Diagnostic Tools to Establish the Presence and Severity of Peripheral Arterial Disease in People With Diabetes
Conditions: Diabetic Foot, Peripheral Arterial Disease, Diabetic Foot Ulcer, Peripheral Vascular Diseases, Peripheral Artery Disease, Critical Limb Ischemia, Critical Lower Limb Ischemia
Sponsor: Imperial College London

DM PAD 
Protocol No: 21CX7046 
Sponsor: Imperial College London 
V 7.0 29 08 2023 
 
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CLINICAL STUDY PROTOCOL 
 
 
 
 
 
 
 
 
 
 
 
 
Full Study Title: 
 
 Diagnostic tools to establish the presence and severity  
                                               of peripheral arterial disease in people with diabetes 
 
 
 
Short Study title / Acronym: DM PAD 
 
Sponsor: 
 
 
      Imperial College London 
 
Version no:                              7.0       
 
 
 
 
 
Protocol Date:  
 
      29 08 2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 This study/project is funded by the National Institute for Health Research (NIHR) Health Technology 
Assessment programme (project reference: NIHR131855). The views expressed are those of the author(s) 
and not necessarily those of the NIHR or the Department of Health and Social Care. 
 

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Sponsor: Imperial College London 
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RESEARCH REFERENCE NUMBERS 
 
 
 
IRAS ID: 
301408 
REC Reference Number: 
21/PR/1221 
ISRCTN Number: 
12358788 
Clinical trials.gov Number: 
NCT05009602 
Sponsor Protocol Number: 
21CX7046 
Funder reference: 
NIHR131855 
 
 
 
Keywords: 
 
Peripheral arterial disease, diabetic foot, comparative diagnostic accuracy, diabetes, 
bedside tests.  
 
 

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CONTACT LIST 
 
Chief Investigators 
 
Mr Usman Jaffer  
Vascular Secretaries office, 2nd floor, Mary Stanford Wing 
St Marys Hospital 
London 
Praed street 
W21NY 
 
Sponsor 
 
Imperial College London  
Contact: Head of Research Governance and Integrity 
Research Governance and Integrity 
Imperial College London and Imperial College Healthcare NHS Trust  
Room 215, Level 2 Medical School Building  
Norfolk Place  
London, W2 1PG  
Tel: 0207 594 1862  
 
Clinical queries 
 
 
Clinical queries should be directed to the Chief Investigator or Study Manager who will direct 
the query to the appropriate person. 
 
 
Funder 
 
National Institute for Health Research (NIHR)  
Health Technology Assessment (HTA) Programme (NIHR131855)  
University of Southampton  
Alpha House  
Enterprise Road  
Southampton, SO16 7NS  
 
Study Manager 
 
Miss Laura Burgess 
Imperial College London, Academic Section of Vascular Surgery 
Room 14, 4th Floor East Wing, Charing Cross Hospital  
Fulham Palace Road, London, W6 8RF 
Tel: 0203 311 5208 
Email: l.burgess@imperial.ac.uk 

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Protocol No: 21CX7046 
Sponsor: Imperial College London 
V 7.0 29 08 2023 
 
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Senior Statistician  
 
Professor John Norrie  
Chair of Medical Statistics and Trial Methodology  
Director of Edinburgh Clinical Trials Unit  
Usher Institute- University of Edinburgh  
9 Little France Road  
Nine Edinburgh BioQuarter  
Edinburgh, EH16 4UX  
Tel: 0131 651 7895  
 
Study Statistician 
 
Roz Pollock 
Clinical Trials Statistician  
Edinburgh Clinical Trials Unit  
Usher Institute- University of Edinburgh  
9 Little France Road, Nine Edinburgh BioQuarter  
Edinburgh, EH16 4UX  
 
 
Health Economist  
 
Dr David Epstein  
Department of Applied Economics  
Faculty of Economics and Business Sciences  
University of Granada  
Email: davidepstein@ugr.es  
 
 
Clinical Trial Unit 
 
Edinburgh Clinical Trials Unit  
Level 2, Nine Edinburgh BioQuarter  
9 Little France Road  
Edinburgh, EH16 4UX  
Tel: +44 (0)131 651 7895  
Fax: +44 (0)131 537 3581  
 
 
 
 
 
 
 
 

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Protocol development group 
 
Mr Usman Jaffer 
Professor Alun Davies 
Mr Pasha Normahani 
Dr David Epstein 
Ms Laura Burgess 
Ms Sasha Smith 
Dr Neghal Kandiyil 
Professor John Norrie 
 
This protocol describes the DM PAD trial and provides information about procedures for 
enrolling participants to the trial. The protocol should not be used as a guide for the 
treatment of other participants; every care was taken in its drafting, but corrections or 
amendments may be necessary. These will be circulated to investigators in the study, but 
centres enrolling participants for the first time are advised to contact the Trial Coordination 
centre to confirm they have the most recent version. Problems relating to this trial should 
be referred, in the first instance, to the Trial Coordination centre.  
 
This trial will adhere to the principles outlined in the International Conference on 
Harmonisation Good Clinical Practice (ICH GCP) guidelines. It will be conducted in 
compliance with the protocol, the Data Protection Act 2018 and other regulatory 
requirements as appropriate. 

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ABBREVIATIONS  
 
AE 
Adverse Event 
CI 
Chief Investigator 
CRF 
Case Report Form 
DMEC 
Data Monitoring and Ethical Committee 
ECTU 
Edinburgh Clinical Trials Unit  
eCRF 
Electronic Case Report Form 
EQ-5D-5L 
European Quality of Life-5 dimensions 5 Level 
HRA 
Health Research Authority 
ICHNT 
Imperial College Healthcare NHS Trust 
ICMJE 
International Committee of Medical Journal Editors 
QA 
Quality Assurance 
QC 
Quality Control  
QoL 
Quality of Life 
REC 
Research Ethics Committee 
REDCap 
Research Electronic Data Capture 
SAE 
Serious Adverse Event 
SAG 
Special Advisory Group 
SAP 
Statistical Analysis Plan 
SOP 
Standard Operating Procedure 
TMG 
Trial Management Group  
TSC 
Trial Steering Committee 
TrEAD 
TEsting for Arterial disease in Diabetes study 
PAD-scan 
Podiatry ankle duplex scan 
ABPI 
Ankle-brachial pressure index 
TBPI 
Toe-brachial pressure index 
TcPO2 
Transcutaneous pressure of oxygen 
PPI 
Patient and publica involvement 
MRA 
Magnetic resonance angiograph 
CTA 
Computed tomography angiography 
eGFR 
Estimated glomerular filtration rate 
QALY 
Quality Adjusted Life Years 
WIfI 
Wound, ischaemia, and foot infection 

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NHS  
National Health Service 
RGIT 
Research Governance and Integrity Team 
 
 
 
 
 
 
 

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Sponsor: Imperial College London 
V 7.0 29 08 2023 
 
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Table of Contents  
 
RESEARCH REFERENCE NUMBERS 
2 
CONTACT LIST 
3 
ABBREVIATIONS (AMEND AS NECESSARY) 
6 
TRIAL SUMMARY 
10 
 
BACKGROUND 
12 
 
OBJECTIVES AND ENDPOINTS 
14 
2.1 Primary Objective ........................................................................................................... 14 
2.2 Secondary Objective ...................................................................................................... 14 
2.3 Primary Endpoint ........................................................................................................... 14 
2.4 Secondary Endpoints ..................................................................................................... 15 
 
STUDY DESIGN 
15 
 
PARTICIPANT ENTRY 
17 
4.1 Study setting and population .......................................................................................... 17 
 
PROCEDURES AND MEASUREMENTS 
18 
5.1 Identification and recruitment of participants .................................................................. 18 
5.2 Screening evaluations .................................................................................................... 19 
5.3 Visit Schedule ................................................................................................................ 19 
5.4 Follow-up ....................................................................................................................... 19 
5.5 Blood and pregnancy tests ............................................................................................. 19 
5.6 Data collection ............................................................................................................... 20 
5.7 Index tests ..................................................................................................................... 20 
5.8 Reference test ............................................................................................................... 22 
5.9 Incidental findings .......................................................................................................... 23 
 
INTERVENTION 
23 
6.1 Permanent Discontinuation of Study Intervention and Withdrawal from Study ............... 23 
 
SAFETY REPORTING 
24 
7.1 Adverse Event (AE) ....................................................................................................... 24 
7.2 Adverse Event recording ................................................................................................ 24 
7.3 Serious Adverse Events (SAE) ...................................................................................... 25 
7.4 Reporting of SAEs ......................................................................................................... 25 
7.5 Reporting urgent safety measures ................................................................................. 26 
 
STATISTICAL ANALYSES 
27 
8.1 Sample Size and power considerations ......................................................................... 27 
8.2 Planned recruitment rate ................................................................................................ 28 
8.3 Internal pilot ................................................................................................................... 28 
8.4 Statistical Analysis ......................................................................................................... 28 
 
REGULATORY, ETHICAL AND LEGAL ISSUES 
31 
9.1 Declaration of Helsinki ................................................................................................... 31 
9.2 Good Clinical Practice .................................................................................................... 31 
9.3 Research Ethics Committee (REC) Approval ................................................................. 31 
9.4 HRA approval ................................................................................................................ 31 
9.5 Other Required Approvals .............................................................................................. 32 
9.6 Non-Compliance and Serious Breaches ........................................................................ 32 
9.7 Insurance and Indemnity and Sponsor ........................................................................... 32 
9.8 Trial Registration ............................................................................................................ 32 
9.9 Informed Consent .......................................................................................................... 32 
9.10 
Contact with General Practitioner .............................................................................. 33 
9.11 
Participant Confidentiality .......................................................................................... 33 
9.12 
Data Protection and Participant Confidentiality .......................................................... 33 
9.13 
End of Trial ................................................................................................................ 33 
9.14 
Study Documentation and Data Storage ................................................................... 33 
 
DATA MANAGEMENT 
34 

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10.1 
Source Data .............................................................................................................. 34 
10.2 
Language .................................................................................................................. 34 
10.3 
Database ................................................................................................................... 34 
10.4 
Data Collection .......................................................................................................... 34 
10.5 
Archiving ................................................................................................................... 34 
 
STUDY MANAGEMENT STRUCTURE 
34 
11.1 
Trial Steering Committee ........................................................................................... 34 
11.2 
Trial Management Group ........................................................................................... 35 
11.3 
Data Monitoring Committee ....................................................................................... 35 
11.4 
Special advisory group .............................................................................................. 35 
11.5 
Patient Advisory Group.............................................................................................. 35 
11.6 
Early Discontinuation of the Study ............................................................................. 35 
11.7 
Risk Assessment ....................................................................................................... 35 
11.8 
Monitoring ................................................................................................................. 36 
11.9 
Quality Control and Quality Assurance ...................................................................... 36 
11.10 Peer review ............................................................................................................... 36 
11.11 Patient and Public Involvement ................................................................................. 36 
11.12 Publication and Dissemination policy ......................................................................... 37 
 
REFERENCES 
39 
 
REVISION HISTORY 
42 
SIGNATURE PAGE 1 (CHIEF INVESTIGATOR) 
44 
SIGNATURE PAGE 2 (SPONSOR) 
45 
SIGNATURE PAGE 3 (STATISTICIAN) 
46 
SIGNATURE PAGE 4 (PRINCIPAL INVESTIGATOR) 
47 
APPENDICES 
48 

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TRIAL SUMMARY 
 
TITLE  
Diagnostic tools to establish the presence and severity of peripheral arterial disease in 
people with diabetes 
 
OBJECTIVES 
Primary:  
To determine the diagnostic performance of index tests (audible handheld Doppler, visual 
handheld Doppler, ABPI, exercise ABPI and TBPI) for the diagnosis of PAD in patients 
with diabetes as determined by a reference test (CTA or MRA). 
Secondary: 
• To determine the cost-effectiveness of tests 
• To determine the performance of tests using exploratory diagnostic thresholds  
• To explore the effect of combining different tests on diagnostic performance 
• To evaluate patient acceptability of tests  
• To evaluate the effect of confounding patient characteristics (e.g., neuropathy and 
ulceration) on diagnostic performance  
• To evaluate the performance of tests for establishing the severity of PAD  
• To evaluate inter- and intra-rater reliability of tests 
• To evaluate the performance of PAD-scan (in selected centres). 
 
