REtinaL Imaging & Ambulatory BLood PrEssure: Validating Ultra-widefield Retinal Imaging Derived Biomarkers Against Ambulatory Blood Pressure
Conditions: Hypertension, Blood Pressure
Sponsor: University of Edinburgh

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Non-CTIMP Study Protocol 
REtinaL Imaging & Ambulatory BLood PrEssure: validating 
ultra-widefield retinal imaging derived biomarkers against 
ambulatory blood pressure  
THE RELIABLE STUDY 
 
 
The University of Edinburgh and/or Lothian Health Board 
ACCORD 
The Queen’s Medical Research Institute 
47 Little France Crescent 
Edinburgh 
EH16 4TJ 
 
Protocol authors 
Dr Iain MacIntyre 
Dr Tom MacGillivary 
Professor David Webb 
Funder 
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Funding Reference Number 
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Chief Investigator 
Dr Iain MacIntyre 
Sponsor number 
AC18080 
REC Number 
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Project registration 
If applicable trials should be registered on a 
publically accessible database.  ACCORD can provide 
log-in credentials for clinicaltrials.gov.  Please email 
resgov@accord.scot to arrange  
Version Number and Date 
Draft Version 1.0 24th September 2018 

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Amendment classification and 
number: 
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amendment 01 Jan 2000 
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protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 

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CONTENTS 
 
1 
INTRODUCTION ............................................................................................................ 7 
1.1 
BACKGROUND ..................................................................................................... 7 
1.2 
RATIONALE FOR STUDY .................................................................................... 7 
2 
STUDY OBJECTIVES ................................................................................................... 8 
2.1 
OBJECTIVES ........................................................................................................ 8 
2.1.1 Primary Objective ............................................................................................... 8 
2.1.2 Secondary Objectives ........................................................................................ 8 
2.2 
ENDPOINTS ......................................................................................................... 8 
2.2.1 Primary Endpoint ................................................................................................ 8 
2.2.2 Secondary Endpoints ......................................................................................... 8 
3 
STUDY DESIGN ............................................................................................................ 9 
4 
STUDY POPULATION .................................................................................................. 9 
4.1 
NUMBER OF PARTICIPANTS .............................................................................. 9 
4.2 
INCLUSION CRITERIA ......................................................................................... 9 
4.3 
EXCLUSION CRITERIA ...................................................................................... 10 
4.4 
CO-ENROLMENT ............................................................................................... 10 
5 
PARTICIPANT SELECTION AND ENROLMENT ....................................................... 10 
5.1 
IDENTIFYING PARTICIPANTS .......................................................................... 10 
5.2 
CONSENTING PARTICIPANTS ......................................................................... 10 
5.3 
SCREENING FOR ELIGIBILITY ......................................................................... 10 
5.4 
WITHDRAWAL OF STUDY PARTICIPANTS ..................................................... 10 
6 
STUDY ASSESSMENTS ............................................................................................. 11 
6.1 
STUDY ASSESSMENTS .................................................................................... 11 
6.2 
SAFETY ASSESSMENTS .................................................................................. 11 
6.3 
LONG TERM FOLLOW UP ASSESSMENTS ..................................................... 12 
6.4 
STORAGE AND ANALYSIS OF SAMPLES ........................................................ 12 
7 
DATA COLLECTION ................................................................................................... 12 
7.1 
Source Data Documentation ............................................................................... 13 
7.2 
Case Report Forms ............................................................................................. 13 
8 
STATISTICS AND DATA ANALYSIS ......................................................................... 13 
8.1 
SAMPLE SIZE CALCULATION ........................................................................... 13 
8.2 
PROPOSED ANALYSES .................................................................................... 14 
9 
ADVERSE EVENTS .................................................................................................... 14 
10 
OVERSIGHT ARRANGEMENTS ................................................................................ 14 
10.1 
INSPECTION OF RECORDS ............................................................................. 14 
10.2 
RISK ASSESSMENT .......................................................................................... 14 
10.3 
STUDY MONITORING AND AUDIT ................................................................... 15 
11 
GOOD CLINICAL PRACTICE ..................................................................................... 15 

