Dual Antiplatelet Therapy to Inhibit Coronary Atherosclerosis and Myocardial Injury in Patients With Necrotic High-Risk Coronary Plaque Disease
Phase: PHASE2
Conditions: Coronary Artery Disease
Sponsor: University of Edinburgh

 
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Study Protocol 
 
 
 
 
 
 
Dual antiplatelet therapy to Inhibit coronary Atherosclerosis and MyOcardial 
injury in patients with Necrotic high-risk coronary plaque Disease  
 
Co-sponsors 
University of Edinburgh & NHS Lothian 
ACCORD 
The Queen’s Medical Research Institute 
47 Little France Crescent 
Edinburgh 
EH16 4TJ 
Funder 
Wellcome Trust and AstraZeneca 
Funding Reference Number 
WT103782AIA - Senior Investigator Award 
AstraZeneca Reference Number 
ISSBRIL0250 
Chief Investigator 
Professor David Newby 
EudraCT Number 
2014-000952-26 
REC Number 
14/SS/0089 
ClinicalTrials.gov ID number 
NCT02110303  
Version Number and Date 
5.0, 31st January 2017 
 

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COORDINATING CENTRE 
Chief Investigator 
Professor David E Newby 
Centre of Cardiovascular Science 
Chancellor’s Building 
51 Little France Crescent 
Edinburgh EH16 4SB  
 
Tel: 0131 242 6515  
Fax: 0131 242 6379  
Email: d.e.newby@ed.ac.uk 
Co-sponsor Representative 
Fiach O’Mahony 
University of Edinburgh  
Queen’s Medical Research Institute 
47 Little France Crescent 
Edinburgh EH16 4TJ  
 
Tel: 0131 242 9418  
Email: fiach.o’mahony@ed.ac.uk 
Trial Statistician 
Steff Lewis 
Centre for Population Health Sciences 
University of Edinburgh 
Teviot Place 
Edinburgh 
EH8 9AG 
 
Tel: 0131 650 3198 
Email: steff.lewis@ed.ac.uk 
PARTICIPATING SITES 
Edinburgh Royal Infirmary  
Principal Investigator 
Philip Adamson  
Centre of Cardiovascular Science 
Chancellor’s Building 
51 Little France Crescent 
Edinburgh EH16 4SB  
Tel: 0745 345 8084 
Email: philadamson.nz@gmail.com 
 
 

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CONTENTS 
 
1 
INTRODUCTION .......................................................................................... 9 
1.1 
BACKGROUND ................................................................................... 9 
1.1.1 
Pathogenesis of Coronary Artery Disease ........................................ 9 
1.1.2 
Ticagrelor .......................................................................................... 9 
1.1.3 
Non-invasive Imaging of the Vulnerable Plaque ............................... 9 
1.1.4 
High-Sensitivity Cardiac Troponin I ................................................ 10 
1.2 
Research Hypothesis ......................................................................... 10 
1.3 
RATIONALE FOR STUDY ................................................................. 10 
2 
STUDY OBJECTIVES ................................................................................ 11 
2.1 
OBJECTIVES .................................................................................... 11 
2.1.1 
Primary Objective ........................................................................... 11 
2.1.2 
Secondary Objectives ..................................................................... 11 
2.1.3 
Safety Objective .............................................................................. 11 
2.1.4 
Exploratory Objectives .................................................................... 11 
2.2 
ENDPOINTS ...................................................................................... 12 
2.2.1 
Primary Endpoint ............................................................................ 12 
2.2.2 
Secondary Endpoints ...................................................................... 12 
3 
STUDY DESIGN ......................................................................................... 12 
3.1 
RATIONAL FOR STUDY DESIGN, DOSES AND CONTROL 
GROUPS ........................................................................................... 12 
4 
STUDY POPULATION ............................................................................... 13 
4.1 
NUMBER OF PARTICIPANTS .......................................................... 13 
4.2 
INCLUSION CRITERIA ..................................................................... 13 
4.3 
EXCLUSION CRITERIA .................................................................... 13 
4.4 
CO-ENROLMENT .............................................................................. 13 
5 
PARTICIPANT SELECTION AND ENROLMENT ..................................... 14 
5.1 
IDENTIFYING PARTICIPANTS ......................................................... 14 
5.2 
CONSENTING PARTICIPANTS ........................................................ 14 
5.3 
SCREENING FOR ELIGIBILITY ........................................................ 14 
5.4 
INELIGIBLE AND NON-RECRUITED PARTICIPANTS .................... 14 
5.5 
PROCEDURES FOR HANDLING SUBJECTS INCORRECTLY 
ENROLLED, RANDOMISED OR INITIATED ON INVESTIGATIONAL 
MEDICINAL PRODUCT .................................................................... 14 
5.6 
RANDOMISATION ............................................................................ 15 
5.6.1 
Randomisation Procedures ............................................................ 15 
5.6.2 
Treatment Allocation ....................................................................... 15 
5.6.3 
Methods to Ensure Blinding ............................................................ 15 

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5.6.4 
Emergency Unblinding Procedures ................................................ 15 
5.6.5 
Discontinuation of Investigational Medicinal Product ...................... 15 
5.6.6 
Withdrawal of Study Participants .................................................... 15 
6 
INVESTIGATIONAL MEDICINAL PRODUCT AND PLACEBO ................ 16 
6.1 
STUDY DRUG ................................................................................... 16 
6.1.1 
Study Drug Identification ................................................................. 16 
6.1.2 
Study Drug Manufacturer ................................................................ 16 
6.1.3 
Marketing Authorisation Holder ...................................................... 16 
6.1.4 
Labelling and Packaging ................................................................. 16 
6.1.5 
Storage ........................................................................................... 16 
6.2 
PLACEBO .......................................................................................... 17 
6.3 
DOSING REGIME ............................................................................. 17 
6.4 
DOSE CHANGES .............................................................................. 17 
6.5 
PARTICIPANT COMPLIANCE AND ACCOUNTABILITY ................. 17 
6.6 
OVERDOSE ...................................................................................... 17 
6.7 
OTHER MEDICATIONS .................................................................... 17 
6.7.1 
Non-Investigational Medicinal Products .......................................... 17 
6.7.2 
Permitted Medications .................................................................... 17 
6.7.3 
Prohibited Medications ................................................................... 18 
7 
STUDY ASSESSMENTS ........................................................................... 18 
7.1 
SAFETY ASSESSMENTS ................................................................. 18 
7.2 
STUDY ASSESSMENTS ................................................................... 18 
7.2.1 
Baseline Assessments .................................................................... 19 
7.2.2 
Follow Up Assessments ................................................................. 20 
7.2.3 
High Sensitivity Cardiac Troponin I ................................................. 20 
7.2.4 
Positron Emission and Computed Tomography Coronary 
Angiography .................................................................................... 20 
7.2.5 
Platelet-Monocyte Aggregates ........................................................ 21 
7.2.6 
Biological Samples ......................................................................... 21 
8 
DATA COLLECTION ................................................................................. 22 
9 
STATISTICS AND DATA ANALYSIS ........................................................ 22 
9.1 
SAMPLE SIZE CALCULATION ......................................................... 22 
9.2 
PROPOSED ANALYSES .................................................................. 22 
9.2.1 
Description of analysis sets ............................................................ 22 
9.2.2 
Methods of statistical analysis ........................................................ 22 
10 
ADVERSE EVENTS ................................................................................... 23 
10.1 
DEFINITIONS .................................................................................... 23 
10.2 
IDENTIFYING AEs AND SAEs .......................................................... 23 
10.3 
RECORDING AEs AND SAEs ........................................................... 24 

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10.4 
ASSESSMENT OF AEs AND SAEs .................................................. 24 
10.4.1 Assessment of Seriousness ........................................................... 24 
10.4.2 Assessment of Causality ................................................................ 24 
10.4.3 Assessment of Expectedness ......................................................... 24 
10.4.4 Assessment of Severity .................................................................. 25 
10.5 
REPORTING OF SAEs/SARs/SUSARs ............................................ 25 
10.6 
REGULATORY REPORTING REQUIREMENTS .............................. 25 
10.7 
ASTRA ZENECA REPORTING REQUIREMENTS ........................... 25 
10.8 
FOLLOW UP PROCEDURES ........................................................... 26 
11 
PREGNANCY ............................................................................................. 26 
12 
TRIAL MANAGEMENT AND OVERSIGHT ARRANGEMENTS ............... 26 
12.1 
TRIAL MANAGEMENT GROUP ........................................................ 26 
12.2 
TRIAL STEERING COMMITTEE ....................................................... 27 
12.3 
DATA MONITORING COMMITTEE .................................................. 27 
12.4 
INSPECTION OF RECORDS ............................................................ 27 
12.5 
RISK ASSESSMENT ......................................................................... 27 
12.6 
BENEFIT/RISK BALANCE ................................................................ 27 
12.6.1 Benefits ........................................................................................... 27 
12.6.2 Risks ............................................................................................... 27 
12.7 
STUDY MONITORING AND AUDIT .................................................. 28 
13 
GOOD CLINICAL PRACTICE ................................................................... 28 
13.1 
ETHICAL CONDUCT ......................................................................... 28 
13.2 
REGULATORY COMPLIANCE ......................................................... 29 
13.3 
INVESTIGATOR RESPONSIBILITIES .............................................. 29 
13.3.1 Informed Consent ........................................................................... 29 
13.3.2 Study Site Staff ............................................................................... 29 
13.3.3 Data Recording ............................................................................... 29 
13.3.4 Investigator Documentation ............................................................ 29 
13.3.5 GCP Training .................................................................................. 30 
13.3.6 Confidentiality ................................................................................. 30 
13.3.7 Data Protection ............................................................................... 30 
14 
STUDY CONDUCT RESPONSIBILITIES .................................................. 30 
14.1 
PROTOCOL AMENDMENTS ............................................................ 30 
14.2 
PROTOCOL VIOLATIONS AND DEVIATIONS ................................. 30 
14.3 
SERIOUS BREACH REQUIREMENTS ............................................. 31 
14.4 
STUDY RECORD RETENTION ........................................................ 31 
14.5 
END OF STUDY ................................................................................ 31 
14.6 
CONTINUATION OF DRUG FOLLOWING THE END OF STUDY ... 31 
14.7 
INSURANCE AND INDEMNITY ........................................................ 31 
15 
REPORTING, PUBLICATIONS AND NOTIFICATION OF RESULTS ...... 32 

