered if data are skewed. 
Differences between the dosing regimens and timepoints groups will be assessed by paired t-tests and by 
repeated measures ANOVA with timepoint and treatment as factors. 
A CONSORT flow diagram will be prepared for inclusion in the report of study findings. 
 
10.3.2 Primary outcome analysis 
The primary endpoint will be based on bleeding time at 2 hours following the last dose of IMP of each 
treatment period and will be determined as the difference in bleeding time between aspirin (aspirin lysine) 
75 mg once-daily alone and either aspirin (aspirin lysine) regimen in combination with rivaroxaban 2.5mg 
bd, allowing comparison of the increase in bleeding time with aspirin (aspirin lysine) 20 mg twice-daily plus 
rivaroxaban 2.5 mg twice-daily vs. aspirin (aspirin lysine) 75 mg once-daily plus rivaroxaban 2.5 mg twice-
daily, compared with a one-tailed paired t-test. 
 
10.3.3 Secondary outcome analysis 
 
Secondary analyses will be as follows: 
1. Bleeding time immediately before the last dose of IMP of the treatment period assessed within-
patients between treatment regimens (aspirin [aspirin lysine] 20 mg BD plus rivaroxaban 2.5 mg BD 
vs aspirin [aspirin lysine] 75 mg OD vs aspirin [aspirin lysine] 75 mg OD plus rivaroxaban 2.5 mg 
BD)  using  repeated measures ANOVA, with pairwise comparisons if found to be significant. 
2. Fibrin clot lag time immediately before the last dose of IMP of the treatment period assessed within-
patients between treatment regimens (aspirin [aspirin lysine] 20 mg BD plus rivaroxaban 2.5 mg BD 
vs aspirin [aspirin lysine] 75 mg OD vs aspirin [aspirin lysine] 75 mg OD plus rivaroxaban 2.5 mg 
BD)  using  repeated measures ANOVA, with pairwise comparisons if found to be significant. 
3. Fibrin clot lag time 2 hours following the last dose of IMP of the treatment period assessed within-
patients between treatment regimens (aspirin [aspirin lysine] 20 mg BD plus rivaroxaban 2.5 mg BD 
vs aspirin [aspirin lysine] 75 mg OD vs aspirin [aspirin lysine] 75 mg OD plus rivaroxaban 2.5 mg 
BD)  using  repeated measures ANOVA, with pairwise comparisons if found to be significant. 
4. Fibrin clot lysis time immediately before the last dose of IMP of the treatment period assessed 
within-patients between treatment regimens (aspirin [aspirin lysine] 20 mg BD plus rivaroxaban 2.5 
mg BD vs aspirin [aspirin lysine] 75 mg OD vs aspirin [aspirin lysine] 75 mg OD plus rivaroxaban 2.5 
mg BD)  using  repeated measures ANOVA, with pairwise comparisons if found to be significant. 
5. Fibrin clot lysis time 2 hours following the last dose of IMP of the treatment period assessed within-
patients between treatment regimens (aspirin [aspirin lysine] 20 mg BD plus rivaroxaban 2.5 mg BD 
vs aspirin [aspirin lysine] 75 mg OD vs aspirin [aspirin lysine] 75 mg OD plus rivaroxaban 2.5 mg 
BD)  using repeated measures ANOVA, with pairwise comparisons if found to be significant. 

 
 
