Pain Management and Patient Education for Physical Activity in Intermittent Claudication (PrEPAID): Feasibility Randomised Controlled Trial
Phase: NA
Conditions: Peripheral Arterial Disease, Intermittent Claudication
Sponsor: Glasgow Caledonian University

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Study full title: Pain Management and Patient Education for Physical Activity in Intermittent 
Claudication: Feasibility Randomised Controlled Trial 
 
Study acronym: PrEPAID 
 
Running title: Pain management and patient education in intermittent claudication 
 
Protocol Version:  
 
 
Version 3.0 
 
Date:  
 
 
 
09/01/2019 
Funding Reference  Number:  
TCS/16/55 
REC Reference Number: 
 
17/WS/0094 
Sponsor’s Protocol Number:  
16-044 
R&D Reference Number:  
 
GN16CE378 
Trial Registration Number: 
 
NCT03204825 
 
Sponsor:  
Glasgow Caledonian University 
Funder:  
Chief Science Office  
Amendment 
number 
Date 
Details  
Protocol 
version 
2 
09/01/2019 
1) Amendment to table of content (p6) and 
section 3.4 (p20), and patient information 
sheet to clarify that follow up timing (visit 
5) is at 3 months post intervention. 
2) Amendment to study synopsis (p10) and 
section 3.3 (p19) to specify that participants 
< 40 years of age will be excluded. 
3) Changes to consent form to specify that 
patients will be audio recorded at focus 
group. 
4) Updating the patient information sheet to 
specify that patients will be audio-
recorded during focus group. 
3.0 
 
Amendment 
number 
Date 
Details  
Protocol 
version 
1 
12/9/2017 
1) Amendments to sections 8 (p26) for accuracy 
related to who will conduct the statistical analysis.   
 
2) Optional blood sample in laboratory tests- 
corrected information to accurately reflect study 
schedule  
(4.3 Laboratory Tests p24) 
 
3) TENS Feedback Questionnaire - to reflect that 
participants will be exiting the study at different 
points, the timing of the TENS questionnaire has 
been amended to be the final data collection for all 
participants. (Study Schedule p13-14 and section 4.1 
2.0 

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p22-23) 
4) Assessment of ABPI has been removed from 
visits 4 and 5 (Study Schedule p13-14). We do not 
intend to analyse ABPI data but only need to control 
for baseline variations in the final analysis.  
5) Amendment made to consent form to correct the 
name of Robertson Centre for Biostatistics.  
6) Participants information sheet amended to 
correctly reflect intervention protocol 
    i. Visit 3: 1 hour or 4 hour maximum instead of 1 
hour max in version 1.0 
   ii) Visit 5: will be a repeat of the first and fourth 
visits where you will complete the questionnaires, 
treadmill test and blood sample (optional). 
7) Participants information sheet amended to specify 
that activPAL physical activity data will be stored at 
Glasgow Caledonian University. 
8) Study schedule Visit 4: Specific queries regarding 
adverse events added  
 
This study will be performed according to the Research Governance Framework for Health 
and Community Care (Second edition, 2006) and WORLD MEDICAL ASSOCIATION 
DECLARATION OF HELSINKI Ethical Principles for Medical Research Involving Human 
Subjects 1964 (as amended). 

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CONTACTS 
Chief Investigator  
Dr Chris Seenan 
Designation: Lecturer in Physiotherapy  
Mailing address: Department of Psychology, Social Work and Allied Health Sciences 
Glasgow Caledonian University Cowcaddens Road Glasgow G4 0BA 
Tel: (0)141 331 8151 
E-mail:  Chris.Seenan@gcu.ac.uk 
 
Co-chief investigator  
Professor Julie Brittenden 
Director of Research and Development/Director of CRF/Professor of Vascular Surgery West 
Glasgow Ambulatory Care Hospital 
Dalnair Street 
Glasgow 
G3 8SW 
Tel: 0141 2019328 
E-mail: Julie.Brittenden@ggc.scot.nhs.uk 
 
Co-Investigators 
Mr Ukachukwu Abaraogu 
PhD Student 
School oh Health and Life Sciences  
Glasgow Caledonian University Cowcaddens Road Glasgow G4 0BA 
Tel: 0141 331 3343 
Email: Ukachukwu.Abaraogu@gcu.ac.uk  
 
Dr Philippa Dall 
Senior Research Fellow  
School of health and Life Sciences 
Glasgow Caledonian University Cowcaddens Road Glasgow G4 0BA 
Tel: 01413318003 
Email: Philippa.Dall@gcu.ac.uk   
 
Professor Jon Godwin 
Institute of Applied Health Research 
Glasgow Caledonian University Cowcaddens Road Glasgow G4 0BA 
Tel: 01413313482 
Fax: 01413318211 
Email: Jon.Godwin@gcu.ac.uk 
 
Mr Wesley Stuart 
Vascular Surgeon and Clinical Director/ Horary Senior Lecturer 
Glasgow and Clyde, Glasgow/ Department of Vascular Surgery University of Glasgow 
1345 Govan Road, Govan, G514TF  
Telephone: 0141 452 5944 
Email: Wesley.Stuart@ggc.scot.nhs.uk  
 
Dr Garry Tew 
Associate Professor 
Department of Sport, Exercise and Rehabilitation 
Northumbria University Newcasctle 
Tel: 0191 2437556 
Email: garry.tew@northumbria.ac.uk  

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Study Statistician 
Professor Jon Godwin 
Professor Institute of Applied Health 
Glasgow Caledonian University 
Glasgow G4 0BA 
Tel: 01413313482 
Fax: 01413318211 
Email: Jon.Godwin@gcu.ac.uk 
 
Data Centre 
Robertson Centre for Biostatistics/Glasgow Clinical Trials Unit 
University of Glasgow 
Level 11, Boyd Orr Building 
University Avenue, Glasgow 
G12 8QQTel: 0141 330 4744 
Fax: 0141 330 5094 
Email: contactus@glasgowctu.org 
 
Professor Jon Godwin 
Professor of Applied Statistics Institute of Applied Health 
Glasgow Caledonian University 
Glasgow G4 0BA 
Tel: 01413313482 
Fax: 01413318211 
Email: Jon.Godwin@gcu.ac.uk 
 
Chair of the Trial Steering Committee 
Dr Stephen McSwiggan 
Designation: Head of Commercial Services at the University of Dundee/NHS Tayside 
Mailing address: School of Medicine  
University of Dundee, Nethergate, Dundee, DD1 4HN, 
Tel: 01382 383233 
Email: s.j.mcswiggan@dundee.ac.uk 
 
Sponsor 
Glasgow Caledonian University 
 
Funding Body 
Chief Scientist Office 
Ground Rear 
St Andrews House 
Regent Road 
Edinburgh 
EH1 3DG 
 
 
 
 
 
 
 
 

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PROTOCOL APPROVAL 
 
Study full title: Pain Management and Patient Education for Physical Activity in Intermittent 
Claudication: Feasibility Randomised Controlled Trial 
 
Study Acronym: PrEPAID  
 
Chief Investigator 
Dr Chris Seenan 
Designation: Lecturer in Physiotherapy  
Mailing address: Department of Psychology, Social Work and Allied Health Sciences, School 
of Health and Life Sciences, Glasgow Caledonian University, Glasgow G4 0BA 
Tel: (0)141 331 8151 
E-mail: Chris.Seenan@gcu.ac.uk 
 
 
Signature: 
 
 
 
 
 
 
Date:  
 
 
5/4/2017 
 
 
Sponsor’s representative 
 
 
 
 
 
 
Signature: 
 
 
 