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11.1 
ETHICAL CONDUCT .......................................................................................... 15 
Before the study can commence, all required approvals will be obtained and 
any conditions of approvals will be met. .............................................................. 15 
11.2 
INVESTIGATOR RESPONSIBILITIES ................................................................ 15 
11.2.1 Informed Consent ............................................................................................. 15 
11.2.2 Study Site Staff ................................................................................................. 16 
11.2.3 Data Recording ................................................................................................ 16 
11.2.4 Investigator Documentation .............................................................................. 16 
11.2.5 GCP Training .................................................................................................... 16 
11.2.6 Confidentiality ................................................................................................... 16 
11.2.7 Data Protection ................................................................................................. 16 
12 
STUDY CONDUCT RESPONSIBILITIES .................................................................... 17 
12.1 
PROTOCOL AMENDMENTS .............................................................................. 17 
12.2 
MANAGEMENT OF PROTOCOL NON COMPLIANCE ...................................... 17 
12.3 
SERIOUS BREACH REQUIREMENTS .............................................................. 17 
12.4 
STUDY RECORD RETENTION .......................................................................... 18 
12.5 
END OF STUDY .................................................................................................. 18 
12.6 
CONTINUATION OF TREATMENT FOLLOWING THE END OF 
STUDY ................................................................................................................ 18 
12.7 
INSURANCE AND INDEMNITY .......................................................................... 18 
13 
REPORTING, PUBLICATIONS AND NOTIFICATION OF RESULTS ........................ 19 
13.1 
AUTHORSHIP POLICY ....................................................................................... 19 
14 
REFERENCES ............................................................................................................. 19 
 

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LIST OF ABBREVIATIONS 
 
Insert abbreviations as required 
LIST OF ABBREVIATIONS 
This is not an exhaustive list.  
Any additional abbreviations used within the protocol must also be added here.  
 
ABPM 
Ambulatory Blood Pressure Monitoring 
ACCORD Academic and Clinical Central Office for Research & Development - Joint office 
for The University of Edinburgh and Lothian Health Board 
AE 
Adverse Event 
AR 
Adverse Reaction 
AUC 
Area Under the Curve 
AVR 
arteriolar-to-venular-width-ratio 
BP 
Blood Pressure 
CI 
Chief Investigator 
CRF 
Case Report Form 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
PI 
Principal Investigator 
QA 
Quality Assurance 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SLO 
scanning laser ophthalmoscope 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
UWF 
ultra-widefield 

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1 
INTRODUCTION 
1.1 
BACKGROUND 
Hypertension, defined as a blood pressure (BP) of ≥140/90 mm Hg, is a common, 
generally asymptomatic condition that is reported to be the leading risk factor for 
death and disability world-wide1. It is estimated that approximately 30% of adults in 
England have hypertension2 with similar rates in Scotland3. Despite its high 
prevalence around 30% of adults in the UK with hypertension remain undiagnosed4, 
leaving them at increased risk of cardiovascular disease and stroke. An opportunistic 
method for detecting people with hypertension may therefore improve detection 
across the population with significant health and economic benefit.  
 
  
An image of the human retina reveals one of the best views of the body’s 
microcirculation that can be achieved without an invasive procedure. Evidence 
suggests that features measured from retinal imaging such as the arteriolar-to-
venular-width-ratio (AVR), which is a combination of measurements of vessel 
diameters near the optic nerve head, and vessel tortuosity are biomarkers of 
hypertension as well as early indicators of increased risk of developing hypertension5-
7. Development of a robust clinical test for hypertension around non-invasive retinal 
imaging would enable opportunistic detection of hypertension in people attending 
routine check-ups at the high-street optometrist or ophthalmic clinics for eye care 
appointments. 
 
1.2 
RATIONALE FOR STUDY 
We hypothesise that AVR measured using the arterioles and venules seen in the 
retina is an indicator for the presence of hypertension. 
 
