Extracorporeal Shockwave Therapy for Diabetic Foot Wounds: A Cohort Study Comparing Extracorporeal Shockwave Therapy to Standard Treatment for Diabetic Foot Wounds
Conditions: Diabetic Foot, Wound
Sponsor: Hull University Teaching Hospitals NHS Trust

Protocol Version 2 
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April 2019 
 
Research Protocol 
 
Project Title: 
Extracorporeal Shockwave Therapy 
for Diabetic Foot Wounds 
A mixed methods feasibility study of extracorporeal shockwave 
therapy for diabetic foot wounds  
 
Protocol Version 2 
IRAS: 233543 
R&D: R2158 
 
Sponsor and Funding: 
Academic Vascular Surgery Unit  
1nd Floor 
Hull Royal Infirmary  
Anlaby Road 
HU3 2JZ 
 
Investigators: 
Chief Investigator: Mr George Smith 
Principal Investigator: Mr George Smith 
Other: Dr Louise Hitchman, Prof. Ian Chetter 
 
 

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Synopsis 
Study Title 
A mixed methods feasibility study of extracorporeal 
shockwave therapy for diabetic foot wounds  
Protocol Number 
2 
Sponsor 
Academic Vascular Surgery Unit 
Funder 
Academic Vascular Surgery Unit 
Objectives 
Primary Aims:  
To assess the feasibility of delivering shockwave therapy to 
patients with diabetic foot wounds 
 
Secondary Aims:  
- 
Assess the clinical outcomes associated with ESWT 
on diabetic foot wounds 
- 
Define the mechanism of action of ESWT on wound 
healing  
- 
Find the effect of ESWT on patient’s quality of life 
- 
Understand patient ideas, beliefs and expectations 
of ESWT 
- 
To determine patient tolerability of undergoing 
ESWT 
 
Study Design 
A mixed methods cohort study 
Participant Time 
12 weeks  
Study Parameters 
- 
 Recruitment rate 
- 
Adherence in treatment 
- 
Follow up rate 
- 
Reason for exclusions 
- 
Reason for drop outs 
- 
Change in wound volume – assessed on 3D imaging 
- 
Incidence of infection – from positive wound swabs 
and clinical evidence of infection 
- 
Incidence of amputation  
- 
Assess local tissue perfusion flow changes – using 
Doppler Flowmetry 
- 
Assess local tissue integrity – using Vapometer 
- 
Assess local bacterial growth  - from bacterial 
analysis from wound swabs 
- 
Changes in quality of life – assessed on the EQ-D5-
3L and SF-12 
- 
Changes in pain score – assessed on Visual 
Analogue Scale and Brief Pain Inventory 
- 
Acceptability and tolerability – assessed on Visual 
Analogue Scale  
- 
Patient’s beliefs around shockwave therapy 
- 
Patient’s reported willingness to try new 
treatments and motivation for that behaviour 

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- 
Patient’s experience of undergoing shockwave 
therapy 
- 
Patient’s perceived effect of shockwave therapy on 
their life 
 
Sample Size 
40 
Sample Sites 
Hull Royal Infirmary 
Data Analysis 
Quantitative: Descriptive analyses  
Qualitative: thematic analysis 
Safety analysis 
Adverse events for each participant will be collected, 
summarised and reported  
 
 