Date:  
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
 
CONTACTS .............................................................................................................. 3 
PROTOCOL APPROVAL ........................................................................................... 5 
TABLE OF CONTENTS ............................................................................................. 6 
ABBREVIATIONS .................................................................................................... 8 
STUDY SYNOPSIS................................................................................................... 9 
GLOSSARY OF TERMS........................................................................................... 11 
STUDY FLOW CHART ............................................................................................ 12 
STUDY SCHEDULE ................................................................................................ 13 
INTRODUCTION ................................................................................................ 16 
1.1 
Background ................................................................................................. 16 
1.2 
Rationale .................................................................................................... 16 
1.3 
Prior experience of intervention in disease area .............................................. 17 
2. 
STUDY AIM, OBJECTIVES, AND RESEARCH QUESTIONS ......................... 18 
2.1 
Aims ........................................................................................................... 18 
2.2 
Research Objectives ..................................................................................... 18 
2.3 
Research Questions: .................................................................................... 19 
3. 
STUDY DESIGN ........................................................................................ 19 
3.1 
Study Population ......................................................................................... 19 
3.2 
Inclusion criteria .......................................................................................... 19 
3.3 
Exclusion criteria ......................................................................................... 19 
3.4 
Identification of participants and consent ....................................................... 19 
3.5 
Retention Rates ........................................................................................... 20 
4 
Trial procedures .......................................................................................... 20 
4.1 
Study schedule ............................................................................................ 21 
Visit 1- First Assessment Visit: .............................................................................. 21 
Visit 2- Second Assessment Visit (usually within 2 weeks after visit 1): .................... 22 
Visit 3 - Intervention Visit (within 3 weeks after randomisation): ............................. 22 
Visit 4- Post Intervention Assessment Visit (end of the 6-week intervention): ........... 22 
Visit 5- Follow-up Assessment Visit (3-months post-intervention): ........................... 23 
Visit 6- Focus Group Visit (usually 1-3 weeks after the final follow-up): .................... 23 
4.2 
Study Outcome Measures ............................................................................. 24 
4.2.1 
Outcomes of feasibility study: ................................................................ 24 
4.2.2 
Outcomes to synthesize data from which the sample size of a definitive RCT 
could be estimated. ............................................................................................. 24 
4.3 
Laboratory Tests .......................................................................................... 25 
5. 
ASSESSMENT OF SAFETY ......................................................................... 25 
6. 
DEVICE INFORMATION ........................................................................... 25 
6.1 
Active TENS: ............................................................................................... 25 
6.1.1 
Treatment schedule: ............................................................................. 25 
6.1.2 
Rationale for chosen TENS frequency: .................................................... 25 
6.1.3 
Attachment: ............................................................................................. 25 
6.2 
Placebo TENS: ............................................................................................. 26 
6.2.1 
Treatment schedule: ............................................................................. 26 
6.2.2 
Attachment: ............................................................................................. 26 
7.0 
ADVERSE EVENTS ....................................................................................... 26 
7.1 
Definitions of adverse events ........................................................................ 26 
7.2 
Serious Adverse Event (SAE) ........................................................................ 26 
7.3 
Recording and reporting of Adverse Events .................................................... 26 
8. 
STATISTICS AND DATA ANALYSIS .......................................................... 27 
8.1 
Statistical analysis plan................................................................................. 27 

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8.2 
Feasibility and acceptability analysis .............................................................. 27 
8.3  
Primary efficacy analysis .............................................................................. 28 
8.4 
Secondary efficacy analysis .......................................................................... 28 
8.5 
Safety analysis ............................................................................................ 28 
8.6 
Software for statistical analysis ..................................................................... 28 
8.7 
Sample size ................................................................................................. 28 
8.8 
Management and delivery ............................................................................ 28 
9.0 STUDY CLOSURE / DEFINITION OF END OF TRIAL ..................................... 28 
10. DATA HANDLING ......................................................................................... 29 
10.1 Randomisation ............................................................................................... 29 
10.2 Case Report Forms / Electronic Data Record ..................................................... 29 
10.3 Record Retention ............................................................................................ 29 
11.0 
TRIAL MANAGEMENT ........................................................................... 29 
11.1 
Routine management of trial: Trial Management Group .................................. 29 
11.2 
Trial steering committee (TSC) ..................................................................... 29 
13. 
PROTOCOL AMENDMENTS ....................................................................... 30 
14. 
ETHICAL CONSIDERATIONS .................................................................... 30 
14.1 
Ethical conduct of the study.......................................................................... 30 
14.2 
Informed consent ........................................................................................ 30 
15. 
INSURANCE AND INDEMNITY ................................................................. 30 
16. 
FUNDING ................................................................................................. 30 
17. 
ANNUAL REPORTS ................................................................................... 30 
18. 
DISSEMINATION OF FINDINGS .............................................................. 31 
19. 
REFERENCES ........................................................................................... 32 
 

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ABBREVIATIONS 
 
ABPI 
Ankle Brachial Pressure Index 
ACD 
Absolute claudication distance  
ACSM 
The American College of Sports Medicine 
AE 
Adverse event 
CI 
Chief Investigator 
CRF 
Clinical Research Facility 
CSO 
Chief Science Office 
DESMOND Diabetes Education and Self-Management for Ongoing and Newly Diagnosed 
FCD 
Functional claudication distance 
GCP 
Good clinical practice  
GGC 
Greater Glasgow and Clyde 
GP 
General Practitioner 
HF-TENS 
High Frequency 
IC 
Intermittent Claudication 
ICD 
Initial Claudication distance 
ICH 
The International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICQ 
Intermittent Claudication Questionnaire 
ICQ 
Intermittent claudication questionnaire 
LF-TENS 
Low Frequency 
MPQ 
McGill Pain Questionnaire 
NHS 
National Health Service 
NICE 
The National Institute for Health and Care Excellence 
PA 
Physical Activity 
PAD 
Peripheral Arterial Disease 
PE 
Patient education 
PrEPAID 
Pain management and Patient Education for Physical Activity in Intermittent 
clauDication  
PROMS 
Patient reported outcome measures 
P-TENS 
Placebo TENS 
OEUH 
Queen Elizabeth University Hospital 
R&D 
Research and Development 
RCB 
Robertson Centre for Biostatistics 
RCT 
Randomised Control Trial 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SEDRIC 
Structured EDucation for Rehabilitation in Intermittent Claudication 
SEP 
Structured Exercise Programme 
SF-36 
General Quality of Life Questionnaire (Short version)  
SOP 
Standard Operating Procedure 
TENS 
Transcutaneous electric nerve stimulation 
TIA 
Transient Ischaemic Attack  
TSC 
Trial Steering Committee 
UK CRN 
United Kingdom Clinical Research Network 
VAS 
Visual Analogue Scale  
WIQ 
Walking impairment questionnaire 

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STUDY SYNOPSIS 
 
Title of Study: 
Pain Management and Patient Education for Physical Activity 
in Intermittent Claudication (PrEPAID): Feasibility 
Randomised Controlled Trial 
Study Centre: 
Clinical Research Facility at Queen Elizabeth University 
Hospital/ Glasgow Caledonian University/ Robertson Centre 
for Biostatistics 
Duration of Study: 
26 months 
Research aims: 
1. To determine the feasibility of conducting a definitive trial 
that would assess the effects of a TENS intervention 
with/or without patient-centred education on physical 
activity in people with intermittent claudication.  
2. To collect preliminary data on the acceptability of TENS 
and patient education, both as separate and combined 
interventions in people with Intermittent Claudication (IC). 
Research objectives:  
1. To estimate rates of recruitment, retention, intervention 
uptake and adherence, and outcome completion for a 
definitive RCT which would investigate the effects of 
TENS and/or patient-centred education in people with IC. 
2. To determine the potential effect of the interventions on 
patient outcomes including walking, physical activity and 
PROMs  
3. To explore participants’ experiences and perceptions of 
the interventions and trial procedures via focus groups   
Primary Endpoints: 
1. Proportion of eligible patients, after full screening, who 
agreed to be randomized; and proportion of randomised 
participants who successfully completed each of the trial 
arm (intervention and outcome measure assessment).  
2. The Absolute Claudication Distance, assessed by a 
treadmill exercise using the Gardner treadmill protocol 
shall be assessed as the primary outcome for this 
feasibility trial. 
Rationale: 
This is a feasibility trial that primarily aim to assess the 
feasibility of conducting a definitive trial that would assess the 
effects of a TENS intervention with and without patient-
centred education on physical activity in people with 
intermittent claudication. Therefore, successful delivery and 
uptake of interventions by patients and evidence of 
improvement in patient outcomes are the most important and 
compelling consideration to make decision regarding 
feasibility of a definitive trial.  
Methodology: 
This a randomised controlled feasibility trial using a 2x2 
factorial design of TENS versus placebo TENS with or without 
patient-centred education. Participants will be blinded to the 
type of TENS they receive. Outcome assessment of the 
primary outcome will be done by a blinded assessor.   
Sample Size: 
80 
Screening: 
Participants will be screened for eligibility by Research Nurse 
Registration/Randomisation: Randomisation by Robertson Centre for Biostatistics 
Main Inclusion Criteria: 
• 
Clinical diagnosis of symptomatic Peripheral Arterial 
Disease (PAD) including resting ABPI <0.9 in at least one 
leg  

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• 
Stable IC for ≥3 months 
• 
Walking limited primarily by claudication  
• 
Able to exercise on a treadmill  
• 
Able to read and speak English to a level allowing 
satisfactory completion of the study procedures 
• 
Able to provide written informed consent for participation 
Main Exclusion Criteria: 
• 
Planned surgical or endovascular intervention for PAD 
within the next 3 months 
• 
Critical limb ischaemia   
• 
The presence of any absolute contraindications to 
exercise testing/training as defined by the American 
College of Sports Medicine (ACSM) 
• 
Previous experience of using TENS/ structured patient 
education for PAD 
• 
Contraindications to TENS (including epilepsy, 
dermatological conditions, indwelling electrical 
pumps/pacemakers) and inability to apply TENS 
independently.  
• 
Patients who require walking aids including artificial limbs  
• 
Major surgery, myocardial infarction or stroke/ TIA in the 
previous 6 months 
• 
Co-morbidities that cause pain or limit walking to a greater 
extent than IC (e.g. severe arthritis) 
• 
>20% variation in baseline ACD on treadmill 
• 
Severe peripheral neuropathies above the ankle. 
• 
Participation in another research protocol 
• 
Participants < 40 years of age 
Product, Dose, Modes of 
Administration:  
One-off 3 hours structured patient education + twice weekly 
phone call follow up to six weeks; High frequency TENS for 
daily use up to  six weeks; placebo TENS for daily use for six 
weeks 
Duration of Treatment: 
Six weeks 
Statistical Analysis: 
Descriptive statistics for participants’ characteristics, 
recruitment and intervention completion rates will be used to 
analyse results related to the feasibility and acceptability 
outcomes. In addition, the transcripts from the focus group 
discussions will be analysed using framework analysis. 
Patient outcomes - 95% CI will be analysed using Chi-
squared tests, Mann-Whitney U or Wilcoxon signed-rank tests 
as applicable; and log-rank method for pooled samples or 
sub-strata.    
 