A pilot study has been performed using a scanning laser ophthalmoscope (SLO) to 
acquire ultra-widefield (UWF) retinal images and BP measurements from 500 
subjects aged 50-59 years recruited to the Northern Ireland Cohort for the 
Longitudinal Study of Aging (www.qub.ac.uk/sites/NICOLA). Automated detection of 
the retinal vasculature was performed. The optic disc boundary and fovea were 
located to establish a measurement zone in each retinal image which encompassed 
a sector subtending 180 degrees on the nasal side of the optic nerve head. Manual 
correction to the automatically detected vessel segments and classification as artery 
or vein was performed within this sector. A computerised method was used to 
measure AVR and an area under receiver operator characteristics curve (AUC) of up 
to 0.720 was found for the diagnosis of hypertension, as established from clinic-
based BP measurement. While this demonstrated diagnosis of hypertension from 
AVR, the method was limited by the accuracy of the BP measurement. A recent 
study has shown that clinic based BP measurement has an AUC of 0.806 for 
diagnosis of hypertension compared to ambulatory BP monitoring (ABPM), the 
current reference standard8.  
 

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To determine the true accuracy of AVR for hypertension diagnosis a further study is 
now required where participants have UWF retinal imaging and a gold standard 
diagnosis of hypertension made using ambulatory BP measurement. 
2 
STUDY OBJECTIVES 
2.1 
OBJECTIVES 
2.1.1 Primary Objective 
• 
To show whether computational measurements made of the retinal vascular 
widths in UWF images can be used as a surrogate for clinical measurements 
to detect people with high BP. 
 
2.1.2 Secondary Objectives 
• 
To determine the ability of semi-automated analysis of UWF retinal images to 
predict untreated hypertension as established through ambulatory BP 
measurement. 
• 
To determine the ability of a single clinical BP measurement taken in the clinic 
to predict untreated hypertension as established through ambulatory BP 
measurement. 
• 
To determine the ability of semi-automated analysis of UWF retinal images to 
monitor change as established through ambulatory BP measurement in 
people receiving BP lowering medication. 
2.2 
ENDPOINTS 
2.2.1 Primary Endpoint 
• 
Is it possible to establish a cut-point in AVR as measured using UWF retinal 
images that will allow us identify people with hypertension?  Where 
hypertension will be clinically defined using the standard ABPM. 
 
2.2.2 Secondary Endpoints 
• 
Is it possible to establish a cut-point in a single clinical BP measurement that 
will allow us identify people with hypertension?   
• 
Is there a relationship between AVR and its component parts with the 
continuous outcome from ABPM? 

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3 
STUDY DESIGN 
This is a single centre, prospective, non-interventional, exploratory study examining if 
there is an association between AVR measurements using UWF retinal images and 
blood pressure measured by ABPM . 
 
After screening and recruitment participants attending the ambulatory blood pressure 
clinic at the Western General Hospital will be invited to have retinal images taken 
using a scanning laser ophthalmoscope to acquire UWF retinal images. A semi-
automatous method will then be used to calculate the AVR and this will then be 
compared to blood pressure recordings. 
 
As this is an exploratory study there in no intention to commercialize or apply for CE 
marking of any device or software used in this study. 
4 
STUDY POPULATION 
Participants attending a hypertensive clinic at the Western General Hospital in 
Edinburgh will be asked to consent to UWF retinal imaging, subject to the inclusion 
and exclusion criteria below. It is expected that between 25 and 50 participants per 
week attend the clinic, of which approximately 50% are attending without a known 
diagnosis of hypertension. 
 
4.1 
NUMBER OF PARTICIPANTS 
For the required statistical power (see Section 8.1 for more detail) the number of 
required participants is 502. Taking into consideration that no more than 10% of 
participants are difficult to image, the target for recruitment is 550. With an estimated 
number of patients attending the hypertension clinic of 25 per week and taking in to 
consideration patients declining to participate in the study (estimated to be no more 
than 10%), the total required number of weeks of recruitment will be 30 factoring in 
staffing needs such as holidays and fluctuating numbers attending the hypertensive 
clinic. 
4.2 
INCLUSION CRITERIA 
• 
Attending ambulatory blood pressure clinic 
• 
Able to undertake ambulatory BP measurement 
• 
Able to undertake single clinic-based BP measurement 
• 
Able to undergo UWF retinal imaging with a SLO 
• 
Aged 18 to 90 
• 
Able to give informed consent 
 
 

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4.3 
EXCLUSION CRITERIA 
• 
People with known history of retinal surgery 
• 
People under the age of 18 years. 
• 
People that cannot: manoeuvre themselves to the SLO unaided, sit upright in 
a chair or wheelchair or position themselves comfortably for imaging. 
• 
People with epilepsy 
4.4 
CO-ENROLMENT 
Since the impact on patients by taking part in this study is minimal co-enrolment will 
be permitted with other interventional and non-interventional studies. Details of co-
enrolment will be recorded at the time of screening.   
 
