Does a Novel Diabetic Foot Offloading Boot Reduce the Pressure Time Integral Compared to Usual Standard Care, in Patients With Diabetic Foot Ulcer? A Proof of Concept Pilot Study
Phase: NA
Conditions: Diabetic Foot Ulcer
Sponsor: University of Leeds

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Leeds Teaching Hospitals NHS Trust  
Research Protocol 
Version 1. January 2017 
 
Study Short Title: Evaluating plantar foot pressure in a novel diabetic offloading 
device 
Study Full Title: Does a novel diabetic offloading boot (PulseFlow DF) reduce the 
plantar foot pressures compared to usual standard care? A proof of concept pilot 
study. 
 
Sponsor Name: University of Leeds 
Sponsor Number:  
 
Protocol status: 
Details of previous amendments 
1. NA 
 
 
 
Key contacts 
Chief Investigators 
Professor Anne-Maree Keenan 
Assistant Director, NIHR Leeds Musculoskeletal Biomedical Unit 
(LMBRU) 
Chapel Allerton Hospital, Leeds 
LS7 4SA 
 
Dr Una Adderley      PhD, RGN, DN 
Lecturer in Community Nursing  
School of Healthcare, Room 2.22 - Baines Wing, University of Leeds 

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Leeds LS2 9JT 
 
Principal Investigator 
Thomas Dickie 
Foot Health Department Manager 
Foot Health Department, Lower Ground Chancellor Wing, St James’s Hospital, 
Beckitt Street, Leeds, LS9 7TF. 
Telephone: 0113 206 4375 
0113 206 5614 
Contact e-mail: Thomas.dickie@nhs.net 
 
 
Trial Co-ordinator  
Same as Principal Investigator 
 
 

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INVESTIGATOR DECLARATION AND SIGNATURE(S) 
DFOBPS Protocol Version 1 18/01/2017 
 
DECLARATION OF PROTOCOL ACCEPTANCE 
I confirm that I am fully informed and aware of the requirements of the protocol and 
agree to conduct the study as set out in this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thomas Dickie 
01/02/2017 
Principal Investigator 
Date 
 
 
Professor Anne-Maree Keenan 
School of Healthcare 
Baines Wing 
University of Leeds 
Leeds LS2 9JT 
Dr Una Adderley      PhD, RGN, DN 
Lecturer in Community Nursing  
School of Healthcare 
Room 2.22 - Baines Wing 
University of Leeds 
Leeds LS2 9JT 
 
 
 

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Table of Contents 
INVESTIGATOR DECLARATION AND SIGNATURE(S) ...................................... 3 
ABBREVIATIONS ................................................................................................. 7 
SCHEMATIC DIAGRAM ..................................................................................... 10 
1. 
INTRODUCTION ......................................................................................... 12 
1.1. 
Background .......................................................................................... 12 
1.2. 
Rationale for the proposed study .......................................................... 16 
2. 
STUDY AIM AND OBJECTIVES ................................................................. 19 
2.1. 
Study aim .............................................................................................. 19 
2.2. 
Primary objective .................................................................................. 20 
2.3. 
Secondary objective(s) ......................................................................... 20 
3. 
STUDY ENDPOINTS .................................................................................. 20 
3.1. 
Primary endpoint .................................................................................. 20 
4. 
STUDY VARIABLES ................................................................................... 20 
4.1. 
Standard variables ................................................................................ 20 
5. 
STUDY DESIGN ......................................................................................... 21 
5.1. 
Study description .................................................................................. 21 
5.2. 
Study duration ...................................................................................... 21 
5.3. 
Rationale for study design .................................................................... 21 
6. 
SELECTION AND WITHDRAWAL OF SUBJECTS .................................... 21 
6.1. 
Target population .................................................................................. 21 
6.2. 
Estimated number of eligible participants ............................................. 21 
6.3. 
Eligibility criteria .................................................................................... 22 
6.3.1. 
Inclusion criteria .................................................................................... 22 
6.3.2. 
Exclusion criteria .................................................................................. 22 
6.3.3. 
Exclusions for general safety ...................Error! Bookmark not defined. 
6.4. 
Withdrawal criteria ................................................................................ 22 
6.5. 
Recruitment, consent and randomisation processes ............................ 23 
6.5.1. 
Recruitment .......................................................................................... 23 
6.5.2. 
Consent ................................................................................................ 23 
6.5.3. 
Randomisation process ........................................................................ 23 
6.5.4. 
STUDY BLINDING ............................................................................... 24 
6.5.5. 
Patients who withdraw consent ............................................................ 24 
6.5.6. 
Definition for the end of the trial ............................................................ 24 

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6.6. 
General information on the products or interventions to be used ......... 24 
6.7. 
Use within the trial ................................................................................ 25 
7. 
METHODS OF ASSESSMENT ................................................................... 26 
7.1. 
Efficacy assessment variables .............................................................. 26 
7.2. 
Routine laboratory assessments .......................................................... 26 
Gait laboratory ................................................................................................... 26 
Pressure Time Integral ...................................................................................... 26 
8. 
STUDY MANAGEMENT AND ADMINISTRATION ..................................... 28 
8.1. 
Good clinical practice (GCP) ................................................................ 28 
8.2. 
Adherence to protocol........................................................................... 28 
8.3. 
Data handling ....................................................................................... 28 
8.3.1. 
CRF completion .................................................................................... 28 
8.3.2. 
Database entry and reconciliation ........................................................ 29 
8.3.3. 
Screening and enrolment logs .............................................................. 29 
8.4. 
Archiving and data retention ................................................................. 29 
8.5. 
Study suspension, termination and completion .................................... 30 
9. 
DATA EVALUATION ................................................................................... 30 
9.1. 
Responsibilities ..................................................................................... 30 
9.2. 
Hypotheses ........................................................................................... 30 
9.3. 
General statistical considerations ......................................................... 31 
9.4. 
Planned analyses ................................................................................. 31 
9.5. 
Data Handling ....................................................................................... 31 
10. ETHICS AND REGULATORY REQUIREMENTS ....................................... 32 
10.1. Good Clinical Practice .......................................................................... 32 
10.2. Subject information and informed consent............................................ 32 
10.3. Subject confidentiality ........................................................................... 33 
10.4. Approval of clinical study protocol and amendments ............................ 34 
10.5. Protocol amendments ........................................................................... 34 
10.6. Ongoing information for Research Ethics Committee ........................... 34 
11. FINANCE AND INSURANCE ...................................................................... 35 
11.1. Indemnity and insurance....................................................................... 35 
11.2. Financial disclosure .............................................................................. 35 
12. PUBLICATION ............................................................................................ 35 

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13. REFERENCES ............................................................................................ 35 
 
 
 

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ABBREVIATIONS 
Abbreviation 
Term 
AE 
Adverse Event 
CI 
Chief Investigator 
CRF 
Case Report Form 
DFU  
DMEC 
Diabetic Foot Ulcer 
Data Monitoring and Ethics Committee 
DRMD 
Division Of Rheumatic And Musculoskeletal Disease 
DSUR 
Developmental Safety Update Report 
ECG 
Electrocardiogram 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
IB 
Investigator Brochure 
ICH 
International Conference On Harmonisation 
IMP 
Investigational Medicinal Product 
LOCF 
Last Observation Carried Forward 
MHRA 
Medicines And Healthcare Products Regulatory Agency 
MRI 
Magnetic Resonance Imaging 
NIMP 
Non-Investigational Medicinal Product 
QA 
Quality Assurance 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SPC 
Summary Of Product Characteristics 
SUSAR 
TCC 
Suspected Unexpected Serious Adverse Reaction 
Total Contact Cast 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PROTOCOL SYNOPSIS 
GENERAL INFORMATION 
Short Title 
Evaluating plantar foot pressure in a novel diabetic 
offloading device 
Full Title 
Does a novel diabetic offloading boot (PulseFlow DF) 
reduce the plantar foot pressures compared to usual 
standard care? A proof of concept pilot study 
Sponsor 
University of Leeds 
Sponsor ID 
 
MREC No. 
 