 
 

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GLOSSARY OF TERMS 
 
I. 
Transcutaneous electric nerve stimulation: the use of electric current produced by a 
device to stimulate the nerves for therapeutic purposes. 
II. 
Initial Claudication Distance (ICD): the distance in metres and centimetres walked by a 
patient on a treadmill under standardized conditions before the onset of claudication 
symptoms, regardless of whether this is manifested or characterized as muscle pain, 
ache, cramp, numbness or fatigue.  This does not include joint pain or other pain not 
associated with claudication. 
III. 
Functional Claudication Distance: the distance, during a treadmill test, a patient with 
peripheral arterial would prefer to stop walking because of claudication pain.  
IV. 
Absolute Claudication Distance (ACD): the maximum distance in metres and 
centimetres walked by a patient on a treadmill under standardized conditions.  The 
patient should continue the test until walking can no longer be tolerated because of 
claudication symptoms.  It is critical that the patient not stop walking when they normally 
would do so.  The patient should be asked to continue to walk until they feel they must 
stop due to claudication symptoms. 
V. 
Patient-centred structured education: a planned and graded programme that is 
comprehensive in scope, flexible in content, responsive to an individual’s clinical and 
psychological needs, and adaptable to his or her educational and cultural background. 
Key criteria of a structured education programme include:  
• 
A clear underlying philosophy on which the programme is based 
• 
A structured written curriculum 
• 
Trained educators familiar with the programme and its delivery 
• 
A quality assurance system applied to the structure, process, content, and 
delivery of the programme. 
• 
A process of audit of programme outcomes including biomedical, psychological, 
and patient experience 
VI. 
Free living physical activity: Accumulation of physical activity in a daily community 
living situation as opposed to laboratory or clinics assessed measures. 
VII. 
Structured exercise programme: Structured exercise includes activities specifically 
geared toward a purpose, usually to improve cardiovascular fitness, strength, flexibility, 
or balance and agility. In the context of this research protocol, Structured exercise 
programme refers to 2 hours of supervised exercise a week (usually 40minutes x3 
day/week) for a 3-month period encouraging people to exercise to the point of maximal 
pain. 
VIII. 
ActivPAL: A small physical activity monitor worn on the front of the thigh, which allows 
researchers to objectively measure time spent sitting/lying, standing and walking, sit-to-
stand transitions and step counts.  
 

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STUDY FLOW CHART 
 
Focus Group  
(1-3 weeks from 
final follow-up) 
Follow-Up 
(3 months post 
intervention) 
Randomisation   
Assessment  
(Week 2)
Assessment  
(Week 1) 
Intervention 
(6 weeks) 
Identification of participants via claudication clinics 
Eligibility assessment based on inclusion criteria
First Assessment Visit 
Second Assessment Visit 
Randomisation (n=80)
Active 
TENS 
(n=20)
Placebo 
TENS 
(n=20)
Placebo 
TENS + 
Education 
(n=20)
Active 
TENS + 
Education 
(n=20)
Post-Intervention Assessment Visit 
Follow-up Assessment Visit  
Focus Group   
Eligible
Discharge from study
Ineligible 
 
  
 

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STUDY SCHEDULE  
Visit  
Study Procedure  
Time 
(mins) 
Responsible  
First Assessment  
(90 mins) 
Review of Inclusion/Exclusion Criteria  
Obtain Informed Consent  
20 
RN/UA 
Participant demographics  
• 
Gender / Date of birth / Height / Weight / Heart rate / Blood pressure 
Patient history 
• 
Diagnosis of PAD (Date of diagnosis/Type of disease) 
• 
Present drug history (Statin/Antiplatelet/Anticoagulants) 
• 
Past Medical History (IHD/MI/LVH) 
• 
Cardiac risk factors (DM/Family History of IHD,CVA/Smoking: Current, Previous, 
Non-smoker/Alcohol excess: Current, Previous, 
Never/Hypercholesterolemia/Hypertension)  
20 
Complete questionnaires: 
1. Generic quality of life questionnaire (SF-36)  
2. Intermittent Claudication Questionnaire (ICQ)  
3. Visual Analogue Scale (VAS)  
4. Geriatric Depression Scale (Short Form) (GDS-SF)  
5. Pain Self-Efficacy Questionnaire (PSEQ) 
6. Illness Perception Questionnaire (IPQ)  
20 
Taking of blood sample 
10 
Treadmill protocol  
• 
ABPI assessment  
• 
McGill Pain Questionnaire (MPQ) (5 minutes post-treadmill protocol)  
20 
Fitting of ActivPAL to participants and instruction for use  
20 
Second Assessment 
(30 mins)   
Return of ActivPAL by participants 
5 
RN/UA 
Treadmill protocol  
McGill Pain Questionnaire (5 minutes after completion of the treadmill protocol) 
20 
Intervention as per 
randomisation  
1. Education session + Placebo TENS & instructions for the use at home 
240 
CS + RN 
2. Education session + Active TENS & instructions for the use at home  
240 

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(Duration depends on 
group; 4 hours max)  
3. Active TENS and instructions for use at home 
60  
4. Placebo TENS and instructions for use at home  
60 
Post-Intervention  
(70 mins)  
a.Complete questionnaires:  
1. Generic quality of life questionnaire (SF-36)  
2. Intermittent Claudication Questionnaire (ICQ)  
3. Visual Analogue Scale (VAS) 
4. Geriatric Depression Scale (Short Form) (GDS-SF) 
5. Pain Self-Efficacy Questionnaire (PSEQ) 
6. Illness Perception Questionnaire (IPQ)  
b.If participant is exiting the study at this point:  
7. TENS feedback questionnaire 
 
c.Questionnaire on adverse events of interest 
20 
UA/JB 
Treadmill protocol  
• 
MPQ (5 minutes post-treadmill protocol) 
20 
Fitting of ActivPAL to participants and instruction for use  
20 
Taking of blood sample 
10 
Follow-up 
(70 mins) 
Complete questionnaires:  
1. Generic quality of life questionnaire (SF-36) 
2. Intermittent Claudication Questionnaire (ICQ) 
3. Visual Analogue Scale (VAS) 
4. Geriatric Depression Scale (Short Form) (GDS-SF) 
5. Pain Self-Efficacy Questionnaire (PSEQ) 
6. Illness Perception Questionnaire (IPQ) 
If participant is exiting the study at this point:  
7. TENS feedback questionnaire 
20 
UA/JB 
Treadmill protocol  
• 
MPQ (5 minutes post-treadmill protocol) 
20 
Fitting of ActivPAL to participants and instruction for use  
20 
Taking of blood sample 
10 
Focus Group  
(90 mins) 
Introduction  
15 
RN + 
Independent 
Focus group interview 
60 

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Debrief and discharge  
If participant is exiting the study at this point:  
1. TENS feedback questionnaire 
15 
researcher  
 
 
 
 
 

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INTRODUCTION 
1.1 
Background 
Peripheral Arterial disease (PAD) affects 2.7 million people in the UK.1 The most 
common symptom that patients experience is Intermittent Claudication (IC), which is 
pain in the buttock, calf or thigh precipitated by exercise and relieved by rest.1 The 
underlying cause of PAD is atherosclerosis, which leads to arterial stenosis, 
inadequate blood flow and build-up of lactic acid during exercise. Patients with IC 
have impaired quality of life due to reduced physical capacity. Furthermore, due to 
the diffuse nature of atherosclerosis and the involvement of other arterial beds, they 
have 3-4 times increased mortality compared to age and sex matched controls.2 
 
Patients with symptomatic PAD should receive the same secondary prevention 
management as patients with symptomatic coronary artery disease. Improving daily 
physical activity (PA) is particularly important in individuals with IC as lower PA levels 
have been recognised as a strong predictor of increased morbidity and mortality in 
this population.3 Current NICE guidelines recommend the use of supervised exercise 
programmes (SEPs), encouraging patients “to exercise to the point of maximal pain”, 
as first line treatment.4 However, while systematic reviews (e.g.5) show that SEPs 
lead to a significant improvement in the absolute walking distances of patients with IC 
on a treadmill, it is unclear if this is sustained or leads to improvement in daily PA.5 
Furthermore, due to the considerable resources required to deliver the recommended 
3 months exercise programme (30-45 minutes 3x weekly), SEPs are not always 
routinely available to NHS patients, and time and travel costs tend to lead to low 
patient uptake and high attrition rates.6 Therefore, investigating the feasibility of using 
low-cost, patient-centred interventions that can support increased PA is warranted. 
 
