Non-invasive Coronary Thrombus Imaging to Define the Cause of Acute Myocardial Infarction
Conditions: Myocardial Infarction, Thrombosis
Sponsor: University of Edinburgh

 
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Non-CTIMP Study Protocol 
 
NON-INVASIVE CORONARY THROMBUS IMAGING 
TO DEFINE THE CAUSE OF ACUTE MYOCARDIAL INFARCTION 
 
Co-Sponsors 
The University of Edinburgh and Lothian Health Board 
ACCORD 
The 
Queen’s 
Medical 
Research 
Institute 
47 
Little 
France 
Crescent 
Edinburgh 
EH16 4TJ 
Protocol authors 
Dr Craig Balmforth 
Dr Michelle Williams 
Prof David Newby 
Funder 
NA at present 
Funding Reference Number 
NA at present 
Chief Investigator 
Prof David Newby 
Sponsor number 
AC23119 
REC Number 
Insert REC number before finalisation 
Project registration 
If applicable studies must be registered on a publically 
accessible database. ACCORD can provide log-in 
credentials 
for 
clinicaltrials.gov. 
Please 
email 
researchgovernance@ed.ac.uk to arrange.  
Version Number and Date 
Version 1  
13/08/23 

 
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CONTENTS 
1 
INTRODUCTION ..............................................................................................................6 
1.1 
BACKGROUND .......................................................................................................6 
1.1.1 Background of coronary artery disease and acute myocardial infarction ............6 
1.1.2 Universal definition of myocardial infarction .........................................................6 
1.1.3 Imaging intracoronary thrombosis ........................................................................6 
1.1.4 Uncertain role of coronary thrombosis in myocardial infarction ...........................7 
1.1.5 Non-invasive imaging of coronary thrombus - Pilot data .....................................8 
1.2 
RATIONALE FOR STUDY.......................................................................................9 
2 
STUDY OBJECTIVES ......................................................................................................9 
2.1 
OBJECTIVES ...........................................................................................................9 
2.1.1 Primary Objective ..................................................................................................9 
2.1.2 Secondary Objectives ...........................................................................................9 
2.2 
ENDPOINTS ......................................................................................................... 10 
2.2.1 Primary Endpoint ............................................................................................... 10 
2.2.2 Secondary Endpoints ......................................................................................... 10 
3 
STUDY DESIGN ............................................................................................................ 10 
4 
STUDY POPULATION .................................................................................................. 10 
4.1 
NUMBER OF PARTICIPANTS ............................................................................. 10 
4.1.1 Cohort 1: Patients with myocardial infarction with non-obstructive coronary 
arteries ............................................................................................................... 10 
4.1.2 Cohort 2: Patients with coronary causes of type 2 myocardial infarction ......... 10 
4.2 
INCLUSION CRITERIA ........................................................................................ 10 
4.3 
EXCLUSION CRITERIA ....................................................................................... 11 
4.4 
CO-ENROLMENT ................................................................................................. 11 
5 
PARTICIPANT SELECTION AND ENROLMENT ........................................................ 11 
5.1 
IDENTIFYING PARTICIPANTS ............................................................................ 11 
5.2 
CONSENTING PARTICIPANTS .......................................................................... 11 
5.2.1 Withdrawal of Study Participants ....................................................................... 11 
6 
STUDY ASSESSMENTS .............................................................................................. 12 
6.1 
STUDY ASSESSMENTS ...................................................................................... 12 
6.2 
Study Screening .................................................................................................... 12 
6.3 
Baseline Visit......................................................................................................... 12 
6.4 
Echocardiography ................................................................................................. 12 
6.5 
Invasive coronary angiography and intravascular imaging .................................. 13 
6.6 
Cardiac magnetic resonance imaging .................................................................. 13 
6.7 
Hybrid 18F-GP1 positron emission tomography and coronary computed 
tomography coronary angiography ....................................................................... 13 
6.8 
Myocardial infarction classification ....................................................................... 13 
6.9 
Schedule of study assessments ........................................................................... 13 
6.10 
LONG TERM FOLLOW UP ASSESSMENTS ...................................................... 14 
6.11 
STORAGE AND ANALYSIS OF SAMPLES ........................................................ 14 
7 
DATA COLLECTION..................................................................................................... 15 
7.1 
Source Data Documentation ................................................................................ 15 

 
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8 
DATA MANAGEMENT .................................................................................................. 15 
8.1 
Personal Data ....................................................................................................... 16 
The following personal data will be collected as part of the research: ......................... 16 
8.2 
Data Information Flow ........................................................................................... 16 
8.3 
External Transfer of Data...................................................................................... 16 
8.4 
Data Controller ...................................................................................................... 16 
8.5 
Data Breaches ...................................................................................................... 16 
9 
STATISTICS AND DATA ANALYSIS .......................................................................... 17 
9.1 
SAMPLE SIZE CALCULATION ............................................................................ 17 
9.2 
PROPOSED ANALYSES ..................................................................................... 17 
10 
ADVERSE EVENTS ...................................................................................................... 17 
10.1 
Definitions ............................................................................................................. 17 
10.2 
Identifiying AEs and ARs ...................................................................................... 18 
10.3 
Recording AEs and ARs ....................................................................................... 18 
10.4 
Assessment of  AEs, SAEs, ARs, SARs and SUSARs........................................ 18 
10.4.1 Assessment of causality .................................................................................... 18 
10.4.2 Assessment of seriousness ............................................................................... 19 
10.4.3 Assessment of severity ...................................................................................... 19 
10.4.4 Assessment of expectedness of SARs ............................................................. 19 
10.5 
Reporting of SARs/SUSARs ................................................................................. 19 
11 
OVERSIGHT ARRANGEMENTS.................................................................................. 20 
11.1 
INSPECTION OF RECORDS ............................................................................... 20 
11.2 
STUDY MONITORING AND AUDIT .................................................................... 20 
12 
GOOD CLINICAL PRACTICE ...................................................................................... 21 
12.1 
ETHICAL CONDUCT ............................................................................................ 21 
12.2 
INVESTIGATOR RESPONSIBILITIES ................................................................. 21 
12.2.1 Informed Consent .............................................................................................. 21 
12.2.2 Study Site Staff .................................................................................................. 21 
12.2.3 Data Recording .................................................................................................. 21 
12.2.4 Investigator Documentation ............................................................................... 22 
12.2.5 GCP Training ..................................................................................................... 22 
12.2.6 Data Protection Training .................................................................................... 22 
12.2.7 Information Security Training ............................................................................. 22 
12.2.8 Confidentiality..................................................................................................... 22 
12.2.9 Data Protection .................................................................................................. 22 
13 
STUDY CONDUCT RESPONSIBILITIES ..................................................................... 23 
13.1 
PROTOCOL AMENDMENTS ............................................................................... 23 
13.2 
MANAGEMENT OF PROTOCOL NON COMPLIANCE ...................................... 23 
13.2.1 Protocol Waivers ................................................................................................ 23 
13.2.2 Management of Deviations and Violations ........................................................ 23 
13.3 
SERIOUS BREACH REQUIREMENTS ............................................................... 23 
13.4 
STUDY RECORD RETENTION ........................................................................... 23 
13.5 
END OF STUDY ................................................................................................... 23 
13.6 
CONTINUATION OF TREATMENT FOLLOWING THE END OF STUDY ......... 24 
13.7 
INSURANCE AND INDEMNITY ........................................................................... 24 
14 
AUTHORSHIP POLICY ................................................................................................. 24 

