A Randomised Feasibility Trial to Define Outcome Measures for Acute Charcot Neuroarthropathy in Diabetes and Their Use in Assessing Clinical Management (CADOM)
Phase: NA
Conditions: Diabetes
Sponsor: Norfolk and Norwich University Hospitals NHS Foundation Trust

 
 
                        
 
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NCTU_O_TaT_7_v3.0_ProtocolTemplate 
Trial Protocol Defining outcome measures for acute Charcot neuroarthropathy in Diabetes and their 
use in assessing clinical management. Version 1.4 11th June 2020  
IRAS 222668 
 
IRAS 222668 
 
CADOM 
A randomised feasibility study to assess the use of serial magnetic resonance 
imaging to reduce treatment times in Charcot neuroarthropathy in people with 
diabetes  
Version 
1.4 
Date 
11th June  2020  
Sponsor 
Norfolk and Norwich University Hospitals NHS 
Foundation Trust 
 
Trial registration 
 
ISCRTN 74101606 
 
 
NRES # 
[insert MREC number] 
 
Authorisation: Chief Investigator 
Name 
Catherine Gooday 
Role 
NIHR Doctoral Research Fellow 
Signature 
 
 
 
 
Authorisation: Sponsor Representative  
Name 
Julie Dawson 
 
Role 
Acting Research Service Manager, NNUH 
 
Signature 
[insert wet signature] 
 
 
 
Date 
[insert date] 
 
 
Authorisation: Senior Operations Staff 
Name 
Dr Erika Sims 
 
Role 
Senior Clinical Trial Operations Manager  
 
Signature 
 
 
 
Date 
 
 
 

 
 
 
 
CADOM 
 
NCTU_O_TaT_7_v3.0_ProtocolTemplate 
Trial Protocol Defining outcome measures for acute Charcot neuroarthropathy in Diabetes and their 
use in assessing clinical management. Version 1.4 11th June 2020  
IRAS 222668 
 
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Authorisation: Trial Statistician 
Name 
Professor Lee Shepstone 
 
Role 
Professor Medical Statistics 
 
Signature 
[insert wet signature] 
 
 
 
Date 
[insert date] 
 
 
 
 

 
 
 
 
CADOM 
 
NCTU_O_TaT_7_v3.0_ProtocolTemplate 
Trial Protocol Defining outcome measures for acute Charcot neuroarthropathy in Diabetes and their 
use in assessing clinical management. Version 1.4 11th June 2020  
IRAS 222668 
 
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Table of Contents 
1 
Administrative information ............................................................................................................. 1 
1.1 
Compliance ............................................................................................................................. 1 
1.2 
Sponsor ................................................................................................................................... 1 
1.3 
Structured trial summary ........................................................................................................ 2 
1.4 
Roles and responsibilities........................................................................................................ 5 
1.4.1 
Protocol contributors ...................................................................................................... 5 
1.4.2 
Role of trial sponsor and funders .................................................................................... 5 
1.4.3 
Trial Team........................................................................................................................ 5 
1.4.5 
Trial Management Group ................................................................................................ 6 
2  
Trial Diagram ................................................................................................................................... 6 
3  
Abbreviations .................................................................................................................................. 7 
4 
Glossary ........................................................................................................................................... 8 
5 
Introduction .................................................................................................................................... 9 
5.1 
Background and Rationale ...................................................................................................... 9 
5.1.1 
Explanation for choice of comparators ......................................................................... 12 
5.2 
Objectives.............................................................................................................................. 12 
5.3 
Trial Design ............................................................................................................................ 12 
6 
Methods ........................................................................................................................................ 13 
6.1 
Site Selection ......................................................................................................................... 13 
6.1.1 
Study Setting ................................................................................................................. 13 
6.1.2 
Site/Investigator Eligibility Criteria ............................................................................... 13 
6.1.2.1 
Principal Investigator’s (PI) Qualifications and Agreements ................................. 13 
6.1.2.2 
Resourcing at site .................................................................................................. 14 
6.2 
Site approval and activation ................................................................................................. 14 
6.3 
Participants ........................................................................................................................... 14 
6.3.1 
Eligibility Criteria ........................................................................................................... 14 
6.3.1.1 
Participant selection ............................................................................................. 14 
6.3.1.2 
Participant Inclusion Criteria ................................................................................. 15 
6.3.1.3 
Participant Exclusion Criteria ................................................................................ 15 
6.3.1.4 
Eligibility Criteria for Individuals Performing the Interventions ........................... 15 
6.3.1.5 
Co-enrolment Guidance ........................................................................................ 15 
6.3.1.6 
Screening Procedures and Pre-randomisation Investigations .............................. 15 

 
 
 
 
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Trial Protocol Defining outcome measures for acute Charcot neuroarthropathy in Diabetes and their 
use in assessing clinical management. Version 1.4 11th June 2020  
IRAS 222668 
 
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6.4 
Interventions - Arm A and Arm B .......................................................................................... 16 
6.4.1 
Arm A (Intervention – Standard Care and Serial MRIs) ................................................ 17 
6.4.2 
Arm B (Control – Standard Care and one additional MRI) ............................................ 17 
6.4.3 
Qualitative Study ........................................................................................................... 17 
6.4.4  
Compliance and Adherence .......................................................................................... 18 
6.4.5  
Concomitant Care ......................................................................................................... 18 
6.4.6 
Protocol Treatment Discontinuation ............................................................................ 18 
6.5 
Outcomes .............................................................................................................................. 19 
6.5.1  
Feasibility Outcomes ..................................................................................................... 19 
6.5.2  
Exploratory Clinical Outcomes ...................................................................................... 19 
6.5.3  
Patient Reported Outcome Measures .......................................................................... 20 
6.5.4  
Qualitative Study ........................................................................................................... 20 
6.6 
Participant Timeline .............................................................................................................. 21 
6.7  
Patient Assessments ............................................................................................................. 21 
6.7.1  
Randomisation Visit ...................................................................................................... 21 
6.7.2  
The “active phase” – up to 12 months .......................................................................... 22 
6.7.3  
At three, six, nine and 12 months ................................................................................. 23 
6.7.4  
Follow up phase ............................................................................................................ 23 
6.7.5  
Alternate Diagnosis ....................................................................................................... 24 
6.7.6 
Early Stopping of Follow-up .......................................................................................... 24 
6.7.7 
Participant Transfers ..................................................................................................... 24 
6.7.8 
Loss to Follow-up .......................................................................................................... 24 
6.7.9 
Trial Closure .................................................................................................................. 24 
6.8 
Sample Size ........................................................................................................................... 25 
6.9 
Recruitment and Retention .................................................................................................. 25 
6.9.1 
Recruitment .................................................................................................................. 25 
6.9.2 
Retention....................................................................................................................... 25 
6.10 
Assignment of Intervention .................................................................................................. 25 
6.10.1 
Allocation ...................................................................................................................... 25 
6.10.1.1 
Sequence generation ............................................................................................ 25 
6.10.1.2 
Allocation concealment mechanism ..................................................................... 25 
6.10.2 
Blinding ......................................................................................................................... 26 
6.11 
Data Collection, Management and Analysis ......................................................................... 26 

 
 
 
 
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use in assessing clinical management. Version 1.4 11th June 2020  
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6.11.1 
Data Collection Methods .............................................................................................. 26 
6.11.2 
Data Management ........................................................................................................ 26 
6.11.3 
Non-Adherence and Non-Retention ............................................................................. 27 
6.11.4 
Statistical Methods ....................................................................................................... 27 
6.11.4.1 
Statistical Analysis Plan ......................................................................................... 27 
6.11.4.2 
Study Outcomes .................................................................................................... 27 
6.11.4.4  
Additional Analyses ............................................................................................... 28 
6.11.5 
Analysis Population and Missing Data .......................................................................... 28 
6.11.5.1 
Economic evaluations ........................................................................................... 28 
6.11.5.2  
Health Economic Analysis Plan ............................................................................. 29 
6.12 
Data Monitoring .................................................................................................................... 29 
6.12.1 
Data Monitoring Committee ......................................................................................... 29 
6.12.2 
Interim Analyses ............................................................................................................ 29 
6.12.3 
Data Monitoring for Harm ............................................................................................ 29 
6.12.3.1 
Safety reporting .................................................................................................... 29 
6.12.3.2 
Procedures to follow in the event of female participants becoming pregnant .... 30 
6.12.4 
Quality Assurance and Control ..................................................................................... 30 
6.12.4.1 
Risk Assessment .................................................................................................... 30 
6.12.4.2 
Central Monitoring at NCTU ................................................................................. 30 
6.12.4.3 
On-site Monitoring ................................................................................................ 30 
6.12.4.3.1 Direct access to participant records ................................................................. 31 
6.12.4.4 
Trial Oversight ....................................................................................................... 31 
6.12.4.4.1 Trial Management Team ................................................................................... 31 
6.12.4.4.2 Trial Management Group.................................................................................. 31 
6.12.4.4.3 Independent Data Monitoring Committee ....................................................... 31 
6.12.4.4.4 Trial Sponsor ..................................................................................................... 32 
7 
Ethics and Dissemination .............................................................................................................. 33 
7.1 
Research Ethics Approval ...................................................................................................... 33 
7.2 
Competent Authority Approvals ........................................................................................... 33 
7.3 
Other Approvals .................................................................................................................... 33 
7.4 
Protocol Amendments .......................................................................................................... 33 
7.5 
Consent ................................................................................................................................. 33 
7.5.1 
Consent to Qualitative Interviews ................................................................................ 34 

 
 
 
 
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Trial Protocol Defining outcome measures for acute Charcot neuroarthropathy in Diabetes and their 
use in assessing clinical management. Version 1.4 11th June 2020  
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7.6 
Confidentiality ....................................................................................................................... 34 
7.7 
Declaration of Interests ........................................................................................................ 35 
7.8 
Indemnity .............................................................................................................................. 35 
7.9 
Finance .................................................................................................................................. 35 
7.10 
Archiving ............................................................................................................................... 35 
7.11 
Access to Data ....................................................................................................................... 35 
7.12 
Ancillary and Post-trial Care .................................................................................................. 35 
7.13 
Publication Policy .................................................................................................................. 35 
7.13.1 
Trial Results ................................................................................................................... 35 
7.13.2 
Authorship..................................................................................................................... 35 
7.13.3 
Reproducible Research ................................................................................................. 36 
8 
Ancillary Studies ............................................................................................................................ 37 
9 
Protocol Amendments .................................................................................................................. 38 
10 
References ................................................................................................................................ 39 
11 
Appendix 1 ................................................................................................................................ 42 
END 
END 

 
 
 
 