Chief Investigator 
Professor Anne-Marie Keenan 
Principal  Investigator 
Thomas Dickie 
Co-ordinating Centre 
University of Leeds, School of Healthcare 
National / International 
Local 
STUDY INFORMATION 
Phase 
Proof-of-concept  
Indication 
Evaluation of a new CE marked device (PulseFlow 
DF) for the treatment of diabetic foot ulcers 
Design 
Proof of concept 
Number of sites 
One 
Study Objective 
To compare plantar foot pressures between 
prescribed usual standard of care and the PulseFlow 
DF boot. 
Secondary Objective(s) 
Explore the effectiveness and acceptability of the 
novel device. 
Study Endpoint 
Collection of data from a single appointment. 
Secondary Endpoint(s) 
NA 
STUDY TIMELINES 
Expected start date 
February  2017 
Subject enrolment phase 
February 2017 to July 1st 2017. 
 
Follow-up duration 
No follow up 
End of Study Definition 
Numbers needed to recruit reached (n36) 
Expected 
completion 
date 
June 2017 
STUDY SUBJECT INFORMATION 
Number of study subjects 36 

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Age group of study 
subjects 
18 plus 
Inclusion criteria 
Diabetes 
Plantar forefoot diabetic foot ulcer over the 1st, 2nd, 
3rd, 4th or 5th metatarsal joints 
Neuropathic or Neuro-Ischaemic classification foot 
ulcer 
Orthotic intervention for offloading/usual standard  
Plantar forefoot ulceration over the metatarsal heads 
Exclusion criteria 
Charcot Arthropathy 
ABPI of <0.8 and >1.29 
Temporary footwear 
Accommodating or footwear not designed to offload. 
Clinically active Infection causing swelling 
Purely ischaemic classification foot ulcer 
Current active osteomyelitis 
Patients with forefoot trans metatarsal amputations  
Fractures of the foot 
Due to alterations in gait, patients with diagnosed 
vascular dementia, Parkinson’s, alcoholism or other 
major medically related gait alterations i.e. intoxication, 
brain cancers, muscular degeneration diseases, 
inflammatory arthritis, etc. This does not include osteo-
arthritis. 
Major amputees 
Pregnancy 
Participating in another trial regarding foot dressings 
or off loading 
 
 

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SCHEMATIC DIAGRAM  
 
2017  
 Jan 
Feb 
Mar 
Apr 
May 
Jun
e 
July 
Aug-
Dec 
Submit ethical & R&D approval 
Audit Categories proportions 
Scoping able participants 
Non study Patient specific gait analysis 
testing 
  
  
  
Receive ethical & R&D approval 
Consent 
Identification 
of 
patients 
through 
database 
Approach patients in routine appointment 
Provide written literature 
  
  
  
Recruit Patients 
Contact and Consent 
Second follow up phone  or appointment 
contact 
Written 
consent 
at 
laboratory 
appointment 
Data collection in gait lab 
  
  
  
Statistical Analysis 
Data analysis 
Statistical analysis 
Member checking usability outcomes 
  
  
  
Close Study 
Results writing 
Research 
 
conclusion 
with 
written  
research project 
Poster presentation 
PPI and research group meeting 
  
  
  
 

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Patient Contact Schematic 
 
 
 
 
 
Patient identified 
by care team 
Patient Approached 
in usual clinic 
Written information 
provided 
Appointment 
Follow up telephone 
Consented 
Variables checklist 
completed 
Start 
measurements 
Booking of gait lab 
appointment 
Random sequence 
identified 
Period of use 
PulseFlow DF use 
PulseFlowDF or 
footwear applied 
Store 
measurements 
Conclude 
observations 
Complete 
questionnaire 
Back up data 
Session END 
Store paperwork in 
relevant folders 

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1. INTRODUCTION 
1.1. Background 
Prevalence 
Diabetes is an endocrine disorder which carries considerable health risks. 
Worldwide estimates from the International Federation of Diabetes (IDF 2016) 
estimate the prevalence of diabetes to be 387 million people. In the next twenty 
years this is set to rise to an estimated 582 million people which is 10% of all adults. 
Estimates (Gonzalez et al., 2009) show that from 1996 to 2005, the diabetic 
population rose by 50% in the United Kingdom (UK). Diabetes UK estimates 
currently 4 million people are living with diabetes  (Diabetes UK, 2015)  
Aetiology 
Treating diabetes includes its co-morbidities and has proved challenging due to the 
rising population. Diabetes can cause damage to the nerves and circulation to the 
lower extremities which can result in the complication of Diabetic foot ulcers (DFU). 
It is estimated that 25% of the diabetic population will develop a DFU in their lifetime 
(Ndip and Jude, 2009). The prevalence of diabetic foot ulcers in a European based 
population of Type 1 and Type 2 Diabetes is 5.5% (Abbott et al., 2005). DFU’s are 
linked to poorer quality of life, higher lower limb amputations and higher mortality 
rates following amputation (Singh et al., 2005). This is important as neuropathy is 
the highest cause of DFUs (Parisi et al., 2016), and a strong predictor of lower 
extremity amputations (Krishnakumar et al., 2015).  
Other causes of developing a DFU can be helped by separating DFUs into different 
causes alongside neuropathy, which are:- 
• 
Neuropathic (caused by lack of sensation) 
• 
Ischaemic (caused by lack of blood supply) 
• 
Neuro-ischaemic (caused by a mix of both sensation and blood supply deficits) 
Common classifications have proven difficult to accept amongst clinicians. A widely 
used system has been incorporated into clinical practice which incorporates the 
above classification called the “Texas Classification” (Armstrong et al., 1998). 
DFUs are consistently considered a chronic wound with increased risk of 
amputation, infection, suffering and death (Jeffcoate and Harding, 2003). Diabetic 
foot ulcerations are mainly caused by the damage to the peripheral nerves that 
causes a loss of protective sensation. This allows the insensate skin to be 
damaged from direct pressure or trauma without the patient realising 
(Konstantikaki, 2008). This pressure can increase over certain areas of the foot 
leading to tissue damage or a break in the skin resulting in the DFU. This is then 
perpetuated due to a lack of feeling (no pain) resulting in an inability to relieve 