 
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15 
REFERENCES .............................................................................................................. 25 
 

 
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LIST OF ABBREVIATIONS 
 
ACCORD Academic and Clinical Central Office for Research & Development - Joint office for The 
University of Edinburgh and Lothian Health Board 
CI 
Chief Investigator 
CRF 
Case Report Form 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
18F-GP1 
Fluoride-18 labelled glycoprotein-1 
PI 
Principal Investigator 
QA 
Quality Assurance 
REC 
Research Ethics Committee 
SOP 
Standard Operating Procedure 
PET 
Positron Emission Tomography 
CT 
Computed Tomography 

 
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1 
INTRODUCTION 
1.1 
BACKGROUND 
1.1.1 Background of coronary artery disease and acute myocardial infarction 
 
Coronary artery disease remains the leading cause of death worldwide, with more than 
23 million annual deaths estimated to occur by 2030 (1). The introduction of high-
sensitivity cardiac troponin measurement has revolutionised the identification and 
management of patients presenting with acute chest pain and myocardial infarction. 
However, elevated cardiac troponin concentrations can result from both ischaemic 
(myocardial infarction) or non-ischaemic (myocardial injury) causes. Moreover, the 
further subclassification of myocardial infarction relies on the underlying aetiology of 
infarction which is often not readily apparent and remains a diagnostic challenge. 
 
1.1.2 Universal definition of myocardial infarction 
 
Acute myocardial infarction is defined as cardiomyocyte injury and necrosis in a clinical 
setting consistent with acute myocardial ischaemia. The fourth universal definition of 
myocardial infarction describes five subtypes of acute infarction (2). Type 1 myocardial 
infarction is characterised by underlying atherosclerotic plaque disruption (rupture, 
ulceration, fissuring, erosion, or calcific nodules) resulting in intraluminal thrombosis, 
distal coronary embolisation and intraplaque haemorrhage that ultimately cause 
myocyte necrosis (3, 4). In contrast, type 2 myocardial infarction is classified as an 
ischaemic myocardial injury secondary to oxygen supply and demand mismatch, and 
importantly is not a consequence of atherosclerotic plaque rupture and coronary 
atherothrombosis. However, some causes of type 2 myocardial infarction do involve 
intracoronary thrombus including coronary thromboembolism and spontaneous 
coronary artery dissection. Currently, invasive coronary angiography remains the 
primary modality to identify patients presenting with plaque related disruption and 
coronary thrombosis, ultimately providing the distinction between type 1 and type 2 
myocardial infarction. However, it is not always definitive (5) and only 10-20% of 
patients presenting with type 2 myocardial infarction undergo further investigations to 
identify the presence of underlying coronary artery disease or to exclude coronary 
atherothrombosis (6). Indeed, we recently demonstrated comprehensive cardiac 
imaging and coronary angiography that identified two thirds of patients had previously 
unrecognised underlying coronary artery disease, and this resulted in diagnostic 
reclassification of many patients (7). These standard techniques were however unable 
to determine whether this plaque was implicated in the presentation or simply a 
bystander finding. A non-invasive imaging technique to reliably detect intracoronary 
thrombus and facilitate this distinction would therefore be of major clinical value. 
 
1.1.3 Imaging intracoronary thrombosis 
 
At present, invasive coronary angiography is the primary modality used to detect the 
presence of intracoronary thrombus in patients presenting with acute myocardial 
infarction, through an abrupt occlusion of the coronary artery or a filling defect in 
partially occluded vessels. This approach has high specificity but low sensitivity for 
detection of intracoronary thrombus, necessitating the introduction of adjunctive 
invasive coronary intravascular imaging including angioscopy, intravascular 
ultrasound and optical coherence tomography to improve rates of identification of 

 
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coronary thrombosis and atherothrombosis (8). Intravascular ultrasound-based 
studies have indicated an incidence of plaque disruption of 30-40% in patients with 
myocardial infarction and non-obstructive coronary arteries (9, 10), although this 
imaging technique cannot differentiate between echo-lucent plaques and acute 
thrombus (8, 11). Optical coherence tomography has replaced intravascular 
ultrasound as the gold standard in high-resolution cross-sectional imaging of the 
arterial intima, providing a more detailed assessment of coronary artery dissection and 
thrombus formation (12). However, these invasive techniques are not always 
available, have limitations in respect to assessing smaller or stenosed vessels, and 
only provide circumstantial evidence of the presence of a thrombus based on the 
characteristic appearances of the images (13-15). As such, atherothrombotic events 
may be missed, resulting in misdiagnosis and, importantly, a missed opportunity to 
establish patients on appropriate treatment and secondary prevention. 
 