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NCTU_O_TaT_7_v3.0_ProtocolTemplate 
Trial Protocol Defining outcome measures for acute Charcot neuroarthropathy in Diabetes and their 
use in assessing clinical management. Version  1.4 11th June 2020  
IRAS 222668 
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1 
Administrative information 
This document was constructed using the Norwich Clinical Trials Unit (NCTU) Protocol template 
Version 3. It describes the CADOM trial, sponsored by Norfolk and Norwich University Hospitals NHS 
Foundation Trust and co-ordinated by the CI with support from NCTU.  
It provides information about procedures for entering participants into the trial, and provides 
sufficient detail to enable: an understanding of the background, rationale, objectives, trial 
population, intervention, methods, statistical analyses, ethical considerations, dissemination plans 
and administration of the trial; replication of key aspects of trial methods and conduct; and appraisal 
of the trial’s scientific and ethical rigour from the time of ethics approval through to dissemination of 
the results. The protocol should not be used as an aide-memoire or guide for the treatment of other 
patients. Every care has been taken in drafting this protocol, but corrections or amendments may be 
necessary. These will be circulated to registered investigators in the trial. Sites entering participants 
for the first time should confirm they have the correct version through a member of the trial team at 
NCTU. 
NCTU supports the commitment that its trials adhere to the SPIRIT guidelines. As such, the protocol 
template is based on the Standard Protocol Items: Recommendations for Interventional Trials 
(SPIRIT) 2012 Statement for protocols of clinical trials 1. The SPIRIT Statement Explanation and 
Elaboration document 2 can be referred to, or a member of NCTU Protocol Review Committee can 
be contacted for further detail about specific items.  
1.1 
Compliance 
The trial will be conducted in compliance with the approved protocol, the Declaration of Helsinki 
(2008), the principles of Good Clinical Practice (GCP) the UK Data Protection Act, and the National 
Health Service (NHS) Research Governance Framework for Health and Social Care (RGF). Agreements 
that include detailed roles and responsibilities will be in place between participating sites and NCTU. 
Participating sites will inform NCTU as soon as they are aware of a possible serious breach of 
compliance, so that NCTU can fulfil its requirement to report the breach if necessary within the 
timelines specified in the UK Clinical Trials Regulations (currently 7 days). For the purposes of this 
regulation a ‘serious breach’ is one that is likely to affect to a significant degree: 
 
The safety or physical or mental integrity of the subjects in the trial, or 
 
The scientific value of the trial. 
1.2 
Sponsor 
The Norfolk and Norwich University Hospitals NHS Foundation Trust is the trial sponsor and has 
delegated responsibility for the overall management of the CADOM trial to the Chief Investigator 
and NCTU. Queries relating to sponsorship of this trial should be addressed to the CI  
 

 
 
 
 
CADOM 
 
 
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Trial Protocol Defining outcome measures for acute Charcot neuroarthropathy in Diabetes and their 
use in assessing clinical management. Version  1.4 11th June 2020  
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1.3 
Structured trial summary 
Primary 
Registry 
and 
Trial 
Identifying 
Number 
ISRCTN – No to be confirmed    
Date 
of 
Registration in 
Primary 
Registry 
Date when trial was officially registered in the primary registry. 
Secondary 
Identifying 
Numbers 
IRAS: 222668 
NNUH R&D Number:  
UEA Reference: R202374 
Source 
of 
Monetary 
or 
Material 
Support 
NHIR Clinical Doctoral Fellowship 
ICA-CDRF-2015-01-050 
Sponsor 
Norfolk and Norwich University Hospitals NHS Foundation Trust,  
Contact 
for 
Public Queries 
Miss Catherine Gooday 
c.gooday@uea.ac.uk 
01603 591019 
NIHR Clinical Doctoral Fellow 
School of Health Sciences 
University of East Anglia 
Contact 
for 
Scientific 
Queries 
Miss Catherine Gooday 
c.gooday@uea.ac.uk 
01603 591019 
NIHR Clinical Doctoral Fellow 
School of Health Sciences 
University of East Anglia 
Short 
Title/Acronym 
CADOM 
Scientific Title 
A randomised feasibility study to assess the use of serial magnetic resonance 
imaging to reduce treatment times in Charcot neuroarthropathy in people with 
diabetes  
Countries 
of 
Recruitment 
United Kingdom 
Health 
Condition(s) 
or Problem(s) 
Studied 
The assessment of Charcot neuroarthropathy in people with diabetes 
Intervention(s) Intervention  
Serial use of MRI at 3, 6, 9 and 12 months to identify disease resolution and thus 
discontinue immobilisation in addition to standard care 
 
 
 

 
 
 
 
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Trial Protocol Defining outcome measures for acute Charcot neuroarthropathy in Diabetes and their 
use in assessing clinical management. Version  1.4 11th June 2020  
IRAS 222668 
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Standard Care 
Immobilisation discontinued on the basis of clinical remission determined by skin 
temperature measurement (Standard Care) 
Key Inclusion 
and Exclusion 
Criteria 
Target population: NHS patients with type 1 or type 2 diabetes and a diagnosis of new or 
suspected acute Charcot neuroarthropathy 
 
Inclusion Criteria: 
 
Participants who are willing and have capacity to give informed consent. 
 
People with diabetes as diagnosed by the WHO criteria  (Appendix 1) 
http://www.who.int/diabetes/publications/diagnosis_diabetes2011/en/ 
 
Age 18 years or over 
 
New or suspected new diagnosis of acute  CN (no previous incidence of 
acute CN within the last 6 months on the same foot) treated with off-
loading 
 
Understand written and verbal instructions in English 
 
Exclusion Criteria: 
 
People who have received a transplant and other patients receiving 
immunosuppressant therapy or using long term oral glucocorticoids other 
than in the routine management of glucocorticoid deficiency. Participants 
on a low doses of oral glucocorticoids (<10mgs for ≤7 days) are eligible to 
participate in the study. 
 
Participation in another intervention study on active CN 
 
Contra-indication for MRI 
 
Treatment for previous suspected CN on the same foot in the last 6 months 
 
Suspected or confirmed bilateral active CN at presentation 
 
Active osteomyelitis 
 
Previous contralateral major amputation 
 
Inability to have an MRI scan 
 
Patients receiving palliative care 
Study Type 
A multicentre, open labelled, two arm randomised controlled feasibility trial  
Date of First 
Enrolment 
September 2017 
Target Sample 
Size 
60 
Feasibility 
Outcomes  
 
The proportion of patients who meet the eligibility criteria 
 
The number of eligible patients recruited 
 
The number of participants in which an alternative diagnosis is made 
during the active phase of the trial 
 
The proportion of patients that withdraw or are lost to follow up. The term  
‘withdrawal’ encompasses two potential scenarios;  withdrawal due to loss 
of consent or withdrawal due to death 
 
Statistical parameters of the key outcome measures to inform a sample 
size calculation for a definitive trial (estimate of effect size) 
 
Ability to collect quality of life and resource use data 
Exploratory 
Analysis of 
Efficacy Outcomes 
 
Preliminary data on days with immobilisation 

 
 
 
 
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Trial Protocol Defining outcome measures for acute Charcot neuroarthropathy in Diabetes and their 
use in assessing clinical management. Version  1.4 11th June 2020  
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Clinical and 
Patient 
Reported 
Outcomes  
 
Progression of foot deformity 
 
Number of new ulcerations on the index foot 
 
Number of new ulcerations on the contralateral foot 
 
Number of new infections on the index foot  
 
Number of new infections on the contralateral foot  
 
Number and severity of falls (Hopkins Fall Grading System)1 
 
Number of minor and major amputations on the index foot at the end of 
the follow up phase of the study  
 
Number of minor and major amputations on the contralateral foot at the 
end of the follow up phase of the study  
 
The number of participants in each arm requiring further intervention for 
CN (e.g. further immobilisation) within 6 months of remission? 
 
Patient Reported Outcome Measures 
 
Level of pain (Numeric Pain Rating Scale) 
 
Health related quality of life (EQ-5D-5L and SF12) 
 
Hospital Anxiety and Depression Scale (HADS) 
 
Economic Evaluation 
 
Resource use (Collected through a patient diary) 
 
Qualitative 
Study (up to 
14 
participants) 
The qualitative study will explore:  
 
The patient’s experience of being treated for CN 
 
The patient’s views on the different approaches to monitoring Charcot 
neuroarthropathy used in this study 
 
 
 
 
 
 
 
 
 

 
 
 
 
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Trial Protocol Defining outcome measures for acute Charcot neuroarthropathy in Diabetes and their 
use in assessing clinical management. Version  1.4 11th June 2020  
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1.4 
Roles and responsibilities 
These membership lists are correct at the time of writing; please see terms of reference 
documentation in the TMF for current lists. 
1.4.1 
Protocol contributors 
Name 
Affiliation 
Role  
Catherine Gooday 
UEA 
Chief Investigator 
Dr Wendy Hardeman 
UEA 
Supervisor 
Professor Fiona Poland 
UEA 
Supervisor 
Professor Fran Game 
Derby Teaching Hospitals 
NHS FT. 
Supervisor & PI  
Professor Jim Woodburn 
Glasgow Caledonian 
University 
Supervisor 
Dr Erika Sims 
UEA 
Senior Clinical Trial Operations Manager 
Debbie Graver 
UEA 
Clinical Trials Project Manager 
Professor Lee Shepstone 
UEA 
Professor of Medical Statistics  
Professor Garry Barton 
UEA 
Professor of  Health Economics 
Dr Ketan Dhatariya 
NNUH 
Consultant Lead, Diabetic Foot Clinic 
Mrs Rachel Murchison 
NNUH  
Lead Podiatrist  
 
1.4.2 
Role of trial sponsor and funders 
Name 
Affiliation 
Role  
Julie Dawson 
NNUH 
Sponsor Representative 
Thom Marshall  
Programme Officer 
NIHR Trainees Coordinating Centre 
NIHR 
Funder Representative 
 
1.4.3 
Trial Team 
Name 
Affiliation 
Role and responsibilities 
Catherine Gooday 
UEA 
Overall responsibility for day to day management 
of the trial. Other responsibilities will include: 
recruiting patients, obtaining consent, collecting 
quantitative and qualitative data and facilitating 
practice development meetings. 
Dr Erika Sims 
UEA 
Responsible for providing operational oversight 
Martin Pond 
UEA 
Head of Data Management 
CTU Data Programmer 
UEA 
Programmer responsible for setting up trial 
database 
Professor Lee 
Shepstone 
UEA 
Statistical Advice  
Professor Fran Game 
Derby Teaching 
Hospitals NHS FT. 
Supervisor & PI at Derby 
Dr Ketan Dhatariya 
NNUH 
Consultant Lead, Diabetic Foot Clinic  

 
 
 
 