DESIGN 
Prospective multicentre diagnostic accuracy study  
 
SAMPLE SIZE 
A total of 600 participants  
 
INCLUSION/EXCLUSION CRITERIA 
 
Inclusion criteria: 
• Aged ≥18 years  
• Known history of diabetes 
 
Exclusion criteria: 
• PAD status known on imaging 
• Known history of PAD intervention 
• CTA and MRA contraindications- renal impairment, pregnancy, contrast medium 
hypersensitivity/allergy, non-compatible implants (MRA only).  
• Unable to provide appropriate informed consent.  
• Interim surgical interventions (occurring in the time interval between index and 
reference tests) will be considered a protocol violation and patients will be excluded.  
 
 
 
 
 
 
 

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MAIN STUDY PROCEDURES (including intervention duration and follow-up) 
 
VISIT 0 
• Remote screening 
 
VISIT 1 (will occur at a routine/planned visit): 
• Eligibility check 
• Recording of demographic detail and medical history 
• Assessment for neuropathy 
• Assessment of diabetic foot ulcer severity, if relevant  
• Quality of Life questionnaire: the validated EuroQoL (EQ-5D-5L) questionnaire will 
be used to assess the generic QoL and will allow economic assessment 
• Index tests for the diagnosis of peripheral arterial disease: 
1. Audible handheld Doppler 
2a. Visual handheld Doppler 
2b. PAD-scan (only in 3 selected centres) 
3. ABPI  
4. TBPI 
5. Exercise ABPI i.e., ABPI performed following repetitive heal raising.  
• Patient acceptability; patients will be asked to rate their experience of each test on a 
Likert scale 
• Blood test to assess renal function* 
• Repeating of index tests by the same and by an alternative operator for the 
assessment intra- and inter-rater reliability, respectively (only performed in the first 
100 volunteering patients) 
 
*In some centres, the blood test to assess renal function may require a separate visit. 
 
VISIT 2 (Within 6 weeks of visit 1) 
 
• Reference scan (MRI or CTA) 
 
OUTCOME MEASURES 
 
Primary outcome 
• Sensitivity of index tests 
 
Secondary outcome(s) 
• Specificity, likelihood ratios, predictive values and diagnostic odds ratio 
• Health economic outcomes: 1) Cost of the test, including direct costs and amortisation 
of capital equipment and use of other healthcare resources for prevention and 
treatment of the disease over a time horizon of 5 years 2) Quality Adjusted Life Years 
at 5 years. 3) Incremental cost-effectiveness ratio at 5 years 
• Patient acceptability  
• Technical success  
• Inter- and intra-rater reliability 

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 BACKGROUND 
Diabetes is a major global healthcare issue with an estimated prevalence of 9.3% (1). 
Over 6% of people with diabetes develop a diabetic foot ulcer (DFU) (2). DFUs are slow to 
heal (3), have a negative impact upon patients quality-of-life (4) and are associated with a 
5-year lower limb amputation and mortality rate of 20% and 40% respectively (5). In 
addition, DFUs cost the NHS an estimated £1 billion per year (6).  
Peripheral arterial disease (PAD) is a key risk factor in the development of DFUs (7) and is 
also associated with delayed DFU healing, increased risk of leg amputation and mortality 
(3,8).  The detection of PAD in people with diabetes is fundamental though challenging. 
Although a variety of bedside tests are available, there is no agreement as to which is the 
most useful.  
 
Review of existing evidence 
Existing reviews (9,10) highlight the lack of evidence in this area. An updated systematic 
review and meta-analysis (11) has been performed to further evaluate the evidence for the 
numerous bedside tests in this cohort of patients.  
MEDLINE and EMBASE databases were systematically searched for studies providing 
data on diagnostic performance of bedside tests used for the detection of PAD in people 
with diabetes. A meta-analysis was performed to obtain pooled estimates of sensitivity and 
specificity for the diagnosis of PAD.  Eighteen studies, reporting on a total of 3016 limbs of 
patients with diabetes, were included in our qualitative review. Of these, 11 studies (1543 
limbs) were included in the meta-analysis of diagnostic accuracy: ABPI (9 studies, 1368 
limbs, sensitivity 63.5% [95% CI 51.7-73.9%], specificity 89.3% [CI 81.1-94.2%]); TBPI (3 
studies, 221 limbs, sensitivity 83.0% [CI 59.1-94.3%], specificity 66.3% [CI 41.3-84.6%]); 
and visual waveform assessment (4 studies, 397 limbs, sensitivity 82.8% [CI 73.3-
89.4%], specificity 86.8% [CI 75.5-93.3%]). Overall, there was a high risk of bias across 
studies, most frequently relating to patient selection and lack of blinding. 
 
TEsting for Arterial disease in Diabetes (TrEAD) study 
The largest study to date has been completed comparing the diagnostic performance of 
tests for the presence of PAD in patients with diabetes (Clinicaltrials.gov: NCT04058626; 
(12,13)).  
This study enrolled 305 participants, across 2 centres. The performance of index tests 
(ABPI, TBPI, TcPO2, pulse palpation, audible waveform (handheld Doppler) and visual 
waveform (handheld Doppler)) were compared to a blinded reference duplex ultrasound 
scan (DUS).   
Alongside these commonly used bedside tests we have also evaluated the performance of 
an ‘enhanced’ visual waveform test that has been termed Podiatry Ankle Duplex scan (PAD-
scan). PAD-scan is a new focussed DUS test that directly visualises the ankle vessels and 
detects more detailed waveforms. The results of the TrEAD study were consistent with the 
findings of our meta-analysis which suggested that visual waveform assessment may be the 
most promising modality. It was found that visual waveform assessment with PAD-scan had 
better sensitivity than visual handheld Doppler (95% vs 83%, p<0.001) justifying further 
evaluation, in a limited number of selected centres, in this proposed study.  Sensitivities of 
other tests were: audible Doppler (74%), TBPI (60%) and ABPI (60%). Pulse palpation 
and TcPO2 had low sensitivities of 43% and 31% respectively, justifying exclusion from this 

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proposed study. Combining ABPI and pulse palpation with audible Doppler (sensitivity 84%, 
specificity 46%) or visual Doppler (sensitivity 87%, specificity 44%) improved sensitivity 
when compared to each test used in isolation. However, their combined performance was 
still inferior to the PAD-scan. 
 
Cost-effectiveness of bedside tests  
The cost-effectiveness of the bedside tests evaluated in the TrEAD study (14) has been 
estimated. A Markov model was constructed to estimate the health outcomes and costs over 
5 years of different testing strategies applied to a cohort of patients with diabetes presenting 
to a hospital diabetic foot clinic where the prevalence of PAD and DFU was 66% and 40%, 
respectively. Health outcomes were incidence of new DFU, major cardiovascular events, 
lower limb amputation, death and DFU healing rates. Costs included those of the index tests 
plus further interventions as recommended by clinical guidelines.  
It was found that visual handheld Doppler was the most cost-effective test. However, when 
including PAD-scan as part of the analysis then this dominated other options with an ICER 
of £11 391 per QALY. Its use would result in a reduction of the number of amputations by 
24% and cardiovascular deaths by 10% over 5 years, as compared to TBPI (the next best 
alternative). PAD-scan had the highest probability (78.7%) of having the greatest net benefit 
at a willingness to pay threshold of £20 000 per QALY. PAD-scans superiority in ICER 
occurred at a PAD prevalence threshold of 24%.  
 
Limitations of existing evidence  
There are a number of important limitations relating to currently available evidence, which 
we aim to address in this proposed study.  
• Patient selection- No single study has represented the full spectrum of patients with 
diabetes seen in primary and secondary care.  
• Index and reference tests- Index tests were performed by experts whose experience 
may not represent the general workforce. All studies have used DUS as the reference 
test, which may be less reliable in interrogating the commonly affected distal vessels in 
diabetes (15,16) as compared to CTA or MRA.   
• Analysis by limb- Most studies evaluated diagnostic performance by performing 
bilateral scans and interpreting results in each limb independently. This is a potential 
source of bias as the presence of PAD in one limb increases the probability of PAD being 
present in the other. 
• Visual waveform assessment- A significant arterial lesion results in morphological 
change in the waveform detected in the downstream circulation. Although visual 
waveform assessment has been shown to be a promising modality there is currently no 
agreed definition of an ‘abnormal’ waveform. Waveform morphology exists on a 
spectrum according to the severity of disease; triphasic (normal), biphasic, and 
monophasic (abnormal). For the diagnosis of PAD, some studies use a monophasic cut-
off (17,18) whilst others use a biphasic waveform as the threshold for diagnosis (19).  
The TrEAD study showed that overall test accuracy can be improved by using an 
enhanced definition for defining abnormal waveforms (13). This involves identifying 
biphasic waveforms with adverse morphological features i.e., spectral broadening, 
infilling of the spectral window, long forward flow or slow systolic rise time. This enhanced 
definition improved sensitivity as compared to the traditional monophasic waveform 

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threshold (95% vs 77%), and improved specificity as compared to the biphasic waveform 
threshold (77% vs 21%). However, a potential limitation of the TrEAD study was that 
visual handheld Doppler assessment may have been disadvantaged by not using this 
enhanced definition, which was only evaluated for the PAD-scan.  In this proposed study 
this enhanced definition, which has been shown to be superior, will be used as the 
primary diagnostic threshold for visual waveform assessment.  
 