1.1.4 Uncertain role of coronary thrombosis in myocardial infarction 
 
An accurate diagnosis is imperative for establishing subsequent appropriate 
therapeutic intervention in patients with myocardial infarction. Patients presenting with 
type 1 myocardial infarction require short-term anticoagulation as well as medium-term 
dual antiplatelet therapy, in conjunction with other secondary prevention therapies. For 
most patients with type 2 myocardial infarction, the above strategy would be both 
ineffective and potentially harmful, such as in patients with bleeding associated 
anaemia. However, intracoronary thrombus formation underpins certain causes of 
type 2 myocardial infarction including coronary thromboembolism and spontaneous 
coronary artery dissection. Accurate identification of intracoronary thrombus is a 
central tenet in both the diagnosis of type 1 myocardial infarction, and in the 
differentiation of the various aetiologies underlying type 2 myocardial infarction. 
 
1.1.4.1 Myocardial infarction with non-obstructive coronary arteries 
 
Co-existing coronary artery disease is common in patients with myocardial infarction 
and non-obstructive coronary arteries, with plaque disruption being the key trigger of 
acute myocardial infarction in many cases (3, 4, 9). Myocardial infarction and non-
obstructive coronary arteries was first documented over 75 years ago when 
pathological studies reported evidence of myocardial necrosis in the absence of 
coronary atherosclerosis (16, 17). Its recognition in clinical practice remains more 
recent, and it comprises a heterogenous group of vascular or myocardial disorders, 
occurring in 5-15% of patients presenting with acute myocardial infarction (18-20). 
Compared to patients with obstructive coronary artery disease, patients with 
myocardial infarction and non-obstructive coronary arteries are younger (21, 22), more 
likely to be female, and have specific genetic and ethnic predispositions (23-25). 
Interestingly, the prevalence of traditional coronary artery risk factors including 
dyslipidaemia, hypertension and diabetes mellitus is lower in patients with myocardial 
infarction and non-obstructive coronary arteries (12, 14-16).  
 
Myocardial infarction and non-obstructive coronary arteries has defined criteria as 
outlined by the European Society of Cardiology in 2017 (26) and the American Heart 
Association/American College of Cardiology in 2019 (19). To fulfil the diagnosis, 
patients must present with (i) acute myocardial infarction as defined by the fourth 
universal definition of myocardial infarction (2), (ii) non-obstructive coronary arteries 
on angiography (no coronary artery stenosis ≥ 50%), and (iii) no specific alternative 
diagnosis for the clinical presentation. Only ischaemic causes of acute myocardial 
infarction are now included in the underlying aetiology of myocardial infarction and 

 
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non-obstructive coronary arteries. This includes patients presenting with either type 1 
or type 2 myocardial infarction but excludes those with takotsubo cardiomyopathy and 
myocarditis. Although this has simplified the diagnostic work-up of this patient cohort, 
there remains a high degree of variability in the way patients with suspected 
myocardial infarction and non-obstructive coronary arteries are investigated and 
treated, because it is a diagnosis of exclusion. The identification and management of 
these patients will depend on local practice and resources, where there may be limited 
access to more advanced diagnostic testing. This is likely one of the contributory 
factors underlying a recent analysis demonstrating that patients with myocardial 
infarction and non-obstructive coronary arteries had a higher one-year adjusted 
mortality than patients with myocardial infarction and obstructive coronary artery 
disease (20). As such, there is a clinical need to improve the accuracy in the 
identification, investigation, and management of this patient population.  
 
1.1.4.2 Coronary thromboembolism 
 
Coronary thromboembolism results in myocardial infarction and non-obstructive 
coronary arteries if it involves the microcirculation or if the epicardial coronary 
thrombus is not associated with atherosclerotic coronary artery disease (19). 
Underlying aetiologies can range from atrial fibrillation, hypercoagulable states, 
inherited thrombophilia, paradoxical embolism, valvular vegetations, valvular 
calcifications and cardiac tumours (19, 27). As this subtype of event typically involves 
smaller calibre coronary vessels, their identification using catheter-based techniques 
is limited by the inability to access smaller vessels due to the size and physical 
limitations of the intravascular probes. A more sensitive novel and non-invasive 
imaging modality that can more accurately assess small calibre coronary vessel 
thrombosis would be of great clinical value to identify coronary thrombosis events 
resulting in type 2 myocardial infarction. 
  
1.1.4.3 Spontaneous coronary artery dissection 
 
Spontaneous coronary artery dissection is an uncommon cause of acute myocardial 
infarction, with a predominance in younger (<50 years) women (28, 29). Myocardial 
ischaemia is driven by obstruction to coronary blood flow, secondary to separation of 
medial and adventitial coronary vascular walls, with associated intramural haematoma 
resulting in protrusion into the coronary arterial lumen. The coronary arteries can 
appear normal or near normal on coronary angiography, due to gradual tapering of the 
vessel, and this is commonly a missed diagnosis. Moreover, the prevalence of 
iatrogenic catheter-induced coronary artery dissection is reported to be increased in 
patients with spontaneous coronary artery dissection, meaning that many clinicians 
are reluctant to perform intravascular imaging in patients with this suspected diagnosis 
(30). Consequently, the true incidence of spontaneous coronary artery dissection is 
likely to be underestimated (19, 29). 
 
1.1.5 Non-invasive imaging of coronary thrombus - Pilot data 
 
We have recently used positron emission tomography (PET) with computed 
tomography (CT) coronary angiography to identify intracoronary thrombus using a 
novel radiotracer, 18F-GP1. This radiotracer is highly selective and specific for the 
activated glycoprotein IIb/IIIa receptor on activated platelets (31-33). As part of a 
previous BHF-funded Clinical Research Training Fellowship (Dr Evangelos Tzolos; 
FS/CRTF/20/24086) and Project Grant (PG/19/40/34422), we have demonstrated that 
18F-GP1 has specificity for the detection of intravascular thrombosis in a range of 