 
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         43 
 
6. Plasma TNFD immediately before the last dose of IMP of the treatment period assessed within-
patients between treatment regimens (aspirin [aspirin lysine] 20 mg BD plus rivaroxaban 2.5 mg BD 
vs aspirin [aspirin lysine] 75 mg OD vs aspirin [aspirin lysine] 75 mg OD plus rivaroxaban 2.5 mg 
BD)  using  repeated measures ANOVA, with pairwise comparisons if found to be significant. 
7. Plasma TNFD 2 hours following the last dose of IMP of the treatment period assessed within-
patients between treatment regimens (aspirin [aspirin lysine] 20 mg BD plus rivaroxaban 2.5 mg BD 
vs aspirin [aspirin lysine] 75 mg OD vs aspirin [aspirin lysine] 75 mg OD plus rivaroxaban 2.5 mg 
BD)  using repeated measures ANOVA, with pairwise comparisons if found to be significant. 
8. Plasma IL-6  immediately before the last dose of IMP of the treatment period assessed within-
patients between treatment regimens (aspirin [aspirin lysine] 20 mg BD plus rivaroxaban 2.5 mg BD 
vs aspirin [aspirin lysine] 75 mg OD vs aspirin [aspirin lysine] 75 mg OD plus rivaroxaban 2.5 mg 
BD)  using  repeated measures ANOVA, with pairwise comparisons if found to be significant. 
9. Plasma IL-6 2 hours following the last dose of IMP of the treatment period assessed within-patients 
between treatment regimens (aspirin [aspirin lysine] 20 mg BD plus rivaroxaban 2.5 mg BD vs 
aspirin [aspirin lysine] 75 mg OD vs aspirin [aspirin lysine] 75 mg OD plus rivaroxaban 2.5 mg BD)  
using repeated measures ANOVA, with pairwise comparisons if found to be significant. 
10. Serum CRP at 2 hours following the last dose of IMP of the treatment period assessed within-
patients between treatment regimens (aspirin [aspirin lysine] 20 mg BD plus rivaroxaban 2.5 mg BD 
vs aspirin [aspirin lysine] 75 mg OD vs aspirin [aspirin lysine] 75 mg OD plus rivaroxaban 2.5 mg 
BD)  using repeated measures ANOVA, with pairwise comparisons if found to be significant. 
11. Circulating leukocyte count immediately before the last dose of IMP of the treatment period 
assessed within-patients between treatment regimens (aspirin [aspirin lysine] 20 mg BD plus 
rivaroxaban 2.5 mg BD vs aspirin [aspirin lysine] 75 mg OD vs aspirin [aspirin lysine] 75 mg OD plus 
rivaroxaban 2.5 mg BD)  using  repeated measures ANOVA, with pairwise comparisons if found to 
be significant. 
12. Circulating leukocyte count 2 hours following the last dose of IMP of the treatment period assessed 
within-patients between treatment regimens (aspirin [aspirin lysine] 20 mg BD plus rivaroxaban 2.5 
mg BD vs aspirin [aspirin lysine] 75 mg OD vs aspirin [aspirin lysine] 75 mg OD plus rivaroxaban 2.5 
mg BD) using repeated measures ANOVA, with pairwise comparisons if found to be significant. 
13. Serum TXB2 immediately before the last dose of IMP of the treatment period assessed within-
patients between treatment regimens (aspirin [aspirin lysine] 20 mg BD plus rivaroxaban 2.5 mg BD 
vs aspirin [aspirin lysine] 75 mg OD vs aspirin [aspirin lysine] 75 mg OD plus rivaroxaban 2.5 mg 
BD)  using  repeated measures ANOVA, with pairwise comparisons if found to be significant. 
14. Serum TXB2 2 hours following the last dose of IMP of the treatment period assessed within-patients 
between treatment regimens (aspirin [aspirin lysine] 20 mg BD plus rivaroxaban 2.5 mg BD vs 
aspirin [aspirin lysine] 75 mg OD vs aspirin [aspirin lysine] 75 mg OD plus rivaroxaban 2.5 mg BD)  
using repeated measures ANOVA, with pairwise comparisons if found to be significant. 
15. Urinary PGI-M  immediately before the last dose of IMP of the treatment period assessed within-
patients between treatment regimens (aspirin [aspirin lysine] 20 mg BD plus rivaroxaban 2.5 mg BD 

 
 