1.2 
Rationale 
Lack of self-efficacy, attributed to poor understanding of the disease and uncertainty 
regarding the importance of exercise, has been shown to be a major barrier to 
exercise uptake in patients with PAD and IC.7 Educating patients with IC about their 
disease pathology and the benefits of walking is key to enhancing success of 
secondary prevention strategies for people with IC.7,8 We recently piloted a 
structured, patient-centred education intervention (SEDRIC)9 with the specific aim of 
educating patients with IC about their condition, improving patient ownership, and 
promoting self-managed walking. In addition to improved treadmill walking distances, 
we found out that there was a trend for patients to increase their daily PA. 
 
For patients with IC to gain benefits of secondary prevention, exercising beyond the 
point when pain occurs is recommended, representing another barrier to 
engagement in PA.10 Despite this, our systematic review11 found that pain 
management as a route to facilitate exercise and PA has rarely been explored. 
Recent interest has focused on the use of TENS (a low-cost, non-invasive pain 
management device) to improve angiogenesis, muscle function,12 pain and walking 
distances in patients with IC.13,14 TENS has a strong placebo effect in pain 
conditions,15 and testing effectiveness against placebo is advocated. In a proof-of-
concept pilot study, we demonstrated that TENS could significantly improve pain and 
increase treadmill walking distances above placebo levels.14Our exploratory study 
also established that home use of TENS was both acceptable and provided self-
reported improvement in PA in individuals with IC.16 
 

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Although patient-centred education (SEDRIC) and TENS have both demonstrated 
potential to improve daily PA in people with IC, the use of these components in 
combination has not previously been evaluated. We therefore propose a 2 x 2 (TENS 
versus placebo TENS x SEDRIC versus no additional education) feasibility RCT17 
that will compare use of TENS against placebo TENS with and without a patient-
centred education programme. 
1.3 
Prior experience of intervention in disease area 
We have conducted a series of pilot studies underpinning both aspects of the 
intervention. In an experimental lower limb ischaemic pain model in healthy 
volunteers (n=28) we have shown that TENS (High frequency TENS, HF-TENS 200 
ms biphasic pulsed currents at 120 Hz in a “continuous” pulse pattern) significantly 
reduced onset of pain (by 29 seconds; 23%), tolerance of pain (by 203 seconds; 
53%) and the pain endurance (by 173 seconds; 67%), compared to placebo TENS, 
P-TENS.18 (See figure 1 below) 
 
Figure 1: Graph of mean time taken (seconds) to report (A) pain threshold, (B) pain 
tolerance, and (C) pain endurance for placebo TENS, P-TENS and (high frequency 
transcutaneous electrical nerve stimulation, HF-TENS. Open bars indicate baseline; 
shaded bars, intervention. Error bars = 95% confidence interval [From Seenan et al 
Clin J P 2012 28(8): 693-699]. 
 
Following this, in a proof-of-concept pilot study, we demonstrated that TENS when 
applied to patient with IC exercising on a treadmill (n=40) significantly improved 
absolute claudication distance (ACD) above placebo levels (approx. mean individual 
increase in ACD of 40%, p=.025, r= .53)14(See figure 2 below). Our phase 2 study 
also established that home use of TENS was both acceptable and provided self-
reported improvement in PA in individuals with IC.16 We have not assessed the ability 
of TENS to improve ACD when used during daily life. 

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Figure 2: Boxplots representing changes in walking measures (meters) with TENS 
intervention. Positive values represent a positive change with TENS (From Seenan et 
al J Cardiovasc Nurs 2016 31(4): 323-30) 
 
Similarly, our group developed and piloted SEDRIC,9 a structured, patient-centred 
education intervention with the specific aim of educating patients about their 
condition, improving patient ownership, and promoting self-managed walking. We 
found that in patients with PAD (n=14), treadmill walking distances (30%) and quality 
of life (32%) improved from baseline after 6 weeks of structured education, and there 
was a trend for patients to increase their daily PA (approx. 8% change from 
baseline). 
 
2. 
STUDY AIM, OBJECTIVES, AND RESEARCH QUESTIONS 
2.1 
Aims 
1. The aim is to determine the feasibility of electrical stimulation via a low-cost 
CE-marked device used within a patient centred education programme to 
improve walking distances in patients with PAD. 
2.2 
Research Objectives 
1. To estimate rates of recruitment, retention, intervention uptake and 
adherence, and outcome completion for a definitive RCT 
2. To monitor, record, manage and follow-up specified adverse events in all 
groups 
3. To collect and synthesise data, including walking outcomes, physical activity 
and PROMs, from which the sample size of a definitive RCT could be 
estimated 
4. To explore participants’ experiences and perceptions of the interventions and 
trial procedures via focus groups   

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2.3 
Research Questions:  
1. What is the feasibility (i.e. recruitment and retention rates, adherence, safety, 
sample size for a definitive trial, potential for effectiveness) of conducting a 
definitive RCT comparing TENS with and without patient-centred education? 
2. How acceptable are TENS and patient-centred education as interventions on 
their own or in combination in patients with IC?  
 
3. 
STUDY DESIGN 
Feasibility Randomised Controlled Trial, blinded for primary outcome 
3.1 
Study Population 
80 patients with a history of stable IC and an ABPI≤0.9 attending the NHS Greater 
Glasgow & Clyde vascular out-patient clinics will be invited to take part in this study. 
3.2 
Inclusion criteria 
• 
Clinical diagnosis of symptomatic Peripheral Arterial Disease (PAD) including 
resting ABPI <0.9 in at least one leg  
• 
Stable IC for ≥3 months 
• 
Walking limited primarily by claudication  
• 
Able to exercise on a treadmill  
• 
Able to read and speak English to a level allowing satisfactory completion of the 
study procedures 
• 
Able to provide written informed consent for participation 
3.3 
Exclusion criteria 
− 
Planned surgical or endovascular intervention for PAD within the next 3 months 
− 
Critical limb ischaemia   
− 
The presence of any absolute contraindications to exercise testing/training as 
defined by the American College of Sports Medicine (ACSM) 
− 
Previous experience of using TENS/ structured patient education for PAD 
− 
Contraindications to TENS (including epilepsy, dermatological conditions, 
indwelling electrical pumps/pacemakers) and inability to apply TENS 
independently.  
− 
Patients who require walking aids including artificial limbs  
− 
Major surgery, myocardial infarction or stroke/ TIA in the previous 6 months 
− 
Co-morbidities that cause pain or limit walking to a greater extent than IC (e.g. 
severe arthritis) 
− 
>20% variation in baseline ACD on treadmill 
− 
Severe peripheral neuropathies above the ankle. 
− 
Participation in another research protocol 
− 
Participant aged <40 years 
 
3.4 
Identification of participants and consent 
Potential participants will be identified by members of the vascular surgery and/or 
direct study team when the potential participants attend the vascular out-patient 
clinics held at various hospital sites within NHS GGC. Potential participants will be 
identified in advance by the study nurse from Trakcare clinic lists. They will be 
provided with a participant information leaflet and contact details will be recorded on 
a study log. The nurse or other members of the study team will contact the patient, 
address any questions, and arrange to meet. At this meeting, assuming the 
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nurse, or if the patient wishes, the patient given more time to consider participating in 
the trial. Potential participants who have recently attended the claudication clinic will 
also be contacted by post and sent a brief outline of the study and the patient 
information leaflet. They will be asked to return a pre-paid response slip stating 
whether they wish to be contacted further regarding the study.  
 
If problems arise with recruitment, then the option of using the Safe Haven or primary 
care records to help identify patients diagnosed with PAD/IC will be explored and 
appropriate approval obtained. Participants recruited within the first eight months of 
recruitment will be followed-up for assessment 3 months post intervention. 
 
3.5 
Retention Rates 
The study is an intention to treat analysis and therefore if a patient does not apply the 
TENS or attend the education class (if randomised to this arm) they will continue to 
be followed up. However, all participants will have the right to withdraw from the 
study at any stage. If willing the reasons for withdrawal will be documented and any 
data already collected from that participant will be analysed.   
 