5 
PARTICIPANT SELECTION AND ENROLMENT 
5.1 
IDENTIFYING PARTICIPANTS 
• 
All Patients receiving an appointment at the ambulatory blood pressure clinic 
will receive a Patient Information Sheet regarding the study from their usual 
care team. 
• 
On attendance at clinic, the patient will again be offered a Patient Information 
Sheet and the opportunity to ask questions of a member of our research 
team. 
• 
If the patient would like to participate then he or she will be asked to sign and 
date the approved version of the consent form before any study specific 
procedures are performed. 
 
5.2 
CONSENTING PARTICIPANTS 
If a patient agrees to partake, informed consent will be received by a trained member 
of our team who takes them through the consent form and obtains their signature. 
One copy of the signed consent form will be given to the participant, the original will 
be retained at the study site in the Investigator Site File. 
 
5.3 SCREENING FOR ELIGIBILITY 
A member of the research team will screen for eligibility based on the study inclusion 
/ exclusion criteria. 
 
 
5.4 
WITHDRAWAL OF STUDY PARTICIPANTS 
Participants are free to withdraw from the study at any point or a participant can be 
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will be documented in the participant’s case report form, if possible. The participant 
will have the option of withdrawal from  
(i) all aspects of the trial but continued use of data collected up to that point 
(ii) all aspects of the trial with removal of all previously collected data.   
(iii) all aspects of the trial with removal of previously collected and stored participant 
samples. 
 
Randomised patients who wish to be withdrawn from the study before they 
have undertaken any study related procedures 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 CRF/database if the participant agrees 
to this. 
 
6 
STUDY ASSESSMENTS 
6.1 
STUDY ASSESSMENTS 
Imaging of each eye with a SLO will be performed by: 
• 
Adjusting the table or seat height so that the patient's eyes are slightly above 
the eye piece.  
• 
Ask the patient to 
i. 
Move in close to the device 
ii. 
Hold the grips on the side of the device  
ii. 
Rest their forehead on the top of the face pad  
iii. 
Turn their head slightly so that their nose is on the outside of the face 
pad 
 
The patient will see a flash of light as a photograph is taken. At least 2 pictures of 
each eye will be taken in this way. The typical time required to complete this imaging 
sessions is 10 minutes. 
 
Blood pressure measurement will be taken as part of normal routine clinical care and 
as such will be dealt with in the normal way by the participant’s clinical team.   
 
6.2 SAFETY ASSESSMENTS 
Local policy is that all research imaging must take into account the possibility 
incidental findings. The consent process for retinal imaging is designed to ensure that 
participants are aware of this. At least two images per eye will be captured to 
distinguish eye “floaters” from other potentially clinically relevant incidental findings. 
These “floaters” are specks of debris in the vitreous fluid within the eyeball.  
 
All retinal images will be reviewed by trained members of the study team within 14 
days of acquisition. This will be in an anonymised format and governed by Data 
Protection. There is a small chance (<1%) of an incidental finding being significant 
and urgent9. The consent process is designed to ensure participants understand this 

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and to give the opportunity to discuss with the research team if desired. A 
requirement of being included in the research is agreement by the participant for their 
GP to be informed of any incidental findings that are found. This is to allow the GP to 
put the participant onto an appropriate track for medical treatment should the 
incidental findings indicate this is required.  
 
 
6.3 
LONG TERM FOLLOW UP ASSESSMENTS 
Not Applicable  
 
6.4 
STORAGE AND ANALYSIS OF SAMPLES 
Not Applicable 
7 
DATA COLLECTION 
Each consenting participant will undergo retinal imaging using SLO.  It will take 
approximately 5-10 minutes for the consenting process and for a member of the 
research team to answer questions that the participant may have. A member of the 
team appropriately trained in the use of the SLO will escort each participant to the 
room for retinal imaging. The operator will position the participant by asking them to 
sit in a seat, place their chin on a chin rest and look into the aperture of the SLO. At 
least two images of each eye will be captured by the operator. After imaging, the 
participant will be escorted back to the clinic reception area. 
 