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15.1 
AUTHORSHIP POLICY ..................................................................... 32 
15.2 
PUBLICATION ................................................................................... 32 
15.3 
PEER REVIEW .................................................................................. 32 
16 
REFERENCES ........................................................................................... 32 
 

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PROTOCOL APPROVAL 
DIAMOND  
EudraCT number 2014-000952-26 
Signatures 
 
Professor David Newby 
 
 
 
Chief Investigator 
Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
Steff Lewis 
 
 
 
Trial Statistician 
Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
Fiach O’Mahony 
 
 
 
Sponsor(s) Representative 
Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
Philip Adamson 
 
 
 
Principal Investigator 
Signature 
 
Date 
 

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LIST OF ABBREVIATIONS 
 
ACCORD 
Academic and Clinical Central Office for Research & Development - 
Joint office for University of Edinburgh and NHS Lothian 
AE 
Adverse Event 
AR 
Adverse Reaction 
CI 
Chief Investigator 
CT 
Computer Tomography 
CTA 
Clinical Trial Authorisation 
CTCA 
Computer Tomography Coronary Angiography 
CTIMP 
Clinical Trial of an Investigational Medicinal Product 
CRF 
Case Report Form 
DNA 
Deoxyribose Nucleic Acid 
eGRF 
Estimated Glomerular Filtration Rate 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
IMP 
Investigational Medicinal Product 
ISF 
Investigator Site File 
MHRA 
Medicines and Healthcare products Regulatory Authority 
NIMP 
Non Investigational Medicinal Product 
PET 
Positron Emission Tomography 
PLATO 
PLATelet Inhibition and Patient Outcomes 
R&D 
Research & Development 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TMF 
Trial Master File 
UAR 
Unexpected Adverse Reaction 
 

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1 
INTRODUCTION 
1.1 
BACKGROUND 
1.1.1 Pathogenesis of Coronary Artery Disease 
Coronary plaque rupture of mildly stenotic coronary atherosclerosis is the commonest cause of 
acute coronary thrombosis and myocardial infarction [Davies, 2000]. This is the dominant type 
of plaque event causing an acute coronary syndrome, especially in men. It is closely linked to 
hypercholesterolaemia and has a dominant inflammatory phenotype. Classical histological 
features include a lipid-rich pool, thin fibrous cap, paucity of vascular smooth muscle cells and 
an intense inflammatory cell infiltrate [Davies, 2000]. 
Plaque rupture does not invariably lead to thrombotic occlusion of the coronary artery. Coronary 
plaque events are very common and the majority of such events do not cause coronary 
occlusion [Mann & Davies, 1999; Davies, 2000]. Here, plaque rupture and thrombosis is 
organised, remodelled and incorporated into the atherosclerotic plaque itself. Indeed, 80% of 
plaques that cause over 50% diameter stenosis have evidence of old healed plaque rupture 
with incorporation of thrombus into the atheroma [Mann & Davies, 1999]. This process 
contributes to the progression of coronary atherosclerosis and explains the first appearance, or 
step change in severity, of angina pectoris. 
Coronary plaque events are often not isolated. Plaque rupture can occur throughout the body 
and is not confined to a single vascular bed. Moreover, in patients with acute coronary 
syndromes, it is common for multiple plaque events to occur simultaneously and beyond the 
culprit lesion itself. Post-mortem studies indicate that, on average, 2.4 coronary thrombotic 
events occur in each patient who presents with fatal coronary heart disease [Mann & Davies, 
1999; Davies, 2000]. This suggests that systemic and generalised mechanisms and mediators 
play an important role in addition to local factors within the coronary artery wall. 
In summary, coronary atherosclerosis is characterised by multiple and recurrent plaque rupture 
events that are often sub-clinical and cause step-wise growth of the plaque as it heals and 
remodels. Patients undergoing repeated plaque rupture events are likely to be at increased risk 
of myocardial infarction, especially if such an event coincides with a period of increased blood 
thrombogenicity. If these patients can be identified then there would be a clear rationale for 
using powerful anti-platelet agents, such as ticagrelor, to dampen down their thrombotic 
potential and the risk of adverse cardiovascular events. 
1.1.2 Ticagrelor 
Ticagrelor (AZD6140) is a reversible and direct-acting oral antagonist of the adenosine 
diphosphate P2Y12 receptor. It provides faster, greater, and more consistent P2Y12 inhibition 
than clopidogrel [Gurbel et al, 2009]. In the PLATelet inhibition and patient Outcomes (PLATO) 
trial of 18,624 patients presenting with an acute coronary syndrome, ticagrelor was superior to 
clopidogrel for the prevention of cardiovascular events and death [Wallentin et al, 2009]. It is 
unknown whether these anti-platelet and anti-thrombotic benefits extend to patients with 
coronary artery disease in the absence of an acute coronary syndrome. 
1.1.3 Non-invasive Imaging of the Vulnerable Plaque 
In the study of coronary artery disease, many researchers have searched for a non-invasive 
imaging biomarker of plaque vulnerability and rupture. For the first time, we have demonstrated 
that 18F-fluoride positron emission tomography can detect high-risk coronary plaque in patients 
with stable coronary artery disease [Joshi et al, 2013].  
In the vasculature, 18F-fluoride acts as a marker of novel calcification activity [Dweck et al, 
2012a; Dweck et al, 2013]. Similar to other conditions, calcification in coronary atheroma occurs 
as a healing response to intense necrotic inflammation, making 18F- fluoride a useful marker 
of high-risk atherosclerotic plaque. We have previously demonstrated increased uptake of this 
tracer in the coronary vasculature localizing to individual coronary lesions and identifying 
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we have conducted a prospective study of 40 patients with myocardial infarction in whom 18F-
fluoride localised to the culprit plaque (Figure 1) in over 90% of patients [Joshi et al, 2013]. This 
finding was confirmed in 12 patients with a recent stroke undergoing carotid endartectomy 
where 18F-fluoride uptake was observed at the site of plaque rupture in 100% of patients and 
this uptake correlated with increased calcification activity and areas of necrosis on histology. 
Finally we studied 40 patients with stable coronary artery disease. Increased uptake was 
observed in 45% of these patients and this again localized to individual coronary plaques 
(Figure 2). Interestingly these lesions were associated with multiple high-risk markers on 
radiofrequency and gray-scale intravascular ultrasound (necrotic core, positive remodeling and 
microcalcification). Importantly, plasma high-sensitivity troponin concentrations were much 
higher in patients with 18F-fluoride positive plaques compared with patients without evidence 
of uptake (7.89±9.34 versus 3.10±1.89 ng/L, P=0·047; Figure 3). The latter observation is of 
particular interest as it supports the hypothesis that 18F-fluoride is detecting subclinical plaque 
rupture in those with stable disease, similar to its mechanism of activity following myocardial 
infarction. Moreover plasma troponin concentrations measured by a high-sensitivity assay also 
predict an adverse outcome amongst patients with stable coronary artery disease [Omland et 
al, 2013] and provide a useful surrogate biomarker of therapeutic efficacy. 
1.1.4 High-Sensitivity Cardiac Troponin I 
Cardiac troponins are regulatory muscle proteins that are released into the circulation following 
acute myocardial injury. Assays that quantify cardiac isoforms of troponin have greater 
specificity and sensitivity for the diagnosis of myocardial infarction than traditional cardiac 
enzymes. Indeed, we have demonstrated that this improved precision can lead to improved 
outcomes in patients with suspected acute coronary syndromes [Mills et al, 2011; Mills et al, 
2012]. 
Recent advances have led to greatly improved assay sensitivity permitting quantification of 
extremely low concentrations of troponin with excellent precision. High-sensitivity cardiac 
troponin assays have limits of detection 10- to 100-fold lower than contemporary assays and 
are able to detect troponin in the circulation of the majority of healthy persons. Indeed, we have 
recently demonstrated important sex-specific thresholds for cardiac troponin when assessing 
patients with suspected acute coronary syndromes [Shah et al, 2013]. However, it is becoming 
increasingly recognized that plasma high-sensitivity troponin concentrations are powerful 
markers of future risk even when within the normal reference range. As previously indicated, 
plasma high-sensitivity troponin concentrations are increased in patients with high-risk 18F-
fluoride positive coronary artery plaque [Joshi et al, 2013] and appear to predict an adverse 
outcome amongst patients with stable coronary artery disease [Omland et al, 2013].  
1.2 
RESEARCH HYPOTHESIS 
Ticagrelor will reduce biomarkers of myocardial injury and inhibit disease progression in 
patients with stable coronary heart disease and evidence of high-risk coronary plaque defined 
by 18F-fluoride uptake on positron emission tomography. 
1.3 
RATIONALE FOR STUDY 
The rationale for this study is based on two main observations relevant to the pathogenesis of 
coronary artery disease.  
1. The majority of episodes of plaque rupture are subclinical because thrombus formation 
is non-occlusive and microembolism causes covert myocardial micro-injury that is 
insufficient to cause overt symptoms.  
2. Cycles of rupture and non-occlusive thrombus formation lead to plaque expansion and 
coronary artery disease progression.  
These two features can now be tracked using a high-sensitivity cardiac troponin I assay and 
computer tomography coronary angiography respectively. 