4 
Trial procedures 
Study design: This is a double-blind, feasibility RCT.17 TENS/placebo and patient 
education interventions will be 6 weeks in duration and all participants will receive 
secondary prevention therapy as recommended by NICE including advice to exercise 
(usual care). A sub-group of participants (those recruited within the first 8 months of 
recruitment) will be followed up for 3 months post-intervention. A qualitative, focus 
group study will also be conducted after final follow up.  
 
Interventions:  
TENS: Participants will be given TENS at intervention visit. They will be instructed to 
use the device daily at home or elsewhere. They will be specifically advised to use 
the device prior to, or during, a challenging walk each day. Challenging walk could be 
for activities of daily living (ADL) or planned exercise. For those with bilateral 
claudication they are advised to wear the device on the worst limb and could 
alternate it as symptoms fluctuates. The active group will receive High Frequency-
TENS (120 Hz, 200µs and a patient-determined intensity of ‘‘strong but 
comfortable’’).14 
Placebo TENS: Participants will receive the same model and instructions for use as 
those in the active group except that the stimulation dose is be safely altered to 
produce non-therapeutic, ineffective stimulation. For the purposes of blinding, 
participants will be told that different dosages of TENS are being tested some of 
which they might not feel anything even though the device is working. This method of 
effecting placebo has been successfully used in previous TENS trials.23,24  
Both the statistician conducting the randomization and the outcome assessor would 
be blinded to active TENS and placebo TENS. Importantly, participants will receive 
the same set of instructions as those in active TENS with the addition of a statement 
that two TENS are being tested. Blinding will be assessed at the end of the 
intervention period. Participants will be asked if they believed their TENS unit was 
functioning properly. 
Patient-Centred Education: Intervention in these groups will be adopted from the 
successfully piloted SEDRIC study:9 A one-off three-hour workshop of structured 
group education (4-5 persons in each group) and three 2-weekly phone calls. Two 
educators will implement the session. Training for educators will involve completion 
of the DESMOND core training, reading and demonstrating understanding of the 
SEDRIC curriculum, and completion of at least two practice workshops that are 

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quality assessed prior to delivering any sessions to patients. The aim of the patient 
education will be to modify patients’ illness beliefs and perceptions about IC/PAD by 
educating them on disease pathology and self-management philosophy. After the 
workshop, each patient will be supported to set goals for walking using the 
pedometer (Yamax SW-200 Digi-Walker pedometers), develop an action plan 
regarding how these goals will be met and encouraged to repeat this process for 
each new walking goal. See SEDRIC curriculum for details. 
 
4.1 
Study schedule 
Participants will be asked to attend the CRF on 6 occasions.   
Visit 1- First Assessment Visit:  
At the first visit, participants will be assessed for eligibility and those eligible will be 
requested to consent for further screening. Baseline outcome measurements will be 
conducted including weight/height/HR/blood pressure, ABPI, Treadmill assessments, 
questionnaires and taking of blood sample (Ukachukwu and/or Research Nurse). 
Participants will be fitted with the activPALTM monitor and advised to wear this 
continuously for seven days. They will be given an instruction on how to use the 
activPAL, and provided with a sleep diary to complete during the duration of wearing 
the activPAL.  
 
First Assessment Visit  
(90 mins)  
Time 
(mins) 
Responsible  
Review of Inclusion/Exclusion Criteria  
Obtain Informed Consent  
20 
RN/UA 
Participant demographics  
• 
Gender / Date of birth / Height / Weight / Heart rate / 
Blood pressure 
Patient history 
• 
Diagnosis of PAD (Date of diagnosis/Type of disease) 
• 
Present drug history (Statin/Antiplatelet/Anticoagulants) 
• 
Past Medical History (IHD/MI/LVH) 
• 
Cardiac risk factors (DM/Family History of 
IHD,CVA/Smoking: Current, Previous, Non-
smoker/Alcohol excess: Current, Previous, 
Never/Hypercholesterolemia/Hypertension 
20 
Complete questionnaires:  
1. Generic quality of life questionnaire (SF-36) 
2. Intermittent Claudication Questionnaire (ICQ)  
3. Visual Analogue Scale (VAS) 
4. Geriatric Depression Scale (Short Form) (GDS-
SF)  
5. Pain Self-Efficacy Questionnaire (PSEQ) 
6. Illness Perception Questionnaire (IPQ) 
20 
Taking of blood sample 
10 
Treadmill protocol  
• 
ABPI assessment  
• 
McGill Pain Questionnaire (MPQ) (5 minutes post-
treadmill protocol)  
20 
Fitting of ActivPAL to participants and instruction for use  
20 
 

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Visit 2- Second Assessment Visit (usually within 2 weeks after visit 1):  
Participants will then attend for a second visit to undergo a second Treadmill test, 
and to return the activPAL and sleep diary. Only participants with ≤20% variation in 
ACD will continue in the trial. After this visit eligible participants will be randomized, 
and given a date for them to return for intervention (TENS/Placebo ± Education) as 
applicable. Recruitment and randomisation will be done in waves to allow groups to 
be formed for the education session. 
 
Second Assessment Visit 
(30 mins)  
Time 
(mins) 
Responsible  
Return of ActivPAL by participants 
5 
RN/UA 
Treadmill protocol  
• 
McGill Pain Questionnaire (5 minutes after 
completion of the treadmill protocol) 
20 
 
Visit 3- Intervention Visit (within 3 weeks after randomisation):  
Participants attend the clinic to receive the TENS and training instructions for its daily 
use as required, plus or minus the patient education per randomization group.  
Participants allocated to receive education will undergo a group structured education 
session (4-6 persons per group). This intervention is adopted from the successfully 
piloted SEDRIC study:9 a one-off three-hour workshop of structured group education 
followed by three 2-weekly phone calls (see SEDRIC curriculum).  
 
The aim of the structured education is to modify patients’ illness beliefs and 
perceptions about IC/PAD by educating them on disease pathology and 
management philosophy. After the workshop, each patient will be supported to set 
goals for walking based around a pedometer and daily steps, develop an action plan 
regarding how these goals will be met and encouraged to repeat this process for 
each new walking goal through a 2-weekly phone calls from the educators (research 
team- Chris and Research Nurse) during which the progress, barrier and challenges 
are further discussed, and new walking goal will be set.  
 
Before the education session, participants allocated to receive TENS will be provided 
with the device and instruction to use of the device. Also, the use of the device will be 
demonstrated, and patients shown how to put on and remove the device. Participants 
will try it out so on that to be sure they understand the procedure.  
 
Intervention Visit (as per randomisation) 
(approx. 4 hours)  
Time 
(mins) 
Responsible  
1. Education session + Placebo TENS & instructions for 
the use at home 
240 
CS + RN 
2. Education session + Active TENS & instructions for 
the use at home  
240 
3. Active TENS and instructions for use at home 
60  
4. Placebo TENS and instructions for use at home  
60 
 
Visit 4- Post Intervention Assessment Visit (end of the 6-week intervention):  
Outcome assessments and procedure followed in Visit 1 will be repeated including 
questionnaires, treadmill protocol, blood sample collection and fitting of activPAL. 
The treadmill test will be by the investigators who are blinded to the participants 
group allocation.  Participants will be given a prepaid envelope to return activPAL.  
 

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Post-Intervention Visit  
(70 mins)  
Time 
(mins) 
Responsible  
a.Complete questionnaires:  
1. Generic quality of life questionnaire (SF-36)  
2. Intermittent Claudication Questionnaire (ICQ)  
3. Visual Analogue Scale (VAS)  
4. Geriatric Depression Scale (Short Form) 
(GDS-SF)  
5. Pain Self-Efficacy Questionnaire (PSEQ) 
6. Illness Perception Questionnaire (IPQ) 
b.If participant is exiting the study at this point:  
7. TENS feedback questionnaire 
c.Questionnaire on adverse events of interest 
20 
UA/JB 
Treadmill protocol  
• 
MPQ (5 minutes post-treadmill protocol) 
20 
Fitting of ActivPAL to participants and instruction for use  
20 
Taking of blood sample 
10 
 
Visit 5- Follow-up Assessment Visit (3-months post-intervention):  
All participants recruited within first eight months of recruitment will be invited to 
return for a 3-month follow-up visit. Outcome assessments and procedure followed in 
Visits 1 and 4 will be repeated including questionnaires, treadmill protocol, blood 
sample collection and fitting of activPAL. The treadmill test will be by the 
investigators who are blinded to the participants group allocation.  Participants will be 
given a prepaid envelope to return activPAL. We shall allow assessment visit window 
of ± 2 weeks. 
 