Data will be analysed by members of our research team who are NHS and University 
of Edinburgh staff. Anonymised participant data including retinal images will also be 
available to Optos PLC for additional computational analysis. 
 
Each participant will be assigned a unique anonymised code. This will be used on the 
study case report form and as the subject ID in the retinal imaging software. A master 
list linking participants to their codes will be kept secure in a password protected file 
accessible by only the chief investigator and the member of the research team taking 
informed consent.  
 
The following data will be collected and entered in the study case report form: 
• 
Demographic data including; Age, sex, weight, height, dominant arm and 
smoking history 
• 
Past medical history 
• 
Current medications 
• 
Clinic blood pressure x 2 (both arms) 
• 
Ambulatory blood pressure results 
 
All anonymised demographic and clinical data will be share with Optos at the end of 
the study. 

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7.1 
 Source Data Documentation 
Subjects electronic medical notes along with information from their GP (referral letter) 
will be used to collect source data. This will only be collected once subjects have 
given their consent. 
7.2 
Case Report Forms 
 
A case report form and electronic case report form will be used with data also being 
inserted into a simple database 
8 
STATISTICS AND DATA ANALYSIS 
8.1 
SAMPLE SIZE CALCULATION 
To determine the sample size required we refer to a previous study comparing the 
effectiveness of clinic based BP measurement versus ambulatory BP monitoring at 
diagnosis of hypertension (the current reference standard)8. The AUC for clinic 
versus ambulatory BP for diagnosis of hypertension was 0.81 with range 0.69-0.89. 
To be confident that AVR for diagnosis of hypertension is at least equivalent to clinic 
BP measurement we would need 502 participants with 0.05 probability of a type-1 
error and 90% power. 
 
UWF retinal imaging was exceptionally well tolerated in the CArdiovascular & Retinal 
Morphology EyescaN (CARMEN) study conducted by members of the research team 
(MacGillivray, Dhillion, Robertson). This study (REC reference: 12/SS/0022) added 
UWF retinal imaging to CT coronary angiography to investigate possible retinal 
vascular markers of coronary heart disease. Within CARMEN the percentage of 
gradable images, where the optic disc and main retinal vessels were clearly visible, 
was 93.3%10. We anticipate that this will be similar in the proposed study. Over 500 
participants (median age 58 years, range 27-75 years) were imaged at the Clinical 
Research Imaging Centre at the Edinburgh Royal Infirmary site over a 18 month 
period, and 92% of those invited to participate consented to eye imaging10. We 
anticipate a similar acceptance rate for the proposed study. 
 
Taking into consideration the likely number of participants with ungradable images, 
we would need an additional number of participants for the required statistical power. 
An extra 10% will mitigate against ungradable images, which gives a target 
recruitment figure of 553 participants.  
 
The estimated number of patients attending the hypertension clinic is 25 per week. 
Taking in to consideration patients declining to participate in the study (estimated to 
be <10%), the total required number of weeks for recruitment will be 23. A more 
conservative estimate is 30 weeks, factoring in staffing needs such as holidays and 
fluctuating numbers attending the hypertensive clinic. 
. 
 

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8.2 
PROPOSED ANALYSES 
The methods of computational analysis to measure retinal features will primarily be 
performed at Optos using software that has been developed from previous studies11, 
12. The software implements computational post-processing to identify blood vessels 
in UWF retinal images and quantifies vessel widths. 
 
BP as measured by ambulatory measurement will be used to establish the presence 
and severity of hypertension.  
 
AVR, established through retinal image analysis, will be compared the classification 
of hypertension (i.e. presence and severity) through analysis of the AUC. 
 
AVR will also be compared to BP through regression analysis to look for general 
terms. 
 
Significance of difference between groups (i.e. hypertensive vrs. normotensive) will 
be investigated through the student’s T-test. 
9 
ADVERSE EVENTS 
 
Imaging of the retina will be performed with a Daytona plus SLO (Optos plc,  
Dunfermline, UK). Imaging is non-invasive and has no known harmful effects. The 
device is CE marked.  No adverse events are expected. If one occurs, it will be fully 
investigated by the study team and reported to study sponsor in line with ACCORDs 
standard operating procedure CR006 (Identifying, Recording and Reporting Adverse 
Events and Urgent Safety Measures for Non-CTIMPs) & CR012 (Identifying, 
Recording and Reporting Adverse Events for Clinical Investigations of Medical 
Devices). Optos will also be notified within 24 hours of any Serious Adverse Device 
Effect or Adverse Device Effect.  
 