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Given this central role of thrombosis in atherogenesis, anti-thrombotic interventions have major 
potential to impact on the consequences and progression of atherosclerotic disease [Williams 
et al, 1997; Rioufol et al, 2004; Kwon et al, 2005]. With the advent of more potent platelet 
inhibition with ticagrelor, there is now the opportunity to assess whether dual anti-platelet 
therapy can improve markers of myocardial injury and disease progression. 
To enhance the opportunity to detect such effects, we propose a stratified medicine approach 
where we will specifically select patients who have evidence of high-risk or subclinical ruptured 
coronary artery plaque identified by coronary 18F-fluoride uptake. We will then compare 
outcomes between those with and those without uptake, anticipating that only patients with 
high-risk plaque will demonstrate evidence of reduced injury and disease progression.  
2 
STUDY OBJECTIVES 
2.1 
OBJECTIVES 
2.1.1 Primary Objective 
To determine whether ticagrelor will reduce plasma high-sensitivity troponin concentrations 
compared with placebo in patients with stable coronary heart disease and high-risk coronary 
atheroma.  
2.1.2 Secondary Objectives 
a) To assess whether ticagrelor will reduce plasma high-sensitivity troponin concentrations in 
patients without increased coronary 18F-fluoride uptake. 
b) To assess whether ticagrelor will reduce plasma high-sensitivity troponin concentrations 
over a 1-year time frame. 
c) To assess whether ticagrelor will reduce coronary plaque volume or calcium score at the 
site of 18F-fluoride uptake. 
d) To confirm the reproducibility of 18F-fluoride PET positivity 
e) To assess the natural history of 18F-fluoride PET positive coronary plaque 
2.1.3 Safety Objective 
To determine whether the addition of ticagrelor to standard optimal medical therapy is safe and 
well tolerated in patients with stable coronary heart disease on optimal medical therapy. All 
bleeding events will be categorised according to the previous PLATO criteria [Wallentin et al, 
2009] and recorded on the CRF. 
2.1.4 Exploratory Objectives 
The study design will also allow us to establish the effect of ticagrelor on disease progression. 
Using the baseline and repeat computed tomography coronary angiograms, we will be able to 
investigate changes in plaque burden, calcium score and lesion severity alongside the end 
points described above. This will be assessed throughout the coronary circulation as well as 
specifically at the site of 18F-fluoride uptake.  As a measurement of treatment compliance and 
efficacy, we will also assess platelet-monocyte aggregates before and after in vitro stimulation 
with 20 µm adenosine diphosphate [Frelinger et al, 2011]. 
We will also record details of cardiovascular events occurring during the period of the study to 
allow an exploration of the association between 18F uptake, treatment allocation and clinical 
events. 

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2.2 
ENDPOINTS 
2.2.1 Primary Endpoint 
Plasma high sensitivity cardiac troponin I (hsTnI) concentration at 30 days in patients with 
coronary 18F-fluoride uptake. 
 
2.2.2 Secondary Endpoints 
a) Plasma hsTnI concentrations at 30 days in patients without coronary 18F-fluoride 
uptake. 
b) High sensitivity cardiac troponin I (hsTnI) concentration at 30 days in total study 
population. 
c) Plasma hsTnI concentrations over 1 year  
d) Calcium score at 1 year  
e) Plaque volume at 1 year  
f) 
Reproducibility of 18F-fluoride uptake detected on PET imaging at 1 week 
g) Natural history of 18F-fluoride uptake over 1 year 
3  
STUDY DESIGN 
3.1 
RATIONALE FOR STUDY DESIGN, DOSES AND CONTROL 
GROUPS 
The study will be a randomised double blind placebo-controlled trial to ensure a rigorous study 
design and the avoidance of systematic biases of outcome measures.  All recruited patients will 
undergo computed tomography coronary angiography and 18F-fluoride positron emission 
tomography (PET) scanning at baseline. Patients will then be randomized to ticagrelor 90 mg 
or matched placebo twice daily [Wallentin et al, 2009]. The dose has been selected on the basis 
of the PLATO trial [Wallentin et al, 2009]. The control groups will be two-fold. First there will be 
the active and inactive comparators of ticagrelor and placebo. Second we will examine for the 
presence and magnitude of an effect in the groups of patients with or without coronary 18F-
fluoride uptake.  
The primary outcome will be the comparison between ticagrelor and matched placebo on the 
change in plasma troponin concentration from baseline to one month in patients with coronary 
18F-fluoride uptake. Secondary analyses will undertake the same assessment in patients 
without coronary 18F-fluoride uptake to determine whether this is particular to patients with 
high-risk coronary plaque or is seen in all patients with multivessel coronary artery disease. 
Further longitudinal comparisons of these groups will determine whether the dominant effect 
on plasma troponin concentrations is seen only in the early phase or whether potential benefits 
are seen throughout the study period. Finally, we will assess whether in comparison to placebo, 
ticagrelor will inhibit progression of coronary atheroma (calcium score and plaque volume) at 
the site of high-risk coronary plaque. 
An additional exploratory component to the study will be to assess the reproducibility and 
natural history of 18F-fluoride uptake within coronary plaques.  This will be investigated with 
repeat PET scanning within a subgroup of the total population. 

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4 STUDY POPULATION 
4.1      Number Of Participants 
We will recruit 220 patients with stable coronary heart disease from the Edinburgh Heart Centre. 
4.2        Inclusion Criteria 
For inclusion in the study subjects should fulfill the following criteria: 
1. 
Patients aged ≥40 years with angiographically proven multivessel coronary artery 
disease defined as at least two major epicardial vessels with any combination of 
either (a) >50% luminal stenosis, or (b) previous revascularization (percutaneous 
coronary intervention or coronary artery bypass graft surgery). 
2. 
Provision of informed consent prior to any study specific procedures 
3. 
Receiving aspirin 
4.3       Exclusion Criteria 
Subjects should not enter the study if any of the following exclusion criteria are fulfilled: 
1. 
An acute coronary syndrome within the last 12 months 
2. 
An indication for dual anti-platelet therapy, such as drug eluting stent 
3. 
Receiving thienopyridine therapy such as clopidogrel or prasugrel 
4. 
Percutaneous coronary intervention or coronary artery bypass graft surgery within the 
last 3 months 
5. 
Inability or unwilling to give informed consent 
6. 
Women who are pregnant, breastfeeding or of child-bearing potential (women who 
have experienced menarche, are pre-menopausal and have not been sterilised) will 
not be enrolled into the trial 
7. 
Known hypersensitivity to ticagrelor or one of its excipients 
8. 
Active pathological bleeding or bleeding diathesis 
9. 
Significant thrombocytopenia: platelets <100 x 109 /L 
10.  
History of intracranial haemorrhage 
11. 
Moderate to severe liver impairment (Child’s Grade B or C) 
12. 
Maintenance therapy with strong CYP3A4 inhibitors, such as ketoconazole, 
nefazodone, ritonavir, indinavir, atazanavir, or clarithromycin 
13. 
Major intercurrent illness or life expectancy <1 year 
14. 
Renal dysfunction (eGFR ≤30 mL/min/1.73 m2) 
15. 
Contraindication to iodinated contrast agents 
16. 
Planned coronary revascularization or major non-cardiac surgery in the next 12 months 
17.        Maintenance therapy with simvastatin or lovastatin at doses greater than 40mg daily 
18. 
Receiving oral anticoagulants including warfarin, rivaroxaban, dabigatran or apixaban. 
 
4.4       Co-Enrolment 
Co-enrolment with another clinical trial of an investigational medical product or of a trial 
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apixaban) or antiplatelet (e.g. clopidogrel, prasugrel) will not be allowed with this study. A 
minimum of 4 months must elapse between studies of this nature prior to patient being eligible.   
Co-enrolment involving trials not excluded above will be allowed provided this is not expected 
to place undue burden upon participants and their families.  Consideration will also be given to 
the total exposure to ionising radiation should additional studies require further exposure. 
Co-enrolment with another CTIMP will require written agreement between the Chief Investigator 
and Trial Steering Committees of the respective trials as well as the trials Sponsors and will be 
performed in accordance with the ACCORD guidelines for co-enrolment (GL001). 
5  PARTICIPANT SELECTION AND ENROLMENT 
5.1 
IDENTIFYING PARTICIPANTS 
Patients will be identified by their usual care team from outpatient clinics and existing clinical 
databases (the Tomcat and TrakCare databases).  They will initially be approached (either 
verbally or in writing) for study recruitment by their usual care team who are based at the 
Edinburgh Heart Centre.  Patients will be provided with a Patient Information Sheet and given 
an opportunity to ask questions about participation in the trial.  
5.2 
CONSENTING PARTICIPANTS 
After 2 days, patients willing to participate in the trial will be asked to attend a consent and 
screening visit at the Clinical Research Facility, Edinburgh. Written informed consent will be 
obtained by a suitably qualified member of the research team before any study related 
procedures are performed.  Patients will be advised to inform their physicians and dentists that 
they are enrolled on the study before any surgery is scheduled and before any new medicinal 
product is taken. 
5.3 
SCREENING FOR ELIGIBILITY 
Screening of clinical records for eligibility will be performed after written consent is obtained.  If 
eligibility cannot be confirmed based on pre-existing clinical investigations (i.e. standard clinical 
biochemical and haematological variables have not been assessed within the past 6 months) 
then blood tests will be obtained to assess these variables.  Once a patient has agreed to 
participate and is deemed eligible they will be invited to attend the baseline visit. 
Baseline assessments will include clinical history and examination, review of patient records to 
confirm study eligibility and record clinical profile, standard clinical biochemical and 
haematological variables, plasma high sensitivity cardiac troponin I measurement, 12-lead 
electrocardiogram, 18F-fluoride positron emission tomography, computed tomography 
coronary calcium score and angiography, and storage of plasma, serum and DNA for future 
analysis. 
5.4 
INELIGIBLE AND NON-RECRUITED PARTICIPANTS 
Ineligible and non-recruited patients will receive standard medical care. An anonymised log will 
be kept of patients who were screened for the study and subsequently found to be ineligible or 
not recruited.   
5.5 
PROCEDURES FOR HANDLING SUBJECTS INCORRECTLY 
ENROLLED, RANDOMISED OR INITIATED ON INVESTIGATIONAL 
MEDICINAL PRODUCT 
Patients incorrectly randomized to the wrong treatment group will be maintained on allocated 
therapy unless blinding has been compromised. Given that this is a mechanistic study and not 
a clinical endpoint trial, they will be assigned to the treatment they actually received as part of 

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the statistical analysis.  Records will be kept of the treatment they were originally assigned to, 
and the treatment they received. 
After the first 30 and 90 patients have been randomized into the trial, ECTU will check to ensure 
that minimization has achieved matching of the two treatment groups. 
5.6 
RANDOMISATION 
5.6.1 Randomisation Procedures 
Eligible patients will be randomized using a web-based randomization service to ensure 
allocation concealment. Given the modest sample size, we will minimise treatment allocation 
according to age, sex, baseline plasma troponin concentration and the presence of coronary 
18F-fluoride uptake. 
 