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NCTU_O_TaT_7_v3.0_ProtocolTemplate 
Trial Protocol Defining outcome measures for acute Charcot neuroarthropathy in Diabetes and their 
use in assessing clinical management. Version  1.4 11th June 2020  
IRAS 222668 
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1.4.5 
Trial Management Group 
Name 
Affiliation 
Role and responsibilities 
Catherine Gooday 
UEA/NNUH 
CI 
Dr Wendy Hardeman 
UEA 
Supervisor 
Professor Fiona Poland 
UEA 
Supervisor 
Professor Fran Game 
Derby Teaching 
Hospitals NHS FT. 
Supervisor and PI  
Professor Jim Woodburn 
Glasgow Caledonian 
University 
Supervisor 
Dr Erika Sims 
UEA 
Senior Clinical Trial Operations Manager 
TBC 
PPRIEs 
PPI 
TBC 
Patient Representative  PPI 
TBC 
NNUH 
Radiologist 
Dr Ketan Dhatariya 
NNUH 
Consultant Lead, Diabetic Foot Clinic 
Professor Lee Shepstone 
UEA 
Statistical Advice  
Martin Pond 
UEA 
Head of Data Management 
2  
Trial Diagram 
 
 
 
 
 

 
 
 
 
CADOM 
 
 
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Trial Protocol Defining outcome measures for acute Charcot neuroarthropathy in Diabetes and their 
use in assessing clinical management. Version  1.4 11th June 2020  
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3  
Abbreviations 
AE 
Adverse Event 
AR 
Adverse Reaction 
CI 
Chief Investigator 
CN 
Charcot neuroarthropathy 
CRF 
Case Report Form 
EQ5D 
Euroqol 5D 
EU 
European Union 
GCP 
Good Clinical Practice 
HADS 
Hospital Anxiety and Depression Scale 
HbA1c 
glycated haemoglobin 
HRQoL 
Health Related Quality of Life 
ITT 
Intention to Treat 
MRI 
Magnetic Resonance Imaging 
NNUH 
Norfolk and Norwich University Hospitals Foundation Trust 
NCTU 
Norwich Clinical Trials Unit 
NICE 
National Institute for Health and Care Excellence 
PI 
Principal Investigator 
PPI 
Patient and Public Involvement  
PIS 
Participant Information Sheet 
PSS 
Personal Social Services 
QA 
Quality Assurance 
QALY 
Quality Adjusted Life Year 
QC 
Quality Control 
QMMP 
Quality Management and Monitoring Plan 
QoL 
Quality of Life 
RCT 
Randomised Controlled Trial 
R&D 
Research and Development 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse Reaction 
SF-12 
Medical Outcomes Short-Form Health Questionnaire 
SF-36 
Medical Outcomes Short-Form Health Questionnaire 
WPD 
Working Practice Document  
TCC 
Total Contact Cast 
TMF 
Trial Master File 
TMG 
Trial Management Group 
TMT 
Trial Management Team 
ToR 
Terms of Reference 
UK 
United Kingdom 
USA 
United States of America 
VAS 
Visual Analogue Score 

 
 
 
 
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Trial Protocol Defining outcome measures for acute Charcot neuroarthropathy in Diabetes and their 
use in assessing clinical management. Version  1.4 11th June 2020  
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4 
Glossary 
 
Charcot Neuroarthropathy commonly referred to as the Charcot foot, is a condition affecting the bones, 
joints, and soft tissues of the foot and ankle, characterized by inflammation in the earliest phase 
Major amputation is an amputation above the ankle 
Minor amputations is an amputation below the ankle 
 
 
 

 
 
 
 
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NCTU_O_TaT_7_v3.0_ProtocolTemplate 
Trial Protocol Defining outcome measures for acute Charcot neuroarthropathy in Diabetes and their 
use in assessing clinical management. Version  1.4 11th June 2020  
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5 
Introduction 
5.1 
Background and Rationale 
 
Worldwide the incidence of diabetes is rising. In 2013 the estimated number of people with diabetes 
worldwide was 382 million people2. The number of people with diabetes in the UK has risen from 1.4 
million in 1996, to 3.6 million in 2016. By 2035 the estimated prevalence of diabetes in the UK will be 
7.4%2 which equates to 4.9 million people living with diabetes.  
Longstanding poorly controlled diabetes can lead to complications.  Macro-vascular disease causes 
strokes and heart attacks. People with diabetes are at twice the risk of developing strokes and heart 
attacks compared to people who do not have diabetes. Diabetes can also cause peripheral arterial 
disease.  Microvascular disease is associated with kidney disease, eye disease, and peripheral 
neuropathy. Both peripheral neuropathy and peripheral arterial disease can lead to diabetes related 
foot complications3. 
Diabetic foot complications are common. They have also been shown to be potentially life 
shortening or even life-threatening4. They place an enormous financial burden on people with 
diabetes, their families, and the healthcare sector5. Management of the diabetic foot disease 
represent 0.6-0.7% of total NHS expenditure which equates to £1 in every £1405 . People with 
diabetes are 23 times more likely to undergo an amputation compared to those without diabetes6. 
CN is a devastating complication of diabetes which primarily affects the foot and ankle. It is a 
relatively painless and progressive inflammatory destructive arthropathy in a single or in multiple 
joints due to underlying neuropathy7. The pathogenesis is multifactorial but it is often precipitated 
by minor trauma in the foot, inflammation secondary to foot ulceration, infection or surgery, which 
goes unrecognised by the patient due to loss of usual sensation8,9.  It was first described 140 years 
ago however it still remains a poorly understood and frequently overlooked complication of 
diabetes10. Population based studies have estimated a life time cumulative incidence of CN of 0.4% 
to 1.3% in people with diabetes rising to as much as 13% in high risk patients11.  
The clinical manifestation of CN is unexplained unilateral inflammation of the foot and/or ankle with 
or without pain. If there has been a delay in the patient seeking medical advice deformity may 
already be present12. The aim of treatment is to stop the inflammatory process, relieve pain and 
maintain foot architecture13. The international consensus is that the foot should be immobilised in a 
non-removable device with weekly or fortnightly review 14. This immobilises the foot, minimising the 
potential for any further damage. Immobilisation is continued until resolution/remission, this is 
when there are no longer clinical signs of inflammation, and x-rays are stable with signs of 
consolidation15. 
Late diagnosis or inadequate off-loading can lead to significant foot deformity, which is the 
precursor of foot ulceration. An observational study from the USA showed that delayed referral by 
primary care practitioners to secondary care was associated with a higher chance of CN progressing 
and subsequent complications developing16. Another observational study reported ulceration rates 
of 37%. 6% of patients developed ulceration during the acute phase of CN, and 31% when the CN 

 
 
 
 
CADOM 
 
 
NCTU_O_TaT_7_v3.0_ProtocolTemplate 
Trial Protocol Defining outcome measures for acute Charcot neuroarthropathy in Diabetes and their 
use in assessing clinical management. Version  1.4 11th June 2020  
IRAS 222668 
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was chronic as a result of footwear design issues, delayed delivery of footwear or patient compliance 
with wearing the footwear17.  Ulceration on a CN foot is extremely difficult to heal, the situation is 
further complicated when infection develops increasing the risk of amputation.  Annual major 
amputation rates for CN  vary between centres from 2.7%-  6.6% 18,19. In many cases, people can no 
longer provide for themselves or their families.  Only 50% of patients who have had a major 
amputation survive for a further two years 20. Mortality is increased; average life expectancy is 
reduced by 14.4 years compared to the general UK population21 
Studies from the UK have demonstrated a median time to remission of between 9-12 months9,22,23. 
However studies from the USA demonstrate considerably shorter immobilisation times between 3-5 
months24–27. Results from Brazil and Germany show remission times of 3-12 months and 3-6 months 
respectively28,29. Such a prolonged period of immobilisation is a source of enormous social limitation 
and consequent reduction in quality of life for the patient30. The literature suggests the duration of 
immobilisation may be influenced by the anatomical location of the CN and the stage of CN when 
immobilisation is initiated31.  
Intervention and outcome studies, based in a few centres of excellence in CN, are limited by 
retrospective design, case note review methods, and small participant numbers (typically in the 
range of 9-55) 9,22–27.  In many studies the lack of standardisation of treatment approaches and 
outcomes further limits advances in the prevention and care of CN9.  
Inconsistencies exist with respect to level of activity prescribed during treatment and the use of 
adjunct treatments such as walking aids and supports.  
As the disease process of CN progresses signs of inflammation resolve however, the clinician faces 
the challenge of determining when complete remission has occurred. The presence of neuropathy 
means that subjective symptoms are often absent and the signs of inflammation can be subtle and 
are sometimes difficult to grade. Pre-treatment temperature differences between the feet have 
been shown to vary at presentation ranging from 5.1 to 14.7 °C 24,32. 
The management guidelines from the most recent systematic review are that immobilisation should 
be continued until the temperature difference between the feet is less than 1-2 °C, and no further 
radiological changes on imaging have occurred. However this recommendation is only based on level 
IV evidence – case series15. Clinical and radiographic diagnosis of CN is difficult 33, normal 
radiographs at presentation do not exclude CN34. Temperature differences have been shown to 
correlate with radiological changes32.  
There is variability in how different teams have measured the temperature difference between the 
feet. The most detailed protocol for measuring temperature discrepancy is described by Armstrong 
et al (1997). It requires a 15 minute acclimatisation period, controlled ambient air temperature, and 
readings collected from nine different anatomical sites on each foot32. This protocol is not easily 
achievable in a busy clinical environment, with time constraints and an inability to control room 
temperatures. These factors may have prevented its wide spread adoption, as many case series 
audits from clinical teams show that they have simplified the approach. One observational study 

 
 
 
 