 
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         44 
 
vs aspirin [aspirin lysine] 75 mg OD vs aspirin [aspirin lysine] 75 mg OD plus rivaroxaban 2.5 mg 
BD)  using  repeated measures ANOVA, with pairwise comparisons if found to be significant. 
16. Urinary PGI-M  2 hours following the last dose of IMP of the treatment period assessed within-
patients between treatment regimens (aspirin [aspirin lysine] 20 mg BD plus rivaroxaban 2.5 mg BD 
vs aspirin [aspirin lysine] 75 mg OD vs aspirin [aspirin lysine] 75 mg OD plus rivaroxaban 2.5 mg 
BD)  using repeated measures ANOVA, with pairwise comparisons if found to be significant. 
17. Urinary TxM  immediately before the last dose of IMP of the treatment period assessed within-
patients between treatment regimens (aspirin [aspirin lysine] 20 mg BD plus rivaroxaban 2.5 mg BD 
vs aspirin [aspirin lysine] 75 mg OD vs aspirin [aspirin lysine] 75 mg OD plus rivaroxaban 2.5 mg 
BD)  using  repeated measures ANOVA, with pairwise comparisons if found to be significant. 
18. Urinary TxM 2 hours following the last dose of IMP of the treatment period assessed within-patients 
between treatment regimens (aspirin [aspirin lysine] 20 mg BD plus rivaroxaban 2.5 mg BD vs 
aspirin [aspirin lysine] 75 mg OD vs aspirin [aspirin lysine] 75 mg OD plus rivaroxaban 2.5 mg BD) 
using repeated measures ANOVA, with pairwise comparisons if found to be significant. 
19. Maximum platelet aggregation responses to arachidonic acid (0.3 and 1 mmol/L), collagen (4 and 
16 Pg/mL) and ADP (20 Pmol/L) immediately before the last dose of IMP of the treatment period 
assessed within-patients between treatment regimens (aspirin [aspirin lysine] 20 mg BD plus 
rivaroxaban 2.5 mg BD vs aspirin [aspirin lysine] 75 mg OD vs aspirin [aspirin lysine] 75 mg OD plus 
rivaroxaban 2.5 mg BD) using a repeated measures ANOVA, with pairwise comparisons if found to 
be significant. 
20. Maximum platelet aggregation responses to arachidonic acid (0.3 and 1 mmol/L), collagen (4 and 
16 Pg/mL) and ADP (20 Pmol/L) 2 hours after the last dose of IMP of the treatment period 
assessed within-patients between treatment regimens (aspirin [aspirin lysine] 20 mg BD plus 
rivaroxaban 2.5 mg BD vs aspirin [aspirin lysine] 75 mg OD vs aspirin [aspirin lysine] 75 mg OD plus 
rivaroxaban 2.5 mg BD) using a repeated measures ANOVA, with pairwise comparisons if found to 
be significant. 
21. Final clot turbidity  immediately before the last dose of IMP of the treatment period assessed within-
patients between treatment regimens (aspirin [aspirin lysine] 20 mg BD plus rivaroxaban 2.5 mg BD 
vs aspirin [aspirin lysine] 75 mg OD vs aspirin [aspirin lysine] 75 mg OD plus rivaroxaban 2.5 mg 
BD)  using  repeated measures ANOVA, with pairwise comparisons if found to be significant. 
22. Final clot turbidity 2 hours following the last dose of IMP of the treatment period assessed within-
patients between treatment regimens (aspirin [aspirin lysine] 20 mg BD plus rivaroxaban 2.5 mg BD 
vs aspirin [aspirin lysine] 75 mg OD vs aspirin [aspirin lysine] 75 mg OD plus rivaroxaban 2.5 mg 
BD) using repeated measures ANOVA, with pairwise comparisons if found to be significant. 
 
10.4 
Subgroup analyses 
No pre-specified subgroup analyses are planned. 
 
10.5 
Adjusted analysis 

 
 
 
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         45 
 
If variables are found to be of skewed distribution, logarithmic transformation will be performed. 
 
10.6 
Interim analysis and criteria for the premature termination of the trial 
No interim analyses are planned.  
 
10.7 Participant population 
x 
The pharmacodynamic analysis set will include all participants who achieve at least 80% 
compliance with study medication during each of the three periods. 
x 
The safety analysis set (for the purposes of adverse event reporting etc.) will include any 
participant randomised into the trial that received at least one dose of IMP. 
 
10.8  Procedure(s) to account for missing or spurious data  
 
x 
MLVVLQJ GaWa ZLOO bH UHcRUGHG b\ QRWaWLQJ ¶NR· (QRW UHcRUGHG) LQ WKH relevant section of the CRF 
x 
Where analysis is performed using ANOVA, missing data will be estimated by multiple imputation 
using the IBM SPSS software package. Sensitivity analyses will be carried out to report the 
robustness of this approach.  
 
10.9 
Other statistical considerations. 
Not applicable to this study 
 
10.10 Economic evaluation 
 Not applicable to this study. 
 
 
 
11 
DATA MANAGEMENT  
11.1 
Data collection tools and source document identification 
Source data will be recorded on the study-specific paper case report form (CRF). A separate paper CRF will 
be used to record laboratory data. Source data will feed from the CRF to the trial master database. 
A paper trial master file will be kept within the Cardiovascular Research Unit at the University of Sheffield, 
maintained by the Research Co-ordinator. 
 