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pressure over the ulcer site to allow appropriate healing. The DFU is a chronic 
wound caused by (Jeffcoate and Harding, 2003):- 
• 
Nerves that help small blood vessels controlling microcirculation to the skin are 
damaged delaying new skin formation 
• 
Motor function controlled by nerves are damaged changing the foot mechanics 
causing hard skin to build increasing pressure areas  
• 
Poor medical management including diagnosis, access to the right specialists 
and patients being unaware of the condition 
 
 
These and other factors related to diabetes such as depression, impairment of the 
inflammation process for healing due to hyperglycaemia and delayed access to a 
specialist treatment centre causes healing to be complex (Jeffcoate and Harding, 
2003, Konstantikaki, 2008). The associated outcomes such as hospitalisation, 
infections, minor or major amputations can have a lasting impact. The estimated 
cost in socio-economic terms varies widely. One of the largest and most recent 
European study showed on average the total direct and indirect costs for treating 
an ulcer to healing and major amputation is €7,772 to €25,222 respectively 
(Prompers et al., 2008). This is in based on 2005 monetary treatment prices. The 
monetary cost burden to patients is also a factor but is rarely reported (Cavanagh 
and Bus, 2010). Other effects on patients include physical and emotional issues 
having negative impacts to their quality of life. This has been shown to be 
significantly reduced in diabetic patients with foot ulcerations (Jaksa and Mahoney, 
2010). 
 
The healing of DFU is therefore paramount to avoiding such devastating disease 
outcomes such as amputations, cost and other patient related factors. One of the 
priority interventions to promote healing of DFUs is allowing the foot to be rested 
or offloaded whilst the patient can continue a reasonable level of independence. 
The offloading of the foot relies on specific techniques guided by evidence based 
guidelines (NICE, 2015). 
 
Previous Studies 
Elevated diabetic plantar foot pressure has been identified as clinically significant 
in the development and deterioration of DFUs (Lavery et al., 2003). This is through 
tissue damage from numerous mechanical pressures on the foot (Yavuz et al., 
2015). The clinical practice of pressure relief to treat DFUs is synonymous with 
offloading and relates to the pressure relief at sites of diabetic foot ulceration. This 
has been based on clinical experience and has lacked good quality research 
evidence. However, a recent systemic review (Bus et al., 2016a) has helped guide 

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clinicians on effectiveness of interventions chosen rather than rely on the historical 
experiences of clinicians. This review provides strong evidence towards the use of 
total contact casting, prefabricated irremovable and removable devices as the 
primary choices to offload DFUs. This is based on empirical research in studies 
using non complicated purely neuropathic ulcers in economically developed 
countries. Additionally reported with consistency in these studies is the evidence 
that poor adherence results in poorer clinical outcomes therefore further research 
is needed to measuring and improving adherence to offloading devices. This is 
important as there is such low use of total contact casting clinically. Ulcer healing 
relates to the time offloading devices are used and the quality of pressure relief 
provided by the devices used (Armstrong et al., 2003). The NICE Guidelines CG19 
relating to off-loading is based on the Cochrane review on “Pressure-relieving 
interventions for treating diabetic foot ulcers” (Lewis and Lipp, 2013). This review 
identifies five out of seven studies showing an associated statistically significant 
improvement of the number of foot ulcers healed with non removable casts rather 
than removable. This was expressed as a risk ratio total at 1.41 as likely to heal 
ulcers (30days, 12weeks and 16weeks) in a non removable device versus a 
removable device.  
 
The management of providing off loading is complex with many patients opting for 
removable devices due to lifestyle, job requirements, caring needs, driving and 
regular ulcer evaluations and/or re-dressings. Other removable pressure relieving 
devices included temporary therapeutic shoes and removable pressure relieving 
devices e.g. rigid rocker bottom sandals with non custom insoles, forefoot 
wedge/off-loading shoes, custom made therapeutic footwear and insoles, Aircasts 
and other removable casted walkers. It is likely that patients would prefer an option 
to use an aesthetically acceptable pressure relieving device such as the PulseFlow 
DF. However there is currently no such evidence for its efficacy in off loading.  
 
Types of pressure affecting the skin 
Since there are different types of pressures or forces that can cause damage to 
the skin there are different ways of measuring this in terms of the outcomes being 
researched. This study is observing plantar pressure over time which is described 
in section 1.2. However, offloading or pressure relief can be confused with terms 
such as force, friction and shear.  
 
Friction and Shear Pressures 
Recently there has been an association of shear and friction with DFU (Yavuz et 
al., 2015, Giacomozzi et al., 2008).  Force is used as simply a measure of influence 
that changes movement or an interaction between structures. In the case of the 
foot this is measured in units of newtons (n) observing force vectors or lines of 

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pressure on the foot, Figure 1. Friction and shear are two other different forces 
compared to plantar pressures described in this study, which are associated with 
DFUs but often used in error describing pressure on the foot.  
Friction 
Friction is a mechanical force describing when two parallel surfaces pass one 
another i.e. skin of the foot, and its supporting structure (shoe or floor for example), 
Figure 1. Friction on a structure (foot on the floor) is associated by the pressure 
exerted from the downward force. The friction occurs when two surfaces in contact 
with each other move against each other. Although this is associated with DFUs, 
research has highlighted the importance that reducing friction force is associated 
more with preventing rather than healing of DFUs (Braun et al., 2014).  
Figure 1. 
 
 
 
 
 
 
 
 
Shear 
Shear is a mechanical force exerted directly parallel to the body’s surface (skin) 
which initiates a parallel shift causing shear within the tissues below or above 
it, Figure 2. Shear has only recently experienced interest from specialists in the 
treatment of DFUs (Yavuz et al., 2015, Giacomozzi et al., 2008). Clinically this 
can be evidenced regularly when dressings over macerated tissues covering a 
DFU cause separation of the macerated tissue from the dermal epidermal 
junction of skin (Braun et al., 2014). Shear is highlighted due to the diabetes 
effect on skin tissue mechanics and the role of skin biochemical changes 
related to ulcer formation and the inability to dissipate shear (Zhu et al., 2011).  
 
 
 
Skin 
Surface 
Lateral movement 
Lateral movement 
Friction 
 Two surfaces moving against each other in 
the absence of force (pressure) 

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Figure 2.  
 
 
 
 
  
 
 
 
  
 
 
 
 
Shear and friction relating to DFU is difficult to measure. Custom built tools have 
had to be used previously to allow appropriate research (Yavuz et al., 2007). There 
is no common validated reliable device to perform shear or friction evaluations to 
show effectiveness on healing DFU compared to plantar pressure relief.  Therefore 
it is unrealistic to be able to measure the shear and friction elements associated 
with DFU within this study and this study will measure downward or a vertical force. 
 