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which did use this protocol achieved disease resolution/remission in 25 of 28 patients referred with 
acute CN, with a re-exacerbation rate of zero after one year follow up28. Other researchers have 
used different protocols to assess temperature,  one study used eight sites on each foot, with three 
readings taken at each site and an average calculated35. Another study used the highest reading in 
each foot36. In a number of studies disease resolution/remission has been defined as a temperature 
difference of ≤2oC on just one occasion. Other studies have required a temperature difference of 
≤2oC to be maintained for two37 or more consecutive appointments23.  These differences could 
extend treatment times by 2-6 weeks as patients need to attend two or more clinic appointments 
before the foot is judged to be in resolution/remission.  
The complications of the diabetic foot, osteomyelitis and CN, have well described appearances on 
MRI. The use of MRI in determining a diagnosis of CN in the early stages of disease when no signs are 
evident on plain radiology is well recognised38. However serial MRI as a tool to monitor for signs of 
disease remission is not widely used in routine clinical practice and was not recommended in the 
systematic review published in 201515. Recently it been suggested that the findings on MRI should be 
adopted as the criterion standard for establishing disease activity and remission39.  MRI has the 
greatest potential to monitor the effect of treatment since the findings are a more direct reflection 
of the degree of tissue and bone inflammation. The literature suggests that MRI maybe superior to 
clinical techniques in determining the timing of termination of immobilisation. A small study 
demonstrated that mean healing time was significantly related to the baseline contrast medium 
uptake40. A significant correlation of intensity of bone marrow oedema in MRI and clinical measures  
of soft tissue oedema and pain was found in another study41. Another small study suggested that 
semi-quantitative scoring for bone marrow oedema and fracture on MRI might be useful in 
monitoring treatment of CN42.  
There are no existing qualitative studies that have been undertaken exploring the patients 
experience and perspectives on the management of CN. It is difficult to make direct comparisons 
from the published literature on the impact of a diagnosis of CN on the patient. There is evidence 
that CN has a negative effect on quality of life (QoL) 43, compared to those with uncomplicated 
diabetes but also in comparison to those with chronic heart failure and Parkinson’s disease44. In one 
small study it was suggested that the health status in CN patients was comparable to that following 
minor lower extremity amputation30. Assessing the impact of CN on QoL is important to help 
establish the optimal methods of treatment and timing of intervention. There are currently no 
validated disease specific patient reported outcome measures (PROMs) for CN. A systematic review 
on measures of health related quality of life (HRQoL) could not recommend a specific tool for use in 
diabetes related foot disease45. The most widely used tool was the SF-36, although current research 
into diabetic foot disease favours the use of SF-12 as it is shorter yet valid alternative to the SF-36 
which is considered by many researchers as too long to administer to studies with large samples 
such as a future definitive RCT.  A recent study comparing the outcomes of SF-12 and SF-36 in 
patients with diabetic foot disease found substantial agreement when comparing the component 
score for each tool46.  In England the National Institute for Health and Care Excellence (NICE) favours 
the EQ-5D. However the use of this particular measure in the treatment of CN may be limited as the 
actual treatment of immobilisation and rest reduces mobility one of the 5 key components of the 

 
 
 
 
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EQ-5D. The systematic review specifically recommended a more detailed analysis of QoL measures 
in CN45. 
The aim of this study is to explore the use of serial MRI in an attempt to reduce the duration of 
immobilisation of the foot and thereby reduce the morbidity associated with its routine 
management and reduce costs. The project will have two components: a feasibility study and 
embedded within this a qualitative study of the patient’s perspective of the experience of being 
diagnosed with CN and undergoing treatment.  
5.1.1 
Explanation for choice of comparators 
Participants will be randomised to one of two arms; 
(a) Serial use of MRI at 3, 6, 9 and 12 months to identify disease resolution and thus discontinuation 
of immobilisation plus standard care (intervention) 
(b) Immobilisation discontinued on the basis of clinical remission determined by skin temperature 
measurement, which triggers an MRI (standard care) 
The complications of the diabetic foot, osteomyelitis and CN, have well described appearances on 
MRI. The use of MRI in determining a diagnosis of CN in the early stages of disease when no signs are 
evident on plain radiology is well recognised47. It has recently been suggested that the findings on 
MRI should be adopted as the criterion standard for establishing disease activity and remission in 
CN38. This is because MRI has the greatest potential to allow monitoring the effect of treatment 
since it shows bone marrow oedema (inflammation). The majority of clinicians use the measurement 
of temperature described earlier, despite the increasing availability of MRI.  
The literature suggests that MRI maybe superior to clinical techniques in determining the timing of 
termination of immobilisation. A small study demonstrated that mean healing time was significantly 
related to the baseline contrast medium uptake. A significant correlation between intensity of bone 
marrow oedema in MRI and clinical measures of soft tissue oedema and pain was found in another 
study41. A further small study suggested that semi quantitative scoring for bone marrow oedema and 
fracture on MRI might be useful in monitoring treatment of CN42. 
There is a need for the use of MRI to be formally evaluated in a trial. This trial aims to explore the 
feasibility of using serial MRI in an attempt to reduce the duration of immobilisation of the foot. 
5.2 
Objectives 
The primary objective of this feasibility study is to determine the feasibility of conducting a large trial 
to investigate the use of serial MRI scanning in the management of CN. Data will be gathered 
regarding clinical efficacy during this trial, though it will not be powered for these outcomes – an 
exploratory analysis of these clinical outcomes will be performed.  
5.3 
Trial Design 
This study will be a 2-arm open labelled randomised controlled study. It will investigate the 
feasibility of using serial MRI to monitor CN. The study will last for 3 years. There will be an 18-

 
 
 
 
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month recruitment period with a further 12 month intervention and 6 month follow up period (18 
months)  
6 Methods 
6.1 
Site Selection 
The trial sponsor has overall responsibility for site and investigator selection and has delegated this 
role to the Chief Investigator. 
6.1.1 
Study Setting 
Participants will be identified at the point of a suspected diagnosis of CN from two diabetic foot 
clinics based in secondary care in the UK. Initially the collaborating centres identified will be the 
Norfolk and Norwich University Hospitals NHS Foundation Trust and Derby Hospitals NHS 
Foundation Trust. As the study progresses the involvement of other centres will be considered, as 
necessary to meet the recruitment target.    
6.1.2 
Site/Investigator Eligibility Criteria 
Once a site has been assessed as being suitable to participate in the trial, the trial team will provide 
them with a copy of this protocol. 
To participate in the CADOM trial, investigators and trial sites must fulfil a set of criteria that have 
been agreed by the CADOM Trial Management Group (TMG) and that are defined below. 
Eligibility criteria: 
 
A named clinician who is willing and appropriate to take Principal Investigator responsibility 
 
Suitably trained staff available to recruit participants, and enter data  
 
The centre is able to recruit suitable number of patients (20 per annum) 
 
Timely access to MRI scanning  
Trial sites meeting eligibility criteria and that are accepted by the TMG as being suitable to recruit to 
the trial, will be issued with the CADOM Trial Master File (TMF) documentation to use when 
considering whether they have the capacity and capability to participate 
6.1.2.1 Principal Investigator’s (PI) Qualifications and Agreements 
The investigator(s) must be willing to sign a compliance statement to comply with the trial protocol 
(confirming their specific roles and responsibilities relating to the trial, and that their site is willing 
and able to comply with the requirements of the trial). This includes confirmation of appropriate 
qualifications, agreement to comply with the principles of GCP, to permit monitoring and audit as 
necessary at the site, and to maintain documented evidence of all staff at the site who have been 
delegated significant trial related duties. 

 
 
 
 
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6.1.2.2 Resourcing at site 
The investigator(s) should be able to demonstrate a potential for recruiting the required number of 
suitable subjects within the agreed recruitment period (i.e. the investigator(s) regularly treat(s) the 
target population). They should also have an adequate number of qualified staff and facilities 
available for the foreseen duration of the trial to enable them to conduct the trial properly and 
safely.  
Sites will be expected to complete a delegation of responsibilities log and provide staff contact 
details.  
The site should have sufficient data management resources to allow prompt data return to NCTU.  
6.2 
Site approval and activation 
On receipt of the signed Clinical Trial Agreement, approved delegation of responsibilities log and 
staff contact details, written confirmation will be sent to the site PI. The CI will notify the PI in writing 
of the plans for site initiation. Sites will not be permitted to recruit any patients until a letter for 
activation has been issued. The CI will be responsible for issuing this after an NCTU green light to 
recruit process has been completed. 
The site must conduct the trial in compliance with the protocol as agreed by the Sponsor and, by the 
regulatory authority(ies) (as appropriate), and which was given favourable opinion by the Research 
Ethics Committee (REC). The PI or delegate must document and explain any deviation from the 
approved protocol, and communicate this to the trial team at NCTU. 
A list of activated sites may be obtained from the research fellow. 
6.3 
Participants 
6.3.1 
Eligibility Criteria 
Patients with previous major amputation or active osteomyelitis have been excluded. This is because 
it prevents the comparison of temperature differences between the feet (standard care). This is 
either due to the possibility of bilateral inflammation confounding the results or the absence of a 
comparator limb. 
6.3.1.1 Participant selection 
There will be NO EXCEPTIONS (waivers) to eligibility requirements at the time of randomisation. 
Questions about eligibility criteria should be addressed PRIOR to attempting to randomise the 
participant.  
The eligibility criteria for this trial have been carefully considered and are the standards used to 
ensure that only medically appropriate participants are entered. Participants not meeting the 
criteria should not be entered into the trial for their safety and to ensure that the trial results can be 
appropriately used to make future treatment decisions for other people with similar diseases or 
conditions. It is therefore vital that exceptions are not made to these eligibility criteria. 

 
 
 
 
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Participants will be considered eligible for enrolment in this trial if they fulfil all the inclusion criteria 
and none of the exclusion criteria as defined below. 
6.3.1.2 Participant Inclusion Criteria 
 
Participants who are willing and have capacity to give informed consent. 
 
People with diabetes as diagnosed by the WHO criteria  
http://www.who.int/diabetes/publications/diagnosis_diabetes2011/en/ 
 
Age 18 years or over 
 
New or suspected  diagnosis of acute CN (no previous incidence of acute CN within the last 6 
months on the same foot) treated with off-loading 
 
Understand written and verbal instructions in English 
 
6.3.1.3 Participant Exclusion Criteria 
 
People who have received a transplant and others receiving immunosuppressant therapy or 
using long term oral glucocorticoids other than in the routine management of glucocorticoid 
deficiency. Participants on a low doses of oral glucocorticoids (<10mgs for ≤7 days) are 
eligible to participate in the study. 
 