5.6.2 Treatment Allocation 
The placebo and active medication will be presented in numbered packages in collaboration 
with the Investigational Supplies Group (University of Edinburgh).  
5.6.3 Methods to Ensure Blinding 
The inactive placebo comparator will be presented and packaged in a form that will be 
indistinguishable from the active medication, ticagrelor. Therefore the treating clinical staff and 
patient will be blind to the allocated treatment.  An indication of treatment allocation will 
potentially be apparent with platelet-monocyte aggregate testing.  This will be undertaken by a 
dedicated technician distinct from the clinical investigational team.  Samples will be presented 
to the technician using anonymised sample codes.  Results will be stored in the database but 
not released to the study investigators until the end of the trial. 
5.6.4 Emergency Unblinding Procedures 
Web-based computer randomisation software will generate a randomisation list based on the 
values used for minimisation. This list will then be provided to the Investigational Supplies 
Group (ISG) for drug labelling purposes. The randomisation software will also contain 
unblinding codes which can only be accessed using a username and password. A username 
and password will only be provided to the Sponsor and Pharmacy department and can be used 
if emergency unblinding is required. Requests for unblinding will either go through the Chief or 
Principal Investigator and unblinding will be performed as required by the duty Pharmacist. 
5.6.5 Discontinuation of Investigational Medicinal Product 
The investigational product will be discontinued under the following circumstances: 
1. 
At the request of the patient or if the patient withdraws from the study. 
2. 
By the investigator or the responsible clinician if this was felt to be in the best 
interests of the patient. 
3. 
On completion of the study. 
Brief interruptions of therapy will be permitted (<14 days) where there is a clinical need, such 
as unavoidable surgical intervention. In such circumstances, the IMP will be withdrawn 5 days 
prior to surgery and recommenced as appropriate by the clinical team. 
5.6.6 Withdrawal of Study Participants 
Participants are free to withdraw from the study at any point or a participant can be withdrawn 
by the investigator. If withdrawal occurs, the primary reason for withdrawal will be documented 
in the participant’s case record form. The patient will have the option of withdrawal from (i) the 
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collection of clinical and safety data (iii) all aspects of the trial but continued use of data collected 
up to that point, (iv) all aspects of the trial with removal of all previously collected data.   
Randomised patients who wish to be withdrawn from the study before they have provided a 
blood sample for the assessment of plasma troponin concentration at one month of the trial, 
will be withdrawn from the study and another participant will be recruited to replace them. Data 
on the original participant will be kept on the database. 
 
 
6 
INVESTIGATIONAL MEDICINAL PRODUCT AND 
PLACEBO 
6.1 
STUDY DRUG 
Investigational product 
Dosage form and strength 
Manufacturer 
Ticagrelor (AZD6410) 
90 mg tablet 
Astrazeneca 
6.1.1 Study Drug Identification 
Ticagrelor is presented as a round biconvex film-coated yellow tablet marked with Œ90¹ 
above ŒT¹ on one side. 
 
6.1.2 Study Drug Manufacturer 
AstraZeneca AB 
Gärtunavägen 
SE-151 85 Södertälje 
SWEDEN 
 
6.1.3 Marketing Authorisation Holder 
AstraZeneca AB 
S-151 85 
Södertälje 
Sweden 
MA number EU/1/10/655/001-006 
6.1.4 Labelling and Packaging 
Astra Zeneca will supply study medication and placebo in prefilled HDPE bottles with Child 
resistant caps. The HDPE bottles will be clearly labelled for the purpose of this trial including 
the study title, trial subject number and study contact by the Investigational Supplies Group, 
Edinburgh (ISG).  
A Qualified Person from ISG will then release the study drug to the Pharmacy Department at 
the Royal Infirmary of Edinburgh. 
6.1.5 Storage 
All study medication will be kept in a secure place under appropriate storage conditions in the 
Pharmacy Department at the Royal Infirmary of Edinburgh.  
 

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6.2 
PLACEBO 
Astra Zeneca will supply a matched placebo in prefilled HDPE bottles with Child resistant caps. 
The placebo will then be labelled by ISG and released to the Pharmacy Department at the 
Royal Infirmary of Edinburgh. 
  
6.3 
DOSING REGIME 
One tablet twice daily for 12 months. 
6.4 
DOSE CHANGES 
No alteration in the planned dosing regime will be allowed. 
6.5 
PARTICIPANT COMPLIANCE AND ACCOUNTABILITY 
Members of the research team will assess treatment compliance at attendance of each of the 
study visits by interview and pill count. Non-compliance with the dosing regime will only be 
considered a protocol deviation if the participant takes less than 90% of the planned dose. Any 
unused study medication will be returned to the Pharmacy Department at the Royal Infirmary 
for destruction.  
6.6 
OVERDOSE 
Ticagrelor is well tolerated in single doses up to 900 mg. Gastrointestinal toxicity was dose-
limiting in a single ascending dose study. Other clinically meaningful adverse reactions which 
may occur with overdose include dyspnoea and ventricular pauses. 
  
In the event of overdose, we will observe for these potential adverse reactions and consider 
ECG monitoring. There is currently no known antidote to reverse the effects of ticagrelor and it 
is not expected to be dialysable. Treatment of overdose will follow local standard medical 
practice. The expected effect of excessive ticagrelor dosing is prolonged bleeding risk 
associated with platelet inhibition. If bleeding occurs appropriate supportive measures will be 
taken.  
If an overdose occurs in the course of the study, the investigators or other site personnel will 
inform appropriate AstraZeneca representatives within one day, ie, immediately but no later 
than the end of the next business day of when he or she becomes aware of it. 
The designated AstraZeneca representative will work with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site. 
6.7 
OTHER MEDICATIONS 
6.7.1 Non-Investigational Medicinal Products 
18F-Sodium Fluoride (18F-NaF) 
 
At the time of positron emission tomography and computed tomography coronary angiography, 
patients may receive oral and/or intravenous beta-blockade, such as metoprolol 5-100 mg, to 
slow the heart rate to below 65 beats per minute to maximise image quality and reduce radiation 
exposure. Glyceryl trintrate spray or tablet will be administered sublingually (200-400 µg) to 
induce coronary vasodilatation to enhance image quality of the coronary angiogram. 
6.7.2 Permitted Medications 
All patients will be maintained on aspirin 75 mg once daily and maximally tolerated dose of 
statin. Patients will be encouraged to be maintained on maximally tolerated doses of 
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in accordance with local guidelines. Following completion of the study, the trial medications will 
be discontinued. 
6.7.3 Prohibited Medications 
• 
Strong CYP3A4 inhibitors, such as ketoconazole, clarithromycin, nefazodone, 
ritonavir, atazanavir.Thienopyridines such as prasugrel, clopidogrel and ticlopidine 
• 
Coumarin anticoagulants such as warfarin 
• 
Direct thrombin inhibitors such as dabigatran 
• 
Factor Xa inhibitors such as rivaroxaban and apixaban 
• 
Ergot alkaloids 
• 
Cisapride 
• 
Simvastatin or lovastatin when taken at doses >40 mg daily 
7 
STUDY ASSESSMENTS 
Trial participants will undergo 8 study visits: screening visit, baseline, randomisation and after 
1, 3, 6, 9 and 12 months. 
7.1 
SAFETY ASSESSMENTS 
The study does not have any pre-specified safety outcome measures. However, all bleeding 
events will be categorized according to the previous PLATO criteria [Wallentin et al, 2009]. 
These will be reported through adverse event reporting mechanisms (see Section 10). 
7.2 
STUDY ASSESSMENTS 
 
This is a prospective single-centre randomized double blind matched placebo controlled trial of 
ticagrelor 90 mg twice daily in patients with stable coronary artery disease for 1 year. Subjects 
will attend for clinical assessments at 30 days, 3, 6, 9 and 12 months with a final computed 
tomography coronary angiogram at the end of the study. The randomisation visit must be 
conducted within 25 days of the baseline visit.  
 
 
 
 
 
 
 
 
 
 
 
 

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Screening 
-183 days  
Baseline 
(-15 days 
±10 days)
 
Randomisation 
(Day 0) 
30 days 
(±5 days) 
3 months 
(±14 days) 
6 months 
(± 14 
days) 
9 months 
(± 14 
days) 
1 year 
(± 14 
days*) 
Eligibility Criteria and 
PIS 
X 
 
 
 
 
 
 
 
Continuing eligibility 
confirmed 
 
 
X 
X 
X 
X 
X 
 
Consent 
X 
 
 
 
 
 
 
 
Concomitant 
medications 
 
X 
 
X 
X 
X 
X 
X 
Clinical History 
 
X 
 
X 
X 
X 
X 
X 
Physical Examination 
 
X 
 
 
 
 
 
 
Clinical Biochemistry 
and haematology 
X  
(if not 
checked 
in past 6 
months) 
X 
 
 
 
 
X 
 
Blood sampling for 
hsTnI 
 
X 
 
X 
X 
X 
X 
X 
Blood sampling for 
PMA 
 
X 
 
X 
 
 
 
 
12-lead ECG 
 
X 
 
X 
X 
X 
X 
X 
AE/SAE Reporting 
 
X 
 
X 
X 
X 
X 
X 
Treatment 
allocation/Medication 
dispensed 
 
 
X 
 
X 
X 
X 
 
Compliance check 
 
 
 
X 
X 
X 
X 
X 
18F-Fluoride PET 
 
X 
X 
 
X 
X 
 
X 
 
 
Additional 18F-Fluoride PET scans will be performed in a 
subgroup only 
CT attenuation 
correction 
 
 
 
 
 
 
 
 
 
 
CT attenuation correction is required prior to each PET scan for 
the subgroups who undergo this 
CT Calcium Score 
 
X 
 
 
 
 
 
X 
CT Coronary 
Angiogram 
 
X 
Repeat CTCA scans will be performed at the time of 
each PET scan for those who are in the reproducibility 
and natural history sub-studies 
X* 
* Where it is not possible for the CT scan at the 1 year visit to be performed at the same time 
as the other 1 year study assessments participants may be asked to attend an additional visit 
during which the CT scan will be performed. In this situation the remainder of the study 
assessments will be performed within the planned visit window (± 14 days) and the CT scan 
will be arranged for the earliest practicable opportunity.  
 