 
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cardiovascular conditions (34, 35). We have recently undertaken studies in patients 
with coronary atherothrombosis in acute type 1 myocardial infarction (35). This was 
the first demonstration that non-invasive imaging can identify in vivo intracoronary 
thrombus in patients presenting with acute myocardial infarction, and for this work, Dr 
Tzolos was awarded the European Society of Cardiology Young Investigator Award in 
2021. We have confirmed the high selectivity and specificity of 18F-GP1 binding to 
activated platelets within fresh human thrombus and coronary thrombectomy 
specimens, and importantly we have observed 18F-GP1 uptake only occurs within the 
culprit coronary arteries of those with acute myocardial infarction (35). For example, 
in patients with triple vessel disease, coronary 18F-GP1 uptake was only seen at the 
site of the culprit lesion. We have also demonstrated preliminary findings of focal 18F-
GP1 uptake at the site of spontaneous coronary artery dissection, coronary 
thromboembolism (36) and extra-coronary thrombus including unrecognized left 
ventricular and atrial thrombus, as well as infarct-related intramyocardial 18F-GP1 
uptake. This changed both the diagnosis (type 1 reclassified as type 2 myocardial 
infarction) and the treatment (initiation of anticoagulation) of patients presenting with 
acute myocardial infarction. These data demonstrate the feasibility of identifying 
patients with intracoronary thrombus and type 1 myocardial infarction, and those with 
type 2 myocardial infarction caused by spontaneous coronary artery dissection and 
coronary thromboembolism. Importantly the pattern of 18F-GP1 distribution differs 
among these three conditions, allowing their differentiation. This technique holds major 
promise in aiding the classification of myocardial infarction, especially in patients with 
myocardial infarction and non-obstructive coronary arteries or where the presence of 
coronary thrombosis is unclear.  
1.2 
RATIONALE FOR STUDY 
 
With the evolving complexity in modern diagnostic criteria and treatments, it has 
become increasingly important to determine the aetiology of acute myocardial 
infarction and specifically determine the presence of intracoronary thrombosis. This 
has major implications for treatment decisions and patient outcome. However, there 
are currently no techniques that can reliably determine the presence of intracoronary 
thrombus throughout the coronary circulation. Here, we will assess a promising highly 
sensitive and accurate technique to determine the contribution of coronary thrombosis 
in patients presenting with uncertain or difficult to diagnose causes of myocardial 
infarction. This will potentially provide a completely novel approach that could provide 
major insights into the diagnosis, investigation and treatment of these patients. 
2 
STUDY OBJECTIVES 
2.1 
OBJECTIVES 
2.1.1 Primary Objective 
The primary objective of this study is to establish the origin, frequency and distribution of 
activated platelets and thus thrombotic causes of myocardial infarction in patients presenting 
with myocardial infarction with non-obstructive coronary arteries 
2.1.2 Secondary Objectives 
To inform the pathophysiology and understanding of acute myocardial subtypes, by providing 
additional mechanistic information regarding the presence of intracoronary activated platelets 
and thrombosis. 

 
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2.2 
ENDPOINTS 
2.2.1 Primary Endpoint 
The primary endpoint will be the degree and location of platelet activation as 
determined by the target to background ratio of 18F-GP1.  
2.2.2 Secondary Endpoints 
The secondary endpoints will include measuring the presence of platelet activation in 
acute myocardial infarction with non-obstructive coronary arteries and identifying the 
presence and site of platelet activation in thrombosis-related coronary causes of type 
2 myocardial infarction. 
3 
STUDY DESIGN 
 
This will be a prospective observational case-control cohort study 
4 
STUDY POPULATION 
4.1 
NUMBER OF PARTICIPANTS 
 
We will recruit two patient populations after invasive coronary angiography has been 
completed. We have established comparator control populations including 50 patients 
with stable coronary artery disease (no angina or recent myocardial infarction) and 
valvular heart disease who underwent 18F-GP1 cardiac PET-CT as part of a concurrent 
study (NCT04073875) (34). 
 
4.1.1 Cohort 1: Patients with myocardial infarction with non-obstructive 
coronary arteries 
 
We will recruit 50 patients with myocardial infarction and non-obstructive coronary 
arteries on coronary angiography 
 
4.1.2 Cohort 2: Patients with coronary causes of type 2 myocardial infarction 
 
We will recruit 10 patients with coronary artery thromboembolism and 10 patients with 
spontaneous coronary artery dissection. Finally, we will include 10 subjects who have had 
iatrogenic coronary artery dissection or intramural haematoma as a complication of their 
percutaneous coronary intervention.  
 
4.2 
INCLUSION CRITERIA 
 
- 
Males and females ≥ 18 years of age 

 
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- 
Clinical presentation of chest pain, ST-segment deviation within a coronary artery 
territory on the electrocardiogram, raised cardiac troponin and non-obstructive 
coronary arteries on invasive coronary angiography as per international societal 
diagnostic criteria (19, 26).  
4.3 
EXCLUSION CRITERIA 
 
- 
<18 years of age 
- 
Takatsubo cardiomyopathy 
- 
Myocarditis 
- 
Renal failure (estimated glomerular filtration rate <30 mL/min/1.73 m2) 
- 
Woman of child-bearing potential who are pregnant or breastfeeding 
- 
Known allergy or contraindication to iodinated contrast or radiotracer  
- 
Patients unable to tolerate the supine position 
- 
Patients unable to provide informed consent 
 
4.4 
CO-ENROLMENT 
 
Co-enrolment with other studies may be considered in line with ACCORD co-enrolment policy. 
Co-enrolment between studies will be agreed by the respective PIs prior to beginning of the 
study. Individual patients who are eligible for co-enrolment will be discussed between research 
fellows and Pis as necessary. This will ensure co-enrolment: 
 
1. Is appropriate (i.e. there are no contra-indications)  
2. Would not jeopardise the integrity of either study 
3. Would not compromise patient care, safety, or result in an undue burden on the 
patient, including exposure to too much radiation. 
5 
PARTICIPANT SELECTION AND ENROLMENT 
5.1 
IDENTIFYING PARTICIPANTS 
 
Potential participants for all the cohorts will be identified by their usual care team whilst in the 
Royal Infirmary of Edinburgh. A member of the study team will provide an information sheet if 
the participant is interested in taking part in the study. 
5.2 
CONSENTING PARTICIPANTS 
 
Participants will be enrolled following an opportunity to read the patient information sheet and 
once written informed consent is obtained, screening for eligibility can begin. Consent will be 
confirmed at the beginning of any study activities.  
5.2.1 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 report form if possible. The participant will have the option of withdrawal from: 
 

 
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(i) 
all aspects of the study but continued use of data collected up to that point. To safeguard 
rights, the minimum personally identifiable information possible will be collected. 
6 
STUDY ASSESSMENTS 
6.1 
STUDY ASSESSMENTS 
All patient’s eligible for the study will have informed consent taken. This will as well as a 
standardised clinical assessment will be performed either whilst still an inpatient or as soon 
as practical possible from symptom onset. The clinical assessment will be carried out in the 
Clinical Research Facility or on participants’ inpatient ward.  
6.2 
Study Screening 
 
Eligible participants in will be approached as described in section 5. We will also assess 
capacity to ensure adequate understanding of the study procedures and their ability to provide 
informed written consent.  
 