Why this research is needed now 
This research is of significant priority given the rising global prevalence of PAD (20) and 
diabetes (21) which will increase the burden of diabetic foot disease and place further 
pressures on healthcare services. Missed diagnosis of PAD is common (22), and is an 
important cause of avoidable amputations (22–24). Our health economics modelling has 
demonstrated that improvements in the detection of PAD are not only cost-effective but also 
may considerably reduce the number of lower limb amputations and cardiovascular deaths 
by enabling clinicians to optimise treatment. This will help mitigate the expected rise in 
disease prevalence.  
The TrEAD study (13), our meta-analysis (11) and cost-effectiveness study have identified 
visual waveform assessment as a putative front runner. We have also demonstrated that a 
new enhanced definition for waveform interpretation and a new enhanced visual waveform 
test (PAD-scan) may further improve diagnosis. These novel findings may deliver significant 
and meaningful impact but require further validation (13).   
 
 OBJECTIVES AND ENDPOINTS 
 
To determine the diagnostic performance of index tests (audible handheld Doppler, visual 
handheld Doppler, ABPI, exercise ABPI and TBPI) for the diagnosis of PAD in patients 
with diabetes as determined by a reference test (CTA or MRA). 
 
 
• To determine the cost-effectiveness of tests over a time horizon of 5 years 
• To determine the performance of tests using exploratory diagnostic thresholds  
• To explore the effect of combining different tests on diagnostic performance 
• To evaluate patient acceptability of tests  
• To evaluate the effect of confounding patient characteristics (e.g., neuropathy and 
ulceration) on diagnostic performance  
• To evaluate the performance of tests for establishing the severity of PAD  
• To evaluate inter- and intra-rater reliability of tests 
• To evaluate the performance of PAD-scan (in selected centres). 
 
 
 
 
• Sensitivity of index tests 
 
 

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• Specificity, likelihood ratios, predictive values and diagnostic odds ratio.  
• Health economic outcomes: 1) Cost of the test, including direct costs and 
amortisation of capital equipment and use of other healthcare resources for 
prevention and treatment of the disease over a time horizon of 5 years 2) Quality 
Adjusted Life Years at 5 years. 3) Incremental cost-effectiveness ratio at 5 years 
• Patient acceptability  
• Technical success  
• Inter- and intra-rater reliability: The first 100 volunteering patients will be consented 
to have index tests repeated by the same operator and by an alternative operator on 
the same leg.  
  
 STUDY DESIGN   
This is a prospective comparative diagnostic accuracy study. The study will be performed 
at 18 investigational sites in the United Kingdom. Figure 1 is a flow chart summarising the 
study design.  

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Figure 1. Study flow chart

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 PARTICIPANT ENTRY 
 
This study is open to all patients at the participating sites with a diagnosis of diabetes 
meeting specific inclusion and exclusion criteria. Potential participants will also be 
identified by community settings who will serve as participant identification centres. 
Our inclusion/exclusion criteria reflect two relevant NICE guidelines: 
 
• Diabetic foot problems: prevention and management (NG19)- all adults with 
diabetes should undergo a foot examination (a critical element of which is PAD 
testing) at least annually, on admission to hospital and if any foot problems arise 
(25).  
 
• Peripheral arterial disease: diagnosis and management (CG147)- Assess people for 
the presence of PAD if they have diabetes, non-healing wound on the legs or feet or 
unexplained leg pain. This guideline also makes recommendations not specific to 
diabetes i.e. assess people for the presence of PAD if they have symptoms, are 
being considered for intervention to the leg or foot, or if they need to use 
compression hosiery (26).  
 
As reflected in both of these guidelines all adults with diabetes require PAD assessment at 
least annually. The clinical presentation of PAD may be more subtle in patients with 
diabetes who often suffer from accompanying peripheral neuropathy and are more likely to 
suffer from distal atherosclerotic disease (16). Therefore, symptoms may be absent or 
atypical. For this reason, inclusion to symptomatic patients has not been restricted.   
Recruiting patients from all relevant healthcare settings (primary & secondary care) 
ensures that the full spectrum of patients with diabetes referred to in NICE guidance are 
represented. This includes patients 1) presenting for routine foot checks, 2) with active 
diabetic foot problems who may need intervention (e.g., local debridement or surgery), and 
3) admitted to hospital.  Recruitment from these healthcare settings also ensures sample 
populations with varying PAD and DFU prevalence and severity.  
 
 Inclusion criteria 
• Aged ≥18 years  
• Known history of diabetes 
 
 Exclusion criteria  
• PAD status known on imaging- prior knowledge may bias index tests. 
• Known history of PAD intervention- prior knowledge may bias index tests. 
• CTA and MRA contraindications- renal impairment, pregnancy, contrast medium 
hypersensitivity/allergy, non-compatible implants (MRA only).  
• Interim surgical interventions (occurring in the time interval between index and 
reference tests) will be considered a protocol violation and patients will be excluded.  
• Unable to provide appropriate informed consent.  

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Sponsor: Imperial College London 
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 PROCEDURES AND MEASUREMENTS  
Primarily to evaluate five index tests (ABPI, exercise ABPI, TBPI, visual handheld Doppler 
and audible handheld Doppler). In three centres, the PAD-scan will be evaluated as a sixth 
test. All participants will have index tests performed in clinic (or on the ward if patient is 
admitted to hospital), during visit 1, by a member of the local clinical team, so that results 
are generalisable.  
Participants will then have a reference scan (CTA or MRA) performed in a 2nd visit which 
will take place within 6-weeks of visit 1. In preparation for this, patients will require an up-
to-date blood test to assess renal function and a pregnancy test (if applicable). The blood 
test may be performed at an additional visit at some centres.  
 
 
 
Adult patients with diabetes presenting at the recruiting site will be identified by the direct 
healthcare team. If the patient indicated to the direct healthcare team, that they are willing 
to speak to the research team, the direct healthcare team will notify the research nurse or 
delegated individual to approach the participant with an information leaflet. This may be in 
person in the clinic, or by a patient invitation letter sent by mail / email or by telephone 
contact. They will be told that formal consent will be taken at visit 1 if they agree to partake 
in the study and that if they choose not to then this wouldn’t affect their usual clinical care.   
 
If necessary, non-English speaking participants will be provided with translations of study 
information and assistance from local NHS translation services will be obtained as per 
standard clinical practice.  
 
Recruitment will be primarily from vascular, diabetic foot and general practice clinics as well 
as inpatient wards. Inpatients will be first identified by the direct care team (inpatient podiatry, 
vascular or diabetes teams) who will seek permission from the patient before any information 
is passed or approach made by the research team. 
 
Potential participants will also be identified from community settings who will act as 
participant identification centres (PICs). These PICs will conduct a search of the patient 
record database and suitable participants will be contacted either via letter, mailout or 
SMS to inform them about the study. Interested participants would contact the study team 
directly for more information.  
 
Posters placed in participating research centres will support recruitment by signposting 
patients to the relevant research teams. Patients can also be identified using mailout, 
advertisements through diabetes support networks, social media and local radio stations.  
With permission of the participant the reasons for non-inclusion will be logged anonymously 
along with a minimum data set of age and reason for exclusion. The anonymised pre-
screening logs will be transferred to the Trial Coordinating Centre for the purposes of 
monitoring recruitment as suggested by the funding (NIHR) panel. 
 
 

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On visit 1, which coincides with a routine/planned visit, informed consent will be obtained 
before the participant undergoes any screening procedures.  
 
 
 
Screening 
Planned/ 
routine 
visit 
Blood test 
(in some 
centres) 
Reference 
scan 
Visit number 
0 
1 
1b 
2 
Screening  
X 
 
 
 
Study information material 
X 
 
 
 
Informed consent 
 
X 
 
 
Inclusion & exclusion criteria 
 
X 
 
 
Demography 
 
X 
 
 
Medical history 
 
X 
 
 
Quality of life questionnaire 
(EQ-5D-5L) 
 
X 
 
 
Index tests 
 
X 
 
 
Repeat of index tests (same 
operator)* 
 
X 
 
 
Repeat of index tests 
(alternative operator)* 
 
X 
 
 
Blood test/ pregnancy test 
 
X 
(X)ƚ 
 
Reference scan (CTA/MRA) 
 
 
 
X 
 
*Repeat tests will only be performed in the first 100 volunteering patients.  
ƚThe blood test to assess renal function may require a separate, additional visit at some 
centres.  
 
 
Patients will also be consented separately for permission to follow up their clinical progress 
through accessing their electronic health records (as part of a potential separately funded 
future study). Data will be collected at 12 months following visit 1 regarding DFU healing, 
new or recurrent ulceration, amputation (minor and major) and revascularisation. 
 
 
 
All patients require a recent blood test to assess their renal function (Creatinine and eGFR) 
prior to the reference scan. This may require a separate, additional visit at a different site. 
Additionally, female patients of reproductive age will require a negative pregnancy test prior 
to the reference scan. These tests will be conducted and interpreted according to local 
protocol.  
 
 

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A screening log will identify all approached patients and reasons for non-participation.  
 
• Demographics: age, gender, equality and diversity information, diabetes type, 
history of smoking, retinopathy, chronic kidney disease, ischaemic heart disease, 
stroke and heart failure  
• Foot history: PAD symptoms, previous history of DFU or amputation  
• Foot examination: neuropathy, presence of DFU, DFU severity using the WIfI 
classification system (27)  
• Quality of Life questionnaire: the validated EuroQoL (EQ-5D-5L) questionnaire will 
be used to assess the generic QoL at visit 1.  
• Technical success of index tests: inability to perform, refusal and discontinuation of 
tests will be documented  
• Results of index tests  
• Evaluation of patient acceptability: patients will be asked to rate their experience of 
each test on a Likert scale (Appendix) 
 
 
Tests will be performed on one limb; the most problematic side in symptomatic patients or 
randomly selected side in asymptomatic patients. Tests and equipment will be 
standardised, and team members will undergo protocol training. 
 
Test order 
Ideally, test order (Figure 2) would be randomised to minimise influence carrying over 
from one test to the other. However, the audible and visual waveform tests involve semi-
objective interpretation and therefore could be influenced by knowledge of the tests with 
an objective output (TBPI, ABPI and exercise ABPI). The study team believes it is better to 
conduct the semi-objective waveform tests first followed by the fully objective tests. 
Randomising the order of tests in these two blocks is not possible: 
 
• Semi-objective tests- audible waveform is less objective than visual waveform 
assessment and so should be performed first. However, in selected centres two forms 
of visual waveform assessment (handheld Doppler and PAD-scan) are to be evaluated. 
The order of these two tests will be randomised (via REDCap) in these selected 
centres.   
 
• Objective tests- TBPI should be performed before ABPI as it could be influenced by 
reactive hyperaemia secondary to proximal cuff inflation. Also, exercise ABPI should be 
performed last as exercise can influence all other tests. 
 