7.2.1 Baseline Assessments 
Baseline assessments will include clinical history and examination, review of patient records to 
confirm study eligibility and record clinical profile, standard clinical biochemical and 
haematological variables, plasma high sensitivity cardiac troponin I measurement, platelet-
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computed tomography coronary calcium score and angiography, and storage of plasma, serum 
and DNA for future analysis. 
7.2.2 Follow Up Assessments 
At 1, 3, 6, 9 and 12 months, participants will undergo repeat clinical assessment, blood 
sampling, and 12-lead electrocardiogram. Compliance will be recorded by patient history and 
tablet count by a delegated member of the research team. At the final study visit (12 months), 
subjects will also undergo a repeat computed tomography coronary calcium score and 
angiography. 
Where it is not possible for the CT scan at the 12 month visit to be performed at the same time 
as the other 12 month study assessments participants may be asked to attend an additional 
visit during which the CT scan will be performed. In this situation the remainder of the study 
assessments will be performed within the planned visit window (± 14 days) and the CT scan 
will be arranged for the earliest practicable opportunity. 
7.2.3 High Sensitivity Cardiac Troponin I 
Plasma cardiac troponin I concentrations will be measured by the accredited Clinical 
Biochemistry Department of the Royal Infirmary of Edinburgh using the ARCHITECTSTAT high-
sensitive troponin I assay (Abbott Laboratories, Abbott Park, IL). This is the first commercially 
available high-sensitivity troponin I assay that has greater precision at very low concentrations 
compared with the contemporary assay. The limit of detection is 1.2 ng/L and the inter-assay 
coefficient of variation <10% at 4.7 ng/L. The upper reference limit (99th percentile) based on 
4,590 samples from healthy men and women is 34 ng/L for men and 16 ng/L for women. 
7.2.4 Positron Emission and Computed Tomography Coronary Angiography 
Study scans will be performed in the Clinical Research Imaging Centre. 
Patients with a heart rate exceeding 65 beats/min may receive intravenous or oral beta-
blockade (e.g. 5 to 100 mg metoprolol) 1 h before computed tomography. All patients will 
receive sublingual glyceryl trinitrate (200-400 µg) just prior to the computed tomography 
coronary angiography.  
All patients will undergo dual cardiac and respiratory-gated positron emission and computed 
tomography imaging of the coronary arteries with a hybrid scanner (64-multidetector Biograph 
mCT, Siemens Medical Systems, Erlangen, Germany). Study subjects will be administered a 
target dose of 250 MBq 18F-fluoride intravenously and subsequently rested in a quiet 
environment for 60 min. An attenuation correction computed tomography scan (non-enhanced 
120 kV and 50 mA) will then be performed, followed by positron emission tomography imaging 
of the thorax in list-mode for 30 min.  
Computed tomography coronary calcium score and angiography will be undertaken in the same 
visit as the 18F-floride scan and again at 1 year. With the patient lying still on the scanner after 
acquisition of the positron emission tomography scan, an electrocardiogram-gated breath-hold 
computed tomography scan (non-contrast-enhanced, 40 mAs/rotation, 120 kV; CareDose, 
Siemens Medical Systems) of the coronary arteries will be performed at the following settings: 
330 ms rotation time, 100 (body mass index [BMI] <25 kg/m2) or 120 (body mass index >25 
kg/m2) kV tube voltage, 160-245 mAs tube current, 3·8 mm/rotation table feed, prospective 
(heart rate regular and <60/min), or retrospective (heart rate >60 /min) electrocardiogram-
gated. Depending on the BMI, a bolus of 80-100 mL of contrast (400 mgI/mL; Iomeron, Bracco, 
Milan, Italy) will be injected intravenously at 5 mL/s, after determining the appropriate trigger 
delay with a test bolus of 20 mL contrast material.  
The positron emission tomography scans will be reconstructed in multiple phases of the cardiac 
cycle, with the diastolic phase (50-75%) used for analysis. The computed tomography coronary 
angiography scans will be reconstructed at 0·75 x 0·7 mm and 0·6 x 0·3 mm for retrospective 
and prospective acquisitions respectively at 60%, 65% and 70% of the cardiac cycle. Additional 
reconstructions will be undertaken as necessary. Positron emission tomography scans will 
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18F-F PET Natural History Sub-study 
Using the same scan process as outlined above a sub-group of patients will be selected for 1 
additional PET scan.  In total this will involve 80 patients out of the total cohort.  The first 20 
participants to be scanned will be to assess the reproducibility of 18F-fluoride uptake and will 
undergo a second PET scan at the randomisation visit (1 week after the baseline scan).  This 
group will comprise 10 patients from both of the PET positive and PET negative samples.  
Following this we will investigate the natural history of 18F-fluoride uptake by performing repeat 
PET scans on 60 patients in total from the initial PET positive sample with 20 patients scanned 
at the 3 month, 6 month and 12 month follow up visits.  No individual patient will undergo more 
than 2 PET scans during the course of the study.  In order to allow accurate co-registration of 
images, repeat CT coronary angiograms will be performed at the time of the repeat PET scans.  
The additional PET scan for those in the sub-study will be performed at the 1 week, 3 month, 6 
month or 12 month visit but the additional CTCA scan will only be performed at 1 week, 3 month 
or 6 month visits as the CTCA scan at 12 months will be performed on all participants 
irrespective of whether they are taking part in the sub-study 
7.2.5 Platelet-Monocyte Aggregates 
The effect of ticagrelor on platelet activation will be assessed before and after in vitro stimulation 
with 20µm adenosine diphosphate to assess inhibition of the P2Y12 receptor [Harding et al, 
2007; Burdess et al, 2010; Frehling et al 2011]. This will be performed at the baseline visit 
(before study medication ingestion) and at the 30 day visit [Gurbel et al 2009; Frehling et al 
2011]. Platelet-monocyte aggregate measurements will be performed by a trained technician 
independent to the study team to ensure blinding of treatment allocation is not compromised. 
Blood will be anticoagulated with D-phenylalanyl-L-prolyl-L-arginine chloromethylketone 
(PPACK; Cambridge Biosciences, UK). Five minutes after sample collection, samples will be 
stained with the following conjugated monoclonal antibodies: APC-conjugated CD14 (Becton-
Dickinson, UK);, PE-conjugated CD62P (Becton-Dickinson, UK); PE-Cy7-conjugated 
CD11b(Becton-Dickinson, 
UK); 
FITC-conjugated 
CD42a(Becton-Dickinson, 
UK); 
and 
appropriate control samples prepared. Once stained, samples will be incubated for 20 min at 
room temperature and fixed with FACS-Lyse (PMA analysis) or paraformaldehyde (platelet 
analysis). Samples will be analyzed using a FACScalibur flow cytometer (Becton-Dickinson, 
UK). Platelet–monocyte aggregates will be defined as monocytes staining positive for CD42a, 
as described previously [Harding et al, 2007]. Analysis will be performed using FlowJo 
(Treestar, USA). 
7.2.6 Biological Samples 
Blood samples will be collected and tested at baseline, 30 days and 3, 6, 9 and 12 months. At 
baseline, blood samples will be taken for routine clinical biochemistry and haematology 
(including full blood count, urea, creatinine and electrolytes, liver function tests, total cholesterol 
and glucose). 
Approximately 20 mL of blood will be obtained on each visit except that an additional 20 mL will 
be taken at baseline for the clinical biochemistry and haematology assessments. Blood will also 
be stored for DNA extraction for subsequent analysis as appropriate. 
Blood samples will be processed and stored in the Clinical Research Facility. Blood sample will 
be processed (plasma and serum) and stored at -80°C for later analysis of potential extracellular 
matrix and inflammatory biomarkers.  Blood will also undergo DNA extraction and flow 
cytometric assessment for platelet monocyte aggregates [Burdess et al, 2010].  
All samples will be stored in locked secure freezers and in compliance with the sponsor’s 
tissue governance policies. 
All samples will be retained unless consent is withdrawn by the participant who specifically 
requests that their samples are destroyed. 