Participation in another intervention study on active CN 
 
Contra-indication for MRI 
 
Treatment for previous suspected CN on the same foot in the last 6 months 
 
Suspected or confirmed bilateral active CN at presentation 
 
Active osteomyelitis at randomisation 
 
Previous contralateral major amputation 
 
Inability to have an MRI scan 
 
Patients receiving palliative care 
6.3.1.4 Eligibility Criteria for Individuals Performing the Interventions 
The clinicians working in the diabetic foot clinic will be asked to become members of the research 
team and as such will be carrying out the trial. They will be identified on the delegation log and must 
have received study specific training to ensure consistency in the way the monitoring is completed.  
6.3.1.5 Co-enrolment Guidance 
Participants who are involved in other studies where there is a known effect or contraindication to 
investigation of CN will also be excluded. The CI should be contacted to discuss any concerns over 
eligibility prior to recruitment. If participants are already involved in trials with exposure to radiation 
then their eligibility for inclusion in this trial will need to be raised with the CI and discussed by the 
TMG. 
6.3.1.6 Screening Procedures and Pre-randomisation Investigations 
Written informed consent to enter and be randomised into the trial must be obtained from 
participants, after explanation of the aims, methods, benefits and potential hazards of the trial and 
BEFORE any trial-specific procedures are performed or any blood is taken for the trial. The only 

 
 
 
 
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procedures that may be performed in advance of written informed consent being obtained are those 
that would be performed on all patients as part of standard care.  
6.4 
Interventions - Arm A and Arm B 
All patients will attend the secondary care clinic for fortnightly visits or as per current standard care, 
outlined in 6.4.5.  Additional visits maybe arranged depending on clinical need. Procedures which are 
part of standard care will be completed according to trial specific WPD. 
In this trial a standardised assessment of serial temperature measurements will be carried out. This 
will be completed according to trial WPD. The temperature of both feet will be recorded at intervals 
of 5 minutes starting at the initial removal of the off-loading device for up to 15 minutes. This will 
assess acclimatisation and the period of equilibration needed for stabilisation of temperature. 
1) Following initial removal of the off-loading device 
2) Following a 5 minute resting period 
3) Following a 10 minutes resting period 
4) Following a 15 minutes resting period 
The sites where the temperature will be recorded reflect the current classification tool developed by 
Sanders and Frykberg48; 
1. distal and proximal interphalangeal joints, metatarsophalangeal, tarsometatarsal joints 
2. naviculo-cunieform joints, talo-navicular joint 
3. calcaneocuboid joint 
4. ankle joint, subtalar joint 
5. calcaneus 
One X-ray will be additional to standard care this will be taken 6 months post remission.  Participants 
who do not reach this time point within the 18 month intervention and follow-up period will not 
have this X-ray. This will enable the progression of foot deformity to be assessed. If a participant 
becomes pregnant during the study they will not have the additional X-ray and will be excluded from 
the analysis of the progression of foot deformity.  Two members of the research team will 
independently evaluate the images to assess the progression of foot deformity. Inter-rater reliability 
will be assessed.  The X-rays will be anonymised prior to evaluation to ensure the researcher is 
blinded to participant number and site. The anonymised scans will also be randomly sequenced to 
avoid bias.  
To allow comparison all X-ray and MRI images will be taken as per trial WPD.  
The participants will also be asked to complete the following questionnaire/assessments. These will 
be completed at randomisation, 3 monthly until remission (3, 6, 9 and 12 months), 1 month after 
remission, and at 6 months post remission;   
1) Pain in the foot and/or leg measured using a numerical 0-10 visual analogue scale 
2) Health related quality of life assessed by the Medical Outcomes Short-Form Health 
Questionnaire (SF12)  

 
 
 
 
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3) Psychological health status measured using the Hospital Anxiety and Depression Scale 
(HADs)  
4) EQ-5D-5L 
Patients will be issued with a patient diary at every visit and ask to complete it over the next 
fortnight. At each visit the old patient diary will be collected and a new one provided until the next 
visit. 
6.4.1 
Arm A (Intervention – Standard Care and Serial MRIs) 
Immobilisation discontinued on the basis of MRI defined disease resolution at 3, 6, 9 or 12 months  
In the intervention arm participants will receive additional MRIs at 3, 6, 9 and 12 months. Patients 
randomised to serial MRI will not undergo further MRI once remission has been diagnosed i.e. if 
remission is diagnosed at 6 months the MRI at 9 and 12 months will not occur. 
6.4.2 
Arm B (Control – Standard Care and one additional MRI) 
Immobilisation discontinued on the basis of clinical remission determined by skin temperature 
measurement and MRI. In the standard care arm participants will receive one additional MRI when 
the temperature measurements, X-ray and/or signs and symptoms indicate to the clinical team that 
the foot is in remission.  
A temperature difference of ≤ 2ºC which is maintained or improves on two separate consecutive 
occasions for a period of ≥4weeks will be the indicator to arrange the second MRI, to confirm the 
diagnosis of remission.  
If participants in either arm of the trial have not reached remission at the end of the 12 month active 
phase of the study they will exit the study. Ongoing standard care will be provided by their clinical 
team. 
6.4.3 
Qualitative Study 
There are no existing qualitative studies exploring participant’s experiences and perspectives on the 
management of CN.   
The purpose of this qualitative study is to understand the personal experiences of being treated for 
CN and the participant’s experience of being involved in this trial. 
The objectives are twofold; 
1. To describe the impact of being treated for CN on participants  
The domains of the questions will include: 
 
The personal experience of being treated for CN (e.g. impact on day to day functional 
activities, employment, leisure pursuits, ability to conduct physical activity, sense of self and 
self-worth) 
 
The impact this has had on family members and relationships 

 
 
 
 
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 
The impact on social participation. 
 
2. Identify ways of refining the trial protocol to improve participant’s experience of 
being involved in any future research; increasing recruitment and retention. 
The domains of the questions will include: 
 
The perceived accuracy of the different approaches to disease monitoring used in the study 
 
The perceived burden (or otherwise) of the different approaches to disease monitoring 
 
The participants willingness to be randomised 
 
The participant’s ideas for improvements that could be made to the study to enhance 
recruitment and retention 
In collaboration with PPI representatives these domains will be developed into an indicative topic 
guide.  
As part of the consent form for the main trial participants will be asked whether they would be 
happy to be approached during the course of the trial to participate in an interview.  
The interview will take the format of an interpretative descriptive approach. 
A purposive sample of 10-14 participants across both sites will be selected. Diversity across the 
sample will be ensured by taking into account randomisation arm, treatment times, employment 
status, gender and age.  
Participants approached for the Qualitative study will receive a further information sheet explaining 
the purpose of the interview and would be consented prior to the interview taking place.  
Interviews will last approximately 30-40 minutes in a place of the participants choosing. The 
interviews will be audiotaped (with participants’ permission) and transcribed in full. 
6.4.4  Compliance and Adherence 
6.4.5  Concomitant Care 
All patients will receive treatment as standard for their CN regardless of randomisation into this trial. 
This will be recorded on the eCRf and form part of the data for this study;  
6.4.6 
Protocol Treatment Discontinuation 
In consenting to the trial, participants are consenting to trial treatments, trial follow-up and data 
collection. However, an individual participant may stop treatment early or be stopped early for any 
of the following reasons: 
 
Adverse event which in the opinion of the treating clinician makes them unsuitable for 
continued participation in the study 
 
Inter-current illness that prevents further treatment 

 
 
 
 
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 
Any change in the participant’s condition that in the clinician’s opinion justifies the 
discontinuation of treatment 
 
Participants who become pregnant during the trial can continue in the trial. They will be 
excluded from the final X-ray at 6 months post remission.  
 
Withdrawal of consent for treatment by the participant 
 
Participant who moves away from the area or decides to transfer to a different hospital for 
the management of their CN. 
As participation in the trial is entirely voluntary, the participant may choose to discontinue trial 
treatment at any time without penalty or loss of benefits to which they would otherwise be entitled. 
Although not obliged to give a reason for discontinuing their trial treatment, a reasonable effort 
should be made to establish this reason, whilst remaining fully respectful of the participant’s rights. 
Participants who discontinue protocol treatment, for any of the above reasons, should remain in the 
trial for the purpose of follow up and data analysis.  
6.5 
Outcomes 
6.5.1  Feasibility Outcomes  
 
The proportion of patients who meet eligibility criteria 
 
The number of eligible patients recruited 
 
The number of participants in which an alternative diagnosis  of the foot disease is made 
during the intervention phase of the trial 
 
The proportion of patients that withdraw or are lost to follow up. The term  ‘withdrawal’ 
encompasses two potential scenarios;  withdrawal due to loss of consent or withdrawal due 
to death 
 
Statistical estimation for key outcome measures to inform a sample size calculation for a 
definitive trial    
 
Feasibility of quality of life and resource data collection  
 
6.5.2  Exploratory Clinical Outcomes 
 
Days with immobilisation, measured at the end study  
 
Progression of foot deformity as documented by measuring radiological foot alignment 
angles. All x-rays will be taken in a weight bearing position with standard views as per WPD. 
Comparison from baseline, diagnosis of remission, and six months after remission. The 
angles that will be assessed are: 
• 
Calcaneal Inclination – the angle formed by the horizontal and a line from the 
base of the heel and inferior cortex of the calcaneus 
• 
Talar Declination –the angle between the line originating from the centre of the 
talus bisecting the talar neck and head and the weight bearing plantar surface 
from the calcaneus to the 5th metatarsal 
• 
Talo-first metatarsal angle – the angle between the line originating from the 
centre of the talus bisecting the talar neck and head, and the line through the 
longitudinal axis of the first metatarsal. 

 
 
 
 
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• 
Hindfoot-forefoot angle - the angle between the talocalcaneal bisector and the 
second metatarsal shaft 
• 
Cuboid height (mm) - the distance from the plantar aspect of the cuboid to a 
horizontal line drawn from the plantar calcaneal tuberosity to the fifth 
metatarsal head. 
Patients who have undergone previous minor amputation and/or previous orthopaedic surgical 
fixation of the foot altering/removing the anatomical landmarks of the foot will be excluded from 
this analysis due to the absence of bony landmarks.  
At each study visits the following will be measured and recorded on the eCRF: 
 
Number of new ulcerations on the index foot 
 
Number of new ulcerations on the contralateral foot 
 
Number of new infections on the index foot  
 
Number of new infections on the contralateral foot  
 
Number and severity of falls (Hopkins Fall Grading System)1 
 
Number of minor and major amputations on the index foot at the end of the follow up phase 
of the study  
 
Number of minor and major amputations on the contralateral foot at the end of the follow 
up phase of the study  
 
The number of participants in each arm requiring further intervention for CN (e.g. further 
immobilisation) within 6 months of remission 
6.5.3  Patient Reported Outcome Measures 
The following outcomes will be collected at randomisation, and three monthly until patient is in 
remission. They will also be collected 1 month and 6 months post remission: 
 
Pain in the foot, ankle or leg measured, using the Numeric Pain Rating Scale.  
 
Health related quality of life assessed by the Medical Outcomes Short-Form Health 
Questionnaire (SF12)  
 
Psychological health status measured using the Hospital Anxiety and Depression Scale 
(HADs)  
 
EQ-5D-5L 
 
Economic Evaluation – Reported through a patient diary  
6.5.4  Qualitative Study  
The following will be explored in a patient interview with up to 14 participants which will take place 
one month after remission has been diagnosed.  
 
The participants’ experience of being treated for CN measured 
 
The participants’ views of the different interventions used in the study measured  

 
 
 
 
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6.6 
Participant Timeline   
 
  
6.7  
Patient Assessments 
Written informed consent to enter the trial must be obtained from participants after explanation of 
the aims, methods, benefits, and potential hazards of the trial and BEFORE any trial specific 
procedures are performed. The only procedures that may be performed in advance of written 
consent being obtained are those that would be performed on all patients in the same situation as 
standard care. 
 