6.3 
Baseline Visit 
All patient’s eligible for the study will have informed consent taken. This will as well as a 
standardised clinical assessment will be performed either whilst still an inpatient or as soon 
as practical possible from symptom onset. The clinical assessment will be carried out in the 
Clinical Research Facility or on participants’ inpatient ward.  
The assessment will include: 
- 
Demographic details  
o Name, initials, age, sex, height, weight, CHI number, telephone number, 
address, postcode and email address if available 
- 
Past medical and surgical history 
- 
Medications 
- 
Allergies 
- 
Clinical examination 
o Blood pressure assessment and heart rate 
o Physical examination by clinically qualified study researcher including 
cardiovascular examination  
- 
Electrocardiography (assessing for evidence of myocardial infarction and 
arrhythmia)  
- 
Clinical haematology and biochemistry will be recorded as part of standard of care. 
- 
A urinary pregnancy test in women of childbearing potential   
6.4 
Echocardiography 
Transthoracic echocardiography will be performed by a British Society of Echocardiography-
accredited research ultra-sonographer according to American Society of Echocardiography 
and European Association of Cardiovascular Imaging guidelines. Patients will be studied with 
a standard 3 MHz transducer and 2- dimensional, M-mode, Doppler and colour Doppler 
measurements taken. Ejection fraction will be quantified using the modified Simpson’s 
technique and regional wall motion abnormalities assessed. Agitated saline and ultrasound 
contrast will be performed to assess for intracardiac shunts and left ventricular thrombus as 
appropriate. If not performed as part of standard of care, we will organise a study specific 

 
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transthoracic echocardiogram to be performed at baseline visit or as soon as possible as when 
is convenient for the participant.  
 
6.5 
Invasive coronary angiography and intravascular imaging 
 
Invasive coronary angiography will be performed in all patients. Adjunctive imaging with optical 
coherence tomography (or intravascular ultrasound) will be encouraged as part of standard of 
care. 
 
 
6.6 
Cardiac magnetic resonance imaging 
 
All patients will undergo cardiac magnetic resonance imaging as standard of care for the 
investigation of patients with myocardial infarction and non-obstructive coronary arteries or 
myocardial infarction of uncertain aetiology. This will be performed prior to 18F-GP1 PET/CT 
coronary angiography to exclude patients without myocardial infarction, such as those with 
myocarditis or takotsubo cardiomyopathy.  
 
 
6.7 
Hybrid 18F-GP1 positron emission tomography and coronary computed 
tomography coronary angiography  
 
18F-GP1 will be synthesized by our radiochemistry facility, the Edinburgh Imaging Facility 
Radiochemistry (EIFR), which is co-located within our Edinburgh Imaging Facility, Queens 
Medical Research Institute (EIF QMRI) using our well-established protocols. Each patient will 
undergo 18F-GP1 PET/CT coronary angiography imaging on our hybrid scanner (Biograph 
mCT, Siemens) as soon as practical after their index event and within a maximum of 7 days 
from symptom onset. In our previous studies the 18F-GP1 signal diminished after this time 
point (35).  Patients will initially be injected with 250 MBq 18F-GP1, before resting in a quiet 
environment for 60 min. A low-dose attenuation correction CT scan (120 kV, 50 mAs, 5/3 mm) 
will be followed by acquisition of PET data in list mode using a two 20-min bed position centred 
on the thoracic aorta and heart. A contrast-enhanced CT coronary angiogram will then be 
performed. After optimal co-registration of the CT and PET data, regions of interest will be 
drawn for PET quantification around areas of uptake in the coronary arteries, ascending and 
arch of the aorta as well as the atria and ventricles of the heart. Mean and maximum 
standardised uptake values (SUV) for 18F-GP1uptake will be measured. Tissue to background 
ratio (TBR) will also be calculated after correcting thrombus uptake for tracer activity in the 
blood pool of the right atrium as described previously (37). 
6.8 
Myocardial infarction classification 
Following the completion of all standard of care investigations the participants investigations 
will be presented to a panel of cardiology experts from the cardiology consultant body at the 
Royal Infirmary of Edinburgh who will be asked to classify the myocardial subtype using the 
Universal definition of myocardial infarction (2). This will help to ensure, with addition of the 
usual care team myocardial infarction classification, a robust classification of the myocardial 
infarction subtype for each patient.  
6.9 
Schedule of study assessments 
 

 
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Assessment  
Screening  
Day 1 – 7 
 
6 – 12 months post 
PET-CT scan 
Assessment of Eligibility Criteria  
☒ 
      
 
Written informed consent  
☒ 
       
 
Demographic data, contact details 
☒ 
      
 
Blood samples as per standard clinical care and study 
protocol 
☒ 
      
 
12-lead ECG as per standard clinical care 
☒ 
 
 
Coronary angiogram as per standard clinical care 
☒ 
 
 
Transthoracic Echocardiogram as per standard 
clinical care 
 
☒ 
 
Urinary pregnancy test  
☒ 
 
 
 
18F-GP1 injection and waiting period  
 
☒ 
 
PET-CT scan of heart  
 
☒ 
 
CT Coronary angiogram  
 
☒ 
 
Review of clinical notes looking for recurrent 
myocardial infarction, stroke or transient ischaemic 
attack, pulmonary embolism, all haemorrhage, 
current medications and death 
 
 
☒ 
A standardized study questionnaire will be posted or 
sent via email  
 
 
☒ 
 
6.10 LONG TERM FOLLOW UP ASSESSMENTS 
We will then follow participants up following their PET-CT scan. This will be performed once 
between 6 and 12 months following their myocardial infarction, with subsequent follow up used 
to obtain as much data as possible. We will collect data on recurrent myocardial infarction, 
stroke or transient issue attack (TIA), pulmonary embolism, all haemorrhage, current 
medications and death. A standardized questionnaire will be posted or sent via email to the 
participants and a review of electronic medical notes will be undertaken between 6 and 12 
months to collect this data. A telephone call to patients will be considered if patients do not 
return the questionnaire or further clarification is needed. Prior to contacting participants, we 
will check case notes to ensure the participants are not deceased and contact would distress 
relatives.  
6.11 STORAGE AND ANALYSIS OF SAMPLES 
Blood samples for storage will be frozen and kept for a minimum of five years. It will be stored 
in a locked freezer in appropriately secured premises in the Laboratory at Edinburgh Royal 
Infirmary. The retained blood samples and participants data (including CT/PET and MRI 
images) will be used for secondary studies separate to this study as hypothesis arise. 
Anonymised blood samples may be sent to other academic institutions or commercial 
companies for analysis. 