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8 
DATA COLLECTION 
All trial data will be recorded onto written case record forms (CRF) by a member of the research 
team and then entered into electronic CRFs designed and developed by the Edinburgh Clinical 
Trials Unit.  
9 
STATISTICS AND DATA ANALYSIS 
9.1 
SAMPLE SIZE CALCULATION 
Patients with increased 18F-fluoride activity had plasma high-sensitivity troponin 
concentrations that were more than double those of patients without increased 18F-fluoride 
uptake (7.89±9.34 versus 3.10±1.89 ng/L; P=0·047) in our recent trail [Joshi et al, 2013]. Based 
upon the assumption that ticagrelor will reduce plasma high sensitivity troponin concentrations 
by one half (i.e from 7.89 to 3.95 ng/L, with standard deviations of 9.34 and 1.89 respectively), 
we will require 48 patients per treatment arm at 80% power and two-sided P<0.05. Allowance 
for missing data brings this to 55 per group. Following review of the first 170 PET scans within 
the DIAMOND study, the proportion of patients who demonstrate coronary tracer uptake is 
60%. Consequently we will need 183 patients with follow-up data available for the primary 
endpoint. In order to allow for participant withdrawal prior to the 30-day visit we will recruit a 
total of 220 patients.  
The Edinburgh Heart Centre performs more than 5,000 diagnostic angiograms and 2,500 
angioplasty procedures per year.  This should allow an adequate pool of potentially suitable 
patients with angiographically proven stable coronary artery disease from which to recruit. 
9.2 
PROPOSED ANALYSES 
9.2.1 Description of Analysis Sets 
The primary analysis will be to determine whether ticagrelor will reduce plasma high-sensitivity 
troponin concentrations compared with placebo in patients with stable coronary heart disease 
and increased coronary 18F-fluoride uptake. For this primary analysis, we will exclude any 
patient who does not have a blood sample for estimation of the one-month plasma troponin 
concentration or whose compliance is deemed inadequate (as estimated from pill counts). The 
required level of medication compliance will be described in the statistical analysis plan. 
9.2.2 Methods of Statistical Analysis 
For the primary analysis, the change in plasma high-sensitivity troponin concentration from 
baseline to 30 days will be compared between the two treatment groups (ticagrelor and 
placebo) using linear regression, adjusting for the minimisation variables, in patients with 
coronary 18F-fluoride uptake. Prior to analysis, tests for normality will be undertaken and, 
where data are skewed, logarithmic transformation will be considered prior to analysis. Effect 
sizes and 95% confidence intervals will be calculated. Similar analyses will be performed for 
the assessment of troponin at 30 days in patients without coronary 18F-fluoride uptake, and in 
the study population as a whole; for troponin at 1 year; and for calcium score and plaque volume 
at 1 year at the site of baseline coronary 18F-fluoride uptake. 
Statistical analysis will be performed using SAS. A two-sided P<0·05 will be taken as 
statistically significant. A full statistical analysis plan will be documented prior to data base lock. 
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10 
ADVERSE EVENTS 
The Investigator is responsible for the detection and documentation of events meeting the 
criteria and definitions detailed below.   
Full details of contraindications and side effects that have been reported following 
administration of the IMP can be found in the relevant Summary of Product Characteristics 
(SmPC). 
Participants will be instructed to contact their Investigator at any time after consenting to join 
the trial if any symptoms develop.  All adverse events (AE) that occur after joining the trial must 
be reported in detail in the Case Report Form (CRF) or AE form.  In the case of an AE, the 
Investigator should initiate the appropriate treatment according to their medical judgment.  After 
initially recording an AE, the Investigator should follow each AE until resolution of the event or 
until no longer medically indicated. 
 
 
 
10.1 DEFINITIONS 
An adverse event (AE) is any untoward medical occurrence in a clinical trial participant which 
does not necessarily have a causal relationship with an investigational medicinal product (IMP). 
An adverse reaction (AR) is any untoward and unintended response to an IMP which is related 
to any dose administered to that participant.  
A serious adverse event (SAE), serious adverse reaction (SAR). Any AE or AR that at any 
dose: 
• 
results in death of the clinical trial participant; 
• 
is life threatening*; 
• 
requires in-patient hospitalisation^ or prolongation of existing hospitalisation; 
• 
results in persistent or significant disability or incapacity; 
• 
consists of a congenital anomaly or birth defect; 
• 
results in any other significant medical event not meeting the criteria above. 
 
*Life-threatening in the definition of an SAE or SAR refers to an event where the participant 
was at risk of death at the time of the event. It does not refer to an event which hypothetically 
might have caused death if it were more severe. 
 
^Any hospitalisation that was planned prior to randomisation will not meet SAE criteria. Any 
hospitalisation that is planned post randomisation will meet the SAE criteria. 
 
A suspected unexpected serious adverse reaction (SUSAR) is any AR that is classified as 
serious and is suspected to be caused by the IMP, that it is not consistent with the information 
about the IMP in the Summary of Product Characteristics (SmPC) or Investigators Brochure. 
10.2 IDENTIFYING AEs AND SAEs 
All AEs and SAEs will be recorded from the time a participant signs the consent form to take 
part in the study until the last study visit. 

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Participants will be asked about the occurrence of AEs/SAEs at every visit during the study.  
Open-ended and non-leading verbal questioning of the participant will be used to enquire about 
AE/SAE occurrence.  Participants will also be asked if they have been admitted to hospital, had 
any accidents, used any new medicines or changed concomitant medication regimens.  If there 
is any doubt as to whether a clinical observation is an AE, the event will be recorded. 
AEs and SAEs may also be identified via information from support departments e.g. 
laboratories.  
10.3 RECORDING AEs AND SAEs 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation 
(e.g. hospital notes, laboratory and diagnostic reports) related to the event.  The Investigator 
will then record all relevant information in the CRF and on the SAE form (if the AE meets the 
criteria of serious). 
Information to be collected includes dose, type of event, onset date, Investigator assessment 
of severity and causality, date of resolution as well as treatment required, investigations needed 
and outcome.   
10.4 ASSESSMENT OF AEs AND SAEs 
Seriousness, causality, severity and expectedness will be assessed by the Principal 
Investigator. For randomised double blind studies, AEs will be assessed as though the 
participant is taking active IMP.  Cases that are considered serious, possibly, probably or 
definitely related to IMP and unexpected (i.e. SUSARs) will be unblinded.  
The Investigator is responsible for assessing each AE.   
The Chief Investigator (CI) may not downgrade an event that has been assessed by an 
Investigator as an SAE or SUSAR, but can upgrade an AE to an SAE, SAR or SUSAR if 
appropriate. 
10.4.1 Assessment of Seriousness 
The Investigator will make an assessment of seriousness as defined in Section 10.1. 
10.4.2 Assessment of Causality 
The Investigator will make an assessment of whether the AE/SAE is likely to be related to the 
IMP according to the definitions below.   
• 
Unrelated: where an event is not considered to be related to the IMP. 
• 
Possibly Related: The nature of the event, the underlying medical condition, 
concomitant medication or temporal relationship make it possible that the AE has a 
causal relationship to the study drug. The assessment of causality will be made against 
the reference safety information found in the Summary of Product Characteristics. 
Where non Investigational Medicinal Products (NIMPs) e.g. rescue/escape drugs are given:  if 
the AE is considered to be related to an interaction between the IMP and the NIMP, or where 
the AE might be linked to either the IMP or the NIMP but cannot be clearly attributed to either 
one of these, the event will be considered as an AR. Alternative causes such as natural history 
of the underlying disease, other risk factors and the temporal relationship of the event to the 
treatment should be considered and investigated. The blind should not be broken for the 
purpose of making this assessment.  
10.4.3 Assessment of Expectedness 
If an event is judged to be an AR, the evaluation of expectedness will be made based on 
knowledge of the reaction and the relevant product information documented in the SmPC/IB. 
The event may be classed as either: 

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Expected: the AR is consistent with the toxicity of the IMP listed in the SmPC/IB. 
Unexpected: the AR is not consistent with the toxicity in the SmPC/IB. 
10.4.4 Assessment of Severity 
The Investigator will make an assessment of severity for each AE/SAE and record this on the 
CRF or SAE form according to one of the following categories: 
Mild: an event that is easily tolerated by the participant, causing minimal discomfort and not 
interfering with every day activities. 
Moderate: an event that is sufficiently discomforting to interfere with normal everyday activities. 
Severe: an event that prevents normal everyday activities. 
Note: the term ‘severe’, used to describe the intensity, should not be confused with ‘serious’ 
which is a regulatory definition based on participant/event outcome or action criteria.  For 
example, a headache may be severe but not serious, while a minor stroke is serious but may 
not be severe. 
10.5 REPORTING OF SAEs/SARs/SUSARs 
Once the Investigator becomes aware that an SAE has occurred in a study participant, the 
information will be reported to the ACCORD Research Governance & QA Office immediately 
or within 24 hours. If the Investigator does not have all information regarding an SAE, they 
should not wait for this additional information before notifying ACCORD.  The SAE report form 
can be updated when the additional information is received. 
The SAE report will provide an assessment of causality and expectedness at the time of the 
initial report to ACCORD according to Sections 10.4.2, Assessment of Causality and 10.4.3, 
Assessment of Expectedness. 
The SAE form will be transmitted by fax to ACCORD on +44 (0)131 242 9447 or may be 
transmitted by hand to the office or submitted via email to Safety.Accord@ed.ac.uk. Only forms 
in a pdf format will be accepted by ACCORD via email. 
Where missing information has not been sent to ACCORD after an initial report, ACCORD will 
contact the investigator and request the missing information.  
All reports faxed to ACCORD and any follow up information will be retained by the Investigator 
in the Investigator Site File (ISF). 
10.6 REGULATORY REPORTING REQUIREMENTS 
The ACCORD Research Governance & QA Office is responsible for pharmacovigilance 
reporting on behalf of the co-sponsors (Edinburgh University and NHS Lothian). 
The ACCORD Research Governance & QA Office has a legal responsibility to notify the 
regulatory competent authority and relevant ethics committee (Research Ethics Committee 
(REC) that approved the trial).  Fatal or life threatening SUSARs will be reported no later than 
7 calendar days and all other SUSARs will be reported no later than 15 calendar days after 
ACCORD is first aware of the reaction.   
ACCORD will inform Investigators at participating sites of all SUSARs and any other arising 
safety information. 
An Annual Safety Report/Development Safety Update Report will be submitted, by ACCORD, 
to the regulatory authorities and RECs listing all SARs and SUSARs. 
10.7 ASTRA ZENECA REPORTING REQUIREMENTS 
All SAEs will be reported to AstraZeneca within 7 days, whether or not considered causally 
related to the investigational product.   