1.2. Rationale for the proposed study 
Diabetic Foot UIcer impacts (including cost) 
The impacts from diabetes are both patient related and healthcare based. DFU is 
associated with a high mortality rate at 34% at 1year. There is an associated 
higher limb amputation rate from DFU than other causes. The high mortality rate, 
high amputation rate and increased socio-economic burden means providing high 
quality evidence based DFU service provision should be a NHS priority. Offloading 
is recognised as the priority treatment for healing neuropathic and neuro-
ischaemic plantar foot ulcers (NICE, 2015). Since the provision of non removable 
devices or total contact casts (TCC) is poor, options have to be available that are 
equivalent in effectiveness at off loading and healing DFU. By improving the 
quality of offloading choices and acceptability for devices this will improve healing 
rates and reduce the cost burden where currently in the UK diabetic foot care in 
2015 accounted for 0.6%/585.5million pounds of the NHS budget (Diabetes UK, 
2015, NHS England, 2016). The evidence for effectiveness of non removable 
devices is poor. Therefore any device that offloads to the equivalent or more than 
previous devices and current usual standard of care must be evidenced. The new 
PulseFlow DF boot is such a device which claims to off load but has little or no 
Bone 
Force acting on the 
skin for example body 
weight  
Lateral movement 
Skin 
Lateral movement 
SHEAR 
SHEAR 
SHEAR 

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evidence on DFU subjects. Thus the primary aim of this study is to observe 
forefoot plantar pressures in a cross sectional purposively selected sample 
compared to usual standard of care. 
 
How pressure relief is studied 
Pressure is measured in a standard unit of kilopascals (kPa).  This can be 
measured by either a static plate embedded in the floor that a person walks 
across or an in-shoe device. There are several devices to measure pressure 
including the Pedar-xf analyser (novel, no date). The important considerations 
for use of such instruments are reliability and repeatability. The Pedar-xf has 
shown good levels of repeatability and reliability from linear loading with low 
errors measuring the coefficient of reliability at less than 10% for 93.4% of the 
parameters tested (Putti et al., 2007). This is practically due to the fact no two 
steps are identical to produce a 100% repeatable result. There is also good 
repeatability of loading at high pressures,  seen in diabetic foot ulcer patients, as 
previous studies use healthy individuals (Hurkmans et al., 2006). The in-shoe 
device uses pressure cells imbedded in an insole which is placed between the 
foot and the device being measured.  The insoles are 1-2mm in thickness. The 
senses imbedded in them can detect pressure in kPa. The Pedar-xf analyser 
being used in this study for example has 99 sensors imbedded in a single insole. 
Since the interest is measuring pressure between a foot and a new offloading 
diabetic boot the appropriate instrument would be an in-shoe device.  
 
 
The Pedar-xf Analyser System  
The Pedar-xf system allows dynamic plantar foot pressures to be collected in-shoe 
simultaneously in both feet. Once this has been achieved the software can be 
instructed to apply masks to parts of the foot (Putti et al., 2007). The masking 
helps measure specified regions of the foot (Lavery et al., 2003, Hughes et al., 
1993) such as the first metatarsal phalangeal joint. This allows clinicians to identify 
specific areas targeting specific off loading treatments such as recurrent ulceration 
sites and explore potential changes to plantar pressures (Arts et al., 2012, Ledoux 
et al., 2013). 
 
Generating Outcome Measurements 
Since pressure can be measured, the outcomes can generate data on contact 
area (cm²), area under the peak pressure time curve (pressure time integral or pti) 
and peak plantar pressure (ppp) known as the single highest pressure calculated 
in kPa. The parameter of pressure time integral is less significant than ppp in risk 
factors for ulceration i.e. preventing DFUs (Bus and Waaijman, 2013). However in 
reducing pressure over an ulcer site rather than reducing the risk of ulceration, the 

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pressure time integral could be considered to be of greater significance (Yavuz et 
al., 2007). Healing requires reducing the pressure over the DFU preventing further 
tissue damage and promoting healing by redistributing pressure measured by both 
ppp and pressure time integral. Specialist have debated the issue of both these 
measurements value and there is no consensus to which one or both to use 
especially with ppp showing low sensitivity and low specificity to ulcer risk factors 
(Yavuz et al., 2007, Yavuz et al., 2015, Bus et al., 2016b, Lavery et al., 2003). One 
of the conclusions was a hypothesis that there must be more complicated diabetic 
pathology to developing diabetic foot ulceration than just elevated ppp or pressure 
time integral. The degree of pressure deemed damaging to the DFU is from the 
length of time in contact (contact time) and the amount of pressure in kPa 
measured at the interested site(s). It has been highlighted (Ledoux et al., 2013) 
that here is no consensus on the range of kPa that causes damage (DFU) as 
studies show numerous variables that affect the measures such as size of 
pressure cells, static platform or in-shoe measuring devices, site of DFU and 
sampling techniques within research. Therefore concentrating on the devices 
used in DFU clinical practice to reduce pressure over DFU sites is more important 
to heal the skin damage than finding the DFU preventative range of kPa on a 
patient’s foot. The priority is therefore identifying whether this new pressure 
relieving device changes (redistributes pressure effectively) plantar pressure 
distribution effectively at the common site (forefoot) of diabetic foot ulcerations. 
 
Sampling Rationale   
The Texas classification (Armstrong et al., 1998) of DFUs helps identify patients 
suitable for pressure relief, being neuropathic or neuro-ischaemic. As this is the 
classification system used at the study site it will be used within the context of this 
study. The proportion of wound classifications within the local population is as 
follows, purely ischaemic 10%, purely neuropathic 54%, neuro-ischaemic 36%. 
Ischaemic DFU prevalence in the UK ranges from 10% to 60% (Ndip and Jude, 
2009). Therefore the maximum sample within this centre, 90% (Neuropathic plus 
Neuro-ischaemic), should be primarily treated by TCC or removable off loading 
devices (NICE, 2015). Within a 2015 audit within this centre only a small proportion 
(3%) of the neuropathic and neuro-ischaemic population are receiving the 
recommended standard of off loading with TCC. This is due to issues around 
patient consent, clinical capacity and funding making the PulseFlow DF boot and 
other removable devices as suitable alternatives.   
 
While it is proven the non removable TCC is an effective modality for the 
successful treatment of diabetic forefoot plantar ulcers related to neuropathy, 
there are factors making it unsuitable for patients. This pragmatic approach to the 
sample population is supported by research (Wu et al., 2008) and also by the local 

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scoping audit showing poor utilisation of TCCs. Current comparative alternatives 
to TCCs (similar to the PulseFlow boot) show a low percentage of patient use (7% 
of the total possible). This highlights the reality of current clinical practice which is 
similar to the provision of pressure relief in the United States (US). According to 
specialist (Wu et al., 2008) DFU teams in the US show a lack of and even non 
existence of following standards on pressure relief for treating neuropathic related 
DFU’s. The products used for pressure relief are bespoke devices, prefabricated 
devices or bespoke TCC’s. There is a lack of products to choose from with 
limitations for devices used including financial constraints, stigma issues, quality 
of pressure relief, staff knowledge and skills needed to prescribe them. The direct 
material cost is lower for the TCC but demands more clinical time, highly 
experienced and trained staff with patient attending weekly applications. Patient 
consent to a TCC appears to be low aswell impacting on its use which has not 
been studied but only hypothesised that it is due to the lack of sensation (Piaggesi 
et al., 2007). Correct classification and providing appropriate pressure relief using 
the NICE guidelines CG19 needs to be considered carefully and closely monitored 
to facilitate efficient and effective use. 
Hypothesis  
Using the novel PulseFlow DF boot is as effective as usual standard care in off 
loading diabetic plantar forefoot ulcers. 
 