The order of tests is summarised in Figure 2.  
 
 
 

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Figure 2. Order of Index tests.  
 
 
 
 
 
 
 
 
 
Conducting index tests   
Prior to the conducting the first index test participants will be rested in the supine position 
for at least 10 minutes with room temperature maintained between 23°C and 25°C.  
 
• ABPI 
ABPI measurements will be performed using a sphygmomanometer cuff placed at the 
ankle and a handheld audible CW Doppler device (Dopplex D900 Audio only Doppler, 
Huntleigh Healthcare Ltd., Cardiff) to measure dorsalis pedis and posterior tibial artery 
systolic pressure. Brachial artery pressures from both arms will be taken and the highest 
reading used to calculate the ABPI.  
 
• Exercise ABPI 
Exercise ABPI traditionally requires a treadmill. This limits its use in primary care, where a 
treadmill is not available. Additionally, the results of the patient and public involvement 
(PPI) work suggest that 43% of patients will not be able to walk on a treadmill (due to 
disability, frailty or DFU) and that an additional visit to a vascular laboratory for this test 
would not be acceptable. To ensure patient acceptability, repetitive heel raising will be 
used. This can be performed in clinics, has excellent correlation with treadmill testing 
(28,29) and has been advocated by the American Heart Association (30). Our PPI focus 
group considered this test acceptable.  
The exercise ABPI protocol, will consist of 50 consecutive repetitions of active dorsiflexion 
whilst standing (28). The knees should be kept fully extended. Participant will be allowed 
fingertip support against a wall to assist with balance. The protocol will be symptoms 
limited, so that premature termination of exercise will be permitted if the subject 
experiences lower limb discomfort, chest pain, shortness of breath or feels unwell for any 
other unspecified reason. Instances of premature termination, and accompanying reasons, 
will be recorded. ABPI will be measured using the same methodology as outlined above.  
In some patients, exercise ABPI may not be possible due to deformities of the foot, e.g., 
those with forefoot amputation, Charcot foot syndrome and forefoot plantar ulceration. 
Foregoing exercise ABPI will be left to the clinical teams discretion. Reasons for foregoing 
exercise ABPI will be documented.  
 

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• TBPI 
Measurements will be made using the Huntleigh toe pressure kit (Huntleigh Healthcare 
Ltd., Cardiff) employing an infrared sensor placed on the hallux.  
Brachial artery pressures from both arms will be taken and the highest reading used to 
calculate the TBPI.  
 
• Audible handheld Doppler 
Audible CW Doppler interrogation of the dorsalis pedis and posterior tibial artery (Dopplex 
D900 Audio only Doppler, Huntleigh Healthcare Ltd., Cardiff). 
 
• Visual handheld Doppler 
Visual CW interrogation of the dorsalis pedis and posterior tibial artery using the handheld 
Huntleigh Digital Dopplex device (Huntleigh Healthcare Ltd., Cardiff). The pseudonymised 
visual blood flow waveforms will be saved and may be used for future analysis. 
 
• PAD-scan (in selected centres) 
The PAD-scan will be performed using a portable ultrasound system (Mindray M7; 
Shenzhen, China) with a linear 6-14Hz transducer. The anterior tibial and posterior tibial 
artery will first be visualised at the ankle, using B-mode imaging and colour Doppler, in 
transverse and then longitudinal planes. Arterial spectral waveforms will then be sampled 
from the centre of each vessel using a Doppler angle of <60°. Waveforms will be optimised 
for interpretation by adjusting sample volume, sample size, Doppler scale, Doppler gain 
and wall thump filter settings. 
 
Repeating index tests 
The first 100 volunteering patients will have tests repeated on the same day by the same 
operator and also by another, blinded, operator for the assessment of intra- and inter-rater 
reliability. Tests will be performed using the same descriptions outlined above. A minimum 
of 10 minutes rest must be provided to the patient prior to each batch of tests to avoid 
influence from previous tests carrying forward.  
 
 
Digital subtraction angiography (DSA) is considered the gold standard for the diagnosis of 
PAD. However, it is invasive and carries risk. Given the previously mentioned limitations of 
DUS our reference test will be CTA or MRA. Both have excellent accuracy compared to 
DSA (31,32). Some of our centres use only CTA, whereas others use only MRA. 
Additionally, some patients in our PPI survey reported that they would not take part if CTA 
was necessitated and suggested the inclusion of MRA as an alternative.  
Reference tests (CTA/MRA) will be performed according to a standardised protocol within 
6-weeks of index tests. The reference test may be performed at a different participating 
site to that of visit 1. The final decision regarding whether the patient undergoes CTA or 
MRA will depend on local protocol and patient choice. Details of reference scan protocols 

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can be found in the Appendix. PAD is a chronic atherosclerotic condition and we do not 
envisage that there will be any change in disease status or reference test results over a 
short 6-week period. Interim surgical interventions (occurring in the time interval between 
index and reference tests) will be considered a protocol violation and patients will be 
excluded.  
Scans will initially be reported locally and then re-reported centrally by a blinded consultant 
radiologist at our core lab (University Hospitals of Leicester NHS Trust). Scans will be 
reported locally for identification of incidental abnormal clinical findings. Local reports will 
not be used as part of the study analysis. To assess inter- and intra-rater reliability in the 
core lab, 15% of scans will be re-reported by our core lab radiologists. 
Scans will be assessed using a validated angiographic scoring system (ANGIO score) 
(33); 10 major arteries supplying the lower limbs are each scored according to the degree 
of stenosis (0, 0-49% stenosis; 1, non-occlusive stenosis of 50%; 2, complete occlusion). 
The presence of one or more arterial lesions of 50% stenosis will be used as threshold 
for the diagnosis of PAD. Tandem lesions with a combined value of 50% will also be 
considered positive for PAD as they are haemodynamically significant and in certain 
scenarios (e.g., non-healing DFU) may prompt treatment. PAD severity will also be 
categorised according to the ANGIO score, as mild (≤4), moderate (5-9) or severe (10). 
These categories have been shown to correlate with risk of amputation and cardiovascular 
events (33).  
 
 
Incidental findings may potentially be identified on the reference scan (CTA or MRA). As 
detailed in section 5.6, all reference scans will be reported locally for identification of 
incidental abnormal clinical findings. These will be reported to the local clinical team and the 
GP.  
Incidental findings may also potentially be identified on blood (e.g., kidney disease) and 
pregnancy tests. These will similarly be dealt with by reporting to the local clinical team and 
the GP.  
 
 INTERVENTION 
 
 Permanent discontinuation of study intervention 
Participants may discontinue study intervention for the following reasons: 
• At the request of the participant. 
• Adverse event/ Serious Adverse Event 
• If the investigator considers that a participant's health will be compromised due to 
adverse events or concomitant illness that develop after entering the study. 
 Withdrawal from Study 
Withdrawal from the study refers to discontinuation of study intervention and study 
procedures and can occur for the following reasons: 
• Participant decision 
• Loss to follow-up 

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• Subject loss of capacity  
 
 Procedures for Withdrawal from Study 
There are no criteria for withdrawal from the study. Patients will be free to withdraw from the 
study without any effect on their usual medical care. The reason for their withdrawal will be 
recorded in the CRF/eCRF and medical records if offered. All randomised participants will 
be followed up to 12 months unless they specifically asked to be withdrawn as per intention 
to treat. In line with this analysis patients lost to follow up or withdrawn from the study will 
not be replaced.  
 
 Procedures for Withdrawal from Study due to loss of capacity 
If a patient loses capacity after consenting to take part in the study, the local Principle 
Investigator may decide it is in the patient’s best interests to be withdrawn. Any identifiable 
data already collected with consent will be retained and may be analysed, but no further 
data will be collected or any other research procedures carried out on or in relation to the 
patient. 
 SAFETY REPORTING 
 
An AE is any untoward medical occurrence in a patient or clinical trial participant. An AE can 
therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom, whether or not considered related to the trial protocol.  
For the purposes of the study, only AEs related to study procedures will be recorded. 
 
 
For the purposes of the study, all AEs will be followed up according to local practice until the 
event has stabilised or resolved, whichever the sooner is. It is essential that all AEs that 
occur during the course of the study are appropriately reported in order to ensure the 
participants continuing safety. Of particular importance is the assessment of any event for 
causality and expectedness in relation to the device.  
 Severity of Adverse Events 
Definitions for assessment of severity: 
Mild:  
Awareness of event but easily tolerated 
Moderate: 
Discomfort enough to cause some interference with usual activity 
Severe: 
Inability to carry out usual activity 
 Causality of Adverse Events 
Definitions for assessment of causality: 
Unrelated: 
No evidence of any causal relationship 
Unlikely: 
There is little evidence to suggest there is a causal relationship (e.g. the 
 
 
event did not occur within a reasonable time after administration of the trial 

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medication). There is another reasonable explanation for the event (e.g. 
 
 
the participant’s clinical condition, other concomitant treatment). 
Possible: 
There is some evidence to suggest a causal relationship (e.g. because the 
 
 
event occurs within a reasonable time after administration of the trial 
 
 
medication). However, the influence of other factors may have contributed 
 
 
to the event (e.g. the participant’s clinical condition, other concomitant 
 
 
treatments). 
Probable: 
There is evidence to suggest a causal relationship and the influence of 
 
 
other factors is unlikely. 
Definite: 
There is clear evidence to suggest a causal relationship and other possible 
 
 
contributing factors can be ruled out. 
 
 
 
 Definition of SAE 
An SAE is defined as any event that  
• Results in death;  
• Is life-threatening*; 
• Requires hospitalisation or prolongation of existing inpatient’s hospitalisation**; 
• Results in persistent or significant disability or incapacity; 
• Is a congenital abnormality or birth defect; 
 
* “Life-threatening” in the definition of “serious” refers to an event in which the participant 
was at risk of death at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more severe. 
** “Hospitalisation” means any unexpected admission to a hospital department. It does not 
usually apply to scheduled admissions that were planned before study inclusion or visits to 
casualty (without admission).  
 
Medical judgement should be exercised in deciding whether an adverse event/reaction is 
serious in other situations. Important adverse events/reactions that are not immediately life-
threatening, or do not result in death or hospitalisation but may jeopardise a participant, or 
may require intervention to prevent one of the other outcomes listed in the definition above 
should also be considered serious. 
 
 
Rapid reporting of all SAEs i.e. within 24 hours, occurring during the study must be 
performed as detailed in SAE reporting instructions. If the investigator becomes aware of 
safety information that appears to be related to the trial, involving a subject who 
participated in the study, even after an individual subject has completed the study, this 
should be reported to the Sponsor.  
 