If the clinical team consider that a patient may be eligible, the patient information sheet should be 
handed to the patient and they should be given adequate time to consider if they wish to consent.  
 
The tests and investigation as per the study protocol will be in addition to all the other treatment as 
standard, offered to patients with CN. 
 
6.7.1  Randomisation Visit 
These visits will take place in secondary care clinics.  
 
Standard Care 
 
The off-loading device will be provided, if one has already been provided it will be removed 
and the foot/leg checked for any problems 
 
Assessment of neuropathy using the 10g monofilament and neurotheisometer 
Remission
Visit Number
1
6
11
18
25
FUV1
FUV2 
FUV3
FUV4
month
3m
6m
9m
12m
1month
2months
3months
6months
Week **
0
2 weekly
W12
2 weeky
26
2 weekly
40
2 weekly
52
Check In/exclusion criteria
*
Hand out PIS
*
Consent 
*
Randomisation
*
Medical History
*
Foot Surgical history
*
Medication
*
*
*
*
*
*
*
*
*
*
*
*
*
*
Record any amputation/s
*
*
*
*
*
*
*
*
*
*
*
*
*
*
Record any infection/s
*
*
*
*
*
*
*
*
*
*
*
*
*
*
Record any ulceration/s
*
*
*
*
*
*
*
*
*
*
*
*
*
*
Record any falls
*
*
*
*
*
*
*
*
*
*
*
*
*
*
Hand out patient diary
*
*
*
*
*
*
*
*
*
*
Collect & upload diary 
*
*
*
*
*
*
*
*
*
Foot temperatures
*
*
*
*
*
*
*
*
*
*
*
*
*
*
MRI (usual care) **
*
*
MRI (Intervention arm) **
*
*
*
*
*
Classification 
*
Neuropathy Assess
*
Vascular Assess
*
BMI
*
*
*
*
*
*
*
HbA1c (use existing if <3months)
*
Pain VAS
*
*
*
*
*
*
*
HADS
*
*
*
*
*
*
*
SF-12
*
*
*
*
*
*
*
EQ5D
*
*
*
*
*
*
*
Study specific X-ray
*
                   Duration of active phase of treatment will be variable
Patient Interview s
Follow  Up  after remission diagnosed 
Active Phase (fortnightly visits throughout active phase of trial) 

 
 
 
 
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 
Palpation of foot pulses 
 
Measurement of ABPI  
 
BMI recorded 
 
Measurement of HbA1c if not previously tested in the last 3 month 
 
Skin and nail care treatment given as necessary  
 
Treatment of any underlying wounds, ulceration and/or infection 
 
The off-loading device will be re-applied 
 
Standard Care (Plus) – these tests and investigations are part of standard care but will be carried our 
according to trial WPDs. This will ensure standardisation across the site. 
 
X-ray of the affected foot 
 
MRI of the affected foot 
 
Foot temperature assessment 
 
Study Specific Procedures 
 
The following questionnaires will be administered; 
o Health related quality of life assessed by the Medical Outcomes Short-Form Health 
Questionnaire (SF12) 
o Psychological health status measured using the Hospital Anxiety and Depression 
Scale (HADs) 
o EQ-5D-5L 
 
Participants will also be asked to complete a VAS to assess the pain they have experienced in 
their foot, ankle or leg over the last two weeks 
 
At each visit a patient diary will be issued and participants asked to complete it recording 
other visits to health care professionals. It will then be collected at the next visit and another 
one issued.  
 
 
 
6.7.2  The “active phase” – up to 12 months 
These visits will take place in the participant’s usual place of care (secondary care). Participants will 
attend for fortnightly visits. Standard care and study specific procedures will be carried out and 
recorded on the eCRF. 
 
Study Specific Procedures 
 
The temperature assessment as per the WPD 
 
The participant diary will be collected and another issued for participants to complete over 
the next 2 weeks, until their next study visit.  
 
In both arms remission will be defined as an absence of sub-chondral bone marrow oedema on MRI, 
as reported by a specialist musculoskeletal radiologist and/or the absence of clinical signs and 
symptoms of CN. The clinical team will interpret the results of the MRI report to determine 
remission. As per standard care at this point patients will have a foot and ankle X-ray. 

 
 
 
 
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Participants who develop bilateral CN during the study can continue in the trial. The trigger to 
arrange the MRI in the standard care arm will be based on the absence of signs and symptoms of 
active CN as assessed by the clinical team.   
Patients randomised to A (Intervention – Serial MRI) 
Patients randomised to the intervention group will have an MRI of their foot and ankle three 
monthly (at 3, 6, 9 and 12 months) until the CN has settled. Where possible the scan should be 
scheduled to coincide with study visits to minimise the number of additional hospital visits.  
For participants in the intervention arm if the MRI report indicates to the clinical team that the CN is 
not in remission participants will continue in the active phase of the study, up to a maximum of 12 
months.  
Patients randomised to B (Standard Care) 
Patients randomised to the standard care will undergo an MRI once the temperature difference 
between their feet is ≤ 2ºC on two separate occasions at least four weeks apart. 
For participants in the standard care arm if the MRI report indicates to the clinical team that the CN 
is not in remission participants off-loading will be recommenced. Participants will continue in the 
follow up phase as per the trial protocol.  
6.7.3  At three, six, nine and 12 months 
In addition to standard care the following questionnaires will be administered to participants in both 
trial arms.  Health related quality of life assessed by the SF-12, Psychological health status measured 
using the HADs and the EQ-5D-5L. Participants will also be asked to complete a VAS to assess the 
pain they have experienced in their foot, ankle or leg over the last 3 months. The three monthly 
assessments will only continue until the patient is in remission. Once the patient is in remission they 
will move to the follow up phase of the study.  
6.7.4  Follow up phase 
In both arms once remission is confirmed by the MRI patients will then enter a 
rehabilitation/weaning phase. They will be transferred into a less restrictive off-loading device and 
then finally into footwear as per standard care. Participants will continue to attend for monthly trial 
visits for 3 months to monitor for any sign of relapse. The final visits will be at 6 months post 
remission. Standard care will continue to be provided. 
At each visit study specific procedures will be carried out: 
 
The temperature will be assessed as per the WPD 
 
The participant diary will be collected and another issued for participants to complete until 
their next study visit. (This is only for the first three follow-up visits)  
 
In addition to standard care and study specific procedures the participant will be asked to complete 
the following questionnaires and additional tests/investigations: 
 
Follow Up - Month 1: VAS, SF-12, HADS and EQ-5D-5Lwill be completed.   

 
 
 
 
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Follow UP Month 6: VAS, SF-12, HADS and EQ-5D-5Lcompleted.  BMI will be recorded and an X-ray 
of the foot and/or ankle will be taken. 
Relapse will be defined as a temperature difference of >2°C compared to the contralateral foot 
maintained for two or more occasions or further changes on imaging15. As per standard care the final 
decision as to whether the participant has relapsed will be at the discretion of the clinic team. If this 
occurs, then the participant will then recommence off-loading with a non-removable device.  They 
will continue to be followed up as per the study protocol.  
6.7.5  Alternate Diagnosis 
The diagnosis of CN can sometimes be difficult, and a confirmed diagnosis may take several weeks to 
reach. As per standard care all participants will be treated for CN until it is proven otherwise. If 
during the course of the trial the clinical team treating the participant decide on an alternative 
diagnosis then the participant will exit the study. Follow-up care will be provided by the appropriate 
clinical team.  
 
6.7.6 
Early Stopping of Follow-up 
If a participant chooses to discontinue their trial treatment, they should continue to be followed up 
as per current standard care. This will be as close as possible to the follow-up schedule defined in 
the protocol, providing they are willing. They should be encouraged and facilitated not to leave the 
whole trial, even though they no longer continue with the trial treatment. If, however, the 
participant exercises the view that they no longer wish to be followed up either, this view must be 
respected and the participant withdrawn entirely from the trial. NCTU should be informed of the 
withdrawal in writing using the appropriate CADOM trial documentation. Data already collected will 
be kept and included in analyses according to the intention-to-treat principle for all participants who 
stop follow up early.  
Participants who stop trial follow-up early will not be replaced. 
6.7.7 
Participant Transfers 
If a participant moves from the geographical area, making continued follow up at their consenting 
centre inappropriate, then it will not be appropriate for the patient to continue in the trial.  
6.7.8 
Loss to Follow-up 
Contact details will be stored in the patient records and usual hospital procedures will be used to 
contact the patient about follow up visits. If this is without success, the patient will be recorded as 
lost to follow up. Number of patients where this has occurred will be monitored by the TMG. CN 
patients are normally seen at least fortnightly during the treatment period and monthly during the 
first 3 months remission period as part of routine care. Six month follow-up visit will be scheduled 
with participants during a three month visit. The trial has been designed in line with clinical practice 
to reduce the burden on participants and therefore the number of participants lost to follow-up 
6.7.9 
Trial Closure 
The end of the trial is defined as 18 months after the final patient consents to take part in the study 

 
 
 
 
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6.8 
Sample Size 
As this is a preliminary, feasibility study a power calculation is not required. The sample size will be 
limited to 60 patients with 30 participants per arm. This number has been chosen based on 
guidelines from the NIHR and Research for Patient Benefit guidance. 
6.9 
Recruitment and Retention 
6.9.1 
Recruitment 
Recruitment will be across two sites Norfolk & Norwich Hospital and Derby Hospital. It is anticipated 
the identified trial centres will be able to recruit 60 patients over an 18-month trial period. If 
recruitment is below the level anticipated, recruitment may be extended to additional sites.   
Clinicians working in the diabetic foot clinics identified for the trial will be asked to identify potential 
patients. They will make an assessment of the patient’s eligibility to join the trial and provide the 
patient information to prospective patients.    
One of the outcomes of the feasibility trial is to assess recruitment and retention, to inform a full 
scale RCT if warranted.  
6.9.2 
Retention 
Discussion with patients and other PPI representatives, prior to the development of this proposal 
showed a willingness to participate in the trial. They did not feel the visit schedule was overly 
burdensome as the majority of visits would be carried out at the same time as their routine clinical 
appointments. A regular six monthly newsletter will be sent out to all participants.   
6.10 Assignment of Intervention 
6.10.1 Allocation 
Randomisation will take place after the patient has consented to participate in the trial  
6.10.1.1 
Sequence generation 
Eligible consented participants will be randomised on a 1:1 basis to one of the two trial arms using a 
web based randomisation process. The randomisation scheme will be generated by the NCTU data 
manager and notified by email to the study team. Allocation will be stratified by centre.  
6.10.1.2 
Allocation concealment mechanism 
The allocation is computer generated so will not be known prior to the participant being 
randomised. The patient will be allocated a participant number at time of consent. When 
confirmation of the diagnosis of CN has been entered, and all other pre-designated questions 
completed in the CRF, the research staff will then have access to the randomisation process for that 
participant. The treatment allocation will be revealed and linked to that participant number. 
Allocation is concealed prior to randomisation to prevent treatment bias. 