Follow-up Assessment Visit  
(70 mins)  
Time 
(mins) 
Responsible  
Complete questionnaires:  
1. Generic quality of life questionnaire (SF-36)  
2. Intermittent Claudication Questionnaire 
(ICQ)  
3. Visual Analogue Scale (VAS)  
4. Geriatric Depression Scale (Short Form) 
(GDS-SF)  
5. Pain Self-Efficacy Questionnaire (PSEQ) 
6. Illness Perception Questionnaire (IPQ) 
If participant is exiting the study at this point:  
7. TENS feedback questionnaire 
20 
UA/JB 
Treadmill protocol  
• 
MPQ (5 minutes post-treadmill protocol) 
20 
Fitting of ActivPAL to participants and instruction for use  
20 
Taking of blood sample 
10 
 
Visit 6- Focus Group Visit (usually 1-3 weeks after the final follow-up):  
All participants be invited to participate in a focus group discussion. The discussion 
sessions, lasting 1 hour, will explore the acceptability of and satisfaction with the 
PrEPAID programme, components that were useful or not (in terms of helping them 
with physical activity), and participants’ suggestions for changes. Each focus group, 
will consist of 4-6 participants, and will be facilitated by an independent investigator. 

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The number of focus groups to be conducted will be determined by data saturation 
and the sessions will be audio-recorded and will be transcribed verbatim.  
 
Focus Group Visit  
(90 mins)  
Time 
(mins) 
Responsible  
Introduction  
15 
RN 
+ 
Independent 
researcher  
Focus group interview 
60 
Debrief and discharge  
If participant is exiting the study at this 
point:  
1. TENS feedback questionnaire 
15 
 
4.2 
Study Outcome Measures 
4.2.1 Outcomes of feasibility study:  
1. Measure recruitment rates -reasons for non-eligibility and non-recruitment of 
eligible patients will be recorded via the study screening log 
2. Measure participant’s retention throughout the trial and reasons for withdrawal 
3. Measure patient reported outcomes proposed for a definitive RCT 
4. Monitor, record, manage and follow-up defined adverse events in all groups  
5. Measure uptake of intervention (log of TENS use and attendance at education) 
and acceptability of these interventions via a questionnaire 
 
4.2.2 Outcomes to synthesize data from which the sample size of a definitive 
RCT could be estimated. 
For sample size calculation, the Absolute Claudication Distance (ACD), assessed 
by a treadmill exercise using the Gardner treadmill protocol19 shall be assessed as 
the primary outcome. 
 
Secondary outcomes will include other patient outcomes including physical activity, 
PROMs and blood biomarkers.  
 
A. Physical activity capacity secondary outcomes 
i. 
Initial Claudication Distance (ICD), assessed by a treadmill exercise using 
the Gardner treadmill protocol.19 Measurement will be obtained at baseline, 
following six weeks intervention and at 3 months follow. 
B. Daily physical activity (ActivPAL data outcomes), total number of i) steps; ii) 
upright events; iii) walking events; iv) Event-based claudication index (ratio of 
walking events to upright events) participants undertake in a day. 20  
C. PROM secondary outcomes 
i. 
Disease specific quality of life will be as assessed using the Intermittent 
Claudication Questionnaire (ICQ). 
ii. 
Generic quality of life via the SF-36; 
iii. 
Pain quality will be recorded using the McGill Pain Questionnaire (MPQ) 5 
minutes after every treadmill test. 
iv. 
Average Pain intensity in the past 7 days will be recorded using a Visual 
Analogue Scale 
v. 
Illness beliefs and psychosocial determinants of health and behaviour 
will be recorded using the Illness Perception Questionnaire (IPQ), Geriatric 
Depression Scale (Short Form) (GDS-SF) and the Pain Self-Efficacy 
Questionnaire (PSEQ). 
D. Blood biomarkers: to assess angiogenesis/inflammatory response.  
 

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4.3 
Laboratory Tests 
20mls of blood will be taken from rested subjects at visits 1, 4 and 5, spun and 
stored as per the SOP at CRF at QEUH for future analysis of markers of 
angiogenesis and inflammatory response.   
 
5. 
ASSESSMENT OF SAFETY 
This is a low risk study which involves a widely-used CE-marked device. The patients 
will continue to see their GP, continue to receive the usual care and normal 
medication throughout the period of the intervention.   
 
There is a low risk of skin itching in small percentage of participants who may be 
allergic to the pads of the TENS, and their skin may become red and irritated. 
Therefore, hypoallergenic electrode pads will be used for all participants. Participant 
will be withdrawn from the study in the unlikely event that they experience a SAR 
related to the medical device. All interventions and assessments including standard 
treadmill protocol and safety precaution will be adhered to and provided by trained 
and qualified individuals. A designated phone number of the CRF will be given to the 
patients to dial in case of any complaint during the office hours. 
 
There is a very low risk that participants will develop a skin reaction to the adhesive 
in the strip used to attach the activPAL3 device to the thigh.  The attachments used 
are all hypoallergenic and medical grade to minimize this possibility.  The participants 
will be given a contact number of the research team to call if they have any concerns 
and are told to remove the device if they encounter any skin irritation.  Some of the 
older participants may have fragile skin, with a very low risk of skin degradation when 
wearing or removing the monitor.  The participants will be trained in appropriate 
removal of the waterproof dressing and monitor.  The PrEPAID team has 
considerable expertise in the use of activPAL monitors, including extended use in a 
frail older adult population. 
 
6. 
DEVICE INFORMATION 
Patients who are eligible for the study will be randomised to receive either active 
TENS or Placebo TENS. 
6.1 
Active TENS: 
A MTR+ Dolito TENS machine (EME Service Ltd., Manchester, United Kingdom) 
calibrated to 120Hz, 200µs, and patient-determined intensity of “strong but 
comfortable.” 
6.1.1 Treatment schedule:  
Participants will be asked to wear active TENS everyday as often as they can when 
they are awake and switch it on when they are standing/ walking or about to engage 
in activity which they anticipate would trigger their IC pain. They will be instructed to 
switch it off after a maximum period of 1hr, for a rest period of at least 10-20 minutes, 
and to repeat this as often as warranted during daily activity.  
6.1.2 Rationale for chosen TENS frequency:  
In a proof of concept study, HF-TENS was found to increase the distance IC patients 
walked before reaching pain tolerance, and that HF-TENS (compared to low 
frequency TENS) was more effective at prolonging the time to reach pain threshold.  
6.1.3 Attachment:  
Patients will fit a TENS unit during wake periods and daily activity using 2 self-
adhesive carbon rubber electrodes measuring 5 x 5 cm (StiMus® Hydrogel Premium 

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Self-Adhesive Electrodes, EME Service Ltd., Manchester, United Kingdom) attached 
to the TENS unit via the manufacturers leads. The area of pain reported by the 
participant would determine the electrode placement sites with the 2 electrodes to be 
placed at least 2cm apart. Before it is handed out to the patients for daily use, the 
TENS machine will be calibrated with a digital oscilloscope and tested manually by 
the research team.   
6.2 
Placebo TENS:  
Placebo effect has been reported while using TENS in other conditions therefore, 
testing active TENS against placebo is advocated.  The same model as used in 
active TENS will be used in the placebo TENS group but an infective setting (current 
intensity of about 6mA) will be used. Patients will be told that different doses of TENS 
are being tested. This will allow the unit to be switched on with the appearance of a 
working unit. All TENS units will be calibrated, checked and confirmed prior to being 
issued to participants. This method of achieving placebo has been successfully used 
in previous TENS trials.23,24     
6.2.1 Treatment schedule:  
Participants will be asked to wear placebo TENS everyday as often as they could 
when they are awake and switch it on when they are standing/ walking or about to 
engage in activity which they anticipate would trigger their IC pain. They will be 
instructed to switch it off after a maximum period of 1hr, for a rest period of at least 
10-20 minutes, and to repeat this as often as warranted during daily activity.  
6.2.2 Attachment:  
The same material will be used and similar instruction related to device attachment 
will be similar as active TENS.  
 
7.0 
ADVERSE EVENTS 
7.1 
Definitions of adverse events 
Adverse Event (AE) – Any untoward medical occurrence in a subject to whom a 
medicinal device has been administered, including occurrences which are not 
necessarily caused by or related to that product. 
7.2 
Serious Adverse Event (SAE) 
Any adverse event or adverse reaction that: 
a. results in death  
b. is life threatening  
c. requires hospitalisation or prolongation of existing hospitalisation  
d. results in persistent or significant disability or incapacity  
e. consists of a congenital anomaly or birth defect 
f. is otherwise considered medically significant by the investigator  
g. Important adverse events/ reactions that are not immediately life-threatening 
or do not result in death or hospitalisation but may jeopardise the subject or 
may require intervention to prevent one of the other outcomes listed in the 
definition above. 
7.3 
Recording and reporting of Adverse Events 
We do not anticipate that the use of the CE-marked TENS device will result in any 
serious adverse events. Participants will be given prior information regarding the 
reporting of adverse events and measure to take including instructions to contact the 
research team via a dedicated phone line.  
 

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Participants will be specifically queried regarding the following adverse events of 
special interest: any case of itching, skin breakdown, mild electrical burn, other skin 
allergies, or mild autonomic responses at each study visit, and reported related 
adverse events will be documented in an applicable adverse event form.  
 