11.2 
Data handling and record keeping  
The investigators will maintain a study database, including an audit trail of data changes ensuring that 
there is no deletion of entered data, and will utilise a security system to protect against unauthorized 
access. They will2 maintain a list of the individuals authorized to make data changes, maintain adequate 
backup of the data, and archiving of any source data (i.e. hard copy and electronic). This will include a clear 

 
 
 
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         46 
 
record of data changes if transformed during processing. The investigators will use an unambiguous 
participant identification code that allows identification of all the data reported for each participant. All 
electronic data will be kept securely stored on University of Sheffield systems, or external handlers 
contracted by the University of Sheffield for this purpose. The Sponsor will be responsible for ensuring 
compliance with the requirements outlined above.  
 
11.3 
Access to Data 
Direct access will be granted to authorised representatives from the Sponsor, host institution and the 
regulatory authorities to permit trial-related monitoring, audits and inspections in line with participant 
consent. 
 
11.4 Archiving 
Archiving will be authorised by the Sponsor following submission of the end of trial report. The sponsor will 
archive all study documents through existing SOPs and external contracts for a minimum of 15 years after 
the end of the study, as per local protocols. Destruction of essential documents will require authorisation 
from the Sponsor. The trial database will be kept by the investigators for an undefined period of time, but at 
least 15 years, in electronic format on University of Sheffield file storage systems. 
 
12 
MONITORING, AUDIT & INSPECTION 
x 
A Trial Monitoring Plan will be developed and agreed by the Trial Management Group (TMG) and 
CI based on the trial risk assessment, which may include on-site monitoring. This will be 
dependent on a documented risk assessment of the trial by the Sponsor. 
x 
It is anticipated that monitoring audits will take place after the first participant first visit and last 
participant last visit. 
x 
The monitoring plan will be kept in the trial master file. 
x 
The monitoring personnel will be determined by the Sponsor. 
x 
The processes reviewed will include participant enrolment, consent, eligibility, and allocation to 
trial groups; adherence to trial interventions and policies to protect participants, including 
reporting of harm and completeness and timeliness of data collection. 
x 
The research team, headed by the PI/CI, will be responsible for verification of the accuracy of 
study data. 
x 
Monitoring will be performed through site visit to review original documentation. 
x 
The investigators will host the site visits. 
 
13  
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1  Research Ethics Committee (REC) review and report, and Health Research Authority (HRA) approval 
x 
Before the start of the trial, approval will be sought from a REC for the trial protocol, informed 
consent forms and other relevant documents e.g. advertisements and GP information letters. 
HRA approval will also be obtained. 

 
 
 
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         47 
 
x 
Substantial amendments that require review by REC will not be implemented until the REC grants 
a favourable opinion for the amendment and HRA amendment approval is received. 
Amendments may also need to be reviewed and accepted by the MHRA and/or NHS R&D 
departments before they can be implemented in practice. 
x 
All correspondence with the REC, MHRA and HRA will be retained in the Trial Master File.  
x 
An annual progress report (APR) will be submitted to the REC within 30 days of the anniversary 
date on which the favourable opinion was given, and annually until the trial is declared ended. 
x 
IW LV WKH CKLHI IQYHVWLJaWRU·V UHVSRQVLbLOLW\ WR SURGXcH WKH aQQXaO UHSRUWV aV UHTXired. 
x 
The Chief Investigator will notify the REC of the end of the trial. 
x 
if the trial is ended prematurely, the Chief Investigator will notify the REC, including the reasons 
for the premature termination. 
x 
Within one year after the end of the trial, the Chief Investigator will submit a final report with the 
results, including any publications/abstracts, to the REC. 
 
13.2  
Peer review 
The study design has been reviewed and approved by multiple independent scientific/medical personnel 
on behalf of the MRC Confidence in Concepts funding scheme, who also reviewed the statistical aspects. 
 
13.3  
Public and Patient Involvement 
The concepts tested in this study have been previously presented to the Sheffield Cardiovascular Patient 
Panel. 
13.4  Regulatory Compliance  
x 
The trial will not commence until a Clinical Trial Authorisation (CTA) is obtained from the MHRA 
and Favourable REC opinion.  
x 
The protocol and trial conduct will comply with the Medicines for Human Use (Clinical Trials) 
Regulations 2004 and any relevant amendments. 
x 
No ionising radiation will be used during this study. 
 
13.5  Protocol compliance  
x 
Prospective, planned deviations or waivers to the protocol are not allowed under the UK 
regulations on Clinical Trials and must not be used e.g. it is not acceptable to enrol a participant if 
they do not meet the eligibility criteria or restrictions specified in the trial protocol. 
x 
Accidental protocol deviations must be adequately documented on the relevant Sponsor-provided 
forms and reported to the Chief Investigator and Sponsor immediately.  
x 
Deviations from the protocol which are found to frequently recur will require immediate action 
and could potentially be classified as a serious breach, at the discretion of the Sponsor. 