 
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7 
DATA COLLECTION 
Clinical Assessment 
Any changes in medication, any hospital admission or any clinical symptoms will be 
assessed at the study visit by the investigator. 
 
Blood Sampling 
Blood samples will be collected as per standard clinical care. The results will be 
uploaded onto the patients electronic NSH Lothian medical record.  
 
Electrocardiogram 
Electrocardiograms will be collected as per standard clinical care and uploaded onto 
the patient’s electronic NHS Lothian medical record. 
 
Echocardiography 
Echocardiography will be performed according to standard clinical care. 
Echocardiograms will be uploaded to the EchoPAC data storage system as part of the 
patient’s electronic NHS Lothian medical record. 
 
Computed Tomography Positron Emission Tomography  
Imaging datasets will be stored on the servers at the Edinburgh Imaging Facility for 
subsequent analysis. Summary imaging DICOM files will be uploaded to the PACS 
system as part of the patient’s electronic NHS Lothian medical record. 
 
7.1 
Source Data Documentation 
The study database will be used to document all data collection in a NHSL computer. All 
patient-related data will be recorded in an anonymized way. Each patient will be unequivocally 
identified by a trial subject number, attributed at recruitment into the study. Key data from 
blood results, echocardiography, CT, MRI and PET-CT/PET-MR reports will be documented 
in the case record form of the study database. The original reports and images will be retained 
by the imaging core laboratory for future reference. 
8 
DATA MANAGEMENT 
Patient NHS electronic records will be accessed following formal and explicit patient consent. 
Anonymised data will be made available for other researchers to use where appropriate.  
 
All identifiable participant information (Name, age, sex, address and postcode, CHI number, 
telephone number, email address, height, weight, clinical condition, date of study enrolment 
and date of PET-CT scan.) will be stored in a secure manner accessible only to members of 
the research team. CHI number is required to review participants relevant medical history, 
medications, medical imaging and standard of care intervention results. This will be stored on 
an NHS password protected onedrive excel file.  
 
All computers will be encrypted and password protected. Electronic data will be stored on (2-
step) password-protected computers (University laptop and NHS computers) and only 
accessible to the study investigators. No personal identifiable information including CHI 
numbers will be accessed by members outside the research team or NHS Lothian. 
 

 
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All University of Edinburgh employed researchers and study staff will complete the Data 
Protection Training through Learn. 
 
All University of Edinburgh employed researchers, students and study staff will complete the 
Information Security Essentials modules through Learn and will have read the minimum and 
required reading setting out ground rules to be complied with. 
 
Only study subject number will be transferred to the password protected University laptop. 
 
The study will be guided by the principles of Good Clinical Practice and Data Protection Act in 
ensuring the confidentiality of personal data. Participant consent forms will contain personal 
data and a linked participant identification number. Hard copies of consent forms will be stored 
in a secure filing cabinet in a locked University Office (Room SU 305, Chancellor's Building). 
Study data will be kept on University password protected computers as linked anonymised 
data. This will enable the identification of each participant's data during the study, in order for 
any participant to withdraw and have personal data destroyed if they wish. All data will be 
anonymised after the study period. 
8.1 
Personal Data 
The following personal data will be collected as part of the research: 
- 
Name, age, sex, address and postcode, CHI number, height, weight, clinical 
condition, date of study enrolment and date of PET-CT scan 
- 
Personal data will be stored or accessed for a period of 6 to 12 months after 
the study has ended on a NHSL password protected onedrive excel file to 
allow participants to be identified so we can follow up on their management 
and clinical course. Thereafter, anonymised data may be stored for a period 
of up to five years. No peronsal identifiable data will be transferred to the 
University of Edinburgh.  
8.2 Data Information Flow 
All data collected or generated by the study (including personal data) will not be transferred to 
any external individuals or organisations outside of the Sponsoring organisation(s).  
8.3 External Transfer of Data 
 
All data collected or generated by the study (including personal data) will not be transferred to 
any external individuals or organisations outside of the Sponsoring organisation(s).  
8.4 Data Controller 
 
The data controller is the University for Edinburgh and NHS Lothian. The data controller is the 
organisation who determines the purposes for which, and the manner in which, any personal 
data are processed. 
8.5 Data Breaches 
Any data breaches will be reported to the University of Edinburgh (dpo@ed.ac.uk) and NHS Lothian 
(Lothian.DPO@nhslothian.scot.nhs.uk) Data Protection Officers who will onward report to the relevant 
authority according to the appropriate timelines if required. 

 
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9 
STATISTICS AND DATA ANALYSIS 
9.1 
SAMPLE SIZE CALCULATION 
 
We have found that 18F-GP1 is markedly discriminatory for the presence of thrombus with an 
accuracy of 96% with 100% specificity and false negatives predominantly seen in patients 
imaged beyond 7 days from presentation (37). The prevalence of coronary thrombosis in 
patients with myocardial infarction and non-obstructive coronary arteries is unknown but 
estimates suggest that plaque disruption may be as high as one third of cases although it is 
unclear if this is bystander disease or the cause of the infarction (19). We have estimated that 
routine clinical evaluation may suggest thrombus in 10-20% of patients with myocardial 
infarction and non-obstructive coronary arteries. For 80-90% power at two-sided p<0.05, we 
will require a study population of 36-50 to detect an incidence of thrombosis of 25-40%. 
Population sizes for coronary thromboembolism and spontaneous coronary dissection are 
based on the proof-of-principle of the detection of coronary thrombosis and have greater than 
95% power to detect a prevalence of coronary thrombus in over two thirds of patients. 
 