 
 
 
 
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6.10.2 Blinding 
It is not possible to blind this study due to the nature of reporting the MRIs, whereby comparison is 
made with the previous images, which indicates the trial arm the participant has been randomised 
to.  
6.11 Data Collection, Management and Analysis 
6.11.1 Data Collection Methods 
Each participant will be given a unique trial Participant Identification Number (PIN), this will consist 
of the centre number and participant number (sequential). Data will be collected at the time-points 
indicated in the Trial Schedule (section 6.6). 
The method of data collection is direct online entry of data onto the central database, stored on 
servers based at NCTU. This will be carried out by members of the trial team working within each 
research site. Data may be entered onto paper Case Record Forms (CRFs) prior to entry onto the 
database (but this is not an essential step).  Staff will receive training on data collection and use of 
the online system. 
X-ray images taken at baseline, remission and six month follow up will be transferred from site to 
the sponsor for analysis using the NHS Image Exchange Portal (IEP) or discs. All images will be 
anonymised by the site prior to transfer.  
Data collection, data entry and queries raised by a member of the CADOM trial team will be 
conducted in line with the NCTU and trial specific Data Management Standard Operating Procedure. 
Identification logs, screening logs, enrolment logs and tapes of qualitative interviews will be kept at 
the trial site in a locked cabinet within a secured room.  
Clinical trial team members will receive trial protocol training. All data will be handled in accordance 
with the Data Protection Act 1998. 
6.11.2 Data Management 
Data will be entered in the approved CADOM database by a members of the trial team at each site 
and protected using established NCTU procedures. 
Data will be entered under the participants PIN number onto the central database stored on the 
servers based at NCTU. Access to the database will be via unique, individually assigned (i.e. not 
generic) usernames and passwords, and only accessible to members of the CADOM trial team at 
NCTU, and external regulators if requested. The servers are protected by firewalls and are patched 
and maintained according to best practice. The physical location of the servers is protected 
physically and environmentally in accordance with University of East Anglia’s General Information 
Security Policy 3 (GISP3: Physical and environmental security). 
The database will be developed by NCTU Data Management, in conjunction with the CADOM trial 
team. The database software provides a number of features to help maintain data quality, including; 

 
 
 
 
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maintaining an audit trail, allowing custom validations on all data, allowing users to raise data query 
requests, and search facilities to identify validation failure/ missing data. 
After completion of the trial the database will be retained on the servers of NCTU and the sponsor 
servers for the X-ray images for on-going analysis of secondary outcomes. 
The identification, screening and enrolment logs, linking participant identifiable data to the 
pseudoanonymised Participant Identification Number, will be held locally by the trial site. This will 
either be held in written form in a locked filing cabinet or electronically in password protected form 
on hospital computers. After completion of the trial the identification, screening and enrolment logs 
will be stored securely by the sites for 15 years  
6.11.3 Non-Adherence and Non-Retention 
The consent form will explain that if a participant wishes to withdraw from the study, the data 
acquired prior to that point will be retained, unless the patient requests otherwise. Reason for 
withdrawal will be recorded, if given, as will loss to follow up. 
6.11.4 Statistical Methods 
6.11.4.1 
Statistical Analysis Plan 
A full Statistical Analysis Plan (SAP) will be developed between the trial statistician and Chief 
Investigator and agreed with the trial’s management group prior to analysis   
The feasibility measures will be presented as point estimates with 95% confidence intervals. There is 
no intention, at this stage, for any formal comparative analyses regarding these measures, though 
levels of missing data will be explored with respect to certain baseline characteristics, e.g. age, 
measures of disease severity. 
Estimates of outcome variability (e.g. the standard deviation) will be made with 95% confidence 
intervals to help inform future sample size calculations. Any between group efficacy analyses are 
exploratory only.  The suggested primary efficacy outcome measure, days with immobilisation, will 
be analysed using a Cox regression model.  Regression models with appropriate error terms (e.g. 
Normal or Poisson distributions) will be applied to the secondary outcomes.  
 
 
 
6.11.4.2 
Study Outcomes 
Feasibility measures  
 
Number of eligible patients recruited, recruitment and retention levels, willingness of 
clinicians to participate in the study, and dropout rates. 
Efficacy outcomes 

 
 
 
 
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 
Days with immobilisation, for the intervention versus standard care will be measured  
 
Number of foot ulcers, infections, falls, minor and major amputations from randomisation to 
the end of the study 
 
Progression of foot deformity from randomisation – remission, and at the end of the study.  
 
Changes in psychological health status assessed by the Hospital Anxiety and Depression 
Scale (HADS) from baseline at, 3, 6, 9 and 12 months, remission and at the end of the study 
period. 
 
Changes in health related quality of life assessed by the Medical Outcomes Short-Form 
Health Questionnaire (SF12) from baseline at, 3, 6, 9 and 12 months, remission and at the 
end of the study period. 
 
Changes in reported pain experienced in the foot, ankle or leg as reported on a Visual 
Analogue Scale (VAS) from baseline at, 3, 6, 9 and 12 months, remission and at the end of 
the study period. 
Economic Evaluation of resource use 
 
Collected through a patient diary 
6.11.4.4  
Additional Analyses 
No subgroup analysis is planned and any proposed subgroup analyses will be agreed with the 
appropriate governance committees.  
6.11.5 Analysis Population and Missing Data 
The exploratory efficacy analyses will be on the ‘Intention-to-treat’ population, i.e. as per 
randomisation rather than intervention actually received. There are no plans to impute missing data, 
i.e. these analyses will be on a ‘complete case’ basis. 
6.11.5.1 
Economic evaluations 
This will explore the feasibility of collecting resource use and quality of life data, to inform the design 
of the health economics component of a future definitive trial. 
Estimation of cost-effectiveness, within a health-technology assessment, is an iterative process49. In 
this trial we aim to monitor levels of resource-use and quality of life (QoL), to inform the decision as 
to how costs and benefits should be measured as part of a future, more definitive study. 
NICE guidance 50recommends that costs are calculated from the perspective of the NHS and personal 
social services (PSS). However, it is acknowledged that not all cost data can be collected, and it is 
suggested that the focus be on large cost drivers and those costs that are likely to differ between 
arms51. We will thereby seek to monitor levels of resource-use associated with the intervention and 
standard care arm of the study.  
Intervention - Serial use of MRI at 3, 6, 9 and 12 months to identify disease resolution and thus 
discontinue immobilisation 

 
 
 
 
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Standard Care - Immobilisation discontinued on the basis of clinical remission determined by skin 
temperature measurement 
Data on other primary, and secondary care visits and admission to hospital will be collected. This 
information will be extracted using a patient diary and secondary care notes. Time off work and 
levels of informal care will also be monitored. Appropriate unit costs will subsequently be attached 
to all items of resource-use52.  
In line with guidance 50 the EQ-5D-5L 53will be used to measure quality of life (QALY (Quality Adjusted 
Life Year) scores can be calculated from the EQ-5D54. Participants will be asked to complete the EQ-
5D-5L at 3 months, at 6 months, 9 months, 12 months, 1 month after remission, and at 6 months 
post remission 
6.11.5.2  
Health Economic Analysis Plan 
The main purpose of the analysis is to inform how the above data on costs and effects would be 
collected within a more definitive study. Thus, we will estimate completion rates and seek to identify 
big cost drivers, in order to inform this decision. Additionally, though the results of this will need to 
be treated with caution, a preliminary cost-effectiveness analysis will also be performed. As such,  
we will estimate the mean incremental cost and mean QALY gain associated with the intervention 
compared to standard care.  
6.12 Data Monitoring 
6.12.1 Data Monitoring Committee 
This has been assessed as a low risk trial.  
6.12.2 Interim Analyses 
No interim analyses is planned 
6.12.3 Data Monitoring for Harm 
The TMG will be provided with safety data from each treatment arm about any adverse event 
related to the monitoring carried out as part of the trial. The TMG will make recommendations to 
the Trial Sponsor on the continuation or early stoppage of the trial in the unlikely event that there 
are concerns over harm to participants.  
6.12.3.1 
Safety reporting 
The intervention in the trial is increased frequency of MRI scanning which is compared with standard 
care of MRI scanning to confirm resolution of following temperature assessment of the affected 
limb.  Contrast is not used for MRI scans in this study.  Thus a pragmatic approach to safety reporting 
will be used.  MRI scans are being performed in NHS trusts under routine clinical protocols.  Adverse 
incidents resulting from MRI scans will be reported by the research site in line with the trusts clinical 
incident reporting policy. A copy of the incident form will be forwarded to the CI of the trial as soon 
as practicable.  They will be forwarded to the Trial Sponsor on receipt by CI and will be reviewed by 
the TMG.   

 
 
 
 
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The following anticipated events are recorded as secondary outcomes.  They will be reported as 
clinical events and reviewed by the TMG.   
 