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Introduction 
 
Diabetes is one of the most common chronic diseases in the world. In the United 
Kingdom 3.6 million people have diabetes and an estimated half a million people have 
undiagnosed diabetes (1), with the incidence rising (2). Diabetic foot complications are 
common with at least 10% of diabetics developing a foot ulcer in their lifetime. Diabetic 
foot ulcers precede 84% of non-traumatic amputations (2-4) and are associated with a 
70% 5 year mortality rate (4, 5). Diabetic foot wounds have a poor healing rate: 30-45% 
(6) of diabetic digital amputations fail to heal, resulting in 75% of patients undergoing 
further higher amputation within the year(7). This is associated with a poor quality of 
life (8).  
The management and prevention of diabetic foot disease is a costly affair 
affecting all healthcare sectors. For every £150 the NHS spends, £1 goes on diabetic foot 
care and amputations (4).  
The current management of diabetic foot wounds includes glycaemic control, 
smoking cessation, pharmacological treatment with statins and anti-platelets (2). As 
well as revascularisation of ischaemic wounds, debridement, off loading and wound 
dressings (2, 7, 9). Advanced therapies used for complex diabetic foot wounds include 
bioengineered skin equivalents, and maggots.  Even with the best wound management 
diabetic foot wounds are associated with protracted treatment courses, predisposing 
patients to developing infection. Proposed advanced therapies include bone marrow 
derived stem cells growth factor therapy, recombination anti-platelet growth factor 
(Becaplermin), hyperbaric oxygen therapy and extracorporeal shockwave therapy 
(ESWT) (2, 7, 9). ECSWT has shown encouraging results in improving the healing of 
diabetic foot wounds (8, 10-17). It has good efficacy, is safe, non invasive, carries a low 
complication rate (8, 18) and is cost effective (8). ECSWT has also been shown to be 
more effective than other treatments in improving poor healing rates in the acute and 
chronic setting of diabetic foot ulcers, chronic venous ulcers and in burns (8, 15). A 
systematic review from 2017 reported ‘mild to moderate’ evidence of the adjuvant use 
of ESWT with standard wound treatment for chronic lower leg wounds. The trial 
commented the need for further research to assess the efficacy of ESWT for wound 
healing (12),.  
Currently no studies have investigated the feasibility of delivering ESWT to patients 
with acute and chronic diabetic foot wounds and have not addressed the potential 
limitations, for example patient acceptability, patient tolerability and logistics of 
integrating ESWT into standard care. 
This study aims to add to the growing evidence base in shaping new treatments of 
diabetic foot wounds to improve the prognosis of diabetic foot wounds and therefore 
patient’s quality of life.  
Background 
The effect of shockwaves on the body was first noted in lungs of victims subjected to 
water bombs in world war two(8).  Later, high energy focused shockwaves were found 
to be effective in treating renal stones in lithotripsy. In 1986 low energy defocused 

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shockwaves were found to improve the healing rate in chronic wounds and delayed 
healing fractures (19). Extracorporeal shockwave therapy continues to be extensively 
researched to uncover its beneficial effect in healing tendon injuries, bone fractions, 
calcific tendonitis and plantar fasciitis (17). More recently its effect on endothelium and 
lymphatics on the promotion of healing has been popularly researched in human and 
animal models (8, 13, 20, 21).   
 
Mechanism of Action of Shockwaves 
A shockwave is high amplitude sound wave that is generated from a piezoelectric 
source and propagated into tissues. The sonic waves pass through tissues with low 
impedance and are reflected by tissues with high impedance. The passing of 
shockwaves through surfaces of difference impedance creates tension forces. These 
forces generate bubbles, which contain a vacuum inside. The collapsing of the bubbles 
induces shear forces on the local tissues. 
The basis of how these mechanical energy are translated into chemical energy is by: 
1. Generation of oxygen free radicals 
2. Hyperpolarisation of cell membranes.  
Both the generation of oxygen radicals and hyperpolarisation of membranes triggers 
release the kinases and growth factors, including Vascular Endothelial Growth Factors 
(VEGF) and transforming growth factor beta 1 mitogen-activated protein kinases (6). 
The generation of oxygen free radicals stimulates the release of VEGF, transforming 
growth factor beta 1, BMP-1, BMP-2 and BMP-7 which induce the differentiation of 
mesenchymal cells (22).  The shockwave used in the treatment of wounds are 
transmitted from a soft focused applicator, which delivers low energy defocused radial 
shockwaves to a depth of around 3cm (8, 12). 
These factors are known to play an active role in regulating inflammation, haemostasis, 
proliferating and remodelling vital in the healing process (8, 12).  
 