Sample and Population 
The population from the Diabetic Limb Salvage Service within Leeds will be used 
for the sample. This is a specialist centre based on the NICE CG19 guidelines 
(NICE, 2015) and provides a service to 252 diabetic foot patients (July 2016).  
Outcome 
To compare the pressure time integral data in kPa between usual standard care 
and the PulseFlow DF boot. 
 
 
 
 
 
 
2. STUDY AIM AND OBJECTIVES 
 
2.1. Study aim 

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The aim of the study is to assess the pressure relief in kPa for pressure time 
integral (PTI) (Melai et al., 2011) over the forefoot between the boot and usual 
standard of care. 
 
2.2. Primary objective 
To identify whether pressure time integral is equivalent or not to usual standard 
of care. 
 
2.3. Secondary objective(s) 
To measure the acceptability and effectiveness of the new boot. 
 
3. STUDY ENDPOINTS 
 
3.1. Primary endpoint 
Due to the study design (proof of concept) the endpoint will be completion of data 
collection. 
 
4. STUDY VARIABLES 
 
4.1. Standard variables 
Gender 
Age 
Ulcer location 
Classification of Ulcer (Texas classification) 
Ulcer duration 
Previous history of foot ulcer 
Previous foot ulcer at same site 
Duration of diabetes 
Weight 
Height 
 

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5. STUDY DESIGN 
 
5.1. Study description 
Observational proof of concept study comparing the ability to redistribute forefoot 
pressure using a new foot offloading device compared to usual standard care. 
The sample will be purposively selected taken from a local population of active 
diabetic foot ulcer patients. The measurements will be taken from patients 
wearing usual standard of care, sham shoe (closest to barefoot or baseline 
pressures) and the PulseFlow DF boot. The measurements from each patient 
will be collated to compute pti averages for the comparison.  
 
5.2. Study duration 
Approximately four months or time to complete required maximum sample size 
of 36 or ending 1st July whichever arrives first.  
5.3. Rationale for study design  
The issue of a novel boot should not influence clinical practice or further research 
until data is produced to support it. 
 
6. SELECTION AND WITHDRAWAL OF SUBJECTS 
 
6.1. Target population 
Patients currently undergoing treatment in the local Diabetic Limb Salvage 
Service who have diabetic neuropathic related plantar forefoot ulceration. 
 
6.2. Estimated number of eligible participants 
For this exploratory study formal methods for estimating sample size are 
inappropriate. The rationale for the size should be based on feasibility and the 
basis that this study will be used to justify the sample size of future studies. 
Therefore the rule of thumb modelling over three factors being explored will 
provide a sample size of 12 in each group (Julious, 2005). Therefore 36 in total 
are required.  From a 2015 audit, theoretically there was a population size of 231 
which identified 23% eligible patients for this study. The current population at 
January 2017 totalled 326 therefore approximately 74 patients should be eligible 
for this study. From the scoping exercise in December 2016, six patients were 
approached regarding the study to review possible challenges to taking part. All 

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six patients were satisfied with the proposal of taking part considering time 
required hospital location, travel arrangements and consenting. Therefore it is 
considered feasible to recruit the required sample of 36 participants (49% of 
available population following inclusion criteria).  
 
6.3. Eligibility criteria 
6.3.1. 
Inclusion criteria 
(a) Plantar forefoot diabetic foot ulcer  
a. over the 1st, 2nd, 3rd, 4th or 5th metatarsal joints 
(b) Neuropathic or Neuro-Ischaemic classification foot ulcer (taken from 
the TEXAS classification system) 
(c) 
(d) 
(e)  
Orthotic intervention for offloading/usual standard 
English speaking and reading 
Palpable foot pulses and/or Ankle Brachial Pressure Indices of values 
0.8 to 1.29. 
 
 
6.3.2. 
Exclusion criteria 
(a) 
Being treated for or having an active Charcot Arthropathy 
(b) 
Ankle Brachial Pressure Indices of <0.8 and >1.29. Using a 
standardised reproducible instrument called the Huntleigh Dopplex 
Ability Unit (DA100PB). 
(c) 
Temporary, accommodating or footwear not designed to offload. 
(d) 
(e) 
Clinically active Infection causing lower leg swelling 
Purely ischaemic classification foot ulcer 
(f) 
Current active osteomyelitis 
(g) 
Patients with forefoot trans metatarsal or major amputations  
(h) 
Fractures of the foot 
(i) 
Due to alterations in gait, patients with diagnosed vascular dementia, 
Parkinson’s, alcoholism or other major medically related gait 
alterations i.e. intoxication, brain cancers, muscular degeneration 
diseases, inflammatory arthritis, etc. This does not include osteo-
arthritis. 
(j) 
Pregnancy 
(k) 
 
 
Under another trial regarding foot dressings or off loading 
 
 
6.4. Withdrawal criteria 
 

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If the participant wishes to withdraw from the study at any point they are free 
to do so. Information regarding this is on the patient information leaflet. If 
withdrawing consent from the study is after data collection the data and 
samples will remain on file and will be included in the final study analysis as 
this will be anonymised. 
 
6.5. Recruitment, consent and randomisation processes 
6.5.1. 
Recruitment 
A verbal explanation of the trial and Patient Information Sheet will be 
provided by the authorised trial clinician in the patient’s usual standard of 
care treatment for the patient to consider. This will include detailed 
information about the rationale, design and personal implications of the 
study. Following information provision, patients will have at least 48 hours to 
consider participation and will be given the opportunity to discuss the trial 
with their family and healthcare professionals before they are asked whether 
they would be willing to take part in the trial. This process will be clearly 
documented into the patient’s medical notes.  
6.5.2. 
Consent 
Identifying patients within their out patient appointments will be by the direct 
care team members with a GCP trained certification. Certification will be 
documented within the study folder. Assenting patients will then be formally 
assessed for eligibility and invited to provide informed, written consent. 
Due to time and financial constraints of this educational study, it will not be 
possible to accommodate the communication needs of participants where 
English is not their first language. The right of the participant to refuse 
consent without giving reasons will be respected. Further, they will remain 
free to withdraw from the study at any time up to 24hours following 
(participant) data collection without giving reasons and without prejudicing 
any further treatment. Immediately after data collection participation will be 
pseudo anonymised. A copy of the consent will be given to the patient, one 
filed in the Study Files, and one filed in the hospital notes. The written 
consent will be taken by the principal investigator. The process of obtaining 
written consent will be clearly documented in the patient’s medical notes. 
6.5.3. 
Randomisation process 
Due to the type of study design patients can not be randomised. However 
the process of measuring usual standard of care, standard shoe and 
PulsFlow DF can be randomised. This will be performed by using a Latin 
3x3 square design below which will be randomly allocated from a computer 
programme at the appointment time of measuring the foot pressures. 