 
 
 
 

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Contact details for reporting SAEs 
RGIT@imperial.ac.uk 
CI email (and contact details below) 
Professor Alun Davies 
Please send any paper SAE forms to: DM-PAD@imperial.ac.uk 
Tel: 0203 311 5208 (Mon to Fri 09.00 – 17.00) 
 
All SAEs will be reviewed by the Chief Investigator or a designated medically qualified 
representative to confirm expectedness and causality.  
Reporting of SAEs and review by the CI will be via the trial data collection system 
(CRF/eCRF).  
SAEs that are related and unexpected will be reported to the RGIT as soon as possible after 
becoming aware of the event. 
 Related SAEs 
Related: resulted from administration of any of the research procedures 
 Unexpected SAEs 
Unexpected: type of event is not listed in the protocol as an expected occurrence 
  Reporting of SAEs that are related and unexpected 
SAEs that are related and unexpected should be notified to the relevant REC and the 
Sponsor in accordance with local requirements.  
 Follow up of patients who have experienced a related and unexpected SAE 
should continue until recovery is complete or the condition has stabilised. 
Annual reporting of Serious Adverse Events 
Annual Progress reports will be submitted to the Sponsor and the Ethics Committee in 
accordance with local requirements.  
 
 
If any urgent safety measures are taken the CI/Sponsor shall immediately and in any event 
no later than 3 days from the date the measures are taken, give written notice to the 
relevant REC of the measures taken and the circumstances giving rise to those measures. 
 
 
 
 
 

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 STATISTICAL ANALYSES 
 
Summary of sample size calculations 
Assuming PAD prevalence of 50%, with 255 with PAD and 255 without PAD, the study will 
have 90% power to estimate an assumed sensitivity (or specificity) to a precision of the 
half width of the 95% confidence interval of 8.2%. For a sensitivity (or specificity) of 80% 
this half width would increase to 10.2%. The level of significance was set at 1% to adjust 
for the 5 tests and ensure the overall level of significance does not exceed 5%. Power 
calculations used R.4.0.0 power.diagnostic.test in package MKmisc. The sample sizes for 
estimating likelihood ratios will also be estimated.  
In the TrEAD study, PAD prevalence was 66%. As there will also be recruitment from 
primary care, with a lower PAD prevalence (34), the estimate to reflect the findings of our 
systematic review have been adjusted; prevalence of 50% across 18 studies (11). In 
TrEAD, TBPI could not be performed in 20% of patients. A similar proportion may be 
unable to tolerate exercise ABPI. It is estimated that 10% of patients may drop out prior to 
the reference test. Therefore, the sample size has been inflated by the cumulative 
missingness across all groups (30%) to be certain of having enough power for each and 
every test comparison. Thus, we aim to recruit a total of 730 patients. 
During a study monitoring meeting in February 2023 with the funder, NIHR, it was agreed 
for the study sample size to be reduced from 730 to 584 based on the current attrition rate 
of 13% (as opposed to 30% estimated when the trial was designed). To account for those 
participants that may not get their reference test performed within the set time frame, a 
final recruitment target of 600 was agreed with the NIHR in August 2023.  
 
Details of sample size calculations   
We used R.4.0.0 routine power.diagnostic.test in package MKmisc to calculate 90% power 
at a notional 5% level of significance for both the sensitivity and specificity. If we assumed 
a 90% sensitivity (or specificity) we need 510 evaluable participants (which at 50% 
prevalence would be 255 with PAD, and 255 without PAD). This would allow the sensitivity 
(or specificity) to be calculated to within ± 8.2% (the half-width of the 95% confidence 
interval). For a lower assumed sensitivity (or specificity) of 80% this would increase to ± 
10.2%. The estimated precision will also be calculated given these numbers for other 
diagnostic performance statistics such as the positive and negative predictive values, and 
the positive and negative likelihood ratios.  
 
The sample size was re-calculated in February 2023 based on the current attrition rate of 
13% (as opposed to 30% estimated when the trial was designed).  
 
 
Sample size calculations for inter- and intra- rater reliability 
In terms of sample size, an indicative calculation shows that using McNemar’s paired test 
on correlated proportions, with 100 participants, with no loss to follow up, the study would 
have 90% power at a 5% level of significance to detect a difference of 0.17 in the 
discordant results (positive – negative vs. negative – positive) between two tests (e.g. 0.22 
positive-negative vs. 0.05 negative-positive). 
 

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Accounting for holidays and unforeseeable circumstances (in a COVID-19 era) we 
originally allowed for 12-months to recruit 730 patients. This equates to 61 patients per 
month across 18 centres i.e., 3 to 4 patients per month/centre.  We believed this is feasible 
given that the TrEAD study recruited 20 patients per month/centre and estimates from our 
centres indicate a minimum recruitment rate of 8 patients per month/centre.  Recruitment 
was extended for an additional 12 months following an NIHR monitoring meeting on 17th 
February 2023 as the original projected targets were not met. During this meeting NIHR 
agreed for the study sample size to be reduced from 730 to 584. To account for those 
participants that may not get their reference test performed within the set time frame, a 
final recruitment target of 600 was agreed with the NIHR in August 2023. 
 
 
 
A stop-go assessment of recruitment feasibility will be included after a 4-month internal 
pilot. The 18 sites will be set up in 4 months – 4 in month -1 (before the recruitment period 
starts, in calendar month 6 of the study), 4 in month 1, 6 in month 2, and the remaining 4 in 
month 3. Allowing a fallow month for holidays, 4 per centre per month will need to be 
achieved to reach the target sample size of 730 in 18 sites in 12 months. Recruitment 
feasibility will be assessed at the end of month 4, when 136 participants should have been 
recruited. If under 90 or fewer have been recruited, the study may be stopped (Red); 
between 90 and 114 adapt (more sites and/or more time – AMBER) and if 115 or more 
continue unchanged (GREEN – within sampling variability of our target). This will be 
discussed with the TSC and the funder.  
During a study monitoring meeting on 17th February 2023 with the funder, NIHR, it was 
agreed for the study sample size to be reduced from 730 to 584. To account for those 
participants that may not get their reference test performed within the set time frame, a 
final recruitment target of 600 was agreed with the NIHR in August 2023. 
 
 
The five individual tests (and the sixth exploratory test in four sites) will be compared against 
the reference test (CTA/MRA), calculating standard diagnostic accuracy metrics of 
sensitivity, specificity, predictive values, likelihood ratio, and diagnostic odds ratio (using the 
bivariate model approach implemented in R). 95% confidence intervals calculated at 99% 
to adjust for the five comparisons will be presented. The robustness of the findings to any 
observed patterns of missing data will be assessed, which are expected to differ by test. A 
multiple imputation approach will be used assuming the data are missing at random. In 
addition, and probably more consistent with the likely missing data generating mechanisms, 
sensitivity type analyses assuming the data are missing not at random (i.e. informatively 
missing) will be explored. This would attempt to identify different types of missing data by 
an underlying reason or reasons, and then imputing values that capture plausible 
measurements for those missing data. The ?-adjustment approach given by van Buuren will 
be followed (Flexible Imputation of Missing Data, Chapman and Hall, 2018, section 3.8ff), 
and also the recommendations of Molenburghs & Kenward (Missing Data in Clinical Studies, 
Wiley, 2007; Section 19ff on sensitivity analyses). These approaches would allow the set of 
reasons for missing values to vary across the tests. The purpose is to stress the calculated  
findings to test their robustness to the observed patterns of missing data. 

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The subgroups of disease severity (both clinically and radiologically defined as detailed 
below) will be explored and those with/without neuropathy or DFU. The subgroups in the 
Statistical Analysis Plan will be pre-specified. Any further subgroup analysis (e.g. if 
suggested later by new data external to the study) will be labelled exploratory. Pre-specified 
subgroup analyses will be unlikely to be adequately powered.  Clinical severity will be graded 
according to the severity of symptoms (from least to most severe; asymptomatic, intermittent 
claudication, rest pain and tissue loss). Severity will be measured radiologically using the 
ANGIO-score as outlined in section 5.7.  Both will be analysed as pre-specified subgroup 
analyses in the Statistical Analysis Plan.   
 
Combinations of tests will be explored to see if using more than one test has incremental 
diagnostic value. The combinations of tests that were clinically felt to potentially offer an 
improvement over individual tests will be pre-specified in the SAP, and then, acknowledging 
the paired data, use the approach of Pepe and Thomson (Biostatistics, 2000; 1, 2; 123-140 
‘Combining diagnostic test results to increase accuracy’), which looks at linear combinations 
of the underlying tests. Post-hoc checks will be made if there were combinations that were 
not pre-specified that performed even better, as hypotheses for subsequent evaluation. 
It is important to quantify the ability of each of the 5 index tests to measure consistently the 
same measurement of interest on the same leg of the same subject using the same test kit 
in the same location and the same environmental conditions, within a short period of time. 
This quantification of the intra-rater repeatability (or reproducibility) will be undertaken 
using the test-retest approach (35,36). The inter-rater reliability (the agreement between 
two or more clinicians measuring the same subject, again as under the conditions above) 
using appropriate methodology (35,36) will be quantified. For the inter- and intra-rater 
repeatability, we will aim for a sample size of 100 per pair of index tests. 
These reliability studies will be performed at the start of the study and analysed as soon as 
the data are mature. If an index test has unacceptable intra-rater repeatability, or 
unacceptable inter-rater reliability, it could be dropped from further consideration, following 
discussions with the independent TSC.  Unacceptable intra- and inter-rater reliability will 
be assessed in two ways—  first, in an absolute sense, by looking at the kappa statistics 
and using the published guidance as to what an acceptable magnitude is (Fleiss, J.L. 
(1981). Statistical methods for rates and proportions (2nd ed.). New York: John Wiley) with 
a kappa of <0.4 considered unacceptable. This is not unanimity over interpreting the 
magnitude of kappa statistics, so our second approach will compare the kappa statistics 
across the tests, and label unacceptable any tests that are substantially worse than the 
other tests.   
Inter- and intra-rater reliability will also be assessed for the reporting of reference tests 
using the methods outlined above.  Reference tests will not be repeated due to feasibility 
and ethical considerations.  
Full details of the methods and justification of the sample sizes will be included in the 
comprehensive Statistical Analysis Plan, authored by the study statistician and agreed by 
the independent TSC. The Statistical Analysis Plan will be prepared and finalised prior to 
database lock.  
 
Index test diagnostic thresholds 
 
The performance of the index tests based on prespecified diagnostic thresholds for PAD will 
be evaluated. These thresholds have been selected as they demonstrated optimal 

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diagnostic performance in the TrEAD study or are commonly used in clinical practice. 
However, other thresholds have been described in the literature and there is no consensus 
as to which are best. Therefore, different ‘exploratory’ thresholds will be evaluated as part 
of our secondary analyses. Tests generating continuous results (ABPI, TBPI and exercise 
ABPI) will be evaluated for performance based on optimised thresholds derived from 
Receiver Operating Characteristics (ROC) analysis. A ‘net benefit’ approach will be used 
(as a sensitivity type analysis over a range of plausible thresholds) following ideas for 
assessing the clinical utility of prognostic models summarised in Riley R et al (Prognostic 
Research in Health Care; 2018; Oxford; section 7.4.3 page 168-170). From this, it should 
be possible to integrate cost-effectiveness parameters into assessing the best threshold.   
 