9.2 
PROPOSED ANALYSES 
 
As with our previous studies, image analysis will be performed on bespoke PET analysis 
software from our long-standing collaborators (FusionQuant, Cedars Sinai Hospital, Los 
Angeles) that provides automated motion correction and advanced cardiovascular PET 
quantification (31, 32, 38). After accurate co-registration of the PET and CT data sets, 18F-
GP1 uptake will be quantified within regions of interest around areas of thrombus on the CT 
images.  
 
Descriptive statistics will incorporate numbers and proportions, means and standard 
deviations or median and interquartile ranges. Proportions will be compared with Chi-squared 
test and continuous variables will be compared with regression analysis, Student’s t-test or 
analysis of variance with repeated measures for longitudinal assessments. Statistical 
significance will be taken as two-sided p<0.05.  
10 
ADVERSE EVENTS 
 
The Investigator, or a delegated researcher, is responsible for the detection and 
documentation of adverse events that may be related to participating in the study and 
that meet the criteria and definitions detailed below.  
 
10.1 Definitions 
 
An adverse event (AE) is an untoward medical occurrence in a study participant.  
An adverse reaction (AR), in the context of this study, is any untoward and 
unintended response which is related to any dose of iodinated contrast agent or PET 
tracer administered to that participant.  
 
A serious adverse reaction (SAR) is any AR that:  
• results in death of the clinical trial participant; is life threatening*;  
• requires in-patient hospitalisation or prolongation of existing hospitalisation; 

 
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• 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.  
 
A suspected unexpected serious adverse reaction (SUSAR) is any AR that is 
classified as serious and is suspected to be caused by the iodinated contrast agent, 
that it is not consistent with the information in PET tracer Investigator Brochure.  
 
*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.  
 
10.2 Identifiying AEs and ARs  
 
All AEs and ARs related to the imaging procedures will be identified from the time a 
PET/CT scan related procedure commences until 7 days after PET/CT scan 
completion.  
 
10.3 Recording AEs and ARs  
 
AEs will be recorded in the study CRF. There is no requirement to complete an additional AE 
form. 
 
When an AE occurs, it is the responsibility of the Investigator to review all documentation (e.g. 
hospital notes, laboratory and diagnostic reports) related to the event. To the extent the CRF 
permits, the Investigator will record relevant safety information in the CRF.  
 
Any adverse reaction (AR) to iodinated contrast or PET tracer that meets seriousness criteria 
(see section 10.1) will be recorded and reported in the study CRF and will also be recorded 
on an ACCORD SAE form, which will then be sent to the Sponsor via email 
(safety@accord.scot).  
 
Pre-existing medical conditions (i.e. existed prior to informed consent) should be recorded as 
medical history and only recorded as AEs/ARs if medically judged to have unexpectedly 
worsened during the study. Events that are consistent with the expected progression of 
underlying disease should not be recorded as adverse events.  
 
10.4 Assessment of  AEs, SAEs, ARs, SARs and SUSARs  
 
Seriousness, causality, severity and expectedness will be assessed by the PI. The Investigator 
is responsible for assessing each adverse event. The CI may not downgrade an event that 
has been assessed by an Investigator as a SAR or SUSAR, but can upgrade an AR, SAR or 
SUSAR if appropriate.  
 
10.4.1 Assessment of causality  
 

 
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The Investigator will make an assessment of whether an AE is likely to be related to the 
administration of iodinated contrast or PET tracer (and therefore be considered an AR) 
according to the definitions below.  
• 
Unrelated: Where an event is not considered to be related to the administration of 
iodinated contrast or PET tracer.  
• 
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 administration of iodinated contrast or PET tracer in this 
study.  
 
10.4.2 Assessment of seriousness  
 
Subsequent to the assessment causality, the Investigator will make an assessment of 
seriousness as defined in Section 10.1 
 
10.4.3 Assessment of severity  
 
The Investigator will make an assessment of severity for each SAR, and record this on the 
ACCORD 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.  
 
10.4.4 Assessment of expectedness of SARs  
 
10.5 No SARs are considered expected by the sponsor for the purpose of 
expedited reporting of SUSARs based upon the reference safety 
information available in the most current version of the PET tracer 
Investigator Brochure. Reporting of SARs/SUSARs  
 
As this trial is a non-CTIMP and involves procedures and interventions that are very well 
established in the medical community, with extensive information available regarding risks, 
only serious adverse reactions (SARs) and Suspected Unexpected Serious Adverse 
Reactions (SUSARs) related to iodinated contrast administration, will be onward reported to 
the Sponsor.  
 
Once the Investigator becomes aware that a contrast or PET tracer related SAR/SUSAR, has 
occurred in a study participant, the information will be reported to the ACCORD Research 
Governance & QA Office within 24 hours. If the Investigator does not have all information 
regarding an event, they should not wait for this additional information before notifying 

 
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ACCORD. The ACCORD SAE report form will be used to submit the event report, and can be 
updated when the additional information is received. SAR/SUSARs relating to the PET tracer 
will also be forwarded onto Life Molecular Imaging SA as stipulated in exhibit D of the legal 
material transfer agreement. This stipulates that within two business days all cases concerning 
Serious Adverse Events independent of their causal relationship to the GP1 tracer will be 
reported to Life Molecular Imaging SA using the email address GRA@life-mi.com by the study 
lead. 
 
The SAE form will be sent via email to safety@accord.scot within 24 hours 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 sent to ACCORD and any follow up information will be retained by the Investigator 
in the Investigator Site File.  
 
10.6 Reporting requirements  
 
The ACCORD Research Governance & QA Office is responsible for pharmacovigilance 
reporting on behalf of the co-sponsors (Edinburgh University and NHS Lothian).  
 
 
10.7 FOLLOW-UP PROCEDURES 
  
After initially reporting a radiotracer related SAR/SUSAR, the Investigator will follow each 
participant until resolution or the completion of study follow-up. Follow-up information will be 
reported to the ACCORD office. 
11 
OVERSIGHT ARRANGEMENTS 
11.1 INSPECTION OF RECORDS 
Investigators and institutions involved in the study will permit study related monitoring and audits on 
behalf of the Sponsor, REC review, and regulatory inspection(s). In the event of 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. 
11.2 STUDY MONITORING AND AUDIT 
The ACCORD Sponsor Representative will assess the study to determine if a study specific risk 
assessment is required.  
If required, a study specific risk assessment will be performed by representatives of the Sponsor(s), 
ACCORD monitors and the QA group, in accordance with ACCORD governance and sponsorship 
SOPs. Input will be sought from the Chief Investigator or designee. The outcomes of the risk 
assessment will form the basis of the monitoring plans and audit plans.  