10 
OVERSIGHT ARRANGEMENTS 
10.1 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 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. 
10.2 RISK ASSESSMENT 
A study specific risk assessment will be performed by representatives of the co-
sponsors, 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. The risk assessment outcomes will also indicate 

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which risk adaptions (delete if no adaptations were possible) could be incorporated 
into to trial design. 
10.3 STUDY MONITORING AND AUDIT 
The ACCORD Sponsor Representative will assess the study to determine if an 
independent risk assessment is required.  If required, the independent risk 
assessment will 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 frequency. 
 
Risk assessment, if required, will determine if audit by the ACCORD QA group is 
required. Should audit be 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. 
 
11 
GOOD CLINICAL PRACTICE 
11.1 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 required approvals will be obtained and any 
conditions of approvals will be met. 
11.2 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.   
11.2.1 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 

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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 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 (if applicable). 
11.2.2 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 trial related duties. 
11.2.3 Data Recording 
The Principal Investigator is responsible for the quality of the data recorded in the CRF at 
each Investigator Site.  
11.2.4  Investigator Documentation 
• 
The Principal Investigator will ensure that the required documentation is 
available in local Investigator Site files ISFs.  
11.2.5 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. However, 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.  
11.2.6 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. 
11.2.7 Data Protection 
All Investigators and study site staff involved with this study must comply with the 
requirements of the UK 2018 Data Protection Act & EU General Data Protection 
Regulation (GDPR) 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 individuals from the research team treating the 

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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. 
12 
STUDY CONDUCT RESPONSIBILITIES 
12.1 PROTOCOL AMENDMENTS 
Any changes in research activity, except those necessary to remove an apparent, 
immediate hazard to the participant in the case of an urgent safety measure, must be 
reviewed and approved by the Chief Investigator.   
Amendments will be submitted to a sponsor representative for review and 
authorisation before being submitted in writing to the appropriate REC, and local 
R&D for approval prior to participants being enrolled into an amended protocol. 
12.2 MANAGEMENT OF PROTOCOL NON COMPLIANCE 
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. 
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.  All protocol deviation 
logs and violation forms should be emailed to QA@accord.scot 
Deviations and violations are non-compliance events discovered after the event has 
occurred.  Deviation logs will be maintained for each site in multi-centre studies.  An 
alternative frequency of deviation log submission to the sponsors may be agreed in 
writing with the sponsors. 
 
12.3 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 (seriousbreach@accord.scot) must be 
notified within 24 hours.  It is the responsibility of the co-sponsors to assess the 
impact of the breach on the scientific value of the trial, to determine whether the 
incident constitutes a serious breach and report to research ethics committees as 
necessary.  

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12.4 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 not be destroyed without permission from the sponsor. 
12.5 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. 
 
12.6 CONTINUATION OF TREATMENT FOLLOWING THE END OF 
STUDY 
Detail if intervention will be continued to be provided following the end of the study.  If 
not provide justification 
 
12.7 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 NHS Lothian.  The University has insurance in place (which 
includes no-fault compensation) for negligent harm caused by poor protocol 
design by the Chief Investigator and researchers employed by the 
University. 
• 
Sites participating in the study will be liable for clinical negligence and other 
negligent harm to individuals taking part in the study and covered by the 
duty of care owed to them by the sites concerned.  The co-sponsors require 
individual sites participating in the study to arrange for their own insurance 
or indemnity in respect of these liabilities. 
• 
Sites which are part of the United Kingdom's National Health Service will 
have the benefit of NHS Indemnity. 

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• 
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. 
13 
REPORTING, PUBLICATIONS AND NOTIFICATION OF 
RESULTS 
13.1 AUTHORSHIP POLICY 
Ownership of the data arising from this study resides with the study team.   
14 
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Pellegrini E, Robertson G, Trucco E, MacGillivray TJ, Lupascu C, van Hemert 
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