 
 
 
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         48 
 
 
13.6  Notification of Serious Breaches to GCP and/or the protocol  
A ´VHULRXV bUHacKµ LV a bUHacK ZKLcK LV OLNHO\ WR HIIHcW WR a VLJQLficant degree ² 
(a) the safety or physical or mental integrity of the participants of the trial; or 
(b) the scientific value of the trial 
The Sponsor will be notified immediately of any case where the above definition applies during the trial 
conduct phase 
x 
The Sponsor will notify the licensing authority in writing of any serious breach of 
(a) the conditions and principles of GCP in connection with that trial; or  
(b) the protocol relating to that trial, as amended from time to time, within 7 days of becoming 
aware of that breach 
 
13.7  Data protection and patient confidentiality  
All investigators and trial site staff must comply with the requirements of the Data Protection Act 2018 with 
regards to the collection, storage, processing and disclosure of personal information and will uphold the 
AcW·V cRUH SULQcLSOHV.  
x 
Personal information will be collected by the investigators, kept secure within a room in the 
Cardiovascular Research Unit that is kept locked and alarmed out-of-hours, and will be 
maintained by the staff of the Cardiovascular Research Unit. This will involve: 
o Within the master trial database the creation of coded, depersonalised data whereby the 
SaUWLcLSaQW·V LGHQWLI\LQJ LQIRUPaWLRQ will be replaced by the study enrolment number. 
o Secure maintenance of the data and the linking code in separate locations using encrypted 
digital files within password protected folders and storage media on NHS or University of 
Sheffield computing systems. 
o Limiting access to the minimum number of individuals necessary for quality control, audit, 
and analysis. 
x 
Monitoring visits will take place at site to avoid any data breaches. Transmission of information 
relating to safety eg. SAE reports will occur by secure NHS email channels. Any sharing of data 
with collaborators will be anonymised. 
x 
Study source documents will be kept for a minimum of 15 years as per Sponsor protocols. 
x 
The data custodian will be the CI. 
 
13.8  Financial and other competing interests for the chief investigator, PIs at each site and committee 
members for the overall trial management  
Robert F. Storey: institutional research grants/support from AstraZeneca; consultancy fees from 
AstraZeneca, Bayer, Bristol Myers Squibb/Pfizer alliance, Haemonetics, Idorsia, Novartis and Thromboserin; 
speaker fees from AstraZeneca, and Bayer and Bristol Myers Squibb/Pfizer alliance. Nominated by 
University of Sheffield as inventor on patent application related to concepts explored in this study. 
William A. E.  Parker: nominated by University of Sheffield as inventor on patent application related to 
concepts explored in this study.  
 

 
 
 
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         49 
 
13.9  Indemnity 
The NHS indemnity scheme will apply for harm arising from management of research and research 
conduct. Additionally, The University of Sheffield will provide insurance against liabilities for which it may be 
legally liable and this cover will include any such liabilities arising out of this research project/study. 
13.10  Amendments  
Any changes to the protocol or informed consent form will be assessed by the Sponsor to determine the 
necessary approvals to be obtained (MHRA, HRA and/or REC). The Sponsor will then approve the amendment 
when the necessary approvals have been granted. 
 
13.11  Post-trial care 
Whilst not able to offer study-VSHcLILc PHGLcaO caUH RQcH a SaUWLcLSaQW·V LQYROYHPHQW LQ WKH VWXG\ HQGV, WKH 
investigators will ensure that participants are signposted to the relevant NHS services should these be 
needed. 
 
13.12  Access to the final trial dataset 
x 
The investigators identified on the delegation log will have access to the full dataset, at the 
discretion of the CI. 
 
14  
DISSEMINATION POLICY 
14.1  
Dissemination policy 
x 
The data arising from the trial will be owned by University of Sheffield. 
x 
On completion of the trial, the data will be analysed and tabulated and a Final Trial Report 
prepared. 
x 
The trial report will be accessible via the EudraCT system, in a medical journal and on request 
from the CI. 
x 
The CI will retain the sole right to publish any of the trial data.  
x 
The MRC and the Sheffield NIHR Clinical Research Facility will be acknowledged within any 
publications but will not have review/publication rights of the data from the trial. 
x 
Participants will be able to obtain a short summary of the results by letter on request. 
x 
It will not be possible for the participant to specifically request results from the investigators. 
x 
The disclosure of the trial protocol, full trial report, anonymised participant level dataset, and 
statistical code for generating the results may be made available to interested parties at the 
discretion of the CI, not before 1 year after study completion. 
 