CN -RELATED SAFETY OUTCOMES 
 
Worsening of existing ulceration 
 
Infection of an ulcer 
 
Secondary ulceration on either limb 
 
Major and minor amputation 
 
Increase in pain 
 
 Off-loading – RELATED SAFETY OUTCOMES 
 
Falls as a consequence of wearing the off-loading device 
 
Iatrogenic skin irritation or lesions from off-loading device 
 
6.12.3.2 
Procedures to follow in the event of female participants becoming pregnant 
In the event of a female participant becoming pregnant they have the option to withdraw from the 
trial. All participants who become pregnant will be excluded from the X-ray at 6 months post 
remission.  
6.12.4 Quality Assurance and Control 
6.12.4.1 
Risk Assessment 
The Quality Assurance (QA) and Quality Control (QC) considerations for the CADOM are based on 
the standard NCTU Quality Management Policy that includes a formal Risk Assessment, and that 
acknowledges the risks associated with the conduct of the trial and proposals of how to mitigate 
them through appropriate QA and QC processes. Risks are defined in terms of their impact on: the 
rights and safety of participants; project concept including trial design, reliability of results and 
institutional risk; project management; and other considerations. 
QA is defined as all the planned and systematic actions established to ensure the trial is performed 
and data generated, documented and/or recorded and reported in compliance with the principles of 
GCP and applicable regulatory requirements. QC is defined as the operational techniques and 
activities performed within the QA system to verify that the requirements for quality of the trial 
related activities are fulfilled.  
6.12.4.2 
Central Monitoring at NCTU 
NCTU staff will review Case Report Form (CRF) data for errors and missing key data points. The trial 
database will also be programmed to generate reports on errors and error rates. Essential trial 
issues, events and outputs, including defined key data points, will be detailed in the CADOM trial 
Data Management Plan. 
6.12.4.3 
On-site Monitoring  
The frequency, type and intensity of routine and triggered on-site monitoring will be detailed in the 
CADOM Quality Management and Monitoring Plan (QMMP). The QMMP will also detail the 

 
 
 
 
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procedures for review and sign-off of monitoring reports. In the event of a request for a trial site 
inspection by any regulatory authority, NCTU must be notified as soon as possible. 
6.12.4.3.1 
Direct access to participant records 
Participating investigators must agree to allow trial related monitoring, including audits, REC review 
and regulatory inspections, by providing access to source data and other trial related documentation 
as required. Participant consent for this must be obtained as part of the informed consent process 
for the trial. 
6.12.4.4 
Trial Oversight 
Trial oversight is intended to preserve the integrity of the trial by independently verifying a variety of 
processes and prompting corrective action where necessary. The processes reviewed relate to 
participant enrolment, consent, eligibility, and allocation to trial groups; adherence to trial 
interventions and policies to protect participants, including reporting of harms; completeness, 
accuracy and timeliness of data collection; and will verify adherence to applicable policies detailed in 
the Compliance section of the protocol. Independent trial oversight complies with the NCTU trial 
oversight policy. 
In multi-centre trials this oversight is considered and described both overall and for each recruiting 
centre by exploring the trial dataset or performing site visits as described in the CADOM 
Management and Monitoring Plan. 
6.12.4.4.1 
Trial Management Team 
The Trial Management Team (TMT) will be set up to assist with developing the design, co-ordination 
and day to day operational issues in the management of the trial, including budget management. 
The membership, frequency of meetings, activity (including trial conduct and data review) and 
authority will be covered in the TMT terms of reference.  
6.12.4.4.2 
Trial Management Group 
A Trial Management Group (TMG) will be set up to assist with developing the design, co-ordination 
and strategic management of the trial. The membership, frequency of meetings, activity (including 
trial conduct and data review) and authority will be covered in the TMG terms of reference. 
The TMG will review serious clinical incidents associated with MRI scanning and adverse events 
described in 6.13.3.1 to  
• 
Detect any trends, such as increases in un/expected events, and take appropriate action 
• 
Provide advice to the CI to when to seek information from investigators where required 
• 
Provide advice to Sponsors on the risk of the trial continuing and take appropriate action 
where necessary 
6.12.4.4.3 
Independent Data Monitoring Committee 
 CADOM is a feasibility trial with no planned interim analyses.  The intervention is low risk thus no 
DMC is required.   

 
 
 
 
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6.12.4.4.4 
Trial Sponsor 
The role of the sponsor is to take on responsibility for securing the arrangements to initiate, manage 
and finance the trial. When an institution is the trial sponsor and has delegated some and/or the 
totality of Sponsor’s responsibilities to the NCTU, the Sponsor’s form for delegated responsibilities 
should be completed and signed by all parties before the start of the trial. 
 
 

 
 
 
 
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7 
Ethics and Dissemination 
7.1 
Research Ethics Approval 
Before initiation of the trial at any clinical site, the protocol, all informed consent forms and any 
material to be given to the prospective participant will be submitted to the relevant REC for 
approval. Any subsequent amendments to these documents will be submitted for further approval. 
Before initiation of the trial at each additional clinical site, the same/amended documents will be 
submitted for local Research and Development (R&D) confirmation of capacity and capability.  
The rights of the participant to refuse to participate in the trial without giving a reason must be 
respected. 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 s/he feels it to be in the best interest of 
the participant. The reasons for doing so must be recorded. After randomisation the participant 
must remain within the trial for the purpose of follow up and data analysis according to the 
treatment option to which they have been allocated. However, the participant remains free to 
change their mind at any time about the protocol treatment and follow-up without giving a reason 
and without prejudicing their further treatment. 
7.2 
Competent Authority Approvals 
This is not a Clinical Trial of an Investigational Medicinal Product (IMP) as defined by the EU Directive 
2001/20/EC. Therefore, a CTA is not required in the UK.  
7.3 
Other Approvals 
 The protocol will be submitted by those delegated to do so to the relevant R&D department of each 
participating site for confirmation of capacity and capability. A copy of the confirmation, site 
agreement and of the Participant Information Sheet (PIS) and consent form on local headed paper 
must be forwarded to the co-ordinating centre before participants are randomised to the trial.  
The protocol has received formal approval and methodological, statistical, clinical and operational 
input from the NCTU Protocol Review Committee. 
7.4 
Protocol Amendments 
Substantial protocol amendments (e.g. changes to eligibility criteria, outcomes, sample size 
calculations, analyses) will be decided by the Chief Investigator. Each site-PI will be informed of the 
potential changes. Such amendments will be submitted to HRA for approval. Once approved, the 
protocol amendments will be circulated to trial personnel and implement within the appropriate 
timescale dependent upon the HRA categorisation 
7.5 
Consent  
Patients will be provided with a Patient Information Sheet (PIS) and given time to read it fully. 
Following a discussion with a medical qualified investigator or suitable trained and authorised 
delegate, any questions will be satisfactorily answered and if the participant is willing to participate, 
written informed consent will be obtained.  During the consent process it will be made completely 

 
 
 
 
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and unambiguously clear that the participant is free to refuse to participate in all or any aspect of 
the trial, at any time and for any reason, without incurring any penalty or affecting their treatment. 
 
Consent will be re-sought if new information becomes available that affects the participant’s 
consent in any way. This will be documented in a revision to the patient information sheet and the 
participant will be asked to sign an updated consent form. These will be approved by the ethics 
committee prior to their use.  
A copy of the approved consent form is available from the NCTU trial team.  
7.5.1 
Consent to Qualitative Interviews 
As part of the consent form for the main trial participants will be asked whether they would be 
happy to be approached to participate in an interview. The interview will explore their experiences 
of being treated for CN, and views about participating in the trial.  
A purposive sample of 10-14 participants across both sites will be selected. Diversity across the 
sample will be ensured by taking into account treatment times, employment, gender and age. 
Selected participants will receive a further information sheet explaining the purpose of the interview 
and will be consented prior to the interview taking place.  
Once informed consent has been obtained, the researcher will seek the participant’s permission to 
audio record the interview, explaining the reasons for doing so.  If a participant does not wish the 
interview to be recorded, the researcher will make written notes of the interview.  Participants will 
be reassured that neither the transcription nor the handwritten notes will contain any personal 
identifying information and that nobody will listen to the tape or read the notes of the interview, 
except for members of the research team and a transcriber who will be asked to sign a 
confidentiality agreement.  
7.6 
Confidentiality 
Any paper copies of personal trial data will be kept at the participating site in a secure location with 
restricted access.  Identifiable data (limited to consent forms for monitoring purposes), will be kept 
at the NCTU office with only authorised NCTU staff members having access.  Only staff working on 
the trial will have password access to this information.  
Confidentiality of patient’s personal data is ensured by not collecting patient names on CRFs and 
storing the data in a pseudonymised fashion at NCTU. At trial enrolment the patient will be issued a 
participant identification number and this will be the primary identifier for the patient, with 
secondary identifiers of month and year of birth and initials.  
The patient's consent form will carry their name and signature. These will be kept at the trial site, 
and a copy sent to NCTU for monitoring purposes. They will not be kept with any additional patient 
data. 

 
 
 
 
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7.7 
Declaration of Interests 
The investigators named on the protocol have no financial or other competing interests that impact 
on their responsibilities towards the scientific value or potential publishing activities associated with 
the trial.  
7.8 
Indemnity 
The NHS indemnity scheme will apply to the potential liability of the sponsor for harm to 
participants arising from the management and conduct of the research.  
7.9 
Finance 
CADOM is fully funded by an NIHR Clinical Doctoral Fellowship grant number ICA-CDRF-2015-01-050. 
It is not expected that any further external funding will be sought. 
7.10 Archiving 
The investigators agree to archive and/or arrange for secure storage of Journey trial materials and 
records for a minimum of 15 years after the close of the trial unless otherwise advised by the NCTU. 
7.11 Access to Data 
Requests for access to trial data will be considered, and approved in writing where appropriate, after 
formal application to the TMG and TSC. Considerations for approving access are documented in the 
TMG and TSC Terms of Reference. The CI and trial statistician at NCTU will have access to the full 
trial dataset 
7.12 Ancillary and Post-trial Care 
The sponsor does not intend to provide any interventions or other care to patients after trial 
completion. 
7.13 Publication Policy 
7.13.1 Trial Results 
The results of the trial will be disseminated regardless of the direction of effect. Ownership of the 
data arising from the study resides with the trial team. The publication policy will be in line with 
rules of the International Committee of Medical Journal Editors. The TMG will decide on the 
dissemination strategy including presentations, publications and authorship with any difficulties 
being resolved by the TSC. 
7.13.2 Authorship 
For main publications, the TMG will nominate a writing group, which will consist of members of the 
TMG supplemented by site PIs and others who have made major contributions, who will be 
responsible for drafting the main manuscripts for publication.  These individuals will be named on 
the final publication.     
 

 
 
 
 
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7.13.3 Reproducible Research 
The CADOM Trial Protocol will be published and made available for public access throughout the 
trial period. 
 
 

 
 
 
 
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8 
Ancillary Studies 
 
 

 
 
 
 
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9 
Protocol Amendments 
[A brief summary of areas of the protocol that have undergone major amendment along with details 
of the ethics and MHRA approval dates. Full details of old and new wording (tracked and cleaned 
versions) should be kept according to the NCTU procedures in relation with filing amendments.] 
2nd August 2019 
6.4.3 and 7.5.1 Changed to allow qualitative interviews to be completed during the whole course of 
the trial. Also updated on 6.6 Patient timeline.  
11th June 2020 
6.4 and 6.5.2 Changed to clarify the analysis of X-rays to monitoring the progression of foot 
deformity  
6.11 and 6.11.2 Updated to confirm the process and storage arrangements for the electronic 
transfer of X-ray images to the sponsor for analysis  
 
 
 

 
 
 
 
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10 
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28. 
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(EQ-5D-5L). Qual Life Res 20, 1727–1736 (2011). 
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11 
Appendix 1  
Use of Glycated Haemoglobin (HbA1c) in the Diagnosis of Diabetes Mellitus. Abbreviated Report of a 
WHO Consultation.  
(Downloaded 22nd June 2017) 
 
hba1c_diagnosis.11
11 (downloaded 22n