Diagnostic thresholds:  
• 
o Visual waveform assessment- monophasic or biphasic waveforms with adverse 
features.  
• 
o Audible waveform assessment- monophasic waveform  
• 
o ABPI- 0.9 in either vessel  
• 
o TBPI- <0.75 in either vessel  
• 
o Exercise ABPI (31)- Post exercise ABPI 0.9 in either vessel.  
 
Health economics analysis 
A literature review will be conducted to identify published health economic studies in similar 
patient groups. Cost-effectiveness of the tests will be estimated using Markov models that 
simulate clinical events in a cohort of hypothetical patients with diabetes over 5 years. The 
structure of the model may follow that developed in previous work by this group (reference 
14). Depending on their PAD status (PAD or no PAD), and ulceration status at presentation 
(DFU or no DFU), patients will be allocated into one of eight initial states following a test: 
True positive (with and without DFU), true negative (with and without DFU), false positive 
(with and without DFU), or false negative (with and without DFU).  
 
True and false positive patients without DFU will be prescribed orthotics and additional foot 
checks, in addition to standard care. True and false positive patients with DFU will undergo 
confirmatory DUS, and, if confirmed positive, angiography, revascularisation and low dose 
rivaroxaban, in addition to standard care. True and false negative patients will continue with 
standard care for the remainder of the 5 year time horizon. The accuracy of test outcomes 
will be obtained from the study. The probability of clinical events (new DFU incidence and 
healing rates of DFU, amputation of unhealed limbs, cardiovascular events and death) and 
treatment effects associated with recommended interventions for diagnosed PAD patients 
(e.g., orthotics, revascularisation, rivaroxaban) will be obtained from NICE evidence reviews 
and the literature. The study will be conducted from the perspective of the UK NHS and 
Personal Social Services according to NICE methodological guidelines and reported 
according to CHEERS standards. Costs, QALYs, ICERs and measures of uncertainty over 
5 years will be estimated. Tests costs will be estimated by bottom-up costings during the 
course of the study that will include  machine capital acquisition cost and one-off training 
(amortised over the useful life and expected  through-put of patients per year), consumables 
and operator time. Prices and unit costs of items will be obtained from manufacturers and 
national databases.  
 

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 REGULATORY, ETHICAL AND LEGAL ISSUES 
 
The investigator will ensure that this study is conducted in full conformity with the 2013 
revision of the 1964 Declaration of Helsinki. 
 
 
The study will be conducted in accordance with the guidelines laid down by the International 
Conference on Harmonisation for Good Clinical Practice (ICH GCP E6 guidelines).  
 
 
 
 
 Initial Approval 
Prior to the enrolment of participants, the REC must provide written approval of the conduct 
of the study at named sites, the protocol and any amendments, the Participant Information 
Sheet and Consent Form, any other written information that will be provided to the 
participants, any advertisements that will be used and details of any participant 
compensation.  
 
 Approval of Amendments 
Proposed amendments to the protocol and aforementioned documents must be submitted 
to the REC for approval as instructed by the Sponsor. Amendments requiring REC approval 
may be implemented only after a copy of the REC’s approval letter has been obtained.  
 
Amendments that are intended to eliminate an apparent immediate hazard to participants 
may be implemented prior to receiving Sponsor or REC approval. However, in this case, 
approval must be obtained as soon as possible after implementation. 
 
 
 Annual Progress Reports and End of Trial Notification  
The REC will be sent annual progress reports in accordance with national requirements and 
will also be informed about the end of the trial, within the required timelines. 
 
 
Health Research Authority (HRA) approval will be obtained prior to starting the study. Each 
participating site will confirm capacity and capability prior to commencing. 
The HRA and all participating sites also need to be notified of all protocol amendments to 
assess whether the amendment affects the institutional approval for each site.  
 

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The procedures are compliant with the Ionising Radiation (Medical Exposure) Regulations, 
and appropriate review by a Medical Physics Expert and Clinical Radiation Expert has been 
undertaken.  
 
 
All protocol deviations and protocol violations will be reported via the eCRF/CRF and 
reviewed by the Chief Investigator. Protocol violations will be reported to the Sponsor. 
An assessment of whether the protocol deviation/violation constitutes a serious breach will 
be made.  
A serious breach is defined as: 
A breach of the conditions and principles of GCP in connection with a trial or the trial 
protocol, which is likely to affect to a significant degree:  
• The safety or physical or mental integrity of the UK trial participants; or 
• The overall scientific value of the trial 
 
The Sponsor will be notified within 24 hours of identifying a likely Serious Breach. If a 
decision is made that the incident constitutes a Serious Breach, this will be reported to the 
REC within 7 days of becoming aware of the serious breach. 
 
 
Imperial College London holds negligent harm and non-negligent harm insurance policies 
which apply to this trial. Imperial College London will act as the main Sponsor for this 
study. Delegated responsibilities will be assigned to the NHS trusts taking part in this 
study. 
 
The study will be registered on a trial database in accordance with requirements of the 
International Committee of Medical Journal Editors (ICMJE) regulations. The study will be 
registered on ISCTRN. 
 
 
Consent will be through standard GCP measures including a patient information sheet and 
signed informed consent form. No minors are eligible to join DM PAD.  
Consent to enter the study will be sought from each participant only after a full verbal 
explanation has been given, and an information leaflet offered. The consent will be 
informed, voluntary and participants will be given an appropriate amount of time to 
consider participation and to ask questions. There will be no set minimum time to consider 
the trial as this will be determined on a case by case basis, this is usually 24 hours but 
could be less if there is agreement from both the researcher and participant that the 
consent is fully informed.  
Signed participant consent will be obtained and participants will be asked to consent for their 
data to be linked with appropriate databases including Hospital Episode Statistics (HES), 
and the National Vascular Database as well as for longer term follow-up in the event the trial 

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is extended. A copy of the signed Participant Information Sheet/Informed Consent Form 
document will be provided to the patient and the original Informed Consent Form should be 
retained with the source documents. 
The right of the participant to refuse to participate without giving reasons will be respected, 
although if the participant is willing a reason for declining will be recorded. After the 
participant has entered the trial the clinician remains free to give alternative treatment to that 
specified in the protocol at any stage if he/she feels it is in the participant’s best interest, but 
the reasons for doing so should be recorded. In these cases, the participants remain within 
the study for the purposes of follow-up and data analysis. All participants are free to withdraw 
at any time from the protocol treatment without giving reasons and without prejudicing further 
treatment. Participants will be asked to consent to long term follow up to allow for linkage to 
routine datasets including Hospital Episode Statistics (HES) and the National Vascular 
Database. 
 
 
It is the investigator’s responsibility to inform the participant’s General Practitioner (where 
applicable) by letter that the participant is taking part in the study provided the participant 
agrees to this, and information to this effect is included in the Participant Information Sheet 
and Informed Consent. A copy of the letter should be filed in the Investigator Site File. 
 
 
The investigator must ensure that the participant’s confidentiality is maintained. On the CRF 
or other documents submitted to the Sponsors, participants will be identified by a participant 
ID number only. Documents that are not submitted to the Sponsor (e.g., signed informed 
consent form) should be kept in a strictly confidential file by the investigator. 
 
The investigator shall permit direct access to participants’ records and source document for 
the purposes of monitoring, auditing, or inspection by the Sponsor, authorised 
representatives of the Sponsor, NHS, Regulatory Authorities and RECs. 
 
 
The investigators and study site staff will comply with the requirements of the Data 
Protection Act 2018 concerning the collection, storage, processing and disclosure of 
personal information and will uphold the Act’s core principles. 
 
 
The end of the Trial will be defined as the last participant’s last visit.  
 
 
The investigator must retain essential documents until notified by the Sponsor, and for at 
least ten years after study completion. Participant files and other source data (including 
copies of protocols, CRFs, original reports of test results, correspondence, records of 
informed consent, and other documents pertaining to the conduct of the study) must be 
retained. Documents should be stored in such a way that they can be accessed/data 
retrieved at a later date. Consideration should be given to security and environmental risks. 
 

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No study document will be destroyed without prior written agreement between the Sponsor 
and the investigator. Should the investigator wish to assign the study records to another 
party or move them to another location, written agreement must be obtained from the 
Sponsor. 
 
 DATA MANAGEMENT 
 
Data will be written directly into the CRF (source data) and then transcribed into the eCRF. 
Source documents include original documents related to the trial, to medical treatment and 
to the history of the participant, and adequate source documentation must be maintained to 
allow reliable verification and validation of the trial data.  
 
CRFs will be in English. Generic names for concomitant medications should be recorded in 
the CRF wherever possible. All written material to be used by participants must use 
vocabulary that is clearly understood, and be in the language appropriate for the study site. 
 
 
Data management will be through the REDCap, a web-based data entry system that builds 
a database for each individual clinical trial. The Data Management Services team (based at 
ECTU) will work with the Investigators, Trial Manager, Trial Statisticians and Trial Teams to 
design and build bespoke eCRFs and validation rules for data entry to ensure the data is 
collected accurately and stored securely. They will also provide the appropriate user training. 
The Trial Manager will visit the sites to verify the quality of the data. 
 
 
Details of procedures for CRF/eCRF completion will be provided in a study manual. 
 
 
All trial documentation, including that held at participating sites and the trial coordinating 
centre, will be archived for a minimum of 10 years following the end of the study.  
 
 STUDY MANAGEMENT STRUCTURE  
The study will be coordinated by a trial manager who will report to the Chief Investigator. 
The trial manager will liaise with local principal investigators to ensure that the trial is 
conducted locally according to protocol and in an expeditious manner. The organisational 
structure and responsibilities are outlined below. 
 
 
A Trial Steering Committee (TSC) will be convened including as a minimum an independent 
Chair, independent clinician, the Chief Investigators and Trial Manager. A TSC meeting will 
be held at the start of the study prior to commencement of recruitment and at least annually 
as per NIHR guidelines. The role of the TSC is to provide overall supervision of trial conduct 

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and progress. Details of membership, responsibilities and frequency of meetings will be 
defined in a separate Charter. A lay PPI representative will be included. 
 
 
A Trial Management Group (TMG) will be convened including the Chief Investigator, co-
investigators and key collaborators, trial statistician and trial manager. The TMG will be 
responsible for day-to-day conduct of the trial and operational issues. Meetings will be held 
monthly throughout the set up and recruitment phase and alternate months subsequently 
until trial closure. Details of membership, responsibilities and frequency of meetings will be 
defined in separate terms of Reference.  
 