8. 
STATISTICS AND DATA ANALYSIS 
8.1 
Statistical analysis plan 
The Robertson Centre for Biostatistics, part of the Glasgow Clinical Trials Unit, a fully 
registered UK CRN Clinical Trials Unit, will manage trial data.  
 
Statistical analysis will be conducted by the Study Statistician from the Institute for 
Applied Health Research, Glasgow Caledonian University who is blinded to group 
allocation. The activPAL data will be downloaded and data input quality inspected 
visually and with diary information prior to statistical analysis. A detailed analysis plan 
will be prepared by the statistician and agreed with the Project Management Group 
and Trial Steering Committee.  
 
Descriptive statistics will be used to characterize the groups at baseline and to 
present the feasibility outcomes. Outcomes related to experience and perception via 
focused group will be analysis by framework analysis. Comparisons will be 
undertaken to investigate the feasibility of studying the proposed outcomes for 
definitive trial and to calculate estimates for the likely effect sizes and 95% 
confidence intervals, even though determining differences in clinical outcomes is not 
the primary purpose of this feasibility trial. Inferential analysis will be implemented 
using the principles of intention-to-treat. The flow of participants through each stage 
of the trial will be presented in a CONSORT diagram. 
 
8.2 
Feasibility and acceptability analysis 
To determine the feasibility of conducting a definitive trial, descriptive statistics will be 
used to report the number and proportion of participants who meet the inclusion 
criteria, who consented to participating, and who dropped out during the trial. Also 
descriptive analysis will report compliance with intervention by recording participants 
attendance to education session, follow up calls, attendance to TENS training 
session, (rate of use of TENS) rate of outcome measure completion, and total 
accelerometer wear time. Specifically, the TENS log (questionnaire) as well as inbuilt 
record of TENS device usage will both be used to analyse patients utilisation of 
TENS. Acceptability of TENS will be obtained by TENS feedback questionnaire  
 
Further exploration will be carried out to determine factors that impact on propensity 
to participate looking at the difference in characteristics between participants and 
non-participants. If less than 10% of the individuals with PAD/IC in the clinic are 
eligible to participate, or if less than 10% of eligible patients agreed to participate, 
then the eligibility criteria and recruitment strategy will be adjusted prior to conducting 
a definitive trial. Adjustment of the recruitment strategy in a definitive trial will be 
made comparing the difference in the baseline characteristics between participants 
and 
non-participants. 
Similarly, 
association 
between 
participants’ 
baseline 
characteristics and trial outcome will also inform decision on adjustment of 
recruitment strategy and stratification factors in the definitive trial. Data collection for 
the definitive trial will be adjusted based on the information related to type, quantity of 
missing data, and the mechanisms by which these data are missing. 
 

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The transcripts from the focus group discussions will be analysed using framework 
analysis. The data gathered from the exit interview will form part of acceptability 
analysis and be used to adapt the intervention to enhance it acceptability in a 
definitive trial. 
 
8.3  
Primary efficacy analysis 
Differences in the change in ACD will be analysed and effect scores calculated using 
Chi-squared tests, Mann-Whitney U or Wilcoxon signed-rank tests as applicable for 
between and within-group comparisons and log-rank method for pooled samples or 
sub-strata. Baseline participants’ variability will be controlled for using the analysis of 
co-variance.  
8.4 
Secondary efficacy analysis 
Differences in the changes in activPAL outcomes, ICD, SF-36 and ICQ scores, MPQ 
score, IPQ, GDS-SF, PSEQ, and Biomarkers will also be analysed and effect scores 
calculated using Chi-squared tests, Mann-Whitney U or Wilcoxon signed-rank tests 
as applicable for between and within-group comparisons and log-rank method for 
pooled samples.  
8.5 
Safety analysis 
The safety data (adverse events)- both numbers of subjects and events – will be 
summarised by randomised group and overall using descriptive statistics. No formal 
statistical tests comparing the randomised groups will be pre-specified.  
8.6 
Software for statistical analysis 
The statistical software to be used is either SAS 9.2 for Windows, Cary, NC, USA or 
SPSS Version 22 
8.7 
Sample size 
For the primary outcome measure, at 80% power and a two-tailed 5% significance 
level, 16 participants per group will allow detection of an effect size of 1.0 standard 
deviations of ACD in active TENS group compared to placebo control. Attrition rates 
in our previous pilot studies ranged from 7.1%9 to 10% 14. We will recruit 20 
participants in each group, allowing for 20% attrition, and therefore aim to recruit 80 
patients. If this effect size were applied to our separate pilot studies, this would 
provide the ability to detect a change of 169m (TENS) or 322m (SEDRIC) in our 
primary outcome measure of ACD. Indeed, in these studies, a sample size of 20 per 
group (TENS) and 14 per intervention group (SEDRIC) was sufficient to detect a 
significant difference in this outcome measure.  
8.8 
Management and delivery 
Data analysis will be implemented by the trial statistician blinded to the group 
allocations. All statistical analyses will be conducted according to a pre-specified 
Statistical Analysis Plan. 
 
9.0 STUDY CLOSURE / DEFINITION OF END OF TRIAL 
The study will end when the steering committee agrees that one or more of the 
following situations applies: 
• 
Last patient last study visit 
 

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10. DATA HANDLING 
10.1 Randomisation 
A central randomisation facility (interactive web response system, IWRS) will allocate 
the randomised therapy per patient.  The IWRS, based at the Data Centre, will be 
available by email.   
10.2 Case Report Forms / Electronic Data Record 
An electronic case report form (e-CRF) will be used to collect study data.  The e-CRF 
will be developed by the study Data Centre at the Robertson Centre for Biostatistics, 
University of Glasgow and access to the e-CRF will be restricted, with only 
authorised site-specific personnel able to make entries or amendments to the 
patients’ data. It is the responsibility of the research team to ensure completion and 
to review and approve all data captured in the e-CRF. 
 
All data handling procedures will be detailed in a Study Specific Data Management 
Plan.  Data will be validated at the point of entry into the e-CRF and at regular 
intervals during the study.  Data discrepancies will be flagged to the study site and 
any data changes will be recorded in order to maintain a complete audit trail (reason 
for change, date change made, who made change). 
10.3 Record Retention 
To enable evaluations and/or audits from regulatory authorities, the investigators 
agree to keep records, including the identity of all participating subjects (sufficient 
information to link records), all original signed informed consent forms, serious 
adverse event forms, source documents, and detailed records of treatment 
disposition in accordance with ICH GCP, local regulations, or as specified in the 
Clinical Study Agreement, whichever is longer.  Data will be retained at the Data 
Centre for a minimum of 5 years. 
 
11.0 TRIAL MANAGEMENT 
This research will fall under the auspices of the clinical governance structure of 
Glasgow Caledonian University (GCU) and NHS GGC Clinical research facility. The 
project is sponsored by GCU and the GCU Research and Development Office will 
have responsibility for oversight, including audit of adherence to protocol and 
research governance Standard Operating Procedures 
11.1 Routine management of trial: Trial Management Group 
The trial will be coordinated from Glasgow Caledonian University by the Trial 
Management Group. This will consist of the co-applicants, CRF research nurse, 
Robertson Centre for Biostatistics, and Glasgow Clinical Trial Unit.  The trial 
Management Group will be responsible for the overall management and completion 
of the project to timescales. The role of the group is to monitor all aspects of the 
conduct and progress of the trial, ensure that the protocol is adhered to and take 
appropriate action to safeguard participants and the quality of the trial itself. The 
group will meet bimonthly mainly via telephone conferences. 
11.2 Trial steering committee (TSC) 
The Steering committee will utilise the strengths of diverse experts, including NHS 
services users. This will help ensure that the research is relevant and accessible to a 
diverse audience. The committee will have an independent chair (Dr Stephen 
McSwiggan). Specifically, the committee will advise on the suitability of the 
interventions for the population group and design and participate in dissemination 
activities. The group members will consist of: the chief investigators; Co-investigator 

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(Ukachukwu); 2 patient representatives; an expert in patient education interventions 
and physical activity behaviour change; and an NHS management representative. 
The steering group will meet four times spread throughout the study and aims to 
provide advice from a broad perspective. 
 
13. 
PROTOCOL AMENDMENTS 
Any change in the study protocol will require an amendment.  Any proposed protocol 
amendments will be initiated by the CIs following discussion with the TSC and any 
required amendment forms will be submitted to the ethics committee, funder, sponsor 
and NHS GGC R&D for approval as appropriate to their role.  The CIs and the TSC 
will liaise with study sponsor to determine whether an amendment is non-substantial 
or substantial.  All amended versions of the protocol will be signed by the CI and 
Sponsor representative.   
 