Basis of Disrupted Healing In Diabetes  
Diabetes disrupts the normal healing pattern in three broad areas (11): 
1. Hyperglycaemia leads to endothelium dysfunction resulting in low nitric oxide 
levels leading to vasoconstriction and impaired immune and inflammatory 
response locally, predisposing to infection.  
2. Impaired healing barriers due to deficiency in growth factors needed for 
inflammation and tissue regeneration. Most notably:  
a.  Deficiency in endothelium growth factor (EGF), VEGF, GM-CSF and IL-8, 
which regulate angiogenesis.  
b. Locally, a lack of PDGF, transformed GF beta and GM CSF leading to 
impaired extracellular matrix deposition.  
c. Shortage of IGF 1, EGF, basis FGF, IL6 and GMCSF leading to reduced 
epithelisation and ketatinocyte proliferation.  
3. Local infection caused by immunosuppression in diabetes results in raised 
neutrophils, monocytes, macrophages that create granulation tissue. Leucocytes 
release cytotoxic, proteolytic and free radicals resulting the disorganised 
collagen layout in healing wounds.  
Analysis of a diabetic wound shows low angiogenic factors, disordered granulation, 
inflammation and disordered immunity all predisposing to poor wound healing.  
 

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Effect of Extracorporeal Shockwave Therapy in Wounds of Various Aetiologies: 
In vitro, animal and humans models researching the effect of ESWT on wounds the 
efficacy of shockwave therapy is currently hypothesised to be through its ability to 
influence factors vital in angiogenesis and regulation of fibroblasts including:  
- 
Nitric Oxide:  
o Vital in vasodilation via the guanylate cyclase cycle (23) 
o Increases the expression of Tissue Growth Factor beta (TGF-β), b-
Fibroblast Growth Factor (b-FGF), Necrosis Factor κb (NF-κb) and Insulin 
Growth Factor (IGF) to regulate collagen synthesis (13) 
o Keeps NO within physiological limits via down regulation of NF-κb to 
decrease inflammation by decreasing cytokine levels (8), locally and 
systemically (24).  
- 
Angiogenesis via: 
o Increasing concentration of Vascular Endothelial Growth Factor (VEGF) to 
stimulate angiogenesis (8, 10, 11, 13, 20) 
o Increasing platelet endothelial cell adhesion molecule 1 (PECAM) 1 on 
leucocytes and endothelium to increase cell migration and angiogenesis 
(8) 
o Increased Stromal Cell Derived Factor 1 (SDF-1) mRNA in endothelial 
progenitor cells which are low in chronic wounds and ischaemia (8) 
- 
Fibroblasts: increase Proliferating Cell Nuclear Antigen (PCNA), stimulate 
proliferation and regulate myofibroblast differentiation (13, 25) 
- 
Decrease inflammation by decreasing leucocytes and Tumour Necrosis Factor 
alpha (TNF-α) (13). 
On samples taken and analysed of human wounds treated with ESWT there was found 
to be higher levels of von Willebrand Factor (vWF), VEGF, endothelium Nitric Oxide 
Synthase (eNOS), stimulating angiogenesis; higher levels of PCNA, Endothelial Growth 
Factor (EGF) for increasing cellular proliferation and lower Terminal deoxynucleotidyl 
transferase dUTP nick end labelling (TUNEL) assay signifying a lower rate of apoptosis 
(10, 13). Clinically wounds treated with ESWT have a higher epithelisation rate, smaller 
wound size, better blood flow and better long term healing for up to one year compared 
to control groups (12, 14-18, 26).  
Less is understood about the bactericidal mechanism of ESWT. Studies into the 
effect of low energy shockwaves on staphlococus aureus have shown in vitro ESWT is 
more effective at eradicating metabolically active bacteria, has a dose dependent 
response and in combination with antibiotics such as fosfomycin, cefuroxime and 
rifampicin is highly effective in eliminating bacteria (27, 28). The hypothesised 
mechanism is derangement of organelles and DNA through free radical formation.  
Aims 
The study aims to assess the feasibility of delivering ESWT to patients with diabetic foot 
wounds and ulcers, investigate the clinical effect of ESWT on wound healing, explore the 
potential mechanism of action and assess whether it offers any patient reported 
benefits.  

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Primary Aim:  
 To assess the feasibility of delivering extracorporeal shockwave therapy to 
patients with a diabetic foot wound. 
 