14.2  Authorship eligibility guidelines and any intended use of professional writers 
Those individuals who contribute significantly to the development, conduct and writing-up of the study will be 
offered authorship of the final trial report. Individually-named authors will meet the authorship criteria of The 
International Committee of Medical Journal Editors. No professional medical writers will be involved in the 
preparation of reports or publications. 

 
 
 
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         50 
 
 
15 
REFERENCES 
x 
1. 
Montalescot, G., et al., 2013 ESC guidelines on the management of stable coronary artery 
disease: the Task Force on the management of stable coronary artery disease of the European 
Society of Cardiology. Eur Heart J, 2013. 34(38): p. 2949-3003. 
x 
2. 
Knuuti, J., et al., 2019 ESC Guidelines for the diagnosis and management of chronic 
coronary syndromes. Eur Heart J, 2019. 
x 
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Eikelboom, J.W., et al., Rivaroxaban with or without Aspirin in Stable Cardiovascular 
Disease. N Engl J Med, 2017. 377(14): p. 1319-1330. 
x 
4. 
Sumaya, W., et al., Fibrin clot properties independently predict adverse clinical outcome 
following acute coronary syndrome: a PLATO substudy. Eur Heart J, 2018. 39(13): p. 1078-1085. 
x 
5. 
Konigsbrugge, O., et al., Plasma clot formation and clot lysis to compare effects of different 
anticoagulation treatments on hemostasis in patients with atrial fibrillation. Clin Exp Med, 2018. 
18(3): p. 325-336. 
x 
6. 
Patrono, C., et al., Antiplatelet Agents for the Treatment and Prevention of Coronary 
Atherothrombosis. J Am Coll Cardiol, 2017. 70(14): p. 1760-1776. 
x 
7. 
Patrono, C., Aspirin as an antiplatelet drug. N Engl J Med, 1994. 330(18): p. 1287-94. 
x 
8. 
Ajjan, R.A., et al., Effects of aspirin on clot structure and fibrinolysis using a novel in vitro 
cellular system. Arterioscler Thromb Vasc Biol, 2009. 29(5): p. 712-7. 
x 
9. 
Parker, W., et al., Ultra-low-dose twice-daily aspirin improves hemostasis and maintains 
platelet inhibition in acute coronary syndrome patients receiving ticagrelor. Journal of the American 
College of Cardiology, 2018. 71(11 Supplement): p. A30. 
x 
10. 
Sumaya, W., et al., Fibrin clot properties independently predict adverse clinical outcome 
following acute coronary syndrome: a PLATO substudy. Eur Heart J, 2018. 
x 
11. 
Kiers, D., et al., A randomised trial on the effect of anti-platelet therapy on the systemic 
inflammatory response in human endotoxaemia. Thromb Haemost, 2017. 117(9): p. 1798-1807. 
x 
12. 
Thomas, M.R., et al., Platelet P2Y12 Inhibitors Reduce Systemic Inflammation and Its 
Prothrombotic Effects in an Experimental Human Model. Arterioscler Thromb Vasc Biol, 2015. 35: p. 
2562-2570. 
x 
13. 
Ridker, P.M., et al., Antiinflammatory Therapy with Canakinumab for Atherosclerotic 
Disease. N Engl J Med, 2017. 377(12): p. 1119-1131. 
x 
14. 
Eliquis 2.5 mg film-coated tablets - Summary of Product Characteristics (SmPC) - (eMC). 
2016  [cited 2019; Available from: https://www.medicines.org.uk/emc/product/4756/smpc. 
x 
15. 
Teng, R., J. Maya, and K. Butler, Evaluation of the pharmacokinetics and 
pharmacodynamics of ticagrelor co-administered with aspirin in healthy volunteers. Platelets, 2013. 
24(8): p. 615-624. 
x 
16. 
Choi, J., S.Y. Hwang, and K. Ahn, Interplay between RNASEH2 and MOV10 controls LINE-1 
retrotransposition. Nucleic Acids Res, 2018. 46(4): p. 1912-1926. 
x 
17. 
van Dievoet, M.A., H. Louagie, and T. Ghys, Performance evaluation of the Sysmex((R)) XP-
300 in an oncology setting: evaluation and comparison of hematological parameters with the 
Sysmex((R)) XN-3000. Int J Lab Hematol, 2016. 38(5): p. 490-6. 
x 
18. 
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