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Sequence 1 
Usual standard 
care 
PulseFlow DF 
Boot 
Standard shoe 
Sequence 2 
B PulseFlow DF 
Boot 
Standard shoe 
Usual standard 
care 
Sequence 3  
Standard shoe 
Usual standard 
care 
PulseFlow DF 
Boot 
 
6.5.4. 
STUDY BLINDING 
Due to the type of study design, patients can not be blinded to the 
intervention. 
 
6.5.5. 
Patients who withdraw consent 
 As soon as the patient withdraws their consent either verbally or in writing 
this will be documented within their medical notes within the principal 
investigators normal working hours.  
 If patient withdraws within 24 hours of data collection (of that patient) any 
data stored for that patient will be destroyed electronically following the 
organisational IT policy.  
6.5.6. 
Definition for the end of the trial 
Numbers completed to the original sample size of 36 or more or by1st July 
2017. 
 
6.6. General information on the products or interventions to be 
used 
PulseFlow DF  
The Diabetic Boot Company Ltd, Trading as PulseFlow Technologies, Midshires 
House, Midshires Business Park, Smeaton Close, Aylesbury, Buckinghamshire, 
HP19 8HL, United Kingdom. 
UK Patent GB 2454089 - Dec 2009 
US Patent US 8,388,562 - Mar 2013 
FDA Registered Facility - Registration Number: 3012177215, Owner Operator 
Number: 10051096 
PulseFlow DF is indicated for the treatment of active diabetic foot ulcer at the 
following sites: Plantar aspect of the 1st metatarsophalangeal joint (MTPJ), 2nd - 
5th MTPJ, Heel, Plantar and dorsum aspects of the toes and the Dorsum of the 
foot. 

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Proof of concept and pilot studies using healthy and patients with diabetic foot 
ulcers were used without reporting any adverse reactions. Diabetic foot ulcer 
patients showed one loss to follow up and one excluded from a small nine patient 
study to healing. All seven out of the nine patients at study end healed within a six 
week period. 
 
6.7. Use within the trial 
PulseFlow DF Boot 
 The PulseFlow DF boot is a trainer design with an integrated ankle foot orthosis. 
This is made of a metal design to immobilise the ankle and house the battery 
component around the calf region which will not be in use but with the same 
weight. Training of application and use of the device will be provided by the 
company producing the offloading device (Pulseflow Technology).   
 The principal investigator will administer and supply the device at the time of 
data capture. This will be applied and then a recommended period of use will 
be given before data capture.  
 Once the principal investigator and patient are satisfied with the safe use of the 
device it will be re-applied with the pressure sensing insole inserted.  
 There will be no implementation or continuation of the offloading device 
following completion of data collection. However, information of the device, 
where it can be purchased from and how much will be offered to the patient as 
they are currently available to the public and healthcare practitioners. 
 A test run will be applied by firstly using it on gait lab engineers and then testing 
the process on 3 active foot ulcer patients who will not be part of the study. 
These pre pilot testing phases for the principal investigator will enable training 
for the principal investigator and identify any anomalies when using the gait lab 
with study patients for the first time. The selection of the patients will be highly 
purposive due to the sampling methods and inclusion criteria. 
Usual Standard Care 
Management of the diabetic foot is guided by NICE with standards on DFU 
treatments modelled on best evidence (NICE, 2015). The basis of treatments 
other than TCC is worded as an alternative.  
“Offer an alternative offloading device until casting can be provided.”  
(NICE, 2015, section 1.5.5)  
The alternative is anything available to the service using local protocols or 
policies and consented to use by the patient. This can be described as below 
and may be any of the following named devices but is not exhaustive:- 
• 
Bespoke removable Boot (CROW meaning Charcot Restraint Orthotic 
Walker) 
• 
Removable prefabricated boot e.g. Aircast, DH Walker, Rebound etc. 

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• 
Forefoot offloader 
• 
Rearfoot offloader 
• 
DH Shoe 
• 
Scotch cast boot/shoe/slipper 
• 
Made to measure footwear and total contact/bespoke insoles 
•  
Total contact/bespoke insoles d plantar forefoot ulcer. 
 
 
7. METHODS OF ASSESSMENT 
This will be lab based data collection via electronic software, a modified validated 
questionnaire and demographic/variable list of specific identifying features of 
diabetic foot ulcers.  
7.1. Efficacy assessment variables 
1. 
 Usual care (offloading) device name/description 
2. 
PulseFlow DF  
3. 
Standard shoe 
 
7.2. Routine laboratory assessments 
Gait laboratory 
Pressure Time Integral  
One laboratory will be used within the Leeds Teaching Hospitals NHS 
Trust. The Gait laboratory is situated within Chapel Allerton Hospital, 
Leeds. The measurements will be collected on pressure in kPa via the 
Pedar-xf analyser (novel, no date) automatically collected within self 
contained password protected computer software package and then held 
on the secure server of University of Leeds M Drive. This will be stored 
electronically, password protected (see 8.3.2 for full details) under patient 
identifiable data (participant study code) for analysis later. The first one 
collected will be analysed for quality analysis in efficacy and validity issues. 
Only the research team ill have access to this data. 
 
 
Questionnaire 
A modified validated Measure of Orthopaedic Shoes (MOS) questionnaire 
will be completed following the pressure measurements. Answers will be 
recorded on coded patient specific sheet to be collected and uploaded onto 
a prepared excel data base after the participant has left the appointment. 

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The first one collected will be checked for completion. The completed 
questionnaire documents will be scanned and stored electronically to 
improve and allow for quality assurance to the transfer of data. This 
questionnaire will be used for the description analysis of patient 
acceptability. 
7.2.1.1. 
Gait analysis details 
Patients will familiarise themselves with the lab with a walking tour taking 
approximately up to 10minutes with question and answer session on the 
process of measurement taking and a chance to ask any questions. Then 
the measurement phase of walk assessment will start approximately 
10minutes into the visit. A further 30minutes (total of 40minutes) is 
allocated to acclimatisation of the novel walking boot before this is used for 
gathering the measurements. 
The combined average of 3 steps or the middle one third of the 30 feet 
walkway will be used for assessment of PTI. The patient will be blinded 
from when the time the measurements are taken when walking for the 
measurement. This will be done by walking with the patient and taking a 
measurement after the patient has become acclimatised on the measured 
walkway. Acclimatisation will be quantified by the patient being able to 
walk and talk without the need of balance assistance i.e. hand on the 
patient’s waist. The middle third of the walk will be used to acquire the 
measurements of PTI (approximately 3 steps of the foot) 
7.2.1.2. 
Duration of gait analysis 
Approximately 60 minutes will be given per patient visit to allow for 
technical and practical issues within the gait measuring room. The process 
for taking the electronic data measurements is estimated to take between 
10 and 15minutes for all three devices however the overall practical 
process will take longer. The participant will then be allowed to complete 
the short questionnaire needed for the secondary analysis. This will take 
no longer than an additional 10minutes. 
 