Secondary Aim: 
- 
Assess the clinical outcomes associated with ESWT on diabetic foot wounds 
- 
Define the mechanism of action of ESWT on wound healing  
- 
Find the effect of ESWT on patient’s quality of life 
- 
Understand patient ideas, beliefs and expectations of ESWT  
Design 
A single centre mixed methods cohort study.  
Setting 
The study will be conducted in the Academic Vascular Surgical Unit Hull York Medical 
School at Hull Royal Infirmary. Patients will be recruited from Diabetic Foot Clinic and 
ward 7 and 70.  
Sample Size 
The sample size will be 40. This is appropriate for a feasibility study and is similar to 
studies of diabetic foot wounds treatment with standard therapy. Interviews will be 
conducted until data saturation.   
Target Population and Recruitment 
Inclusion Criteria 
- 
Diagnosis of diabetes mellitus  
- 
Open wound of the foot 
- 
ABPI >0.8 
- 
Age greater than 18 years old 
- 
Able and willing to give written informed consent 
- 
Be able to adhere to protocol and attend all follow up appointments 
Exclusion Criteria 
- 
Pregnancy or breast-feeding  
- 
Current malignancy  
- 
Allergy to materials used in the treatment 
- 
Palliative 
- 
Unable or unwilling to give consent  
- 
Anticoagulation 

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Screening and Consent 
Patient Identification  
 
Potential participants will be identified from the diabetic foot clinic, vascular ward, 
endocrinology ward and the vascular theatre lists. We will liaise with the appropriate 
clinical team before approaching potential patients to ensure suitability. If suitable we 
will introduce the study to the patient, explain what is involved and provide the patient 
information sheet (Patient Information Sheet Version 3.1 April 2019).  
 
Patient Consent 
 
Informed consent will be taken from participants who express an interest in taking part. 
We will ensure the participant understands the purpose of the study, what is involved, 
the possible risks and reinforce the participant is not obliged to take part. The 
discussion will be documented on the consent form (Consent Form Version 2.1 April 
2019).  
 
Following project review (July 2019), all participants will be offered the opportunity to 
take part in qualitative interviews. New participants will be asked for consent at the 
start of the study, whereas existing participants will be approached either at a follow up 
appointment or by telephone. For the latter, we will explain what is involved and 
provide them with a copy of the Qualitative Study Patient Information Sheet (Version 
1.0 April 2019). 
 
Evaluation 
Baseline data will be collected from all consenting participants includes: 
- 
Informed consent 
- 
Participants name, date of birth, NHS number, HEY number, address, contact 
number and name and address of their registered GP 
- 
Past medical and surgical history  
- 
Co-morbidities  
- 
Assessment of concurrent medications 
- 
Smoking history 
- 
Allergy status 
- 
Pregnancy test, if applicable 
- 
BMI 
- 
Baseline pain score 
- 
Baseline quality of life 
- 
Surface area of the wound 
- 
Physical examination, including level of neuropathy and vital observations 
- 
Ankle Brachial Pressure Index  

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Restrictions 
Dietary 
There are no dietary restrictions. 
Smoking 
Smoking will not be permitted in the Study Centre or in hospital groups except in 
designated smoking areas.  
Concurrent medications 
Concurrent medications and new medications commenced during the trial will be 
recorded. Patients taking anti-coagulation medication will be excluded.  
Study Protocols 
Study Treatments 
Extracorporeal shockwave therapy will be applied using the PeizoWave 2 shockwave 
system within the device’s licensing. The shockwave therapy will be given at 120 
pulses/cm2, penetration 5mm at a dose of 0.1mJ/mm2 at 5 pulses/second (17).  
Participants will receive 3 sessions of shockwave therapy in a 7-day period alongside 
standard wound care. 
 
Environmental Conditions 
Patients will be assessed and treated at the Diabetic Foot Clinic, Brocklehurst Centre, 
ward 7/70, Hull Royal Infirmary and/or Academic Vascular Unit, Hull Royal Infirmary.  
Outcome measures 
Primary outcome 
Feasibility of delivering extracorporeal shockwave therapy to patients with a diabetic 
foot wound, assessed by: 
- 
Recruitment rate 
- 
Adherence in treatment 
- 
Follow up rate 
- 
Reason for exclusions 
- 
Reason for drop outs 
 
Secondary outcomes: 
Clinical outcomes: 
- 
Change in wound volume – assessed on 3D imaging 

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- 
Incidence of infection – from positive wound swabs and clinical evidence of 
infection 
- 
Incidence of amputation  
 
Mechanism of action outcomes: 
- 
Assess local tissue perfusion flow changes – using Doppler Flowmetry 
- 
Assess local tissue integrity – using Vapometer 
- 
Assess local bacterial growth  - from bacterial analysis from wound swabs 
 