 
A data monitoring committee meeting will be held prior to first patient first visit and will then 
be held prior to each TSC meeting. Further details will be defined in the separate DMC 
Charter. Statistical advice and analysis will be conducted by Professor John Norrie 
(ECTU), who has advised on this studies design and sample size. Professor Norrie will 
produce the Statistical Analysis Plan and subsequent reports for the Data Monitoring 
Committee 
 
 
As successful primary (general practice & community) care recruitment is a priority, a 
Special Advisory Group (SAG) chaired by two leading experts in primary care diabetes 
and vascular medicine (Professor Kamlesh Khunti and Professor Azeem Majeed) will be 
formed. Other members of  the SAG include, Ms Trusha Coward (community  podiatrist), 
Ms Joanna Pitt (primary care nurse), Ms Caroline Durack (primary care  manager), Dr 
Patrick Holmes (General Practitioner) and Professor Ahmet Fuat (General  
Practitioner).The SAG  will advise on the recruitment and delivery of the study outside of 
secondary care to ensure that patients  from these healthcare settings are adequately  
represented. Both chairs will sit on the TMG.    
 
 
A Patient Advisory Group (PAG) will be convened. PAG will be meet annually prior to TSC 
meetings to ensure that a wide range of patient perspectives are considered during the 
study.  
 
 
There are no formal stopping rules but safety will be reviewed periodically by the DMC who 
could recommend early discontinuation of the study.  
 
 
A study-specific risk assessment will be performed prior to the start of the study by the study 
sponsor. The risk assessment will consider all aspects of the study and will be updated as 
required during the course of the study. The risk assessment will consider all aspects of the 
study and will be updated as required during the course of the study. 
 

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The study will be monitored periodically by trial monitors to assess the progress of the study, 
verify adherence to the protocol, ICH GCP E6 guidelines and other national/international 
requirements and to review the completeness, accuracy and consistency of the data. 
Monitoring procedures and requirements will be documented in a Monitoring Plan, in 
accordance with the risk assessment. 
 
 
Quality Control will be performed according to Imperial College internal procedures. The 
study may be audited by a Quality Assurance representative of the Sponsor. All necessary 
data and documents will be made available for inspection.  
The study may be subject to inspection and audit by regulatory bodies to ensure adherence 
to GCP and the UK Policy Framework for Health and Social Care. 
 
 
This research has been reviewed by the Surgery Peer Review Board at Imperial College 
London, the DM PAD multicentre research group and the Collaborations Committee at 
Edinburgh Clinical Trials Unit. The scientific quality of the research was also reviewed and 
assessed by the NIHR HTA external reviewers as part of the grant application for funding, 
which was subsequently awarded. 
 
 
The development of the proposal has been informed by patients and the public and PPI 
activities have been conducted in line with INVOLVE recommendations (37). 
 
Developing the research question 
An emotional mapping exercise of a group of patients with diabetes identified anxiety 
associated with PAD diagnosis. This helped identify and prioritise the current topic prior to 
this HTA call.  
 
Learning from the experience of patients in the TrEAD study 
A phone survey of 57 patients from the TrEAD study followed by a focus group discussion, 
led by our PPI co-applicant Elizabeth Pigott who has personal experience of diabetic foot 
disease and working in study steering groups was conducted. The strength of this 
approach is that the PPI is not centred around hypothetical discussions but incorporates 
the perspective of patients involved in a similar study. Furthermore, the PPI is truly 
inclusive as a significant proportion of patients in the TrEAD study were from BAME 
groups (28%) and suffered from disabilities (52%). This informed the following changes: 
• Incorporating a non-treadmill exercise ABPI test (see ‘Index tests’).  
• Advertising the study online to improve accessibility for all patients (see ‘Equality, 
Diversity and Inclusion’)  
• Providing a lay summary of individual test results with actionable recommendations, in 
addition to the GP letter (see ‘Dissemination, engagement and projected outputs’)  
• Patients anticipated difficulties in accessing different parts of hospitals for blood tests 
and imaging, due to difficult directions and access issues for those with disabilities. 

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After discussion it was agreed that we should work with local sites to ensure that clear 
written directions are made available to patients and blood tests are performed in the 
same place as index tests (where feasible). 
 
Learning from the wider diabetic community  
An online survey of 123 people was conducted; 96% felt the research was important. 6% 
indicated that they would not take part if CTA was necessitated and 10% felt the study was 
not easy to understand.  This prompted us to make the following changes, which were 
accepted by our study focus group: 
• Include MRA as an alternative reference imaging modality 
• Incorporate information regarding CTA radiation exposure with a ‘real world’ 
comparison in our patient information sheet.   
• Drafting and revising our ‘Plain English Summary’ 
 
 
Management, analysis and dissemination 
Our patient co-investigator, Ms Elizabeth Pigott will chair a Patient Advisor Group who will 
meet annually to ensure that a wide range of patient perspectives are considered during the 
study. Other members of the Patient Advisory Group were also involved in the development 
of this proposal. 
The Patient Advisory Group will also contribute to the interpretation of study findings, thereby 
allowing us to integrate patients perspectives in the analysis phase. 
 
Results will be disseminated via NIHR INVOLVE website, social media, patient forums, 
blogs, podcasts and presentation at patient meetings (by Ms Elizabeth Pigott, PPI lead). 
Educational patient video and infographics explaining the rationale behind the study and 
presenting the study results will also be disseminated. 
 
 
The Consort Guidelines and checklist should be reviewed prior to generating any 
publications for the trial to ensure they meet the standards required for submission to high 
quality peer reviewed journals etc. http://www.consort-statement.org/. Results will be 
reported according to the Standards for Reporting of Diagnostic Accuracy Studies 
(STARD) checklist.  
Information concerning the study, patent applications, processes, scientific data or other 
pertinent information is confidential and remains the property of the Sponsor. The 
investigator may use this information for the purposes of the study only. 
It is understood by the investigator that the Sponsor will use information developed in this 
clinical study and, therefore, may disclose it as required to other clinical investigators. In 
order to allow the use of the information derived from this clinical study, the investigator 
understands that he/she has an obligation to provide complete test results and all data 
developed during this study to the Sponsor. 
Verbal or written discussion of results prior to study completion and full reporting should only 
be undertaken with written consent from the Sponsor. 
Therefore all information obtained as a result of the study will be regarded as 
CONFIDENTIAL, at least until appropriate analysis and review by the investigator(s) are 
completed.  

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A Clinical Study Report summarising the study results will be prepared and submitted to the 
REC within a year of the end of study. 
 
The project output will include the following: 
 
• Healthcare providers- Results will be disseminated through publication (study 
protocol, main study results, cost-effectiveness analysis, follow-up analysis), 
presentation at conferences, social media, blog posts and podcasts to increase 
reach. A press release via the press offices of partaking centres will be issued. 
Seminars will be run to engage podiatrists and primary care nurses. 
• Commissioners- The results will be shared with local CCGs and NICE.   
• Patients- Results will be disseminated via NIHR INVOLVE website, social media, 
patient forums, blogs, podcasts and presentation at patient meetings (by Ms Elizabeth 
Pigott, PPI lead). Educational patient video and infographics explaining the rationale 
behind the study and presenting the study results will also be disseminated.  
• Study participants- As per our PPI feedback patients will receive lay summaries of 
their individual test results. They will be kept up to date with study progress through 
our monthly newsletter which will be emailed and also made available via the study 
website. Educational video and infographics will also be circulated to study participants 
as per our PPI feedback.   
• Study centres- Staff at study centres will be kept up to date via the monthly study 
newsletter.  
 
Professional networks of all co-applicants and TSC members will be utilised for 
dissemination of our findings. To further maximise reach support has been gained from 
relevant organisations including:  Diabetes UK, College of Podiatry, Circulation 
Foundation, The Society of Vascular Nurses, Vascular and Endovascular Research 
Network (VERN), The Lindsay Leg Club Foundation, Vascular Society, 
knowdiabetes.org.uk and The Royal Society of Medicine (Section of the Vascular, Lipid & 
Metabolic Medicine).  We have also gained support from the London and West Midlands 
Diabetic Footcare Networks. 
 
 

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28.  McPhail IR, Spittell PC, Weston SA, Bailey KR. Intermittent claudication: an objective 
office-based assessment. J Am Coll Cardiol. 2001 Apr;37(5):1381–5.  
29.  Amirhamzeh MM, Chant HJ, Rees JL, Hands LJ, Powell RJ, Campbell WB. A 
comparative study of treadmill tests and heel raising exercise for peripheral  arterial 
disease. Eur J Vasc Endovasc Surg  Off J  Eur Soc Vasc Surg. 1997 Mar;13(3):301–
5.  
30.  Aboyans V, Criqui MH, Abraham P, Allison MA, Creager MA, Diehm C, et al. 
Measurement and interpretation of the ankle-brachial index: a scientific statement  
from the American Heart Association. Circulation. 2012 Dec;126(24):2890–909.  
31.  Menke J, Larsen J. Meta-analysis: Accuracy of contrast-enhanced magnetic 
resonance angiography for  assessing steno-occlusions in peripheral arterial 
disease. Ann Intern Med. 2010 Sep;153(5):325–34.  
32.  Met R, Bipat S, Legemate DA, Reekers JA, Koelemay MJW. Diagnostic performance 
of computed tomography angiography in peripheral arterial  disease: a systematic 
review and meta-analysis. JAMA. 2009 Jan;301(4):415–24.  
33.  Morris DR, Singh TP, Moxon J V, Smith A, Stewart F, Jones RE, et al. Assessment 
and validation of a novel angiographic scoring system for peripheral  artery disease. 
Br J Surg. 2017 Apr;104(5):544–54.  
34.  Hirsch AT, Criqui MH, Treat-Jacobson D, Regensteiner JG, Creager MA, Olin JW, et 
al. Peripheral arterial disease detection, awareness, and treatment in primary care. 
JAMA [Internet]. 2001 Sep 19 [cited 2014 Nov 10];286(11):1317–24. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/11560536 
35.  Bland JM, Altman DG. Statistical methods for assessing agreement between two 
methods of clinical  measurement. Lancet (London, England). 1986 
Feb;1(8476):307–10.  
36.  Altman D. Practical Statistics for Medical Research. Practical Statistics for Medical 
Research. Chapman & Hall/CRC; 1991. 369ff p.  
37.  Hayes H, Buckland S, Tarpey M. Briefing notes for researchers: public involvement in 
NHS, public health and social care research. National Institute for Health Research 
(NIHR) Involve. 2012.  
 