 
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If considered necessary, ACCORD clinical trial monitors, or designees, will perform monitoring activities 
in accordance with the study monitoring plan. This will involve on-site visits and remote monitoring 
activities as necessary. ACCORD QA personnel, or designees, will perform study audits in accordance 
with the study audit plan. This will involve investigator site audits, study management audits and facility 
(including 3rd parties) audits as necessary (delete where not required). 
12 
GOOD CLINICAL PRACTICE 
12.1 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). 
Before the study can commence, all necessary approvals will be obtained and any conditions of 
approvals will be met. 
12.2 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. 
Delegated tasks must be documented on a Delegation Log and signed by all those named on the list 
prior to undertaking applicable study-related procedures.   
12.2.1 Informed Consent 
The Investigator is responsible for ensuring informed consent is obtained before any study 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). 
The Investigator or delegated member of the study team and the participant will sign and date the 
Informed Consent Form(s) to confirm that consent has been obtained. The original will be signed in the 
Investigator Site File (ISF). The participant will receive a copy of the signed consent form and a copy 
will be filed in the participant’s medical notes. 
12.2.2 Study Site Staff 
The Investigator must be familiar with the 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 protocol 
and their study related duties. 
12.2.3 Data Recording 
The Principal Investigator is responsible for the quality of the data recorded in the CRF at each 
Investigator Site.  

 
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12.2.4  Investigator Documentation 
The Principal Investigator will ensure that the required documentation is available in local Investigator 
Site files (ISFs). 
12.2.5 GCP Training 
For non-CTIMP (i.e. non-drug) studies all researchers are encouraged to undertake GCP training in 
order to understand the principles of GCP. This is not a mandatory requirement unless deemed so by 
the Sponsor. GCP training status for all investigators should be indicated in their respective CVs. 
12.2.6 Data Protection Training 
All University of Edinburgh employed researchers and study staff will complete the Data Protection 
Training through Learn. 
NHS Lothian employed researchers and study staff will comply with NHS Lothian mandatory Information 
Governance Data Protection training through LearnPro. 
Non-NHS Lothian staff that have access to NHS Lothian systems will familiarise themselves and abide 
by all NHS Lothian IT policies, as well as employer policies 
12.2.7 Information Security Training 
All University of Edinburgh employed researchers, students and study staff will complete the Information 
Security Essentials modules through Learn and will have read the minimum and required reading setting 
out ground rules to be complied with. 
NHS Lothian employed researchers and study staff will comply with NHS Lothian mandatory Information  
Governance IT Security training through LearnPro. 
Non-NHS Lothian staff that have access to NHS Lothian systems will familiarise themselves and abide 
by all NHS Lothian IT policies, as well as employer policies 
12.2.8 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 information, which is 
confidential or identifiable, and has been 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. 
12.2.9 Data Protection 
All Investigators and study site staff involved with this study must comply with the requirements of the 
appropriate data protection legislation (including the General Data Protection Regulation and Data 
Protection Act) with regard to the collection, storage, processing and disclosure of personal information.  
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. 

 
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13 
STUDY CONDUCT RESPONSIBILITIES 
13.1 PROTOCOL AMENDMENTS 
Any changes in research activity, except those necessary to remove an apparent, immediate hazard to 
the participant in the case of an urgent safety measure, must be reviewed and approved by the Chief 
Investigator. 
Proposed amendments will be submitted to the Sponsor for classification, review and authorisation. 
Amendments to the protocol must be submitted in writing to the appropriate REC and local R&D for 
approval prior to implementation and prior to participants being enrolled into the amended protocol. 
13.2 MANAGEMENT OF PROTOCOL NON COMPLIANCE 
13.2.1 Protocol Waivers 
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 and local R&D for review and approval if appropriate. 
13.2.2 Management of Deviations and Violations 
Deviations and violations are non-compliance events discovered after the event has occurred. 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 of becoming aware of 
the violation. 
Deviation logs will be maintained for each site in multi-centre studies. 
Deviation logs/violation forms will be transmitted via email to QA@accord.scot. Only forms in a pdf 
format will be accepted by ACCORD via email. Forms may also be submitted by hand to the office. 
Where missing information has not been sent to ACCORD after an initial report, ACCORD will contact 
the Investigator and request the missing information. The Investigator must respond to these requests 
in a timely manner. 
13.3 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 study; or 
(b) the scientific value of the study. 
If a potential serious breach is identified by the Chief investigator, Principal Investigator or delegates, 
the Sponsor(s) (qa@accord.scot) must be notified within 24 hours. It is the responsibility of the 
Sponsor(s) to assess the impact of the breach on the scientific value of the study, to determine whether 
the incident constitutes a serious breach and report to research ethics committees as necessary. 
13.4 STUDY RECORD RETENTION 
All study documentation will be kept for a minimum of 3 years from the protocol defined end of study 
point. When the minimum retention period has elapsed, study documentation will be destroyed with 
permission from the Sponsor. 
13.5 END OF STUDY 
The end of study is defined as the last participant’s last visit. 
The Investigators and/or the Sponsor(s) have the right at any time to terminate the study for clinical or 
administrative reasons.  

 
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The end of the study will be reported to the REC, and R&D Office(s) and Sponsor(s) 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 Sponsor(s) via email to researchgovernance@ed.ac.uk. 
A summary report of the study will be provided to the REC within 1 year of the end of the study. 
13.6 CONTINUATION OF TREATMENT FOLLOWING THE END OF STUDY 
The end of study is defined as the last participant’s last visit. The Investigators 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, and 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 resgov@accord.scot. 
A summary report of the study will be provided to the REC within 1 year of the end of the 
study. 
 
13.7 INSURANCE AND INDEMNITY 
The Sponsor(s) 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 Sponsor(s)' 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 Sponsor(s) require individual sites participating 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 National 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. 
14 
AUTHORSHIP POLICY 
Ownership of the data arising from this study resides with the study team. 

 
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15 
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