Patient Outcomes 
- 
Changes in quality of life – assessed on the EQ-D5-3L and SF-12 
- 
Changes in pain score – assessed on Visual Analogue Scale and Brief Pain 
Inventory 
- 
Acceptability and tolerability – assessed on Visual Analogue Scale  
 
Qualitative Outcomes: 
- 
Patient’s beliefs around shockwave therapy 
- 
Patient’s reported willingness to try new treatments and motivation for that 
behaviour 
- 
Patient’s experience of undergoing shockwave therapy 
- 
Patient’s perceived effect of shockwave therapy on their life 
As assessed during qualitative in depth interviews  
Assessments 
1. Quantitative Measures: 
 
Baseline 
After consent participant’s baseline data, wound measurements, local perfusion, tissue 
integrity and wound swabs will be taken and quality of life and pain questionnaires will 
be completed at baseline before the first treatment.  
 
Follow-up 
The participant will receive 3 treatments in the first 7 days after surgery. After the third 
wound measurements, Vapometry, Laser Doppler Flowmetry and wound swabs will be 
taken and quality of life, pain and tolerability questionnaires will be completed. Wound 
imaging, quality of life and pain scores will then be repeated at weeks 4, 8 and 12. 
Infection and amputation rate will be recorded at each contact with the research team.  
 
2. Qualitative Interviews: 
 
We will conduct semi-structured interviews after the last treatment of ESWT. The 
interviews will be undertaken in a way acceptable to the patient. They may take place in 
person or over the phone or be located in the hospital and occur at a time convenient 
for the patient. The interviews will last 30-40minutes.  
 
If the patient gives their permission interviews will be recorded on a digital device that 
is password protected. 

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The interviews will explore the participant’s experience of undergoing ESWT. We will 
draw on previous research investigating patient’s experience of different therapies to 
treat wounds to create a focused topic guide but also allows for flexibility into areas not 
previously considered by the researcher or identified in the literature (29-32). 
The topic guide will include patient experience in attending for treatment, experience of 
receiving ESWT, experience after ESWT and any effect it has had on their life.  
 
The researcher will be supervised by experts in qualitative research based at the 
University of York and the Academic Vascular Surgery Unit, Hull University Teaching 
Hospitals.  
 
3. Clinician Surveys; 
 
We will explore clinician stakeholder’s beliefs of extracorporeal shockwave therapy 
through questionnaires. We will approach vascular surgeons and trainees, 
endocrinologists, infectious diseases specialists and podiatrists. Our aim is to explore 
their opinion of offering ESWT to acute wounds, knowledge of the evidence base, 
reservations they may have, willingness to refer for ESWT and potential to deliver the 
therapy in their clinics.  
Concurrent Medications 
No restrictions of medications.  
Assessment of Concomitant Medications 
Concomitant medications at the start of the trial will be recorded. Any subsequent 
medication prescribed during the trial period will also be recorded.  
Method of Analysis: 
 
Quantitative Data 
Recruitment rate, reasons for exclusion and non-consent, as well as follow-up rates and 
reasons for drop-out (where known) will be presented descriptively. Compliance with 
treatment will be presented descriptively. 
 
Continuous patient reported and clinical outcomes will be presented as means and 
standard deviations and categorical outcomes as counts and percentages as at all 
available follow-up points. Outcomes over time will be summarised graphically where 
appropriate. Any change in outcomes will be presented with 95% confidence intervals. 
 
Data will be analysed using the SPSS software package.  
 