 
 
 
 
 

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Protocol No: 21CX7046 
Sponsor: Imperial College London 
V 7.0 29 08 2023 
 
DM PAD Protocol v7.0, 29082023 Page 42 of 50 
(Approved by REC: London - Central on 31/08/2023) 
 
 
REVISION HISTORY  
 
Version  
Date 
Summary of changes 
1.0 
30/07/2021 
First version  
2.0 
02/03/2022 
Changes to the screening / recruitment process: 
patients can be approached in clinics / inpatient 
wards / GP practices etc. by the research team 
after being identified by the direct healthcare 
team (removing the need to contact the patient 
72 hours ahead of their routine clinical 
appointment). 
Addition of a QoL questionnaire (EQ-5D-5L) at 
visit 1. 
Minor changes to wording of "diabetic patients" / 
"diabetic population" to "patients with diabetes". 
Clarification to the data set collected on the 
screening logs. 
TBPI index test – to use brachial (arm) 
measurements rather than from the index 
fingers.   
3.0 
04/04/2022 
Change the order the index tests are performed - 
TBPI to be performed before ABPI 
4.0 
18/05/2022 
At some participating centres, participants may 
be required to attend an additional visit for the 
purposes of taking blood to assess renal 
function (if no up-to-date renal blood test). 
Participants may be required to attend a different 
participating centre for visit 2 (reference scan) to 
that of visit 1. 
Extension of the time window between the index 
tests being performed (visit 1) and the reference 
scan (visit 2) from 2 weeks to 6 weeks. 
5.0 
25/07/2022 
Include the option to recruit from community 
settings via participant identification centres 
(PICs) 
6.0 
28/02/2023 
Minor wording change to clarify the recruitment 
period was extended for an additional 12 months 
in February 2023.  
7.0 
29/08/2023 
Minor wording change to clarify a reduction in 
sample size from 730 to 600.  

DM PAD 
Protocol No: 21CX7046 
Sponsor: Imperial College London 
V 7.0 29 08 2023 
 
DM PAD Protocol v7.0, 29082023 Page 43 of 50 
(Approved by REC: London - Central on 31/08/2023) 
 
Minor wording change to clarify that three 
participating centres will be performing the PAD-
scan (from four). 
 

DM PAD 
Protocol No: 21CX7046 
Sponsor: Imperial College London 
V 7.0 29 08 2023 
 
DM PAD Protocol v7.0, 29082023 Page 44 of 50 
(Approved by REC: London - Central on 31/08/2023) 
 
SIGNATURE PAGE 1 (CHIEF INVESTIGATOR) 
 
The signature below constitutes approval of this protocol by the signatory, on behalf of the 
Protocol Development Group, and provides the necessary assurances that this study will be 
conducted according to all stipulations of the protocol including all statements regarding 
confidentiality. 
 
 
Study Title: 
 
 
Diagnostic tools to establish the presence and severity  
                                               of peripheral arterial disease in people with diabetes 
 
 
Protocol Number:  
7.0 
 
 
 
Signed: 
 
 
 
 
 
 
Usman Jaffer        
 
 
 
Mr                                      
 
 
 
 
 
Date:  
 
 
 
 
 
 

DM PAD 
Protocol No: 21CX7046 
Sponsor: Imperial College London 
V 7.0 29 08 2023 
 
DM PAD Protocol v7.0, 29082023 Page 45 of 50 
(Approved by REC: London - Central on 31/08/2023) 
 
SIGNATURE PAGE 2 (SPONSOR) 
 
The signatures below constitute approval of this protocol by the signatory.  
 
 
Study Title: 
 
 
Diagnostic tools to establish the presence and severity  
                                               of peripheral arterial disease in people with diabetes 
 
 
 
Protocol Number:  
7.0 
 
 
 
 
Signed: 
 
 
 
 
 
 
 
 
Keith Boland 
 
 
 
 
 
 
 
Imperial College London 
 
 
 
 
 
 
Date:  
 
 

DM PAD 
Protocol No: 21CX7046 
Sponsor: Imperial College London 
V 7.0 29 08 2023 
 
DM PAD Protocol v7.0, 29082023 Page 46 of 50 
(Approved by REC: London - Central on 31/08/2023) 
 
SIGNATURE PAGE 3 (STATISTICIAN) 
 
The signatures below constitute approval of this protocol by the signatory.  
 
 
Study Title: 
 
 
Diagnostic tools to establish the presence and severity  
                                               of peripheral arterial disease in people with diabetes 
 
 
 
Protocol Number:  
7.0 
 
 
 
 
Signed: 
 
___________________________________________ 
 
 
 
 
John Norrie 
 
 
 
Professor  
 
 
 
Usher Institute- University of Edinburgh  
 
 
 
Date:  
 
 
 
 

DM PAD 
Protocol No: 21CX7046 
Sponsor: Imperial College London 
V 7.0 29 08 2023 
 
DM PAD Protocol v7.0, 29082023 Page 47 of 50 
(Approved by REC: London - Central on 31/08/2023) 
 
SIGNATURE PAGE 4 (PRINCIPAL INVESTIGATOR) 
 
The signature of the below constitutes agreement of this protocol by the signatory and 
provides the necessary assurance that this study will be conducted at his/her investigational 
site according to all stipulations of the protocol including all statements regarding 
confidentiality. 
 
 
Study Title: 
 
 
Diagnostic tools to establish the presence and severity  
                                               of peripheral arterial disease in people with diabetes 
 
 
 
Protocol Number:  
7.0 
 
 
Address of Institution:  
____________________________________________ 
 
 
 
 
 
 
 
 
 
 
____________________________________________ 
 
 
 
 
 
 
____________________________________________ 
 
 
 
Signed: 
 
 
____________________________________________ 
 
 
Print Name and Title: 
____________________________________________ 
 
 
Date:  
 
 
_____________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

DM PAD 
Protocol No: 21CX7046 
Sponsor: Imperial College London 
V 7.0 29 08 2023 
 
DM PAD Protocol v7.0, 29082023 Page 48 of 50 
(Approved by REC: London - Central on 31/08/2023) 
 
 APPENDICES 
 
Evaluation of patient acceptability- Likert scale 
 
Overall, how satisfied were you with each of the tests you have had today? 
 
  
Very unsatisfied 
 
Unsatisfied 
 
Neutral 
 
Satisfied 
 
Very satisfied 
Ankle-brachial pressure index 
(ABPI) 
  
   
 
 
Exercise ankle-brachial pressure 
index (Exercise ABPI) 
 
  
 
 
Toe-brachial pressure index  
 
 
  
 
 
Audible handheld Doppler 
 
 
  
 
 
Visual handheld Doppler 
 
 
  
 
 
PAD-scan (if applicable) 
 
 
  
 
 

DM PAD 
Protocol No: 21CX7046 
Sponsor: Imperial College London 
V 7.0 29 08 2023 
 
DM PAD Protocol v7.0, 29082023 Page 48 of 50 
(Approved by REC: London - Central on 31/08/2023) 
 
 
CTA reference scan protocol 
Peripheral CT angiograms can be obtained with all current multiple–detector row CT  
scanners (i.e., four or more channels). A standardised scanning protocol programmed into 
the scanner and the study can easily be performed in 10–15 minutes of room time. Breath 
holding is required only at the beginning of the CT acquisition through the abdomen and 
pelvis. A medium to small imaging field of view (with the greater trochanter used as a bony 
landmark) and a medium to soft reconstruction kernel are generally used for image 
reconstruction, imaging continues to the whole foot. Series 1 is imaged from Diaphragm to 
Ankles and then from the Knees to Ankles to achieve a delayed phase of imaging 
especially if there is a proximal stenosis/occlusion causing a delayed flow of contrast to the 
ankles. A region of interest is taken in the level of the descending thoracic aorta (DTA) or 
coeliac axis. 
 
A 10–15 mm2 circular region of interest is placed inside the middle of the aortic lumen and  
this will subsequently measure the Hounsfield units of the aortic lumen on subsequent  
scanning. At 10 seconds following IV contrast administration, serial low-dose monitoring 
CT scans are obtained at the same table position (DTA or coeliac axis level) at 2-second  
intervals. When the region of interest detects a pre-set contrast enhancement level 
(usually a 100– 150 HU value), there is automatic triggering of the scanner to acquire 
images in the desired scan range, usually from the level of the celiac axis to the feet. This 
time-efficient method ensures optimal arterial enhancement within the region of interest. In 
general, 75 mls contrast is used with a chasing bolus of 100 mls Saline to produce a 
compact volume load.  
 
This is injected at a rate of 4 ml/sec from a Venflon in the antecubital fossa. CT settings;  
kVp: 100-120, TI/pitch: 1.3/111 (fast) 0.8/27-65; FOV: 350-400(L), Rotation time: 0.35-0.5;  
SD: 12-12.5 (all standard sure exp), Detector configuration: 0.5x80 (depending on centres’  
CT scanner channel). This protocol allows reconstruction of the dataset on a 3D 
workstation, therefore all images will be able to be reconstructed at any plane by the 
reporting radiologist. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

DM PAD 
Protocol No: 21CX7046 
Sponsor: Imperial College London 
V 7.0 29 08 2023 
 
DM PAD Protocol v7.0, 29082023 Page 49 of 50 
(Approved by REC: London - Central on 31/08/2023) 
 
 
MRA reference scan protocol 
MR angiography will be performed in the local hospitals scanner 1.5-3T MR. An AP 
phased array surface body coil will be used in conjunction with a standard receivers for 
signal transmission and reception. The coil is placed to cover the lower region of the 
abdominal portion of the aorta and included the iliac arteries to the level of the inguinal 
ligament. 
 
Coverage is from the diaphragm to the foot. Depending on the centre either a test bolus of  
Gadolinium based contrast agent is injected via the antecubital vein or to the infrarenal  
region of the abdominal aorta, which combines a test bolus with a multiphase, single 
section, gradient recalled echo sequence. A bolus tracking method will be obtained with a 
ROI in the aortic lumen at the level of the coeliac axis where repeat scanning is performed, 
the full bolus of contrast is injected at a rate of 2-3mls/sec from a Venflon in the antecubital 
fossa is administered, and when the bolus is detected within the vessel, the technologist 
can trigger scan acquisition. The coronal oblique plane is preferred for bolus-chase MRA 
because it covers the largest field of view in the shortest scanning time while maintaining 
high spatial resolution in the slice-select direction. Subtraction techniques will be employed 
to improve contrast resolution in CE-MRA. 
 
Short TR and TE for fast acquisition are accomplished with 3D spoiled gradient-echo pulse  
sequences. Spoiling increases the contrast-to-noise ratio (CNR) by suppressing residual  
background signal. As in other MR applications, the acquisition time is determined by the  
TR, the number of phase-encoding steps, the number of slices, the fraction of k-space  
sampled, and the acceleration factor (when parallel imaging is used). The gradient 
strength governs the shortest possible TR (< 5 milliseconds) and TE (< 3 milliseconds), 
although parameters such as wider bandwidth, smaller flip angles, and fractional echo can 
shorten the TR and TE. A flip angle of 15-45° is typically used. MRA can be acquired with 
either a single phase or a time-resolved MRA, depending on the centres preference. Using 
these sequences, it provides anisotropic images, which allows reconstruction of the 
dataset on a 3D workstation, therefore all images will be able to be reconstructed at any 
plane by the reporting radiologist.