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The report will indicate, either in the SAE report or the cover page, the causality of events in 
relation to all study medications and if the SAE is related to disease progression, as determined 
by the principal investigator. 
A cover page/the SAE report will detail the following: 
• 
Investigator Sponsored Study (ISS) 
• 
The Investigator IND number assigned by the FDA 
• 
The Investigator’s name and address 
• 
The trial name/title and AstraZeneca ISS reference number 
The SAE report will be sent [with the accompanying cover page] by fax to AstraZeneca’s 
designated fax line: 01582 838 010 or by email to: 
CRGSAERportingGlobalStudies@astrazeneca.com  
10.8 FOLLOW UP PROCEDURES 
After recording and reporting an SAE, the Investigator will follow each participant until resolution 
or death of the participant.  Follow up information on an SAE will be reported to the ACCORD 
office. 
After initially recording an AE, the Investigator should follow each AE until resolution of the 
event or until no longer medically indicated. 
11 
PREGNANCY 
Woman of child-bearing potential will not be enrolled into the trial (woman who have 
experienced menarche, are pre-menopausal, have not been sterilised or who are currently 
pregnant). 
Pregnancy is not considered an AE or SAE; however, the Investigator will collect pregnancy 
information for any female participants or female partners of male participants who become 
pregnant while participating in the study.  The Investigator will record the information on a 
Pregnancy Notification Form and submit this to the ACCORD office within 14 days of being 
made aware of the pregnancy. 
All pregnant female participants and partners of male participants will be followed up until 
following the outcome of the pregnancy. 
All outcomes of pregnancy will be reported to AstraZeneca. 
12 
TRIAL MANAGEMENT AND OVERSIGHT 
ARRANGEMENTS 
12.1 TRIAL MANAGEMENT GROUP 
The trial will be coordinated by a Project Management Group, consisting of the grant holders 
(Chief Investigator and Principal Investigator in Edinburgh) and a coordinating Clinical 
Research Facility nurse. 
The Principal Investigator will oversee the study and will be accountable to the Chief 
Investigator.  The Principal Investigator will be responsible for checking the CRFs for 
completeness, plausibility and consistency.  Any queries will be resolved by the Investigator or 
delegated member of the trial team.  
A Delegation Log will be prepared for each site, detailing the responsibilities of each member 
of staff working on the trial.   

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12.2 TRIAL STEERING COMMITTEE 
A Trial Steering Committee (TSC) will be established to oversee the conduct and progress of 
the trial. The review of SAEs will be added to the TSC agenda to ensure that appropriate action 
is taken if any safety issues arise.   
12.3 DATA MONITORING COMMITTEE 
In the PLATelet inhibition and patient Outcomes (PLATO) trial of 18,624 patients presenting 
with an acute coronary syndrome, ticagrelor was superior to clopidogrel for the prevention of 
cardiovascular events and death [Wallentin et al, 2009]. There were modest increases in the 
risks of bleeding and low rates of other side effects, such as dyspnoea. It is extremely unlikely 
that we will observe any substantial increased risk in our trial population given the small sample 
size of 250 patients and the very similar disease population in the PLATO trial that had a 100-
fold larger trial population size. For this reason, an independent Data Monitoring Committee 
(DMC) will not be convened for this study and all study adverse events will be reported to the 
sponsors and AstraZeneca and will be discussed by the TSC. 
12.4 INSPECTION OF RECORDS 
Investigators and institutions involved in the study will permit trial related monitoring and audits 
on behalf of the sponsor, REC review, and regulatory inspection(s).  In the event of an audit or 
monitoring, the Investigator agrees to allow the representatives of the sponsor direct access to 
all study records and source documentation. In the event of regulatory inspection, the 
Investigator agrees to allow inspectors direct access to all study records and source 
documentation. 
12.5 RISK ASSESSMENT 
An independent risk assessment will be performed by an ACCORD Clinical Trials Monitor to 
determine if monitoring is required and if so, at what level. An independent risk assessment will 
also be carried out by the ACCORD Quality Assurance Group to determine if an audit should 
be performed before/during/after the study and if so, at what locations and at what frequency. 
12.6 BENEFIT/RISK BALANCE 
12.6.1 Benefits 
Patients may benefit from the treatment intervention. The benefits of ticagrelor in addition to 
standard medical therapy may include a reduction in the consequences and progression of 
coronary artery disease. In the PLATO trial [Wallentin et al, 2009], there appeared to be an 
ongoing and continuous improvement in outcomes beyond three months of an acute coronary 
syndrome. Ticagrelor may therefore have important ongoing secondary preventative benefits 
even in patients with apparently stable coronary artery disease. This is the rationale for the 
ongoing trial of the prevention of cardiovascular events in patients with prior myocardial 
infarction using ticagrelor compared with placebo on a background of aspirin: the PEGASUS 
trial (NCT01225562). 
Patients may also benefit from additional procedures and investigations that they will undergo 
as part of the study. This will include closer medical supervision and non-invasive imaging 
investigations that may identify important incidental findings. 
12.6.2 Risks 
The risks of ticagrelor principally relate to bleeding, transient bradyarrhythmias and dyspnoea. 
As with most anti-thrombotic treatments, there is a risk of excess bleeding. The incidence of 
excess major bleeding was modest and we will ensure robust exclusion criteria to prevent 
inclusion of patients at risk of bleeding. Bradyarrhythmias have been described but are 
generally transient and do not require intervention. We will record 12-lead electrocardiograms 
at subject visits and question patients regarding symptoms of dizziness and syncope. For 

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dyspnea, there is a 14% rate of breathlessness associated with ticagrelor in the PLATO trial 
[Wallentin et al, 2009]. However, again this is usually mild and self-limiting, and discontinuation 
of study medication was necessary in only 1% of patients. 
There are some potential hazards of the non-invasive investigations that we will perform as part 
of the trial. The main issues relate to exposure to ionising radiation and contrast agent 
administration. We have a well-developed protocol for cardiac positron emission and computed 
tomography imaging that minimizes radiation exposure and has clear procedures for managing 
adverse contrast reactions. We anticipate that the total research protocol dose (TPRD) radiation 
exposure will be 30 mSv. The TRPD includes radiation exposure from both the PET and CT 
scans combined.  The estimated associated risk of developing fatal cancer is proportional to 
dose.  Using a risk of 5% per Sv [ARSAC Notes] in a healthy population in this age group the 
estimated associated risk of developing fatal cancer as a result of this exposure is in the region 
1 in 650.  This risk can be classified as moderate.  It is likely that in a population of any patients 
in the age group 40-50 years the cancer risk is approximately 5% per Sv (and correspondingly 
less than 5% per Sv as age increases above 50 years).  For comparison the average annual 
background radiation dose arising from natural sources of ionising radiation in the environment 
in the UK is 2.2 mSv.  The TRPD of 30 mSv incurred in this study is approximately 13-14 times 
annual background radiation from natural sources.   An objective of this study is to assess 
reproducibility of NaF PET/CT.  A subgroup of 80 subjects will receive a second PET/CT and 
additional CT coronary angiogram.  This increases the TRPD to 46 mSv in those subjects that 
have their repeat scan at the randomisation visit, 3 months or 6 months and to 38mSv in those 
that undergo their repeat scan at 12 months.  The associated risk of developing cancer as a 
result of this exposure is in the region of 1 in 450.  This risk can be classified as moderate.  A 
TRPD of 46 mSv is approximately 21 times annual background radiation from natural sources 
in the UK.  All subjects will have two CT coronary angiograms and those in the sub-studies 
returning at the randomisation visit, 3 months or 6 months will have 3 CT coronary angiograms.  
We note that in occasional individual cases the effective dose from CT coronary angiography 
may increase to approximately 20 mSv, if the subject’s heart rate cannot be kept sufficiently 
low, requiring an alternative retrospective gating technique to be used. This will add 
approximately 12 mSv to the total research protocol dose for all subjects having CTCA. 
This can be compared with other commonly used cardiovascular imaging techniques, such as 
nucleotide myocardial perfusion imaging (15-20 mSv) and diagnostic coronary angiography (7 
mSv) [Einstein et al, 2007]. The risks of exposure to the contrast medium include allergic 
reactions and impairment of kidney function. Amongst patients with moderate-to-severe chronic 
kidney disease, there is a 2-4% risk of kidney impairment after computed tomography 
angiography [Barrett et al, 2006]. The risk of contrast exposure in this study will be minimised 
by exclusion of high-risk patients who have significant kidney disease (estimated glomerular 
filtration rate <30 mL/min/1.73m2). 
12.7 STUDY MONITORING AND AUDIT 
An ACCORD Clinical Trials Monitor or an appointed monitor will visit the Investigator site prior 
to the start of the study and during the course of the study if required, in accordance with the 
monitoring plan if required. Risk assessment will determine if audit, by the ACCORD QA group, 
is required. Details will be captured in an audit plan. Audit of Investigator sites, study 
management activities and study collaborative units, facilities and 3rd parties may be performed. 
13 
GOOD CLINICAL PRACTICE 
13.1 ETHICAL CONDUCT 
The study will be conducted in accordance with the principles of the International Conference 
on Harmonisation Tripartite Guideline for Good Clinical Practice (ICH GCP). 

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A favorable ethical opinion will be obtained from the appropriate REC and local R&D approval 
will be obtained prior to commencement of the study. 
13.2 REGULATORY COMPLIANCE 
The study will not commence until a Clinical Trial Authorisation (CTA) is obtained from the 
appropriate Regulatory Authority. The protocol and study conduct will comply with the 
Medicines for Human Use (Clinical Trials) Regulations 2004, as amended. 
13.3 INVESTIGATOR RESPONSIBILITIES 
The Investigator is responsible for the overall conduct of the study at the site and compliance 
with the protocol and any protocol amendments.  In accordance with the principles of ICH GCP, 
the following areas listed in this section are also the responsibility of the Investigator.  
Responsibilities may be delegated to an appropriate member of study site staff.   
13.3.1 Informed Consent 
The Investigator is responsible for ensuring informed consent is obtained before any protocol 
specific procedures are carried out.  The decision of a participant to participate in clinical 
research is voluntary and should be based on a clear understanding of what is involved. 
Participants must receive adequate oral and written information – appropriate Participant 
Information and Informed Consent Forms will be provided.  The oral explanation to the 
participant will be performed by the Investigator or qualified delegated person, and must cover 
all the elements specified in the Participant Information Sheet and Consent Form. 
The participant must be given every opportunity to clarify any points they do not understand 
and, if necessary, ask for more information.  The participant must be given sufficient time to 
consider the information provided.  It should be emphasised that the participant may withdraw 
their consent to participate at any time without loss of benefits to which they otherwise would 
be entitled. 
The participant will be informed and agree to their medical records being inspected by 
regulatory authorities and representatives of the sponsor(s) but understand that their name will 
not be disclosed outside the hospital. 
The Investigator or delegated member of the trial team and the participant will sign and date 
the Informed Consent Form(s) to confirm that consent has been obtained.  The participant will 
receive a copy of this document and a copy filed in the Investigator Site File (ISF) and 
participant’s medical notes. 
13.3.2 Study Site Staff 
The Investigator must be familiar with the IMP, protocol and the study requirements.  It is the 
Investigator’s responsibility to ensure that all staff assisting with the study are adequately 
informed about the IMP, protocol and their trial related duties. 
13.3.3 Data Recording 
The Principle Investigator is responsible for the quality of the data recorded in the CRF at each 
Investigator Site. The source data plan identifies which source data correspond to CRF data 
and states which data are recorded directly into the CRF. 
13.3.4 Investigator Documentation 
Prior to beginning the study, each Investigator will be asked to provide particular essential 
documents to the ACCORD Research Governance & QA Office, including but not limited to: 
• 
An original signed Investigator’s Declaration (as part of the Clinical Trial Agreement 
documents); 