14. 
ETHICAL CONSIDERATIONS 
14.1 Ethical conduct of the study 
The study will be carried out in accordance with the World Medical Association 
Declaration of Helsinki (1964) and its revisions (Tokyo [1975], Venice [1983], Hong 
Kong [1989], South Africa [1996] and Edinburgh [2000]). Favourable ethical opinion 
will be sought from an appropriate REC before patients are entered into this clinical 
trial.  Patients will only be allowed to enter the study once they have provided written 
informed consent. The CI will be responsible for updating the Ethics committee of 
any new information related to the study. 
14.2 Informed consent 
Written informed consent shall be obtained from each trial participant. The Research 
Nurse will explain the exact nature of the study in writing, provision of patient 
information sheet, and verbally and will be responsible for consenting the 
participants.  Trial participants will be informed that they are free to withdraw their 
consent from the study or study treatment at any time. 
 
15. 
INSURANCE AND INDEMNITY 
NHS indemnity is provided under the Clinical Negligence and Other Risks Indemnity 
Scheme (CNORIS), and the Glasgow Caledonian University Indemnity insurance  
 
16. 
FUNDING 
The trial is funded by CSO, grant award number TCS/16/55 (10 January 2017). 
 
17. 
ANNUAL REPORTS 
An annual progress report will be submitted to the funder (CSO), the first being 
submitted 6 months from the date that all trial related approvals are in place.  Annual 
reports will be submitted to the ethics committee and sponsor with the first submitted 
one year after the date that all trial related approvals are in place.  
 
Recruitment data will, on a monthly basis, be uploaded to the UKCRN Portfolio 
database (and agreed successor to the database) through the mechanisms provided 
for the purpose, as part of CSO requirement. Also, updated information on the 
outputs from the project shall be uploaded through the e-VAL system, which is now 
accessed through the ResearchFish website - https://www.researchfish.com/.  A final 
project report and other information and actions as required by CSO as part of the 
project completion will be available and completed to the satisfaction of CSO by the 

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end of the funding period.  Copies of all publications originating from this trial shall be 
provided to CSO.  
 
The Chief Investigators and Project Management Group will produce all reports. All 
statistical reports will be produced by the Study Statistician from the Institute for 
Applied Health Research, Glasgow Caledonian University.   
 
18. 
DISSEMINATION OF FINDINGS 
Findings of this feasibility study will be disseminated to a range of stakeholders, 
including researchers, clinicians, individuals with IC, and students. At least 1 paper 
will be submitted to international peer-reviewed journals (i.e. Circulation and 
European Heart Journal). Also at least 1 abstract will be submitted to international 
conferences. We will hold a stakeholder event at the end of the project as a method 
for guiding best practice for researchers. Glasgow Caledonian University is rated No. 
1 in Scotland for physiotherapy education, and this research will be used to inform 
undergraduate and postgraduate modules on clinical research. The project will also 
form part of a PhD thesis at the Glasgow Caledonian University. 
 

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19. 
REFERENCES 
1. Hankey GJ, Norman PE, Eikelboom JW. Medical treatment of peripheral 
arterial disease JAMA2006;295:47-53 
2. McDermott MM. Lower extremity manifestations of peripheral artery disease: 
thepathophysiologic and functional implications of leg ischemia Circ Res 
2015;116:1540-50  
3. Garg PK, Tian L, Criqui MH, Liu K, Ferrucci L, Guralnik JM, Tan J, McDermott 
MN. Physical activity during daily life and mortality in patients with 
peripheralarterial disease Circ 2006;114:242-8  
4. NICE Peripheral Arterial Didease quality standard 2014  
5. Fokkenrood HJ, Bendermacher BL, Lauret GJ, Willigendael EM, Prins MH, 
Teijink JA.Supervised exercise therapy versus nonsupervised exercise 
therapy for intermittent claudication Cochrane Database Syst Rev 
2013;8:CD005263  
6. Shalhoub J, HAMISH, M, DAVIES AH. Supervised exercise for intermittent 
claudication - an under-utilised toolAnn R CollSurgEngl2009;99:4736 
7. Gorely T, Crank H, Humphreys L, Nawaz S, Tew G. “Standing still in the 
street’’:Experiences, knowledge and beliefs of patients with intermittent 
claudication—A qualitative study. J VascNurs 2015;33:4-9  
8. Abaraogu UO, Dall P, Seenan C. Patient education interventions to improve 
physical activity in patients with intermittent claudication: a protocol for a 
systematic mixed-studies review. BMJ Open 2016;6:e011405.  
9. Tew GA, Humphreys L, Crank H, Hewitt C, Nawaz S, Al-Jundi W, Trender 
H, Michaels J, Gorely T. The development and pilot randomised controlled 
trial of a group education programme for promoting walking in people with 
intermittent claudication Vasc Med 2015;20:348-7  
10. Galea MN, Bray SR, Ginis KA. Barriers and facilitators for walking in 
individuals with intermittent claudication. J Aging Phys Act 2008;16:69-83  
11. Abaraogu UO, Dall P, Seenan C. Non-Operative pain management 
interventions in patients with Intermittent Claudication: A protocol for a 
systematic mixed studies review with meta-analysis. Pain Rehabil 
2016;41:18-26  
12. Shang Y, Lin Y, Henry BA, et al. Noninvasive evaluation of electrical 
stimulation impacts on musclehemodynamics via integrating diffuse optical 
spectroscopies with muscle stimulator. J Biomed Opt 2013;18:105002 
13. Labrunée 
M, Boned 
A, Granger 
R, Bousquet 
M, Jordan 
C, Richard 
L, Garrigues D, Gremeaux V, Sénard JM, Pathak A, Guiraud T. Improved 
Walking Claudication Distance with Transcutaneous Electrical Nerve 
Stimulation: An Old Treatment with a New Indication in Patients with 
Peripheral Artery Disease. Am J Phys Med Rehabil 2015;94:941-9  
14. Seenan 
C, McSwiggan 
S, Roche 
PA, Tan 
CW, Mercer 
T, Belch 
JJ. 
Transcutaneous Electrical Nerve Stimulation Improves WalkingPerformance 
in Patients With Intermittent Claudication J Cardiovasc Nurs 2016;31:323-30  
15. Chesterton LS, Foster NE, Wright CC, Baxter GD, Barlas P. Effects of TENS 
frequency, intensity and stimulation site parameter manipulation on pressure 
pain thresholds in healthy human subjects. Pain 2003;106:73– 80  
16. Seenan C. Laboratory and clinical investigation into lower limb ischaemic 
pain, and the effect of transcutaneous electrical nerve stimulation (Tens) on 
measures of pain and walking performance. PhD Thesis, Queen Margret 
University 2013  
17. Seenan C, Roche PA, Tan CW, Mercer T. Modification of experimental, lower 
limb ischemic pain with transcutaneous electrical nerve stimulation Clin J Pain 
2012;28:693-9  

PrEPAID/Protocol 
Version 3.0 08/01/2019  
 
 
33 
18. Craig P, Dieppe P,Macintyre S, Michie S, Nazareth I, Petticrew M. Developing 
and evaluating complex interventions Medical Research Council UK 2011  
19. Gardner AW, Skinner JS, Cantwell BW, Smith LK. Progressive vs single-
stage treadmill tests for evaluation of claudication. Med Sci Sports Exerc 
1991;23:402-8  
20. Clarke CL, Holdsworth RJ, Ryan  CG, Granat MH. Free-living physical activity 
as a novel outcome measure in patients withIntermittent Claudication. Eur J 
Vasc Endovasc Surg 2013;45:162-7. 
21. Rakel B, Cooper N, Adams HJ, Messer BR, Frey Law LA, Dannen DR, Miller 
CA, Polehna AC, Ruggle RC, Vance CG, Walsh DM, Sluka KA. A new 
transient sham TENS device allows for investigator blinding while delivering a 
true placebo treatment. J Pain. 2010; 11(3):230-8. 
22. Labrunée 
M, Boned 
A, Granger 
R, Bousquet 
M, Jordan 
C, Richard 
L, Garrigues D, Gremeaux V, Sénard JM, Pathak A, Guiraud T. Improved 
Walking Claudication Distance with Transcutaneous Electrical Nerve 
Stimulation: An Old Treatment with a New Indication in Patients with 
Peripheral Artery Disease. Am J Phys Med Rehabil. 2015; 94(11):941-9. 
23. Ryan CG, King R, Robinson V, Punt TD, Dinse HR, Grunenberg C, Johnson 
MI, Martin DJ. Transcutaneous electrical nerve stimulation using an LTP-like 
repetitive stimulation protocol for patients with upper limb complex regional 
pain syndrome: A feasibility study. Hand Therapy; online first 07 Nov 2016 : 
DOI: 0.1177/1758998316678588.  
24. Francis RP, Marchant P and Johnson MI. Conventional versus acupuncture-
like transcutaneous electrical nerve stimulation on cold-induced pain in 
healthy 29 human participants: effects during stimulation. Clin Physiol Funct 
Imaging 2011; 31: 363–370.