General Safety 
Those experiencing hypoglycaemia from their diabetes at time of 
measurements will need to be addressed for patient safety reasons. 
Hypoglycaemia is measured or determined by the patient or the symptoms 
related to hypoglycaemia i.e. shaking, unbalanced walking, speaking 
incoherently, slow/slurred speech, sweating, feeling hot, disorientated and 
measured low blood sugars via the patient’s blood sugar machine. When 
any participant has a hypoglycaemic event or becomes unwell the 
proceedings will be stopped. Hypoglycaemic events are not considered to 

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be caused by the intervention. The researcher will then seek appropriate 
medical care. The use of the nursing out patient hospital setting where the 
gait lab is situated will be used as support to any first aid issues. More 
serious events will be referred as appropriate to the nearest emergency 
care services. Rearranging the appointment will be offered following 
recovery. 
 
7.2.1.3. 
Data capture 
Data will be via the CE marked Novel Pedar Inshoe pressure analysis 
system. This system has been shown to have a higher accuracy than a 
similar competitor (Hsiao et al., 2002). It has also been piloted in a small 
study looking at sensitivity and valuable in post ulceration footwear 
analysis (Giacomozzi and Uccioli, 2013). 
7.2.1.4. 
Data analysis 
IBM SPSS Statistics 22 software will be used to analyse data. See 9.4. 
 
8. STUDY MANAGEMENT AND ADMINISTRATION 
 
8.1. Good clinical practice (GCP)  
This clinical trial will be run in accordance with the Principles of ICH GCP and the 
Research Governance Framework 2005. 
 
8.2. Adherence to protocol 
The Investigator should not deviate from the protocol. In medical emergencies, the 
Investigator may use his/her medical judgment and may remove a study 
participant from immediate hazard before notifying the Sponsor and the REC in 
writing regarding the type of emergency and the course of action taken. 
 
8.3. Data handling 
8.3.1. CRF completion 
The research team is responsible for prompt reporting of accurate, complete, 
and legible data in the CRFs and in all required reports. Any change or 
correction to the CRF should be dated, initialled, and explained (if necessary) 
and should not obscure the original entry. Use of correction fluid is not 
permitted. The Investigator is the sole authorizer to enter data into the CRF. 
Detailed instructions will be provided in the CRF Instructions. 

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8.3.2. Database entry and reconciliation 
Case report forms and all electronic data will be entered/loaded in a 
password protected information technology platform internally secured by 
Leeds Teaching Hospitals and University of Leeds information technology 
infrastructure. This is on the NHS Leeds Teaching Hospitals F Drive which is 
a secured server only accessible by named individuals and password 
protected. The University of Leeds data will be stored on named individual 
password protected accounts on the secure server, M Drive. Regular 
backups of the electronic data will be performed after each entry on the 
secure One Drive at University of Leeds at https://leeds365-
my.sharepoint.com/personal/hc15td_leeds_ac_uk/_layouts/15/onedrive.aspx 
8.3.3. 
Screening and enrolment logs  
Subject’s Screening will be recorded in the Subject Screening Log. 
The Investigator will keep a list containing all subjects screened and 
enrolled into the study. This list remains with the Investigator and is used 
for unambiguous identification of each subject. Subject’s Screening will be 
recorded in the Participant Log Entry. The researcher will keep a list 
containing all subjects screened and enrolled into the study. This is the 
anonymised case report file. This is in addition to the Participant Name 
Study Identity Log. The list contains the subject identification number which 
links to the full name, date of birth and National Health Security number of 
each participant. This will be held in a separate password protected data 
sheet and folder within the infrastructure detailed in 8.3.2. 
The subject’s consent and enrolment in the study will be recorded in the 
subject’s medical record. These data should identify the study and document 
the dates of the subject’s participation. 
 
8.4. Archiving and data retention 
Although not required by law for non-CTIMPs, in line with the principles of ICH 
GCP essential study documents will be retained for a minimum of 5 years following 
the completion of the study. For the purpose of a need for 5 year access this will 
be within the Principle Investigator’s Leeds Teaching Hospitals NHS Trust F Drive 
not the University Of Leeds M Drive due to the Principle Investigators student role 
terminating in September 2017. The study will be removed from any university 
data storage and transferred to the Principle Investigator’s NHS secured M drive 
via secure transfer, i.e. encrypted USB device or secure e-mail with password 
protected documents.  Arrangements for confidential destruction will then be 
made. If a patient withdraws consent for their data to be used, it will be 
confidentially destroyed immediately. No records/study documentation/data may 
be destroyed without first obtaining written permission from the Sponsor. 

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Essential documents include (this list is not exhaustive): 
• Signed informed consent documents for all subjects. 
• Subject identification code list, screening log (if applicable) and enrolment log. 
• Record of all communications between the Investigator, the REC and the 
Sponsor. 
• Copies of case report forms and documentation of corrections for all subjects. 
• Investigational product accountability records. 
• All other source documents (subject medical records, hospital records, 
laboratory records, etc.). 
• All other documents as listed in section 8 of the ICH E6 Guideline for Good 
Clinical Practice (Essential Documents for the Conduct of a Clinical Trial). 
Normally, these records will be held in the Investigator's archives. If the 
Investigator is unable to meet this obligation, he or she must ask the Sponsor for 
permission to make alternative arrangements. Details of these arrangements 
should be documented. 
 
 
8.5. Study suspension, termination and completion 
Suspension or termination of the study may occur at any time for any reason, 
following discussion between the Investigator and the Sponsor. Upon study 
completion, the Investigator will provide the Sponsor with final reports and 
summaries as required by regulations, and will be responsible for completing a 
premature end of study report to the Research Ethics Committee (REC) within 15 
days. 
 
9. DATA EVALUATION 
 
9.1. Responsibilities 
The principal investigator will be the sole responsible person as part of the Master 
of Science qualification will perform all tasks in collecting, storing, analysing and 
reporting the data for the research. 
 
9.2. Hypotheses 
Using the novel PulseFlow DF boot is as effective as usual standard care in 
off loading diabetic plantar forefoot ulcers. 

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9.3. General statistical considerations 
In general, summary statistics (number of available measurements), arithmetic 
mean, standard deviation, median, minimum and maximum for quantitative 
variables and absolute and relative frequency tables for qualitative data will be 
presented.  
 
9.4. Planned analyses 
All data will be explored to check for assumptions of normality and homogeneity 
of variance for each variable, and to assess which statistical tests i.e. parametric 
or non-parametric test will be more appropriate to explore the data. The 
assumption of normality will be assessed graphically by histogram, box-plots and 
confirmed by statistical testing of significance of skewness and kurtosis. The 
spread, homogeneity and type of data will determine the type of statistical test. 
The paired t Test is predicted to be the statistical test of choice following 
statistician advice. This may change due to abnormal distribution of data once 
collection is complete. 
Gait data will be checked for corruption or incomplete results associated with 
data capture or software error and rectified where possible either at the point of 
data collection or data analysis.   
Exploratory statistical analyses will be performed to identify any potential 
associations between gait kinematics, clinical data and patient-reported 
outcomes.  We will also explore the data for unexpected findings, including 
influential outliers, multicollinearity, truncation and missing data.   
The primary outcome (section 2.2) will then be compared for systematic 
differences between the usual standard care and the PulseFlow DF boot using 
statistical tests based on the assumptions tested previously. 
 