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• 
Curriculum vitae (CV) signed and dated by the Investigator indicating that it is 
accurate and current. 
The ACCORD Research Governance & QA Office will ensure all other documents required by 
ICH GCP are retained in a Trial Master File (TMF), where required, and that appropriate 
documentation is available in local ISFs. 
13.3.5 GCP Training 
All study staff must hold evidence of appropriate GCP training.  
13.3.6 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records must be identified in a 
manner designed to maintain participant confidentiality.  All records must be kept in a secure 
storage area with limited access.  Clinical information will not be released without the written 
permission of the participant.  The Investigator and study site staff involved with this study may 
not disclose or use for any purpose other than performance of the study, any data, record, or 
other unpublished, confidential information disclosed to those individuals for the purpose of the 
study.  Prior written agreement from the sponsor or its designee must be obtained for the 
disclosure of any said confidential information to other parties. 
13.3.7 Data Protection 
All Investigators and study site staff involved with this study must comply with the requirements 
of the Data Protection Act 1998 with regard to the collection, storage, processing and disclosure 
of personal information and will uphold the Act’s core principles. Access to collated participant 
data will be restricted to those clinicians treating the participants, representatives of the 
sponsor(s) and representatives of regulatory authorities. 
Computers used to collate the data will have limited access measures via user names and 
passwords. 
Published results will not contain any personal data that could allow identification of individual 
participants. 
14 
STUDY CONDUCT RESPONSIBILITIES 
14.1 PROTOCOL AMENDMENTS 
Any changes in research activity, except those necessary to remove an apparent, immediate 
hazard to the participant in the case of a urgent safety measure, must be reviewed and 
approved by the Chief Investigator.   
Amendments to the protocol must be submitted in writing to the appropriate REC, Regulatory 
Authority and local R&D for approval prior to participants being enrolled into an amended 
protocol. 
14.2 PROTOCOL VIOLATIONS AND DEVIATIONS 
Prospective protocol deviations, i.e. protocol waivers, will not be approved by the sponsors and 
therefore will not be implemented, except where necessary to eliminate an immediate hazard 
to study participants. If this necessitates a subsequent protocol amendment, this should be 
submitted to the REC, Regulatory Authority and local R&D for review and approval if 
appropriate. 
Protocol deviations will be recorded in a protocol deviation log and logs will be submitted to the 
sponsors every 3 months. Each protocol violation will be reported to the sponsor within 3 days 
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14.3 SERIOUS BREACH REQUIREMENTS 
A serious breach is a breach which is likely to effect to a significant degree: 
(a) the safety or physical or mental integrity of the participants of the trial; or 
(b) the scientific value of the trial. 
If a potential serious breach is identified by the Chief investigator, Principal Investigator or 
delegates, the co-sponsors (accord.seriousbreach@ed.ac.uk) must be notified within 24 hours.  
It is the responsibility of the co-sponsors to assess the impact of the breach on the scientific 
value of the trial, to determine whether the incident constitutes a serious breach and report to 
regulatory authorities and research ethics committees as necessary.  
14.4 STUDY RECORD RETENTION 
All study documentation will be kept for a minimum of 5 years from the protocol defined end of 
study point. When the minimum retention period has elapsed, study documentation will not be 
destroyed without permission from the sponsor. 
14.5 END OF STUDY 
It is anticipated that the study will last 3 years: two years for recruitment and one year of follow-
up. The end of study is defined as the last participant’s last visit.   
The Investigators and/or the trial steering committee and/or the co-sponsor(s) have the right at 
any time to terminate the study for clinical or administrative reasons.  
The end of the study will be reported to the REC, Regulatory Authority, R&D Office(s) and co-
sponsors within 90 days, or 15 days if the study is terminated prematurely. The Investigators 
will inform participants of the premature study closure and ensure that the appropriate follow 
up is arranged for all participants involved. End of study notification will be reported to the co-
sponsors via email to researchgovernance@ed.ac.uk. 
In accordance with ACCORD SOP CR011, a Clinical Study Report (CSR) will be provided to 
the Sponsor (QA@accord.scot) and REC within 1 year of the end of the study. 
Upon completion of the study, the Investigator will upload clinical trial results onto the EudraCT 
database on behalf of the Sponsor.  
 
14.6 CONTINUATION OF DRUG FOLLOWING THE END OF STUDY 
The study medication will not be continued at the trial conclusion as it is not currently licensed 
for use in stable coronary artery disease.  Patients will remain eligible to use ticagrelor for any 
approved indication however (i.e. for 12 months following an acute coronary syndrome). 
14.7 INSURANCE AND INDEMNITY 
The co-sponsors are responsible for ensuring proper provision has been made for insurance or 
indemnity to cover their liability and the liability of the Chief Investigator and staff. 
The following arrangements are in place to fulfil the co-sponsors' responsibilities: 
• 
The Protocol has been designed by the Chief Investigator and researchers employed 
by the University and collaborators.  The University has insurance in place (which 
includes no-fault compensation) for negligent harm caused by poor protocol design 
by the Chief Investigator and researchers employed by the University. 
• 
Sites participating in the study will be liable for clinical negligence and other negligent 
harm to individuals taking part in the study and covered by the duty of care owed to 
them by the sites concerned.  The co-sponsors require individual sites participating 

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in the study to arrange for their own insurance or indemnity in respect of these 
liabilities. 
• 
Sites which are part of the United Kingdom's Nation Health Service will have the 
benefit of NHS Indemnity. 
• 
Sites out with the United Kingdom will be responsible for arranging their own 
indemnity or insurance for their participation in the study, as well as for compliance 
with local law applicable to their participation in the study. 
• 
The manufacturer supplying IMP has accepted limited liability related to the 
manufacturing and original packaging of the study drug and to the losses, damages, 
claims or liabilities incurred by study participants based on known or unknown 
Adverse Events which arise out of the manufacturing and original packaging of the 
study drug, but not where there is any modification to the study drug (including without 
limitation re-packaging and blinding). 
15 
REPORTING, PUBLICATIONS AND NOTIFICATION OF 
RESULTS 
15.1 AUTHORSHIP POLICY 
Ownership of the data arising from this study resides with the study team.  On completion of 
the study, the study data will be analysed and tabulated, and a clinical study report will be 
prepared in accordance with ICH guidelines.  
15.2 PUBLICATION 
The clinical study report will be used for publication and presentation at scientific meetings. 
Investigators have the right to publish orally or in writing the results of the study. 
Summaries of results will also be made available to Investigators for dissemination within their 
clinics (where appropriate and according to their discretion). 
15.3 PEER REVIEW 
The study protocol and outcomes data have been reviewed by AstraZeneca who have agreed 
to help support the conduct and part funding of this clinical trial.  There is additional peer review 
from the Trial Steering Committee and the Edinburgh Clinical Trials Unit statistician as well as 
the Medical Research Council. 
16 
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FIGURE 1  Focal 18f-Fluoride Uptake in Patients with 
Myocardial Infarction and Stable Angina 
Patient with acute ST-segment elevation myocardial infarction with (A) proximal occlusion (red 
arrow) of the left anterior descending artery on invasive coronary angiography and (B) intense 
focal 18F-fluoride uptake (yellow-red) at the site of the culprit plaque (red arrow) on the 
combined positron emission and computed tomogram.  
Patient with anterior non-ST-segment elevation myocardial infarction with (C) culprit (red arrow; 
left anterior descending artery) and bystander non-culprit (white arrow; circumflex artery) 
lesions on invasive coronary angiography that were both stented during the index admission. 
Only the culprit lesion had increased 18F-fluoride uptake on combined positron emission and 
computed tomography (D) following percutaneous coronary intervention.  
 

 
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FIGURE 2:  Patients with Stable Angina and 18F-Fluoride 
Uptake 
Representative examples for 18F-fluoride uptake in patients with stable angina. Panels A-D, 
computed tomography coronary angiograms; panels E-H, 18F-fluoride positron emission 
tomograms; and panels I-L, fused positron emission tomograms and computed tomography 
coronary angiograms.  
 
Fused&PET/CTCA&&
VH/IVUS&&
I&
A&
K&
C&
G&
D&
L&
H&
E&
B&
F&
J&

 
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FIGURE 3:  High-Sensitivity Troponin I Levels in Patients With 
Stable Angina Who Have and Do Not Have Increased 
Coronary 18F-Fluoride Uptake 
 
 

 
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APPENDIX 1: Trial Investigators 
Chief Investigator: 
 
 
Professor David Newby 
 
Principal Investigator: 
 
             Dr Philip Adamson 
 
Co-Investigators: 
 
 
Dr Marc Dweck 
 
 
 
 
 
Dr Nicholas Mills 
 
 
 
 
 
Dr Anoop Shah 
 
 
 
 
 
Dr James Rudd 
 
 
 
 
 
Professor Edwin van Beek 
 
 
 
 
 
Dr Alison Fletcher 
 
 
 
 
 
Dr Christopher Lucatelli 
                                                                 Dr Tom MacGillivray