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Qualitative Analysis 
We will use thematic analysis approach to data analysis using the phases described as 
Braun and Clarke, 2006 for analysis of the interviews(33). We will complete the 
following steps (33): 
1. Familiarisation: the interviews will be transcribed and re-read to ensure 
familiarity with the generated data 
2. Code generation: from reading through the interviews potential codes will be 
assigned to the data 
3. Identifying theme: after codes have been assigned they will be reviewed and 
grouped into themes 
4. Reviewing themes: to ensure the themes represent the data we will compare 
the theme to the codes and the data from which they were derived, in doing 
this we will create a thematic map of analysis 
5. Define theme: we will explore each theme separately, looking at the codes 
and extracts, to assign names to the themes. The themes will be compared for 
fit with the rest of the data 
6. Produce a report: thematic analysis, along with example extracts, will be 
reported to answer our research question and be discussed in the context of  
existing literature 
The data will be transcribed using NVIVO and reviewed by two researchers (LH and GS) 
to ensure internal validity. The results discussed between three researchers (LH, GS, IC) 
to ensure appropriate interpretation. The results will be also be reviewed by the 
University of York Masters supervisors to reduce any researcher associated bias.  
Adverse events 
Any Serious Adverse Events will be reported to the Sponsor and National Research 
Ethics Service recognised Research Ethics Committee. All side effects reported will be 
recorded throughout the study.  
The Device 
The PiezoWave 2 FBL 10x5 G2 device will be used to deliver extracorporeal shockwave 
therapy.  
Safety and Tolerability 
The device will only be used by trained staff members familiar will be device and 
deliverance of treatment. The environment of application of treatment will be equipped 
for emergency situations. 
Ethics and Safety Reporting 
Ethical approval will be sought from IRAS and the recruitment of participants will be in 
line with the declaration of Helsinki (2008). All patients will be informed of the study 
purpose, design, treatments, duration, risk and benefits and allowed to clarify additional 
questions during the consenting procedure. All participants must give informed consent 
and the consent form must be signed by the relevant parties, dated and kept with the 

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clinical trial forms in the patient’s notes.  The participant will be informed if any new 
information arises and informed consent must be gained again before carrying on with 
the trial. 
The device will be used under the licensed indications and there are no anticipated 
adverse reactions. All adverse events or reactions and device failure will be reported on 
specific forms and action will be taken to treat the patient. If the event is deemed to be a 
serious adverse event or reaction the principal investigator will be informed within 24 
hours. If an adverse event or reaction occurs the investigator will collect all possible 
information and the Principal Investigator will be informed to undertake the necessary 
action. Previous adverse reactions reported in the literature associated with 
extracorporeal shockwave therapy include: itching, burning, pain, skin pigmentation 
(12). Each participant will be given emergency contact details for the Principal 
Investigator if any concerns develop about the trial.  
The trial will also comply with HEY research and development standards.  
Withdrawals and Drop Outs 
 
Patients are permitted to drop out at any point during the trial. The research 
investigators reserve the right to withdraw any participant if their health is at risk or if 
the participant fails to comply with the study protocol. If the subject develops an 
adverse event or reaction they will also be withdrawn from the trial.  
Trial Exit 
Participants will exit the trial completely when they complete the follow up period or if 
they: 
 Withdrawn their consent to continue 
 Withdrawn by the investigator due to health concerns or non-compliance 
 Undergo angioplasty, bypass grafting or further surgery 
 Experience an adverse event or reaction 
 Die 
Overall timescale for the study 
Recruitment will begin when Ethics and Trust Research and Development approval has 
been gained. The patients will be involved in the trial for 12 weeks.  
 
Follow up assessments 
Where possible all follow up will coincide with standard dressing and clinic follow ups 
to minimise the additional visits for participants. The follow up weeks are 4, 8, 12 after 
randomisation.  

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Data management 
Data will be handled in line with the Data Protection Act 1998. The trial data will be 
registered with the local Data Protection officer.  
For participants entering the study after the second amendment data will be handled in 
line with the GDPR 2018 guidelines. Patients will also be given information relating to 
this in the patient information sheets.  
The data will be collected entered onto a excel spreadsheet created by the research 
team.  The data will be kept on password protected NHS trust computers with firewalls 
and antivirus software on files with limited access to the trial investigators.  
The storage of data will be in line with the IT department standards. Data will remain on 
the servers and be backed up on secure HEY IT systems. The data will be accessible to 
investigators and those seeking permission for monitoring and auditing.  
Paper records will be stored and locked in the Academic Vascular Unit when not in use. 
Study Report 
The final pilot study report will outline the background, methods, results, discussion 
and conclusion of the trial in line with the CONSORT guidelines. The data from the 
participants will be anonymous. It will be submitted for publication in a peer-reviewed 
journal.  
Administration 
Participant Reimbursement 
There is no provision for participant reimbursement. The trial follow up will coincide 
with routine follow up appointments.  
 
Finance  
Sponsors will not influence the trial or its publication.  
 
 
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