9.5. Data Handling  
All electronic data will be stored on secure University IT systems with password 
protected documents backed after each participant entry. All electronic data will 
be entered in a password protected documented information technology platform 
internally secured by Leeds Teaching Hospitals and University of Leeds 
information technology infrastructure. This is on the NHS Leeds Teaching 
Hospitals F Drive which is a secured server only accessible by named 
individuals and password protected. In the University of Leeds data will be stored 
on named individual password protected accounts on the secure server, M 
Drive. Regular backups of the electronic data will be performed after each entry 

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on the secure One Drive at University of Leeds at https://leeds365-
my.sharepoint.com/personal/hc15td_leeds_ac_uk/_layouts/15/onedrive.aspx. 
All paper copy data will be immediately transferred to electronic format and paper 
systems shredded as confidential waste. 
 
10. ETHICS AND REGULATORY REQUIREMENTS 
 
10.1. Good Clinical Practice 
This study will be conducted in accordance with applicable laws and regulations 
including, but not limited to, the International Conference on Harmonisation (ICH) 
Guideline for Good Clinical Practice (GCP) and the recommendations guiding 
ethical research involving human subjects adopted by the 18th World Medical 
Assembly, Helsinki, Finland, 1964, amended at the 48th General Assembly, 
Somerset West Republic of South Africa, October 1996. The Research Ethics 
Committee (REC) must review and approve the protocol and informed consent 
form before any subjects are enrolled. Before any protocol-required procedures 
are performed, the subject must sign and date the REC-approved informed 
consent form. The right of a patient to refuse participation without giving reasons 
must be respected. The patient must remain free to withdraw at any time from the 
study without giving reasons and without prejudicing his/her further treatment. The 
study will be submitted to and approved by a main Research Ethics Committee 
(REC) and the appropriate regulatory authorities prior to entering patients into the 
study. 
 
10.2. Subject information and informed consent 
Before being enrolled in the study, subjects must consent to participate after the 
nature, scope, and possible consequences of the study have been explained in a 
form understandable to them. 
An informed consent document (Patient Information Leaflet) that includes both 
information about the study and the consent form will be prepared and given to 
the subject at least 24 hours prior to the screening visit. This document will contain 
all the elements required by the ICH E6 Guideline for Good Clinical Practice and 
any additional elements required by local regulations. 
At the screening visit, patients will be given the opportunity to ask questions and 
the nature and objectives of the study will be explained. A podiatry team member 
caring for the potential participant may help in this process but the principal 
investigator is responsible for the informed consent discussions.  

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After reading the informed consent document, the subject must give consent in 
writing. The subject's consent must be confirmed at the time of consent by the 
personally dated signature of the subject and by the personally dated signature of 
the person conducting the informed consent discussions. 
The original signed consent document will be retained in the study files. Other 
copies of the consent form are required: 
 One copy of the informed consent document will be kept in the patient’s clinical 
notes. 
 One copy will be given to the patient. 
 One copy will be stored in the master trial file 
Consent is an ongoing process and will be reassessed at each study visit. 
The Investigator will not undertake any measures specifically required only for the 
clinical study until valid consent has been obtained. 
The Investigator must inform the subject’s primary physician about the subject’s 
participation in the trial if the subject has a primary physician and if the subject 
agrees to the primary physician being informed. 
 
10.3. Subject confidentiality 
Only the subject number will be recorded in the case report form, and if the subject 
name appears on any other document (e.g. laboratory report), it must be 
obliterated on the copy of the document to be supplied to anyone outside the 
clinical care team. The subjects will be informed that representatives of the 
Sponsor, Research Ethics Committee (REC) or regulatory authorities may inspect 
their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence. 
All information collected during the course of the trial will be kept strictly 
confidential.  
Information will be held securely on paper and electronically. All paper hard copies 
with patient identifiable data will be kept in the trial master file locked in a filing 
cabinet within a locked staff only access room on the NHS clinical site where 
consent is being taken (Chapel Allerton Hospital). All data transferable to 
electronic format will be performed directly after any paper data collection and the 
paper data destroyed as confidential waste. A site file at the recruiting centre 
(Leeds Teaching Hospitals NHS Trust) will store only copies of information for the 
participants and research protocol information accessible to staff within the team 
treating potential participants. 
The University of Leeds via the Chief Investigator will comply with all aspects of 
the Data Protection Act 1998. 

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The Principle Investigator at each site will maintain a personal subject 
identification list (subject numbers with the corresponding subject names) to 
enable records to be identified. 
 
10.4. Approval of clinical study protocol and amendments 
Before the start of the study, the clinical study protocol, informed consent 
document, and any other appropriate documents will be submitted to the REC and 
the Sponsor with a cover letter or a form listing the documents submitted, their 
dates of issue, and the site (or region or area of jurisdiction, as applicable) for 
which approval is sought.  
Before the first subject is enrolled in the study, all ethical and legal requirements 
must be met, including approval of the study by the NHS, the Sponsor Research 
and Development department and the REC. 
Amendments must be evaluated to determine whether formal approval must be 
sought and whether the informed consent document should be revised, thus all 
protocol amendments and administrative changes must first be discussed with and 
approved by the Sponsor before being submitted to the REC, in accordance with 
legal requirements. Amendments must be evaluated to determine whether formal 
approval must be sought and whether the informed consent document should be 
revised. 
The Investigator must keep a record of all communication with the REC and the 
Sponsor.  
 
10.5. Protocol amendments 
Requests for any amendments to the study must be sent to the Sponsor by the 
Principal and Chief Investigator. The Sponsor will determine whether said 
amendments are substantial or non-substantial prior to their submission to the 
appropriate bodies for approval. Patients should be re-consented to the study if 
the amendments affect the information they have received, patient safety, or if the 
change alters the type or quality of the data collected for the study. Patients should 
only be re-consented AFTER an amendment has been fully approved. 
 
10.6. Ongoing information for Research Ethics Committee 
Unless otherwise instructed by the REC and the Sponsor, the Investigator must 
submit to the REC and the Sponsor: 
• Information on serious adverse events that are unexpected and related to 
study procedures (RUSAEs) from the Investigator’s site, within 15 calendar 
days of the research team becoming aware of them. 

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• Expedited safety reports, as soon as possible. 
• Annual reports on the progress of the study. 
• The NRES Declaration of End of Study form. 
 
11. FINANCE AND INSURANCE  
 
11.1. Indemnity and insurance 
UoL sponsored study: The University of Leeds is able to provide insurance to cover 
for liabilities and prospective liabilities arising from negligent harm. Clinical 
negligence indemnification will rest with the participating NHS Trust or Trusts under 
standard NHS arrangements.  
 
11.2. Financial disclosure 
None of the Investigators or members of the research team have any financial 
involvement with the sponsorship or funding bodies or will receive personal 
benefits, incentives or payment over and above normal salary. 
 
12. PUBLICATION 
Owning rights and any publication in relation to the study is by the Principal and 
Chief Investigator and/or the sponsor only. 
 
 
 
 
 
 
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