A Multicenter Randomised Controlled Study: Does Neuromuscular Electrical Stimulation Improve the Absolute Walking Distance in Patients With Intermittent Claudication (NESIC) Compared to Best Available Treatment?
Phase: NA
Conditions: Intermittent Claudication, Peripheral Vascular Diseases
Sponsor: Imperial College London

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CLINICAL STUDY PROTOCOL 
 
 
 
 
 
 
 
 
Full Study Title:  
A Multicenter Randomised Controlled Study: Does 
Neuromuscular Electrical Stimulation Improve the Absolute 
Walking Distance in Patients with Intermittent Claudication 
(NESIC) compared to best available treatment?  
 
 
Short Study title / Acronym: 
NESIC 
 
Product:   
 
 
 
Revitive IX 
Sponsor: 
 
 
 
Imperial College London 
Version no:                         
6.0       
Protocol Date:  
 
 
24 MAR 2020 
 
Property of Imperial Clinical Trials Unit (ICTU)  
May not be used, divulged or published without the consent of ICTU 
This protocol has regard for the HRA guidance 
 
 
This project is funded by the Efficacy and Mechanism Evaluation (EME) Programme, 
an MRC and NIHR partnership. The views expressed in this publication are those of 
the author(s) and not necessarily those of the MRC, NHS, NIHR or the Department 
of Health. 

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RESEARCH REFERENCE NUMBERS 
 
IRAS ID: 
229435 
REC Reference number: 
17/LO/1918 
ISRCTN number  
18242823 
Clinical trials.gov number 
NCT03446027 
Sponsor Protocol number: 
17HH4216 
Funder reference: 
EME 15/180/68 
 
REVISION SUMMARY 
 
Protocol 
Version 
Date  
Revision summary  
V1.0 
16/10/2017 N/A – Original Protocol 
V2.0 
05/12/2017 
Revision of statistical analysis section and 
change of Bristol Trust name 
V3.0 
22/03/2018 Dosage clarification for patients with diabetes. 
V4.0 
07/09/2018 Add three new participating NHS organisations    
V5.0 
09/09/2019 Additional exclusion criteria. SET centres 
permitted to recruit nonSET patients.  
V6.0 
24/03/2020 
To allow 3 Month, 6 Month and 12 Month visits to 
take place remotely (i.e. over the telephone 
completely or in combination with postal 
questionnaires) in the event that the participant is 
unable to attend in clinic or the site is unable to 
accommodate the on-site visit.  
  

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Keywords: 
Peripheral arterial disease; intermittent claudication; neuromuscular electrical 
stimulation; supervised exercise therapy 
 
 

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CONTACT LIST 
 
Chief Investigator  
 
Professor Alun H Davies 
Room 4E4, 4th Floor East Wing 
Charing Cross Hospital,  
Fulham Palace Road, 
London W6 8RF 
Tel: 
020 3311 7309 
 
Co-Investigators: 
Mr Adarsh Babber 
Mrs Laura Burgess 
Mr Bruce Braithwaite 
Dr Richard Simpson  
Professor Ian Chetter 
Mr James Coulston 
Dr David Epstein 
Dr Francesca Fiorentino 
Mr Manj Gohel 
Professor Robert Hinchliffe 
Professor Peter Holt 
Ms Sarah Horgan 
Mr James Metcalfe  
Ms Nandita Pal 
Mr Dynesh Rittoo  
Mr Joseph Shalhoub 
Professor Gerard Stansby 
 
 

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Sponsor 
Joint Research Compliance Office  
Imperial College London and Imperial College Healthcare NHS Trust 
Room 215, Level 2, Medical School Building 
Norfolk Place 
London, W2 1PG 
Email: jrco@ic.ac.uk  
 
Becky Ward 
Research Governance Manager 
Tel: 
0207 594 9459 
Email: becky.ward@imperial.ac.uk  
 
Funder 
Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership 
National Institute for Health Research 
Evaluation, Trials and Studies Coordinating Centre 
University of Southampton  
Alpha House, Enterprise Road 
Southampton, SO16 7NS 
 
Trial Coordination / Study Manager  
Miss Laura Burgess 
Imperial College London, Academic Section of Vascular Surgery 
Room 14, 4th Floor East Wing, Charing Cross Hospital  
Fulham Palace Road, London, W6 8RF 
Tel: 0203 311 5208 
Email: l.burgess@imperial.ac.uk 
 
 

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Senior Statistician 
Dr Francesca Fiorentino  
Statistician and Epidemiologist 
Imperial College Trial Unit & Division of Surgery 
Queen Elisabeth the Queen Mother Building (10th Floor/1091) 
St Mary’s Hospital, Imperial College London 
Praed Street, London W2 1NY 
Tel: 0203 3123761 
 
Health Economist 
Dr David Epstein 
Department of Applied Economics  
Faculty of Economics and Business Sciences  
University of Granada  
Email: davidepstein@ugr.es  
 
Device Manufacturing Facilities 
Actegy Limited 
REFLEX, Cain Road 
Bracknell 
RG12 1HL 
United Kingdom 
Name of contact person: Roseanna Penny  
Title: Director  
Tel: 01344 636 940 
roseanna.penny@actegy.com 
 
 
 
 
 

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Other Vendors/suppliers 
Facility name: Moor Instruments Ltd 
Address: Millwey, Axminster, EX13 5HU, United Kingdom 
Tel: (general) 01297 35715  
Fax: (general) 01297 35716 
 
Name of contact person: Brian Lock 
Title: Senior Sales Engineer 
Tel: 01297 630915 
Mobile: 07740 920 832 
Fax: 0129735716 
Supplier name: THE 3rd DEGREE LIMITED 
Address: 4 Tregarne Terrace, St Austell, Cornwall, PL25 4B 
Name of contact person: Philip Martin 
Title: Managing Director 
Email: phil@the3rddegree.co.uk 
 
 
Protocol development group  
 
Professor Alun Davies 
Ms. Francine Heatley 
Ms. Rebecca Lawton 
Mrs Natalia Klimowska-Nassar 
Dr David Epstein 
Dr. Francesca Fiorentino 
Mr Adarsh Babber 

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ABBREVIATIONS  
ABPI 
Ankle Brachial Pressure Index 
AE 
Adverse Event 
ADE 
Adverse Device Effect 
ASADE 
Anticipated Serious Adverse Device Effect 
AWD 
Absolute Walking Distance  
BMT 
Best Medical Therapy 
CI 
Chief Investigator 
CRF 
Case Report Form 
DMC 
Data Monitoring Committee 
DU 
Duplex Ultrasound 
EA 
Exercise Advice  
eCRF 
Electronic Case Report Form 
EQ5D-5L 
EuroQoL-5D-5L 
GMP 
Good Manufacturing Practice 
HRA 
Health Research Authority 
IC 
Intermittent Claudication 
ICD 
Initial Claudication Distance  
ICMJE 
International Committee of Medical Journal Editors 
ICTU 
Imperial Clinical Trials Unit 
ICQ 
Intermittent Claudication Questionnaire  
IPC 
Intermittent Pneumatic Compression 

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LDF 
Laser Doppler Flowmetry 
NICE 
National Institute for Health and Care Excellence 
RCT 
Randomised Controlled Trial  
REC 
Research Ethics Committee 
SF-36 
Short Form 36 
TAMV 
Time Averaged Mean Velocity 
NMES 
Neuromuscular Electrical Stimulation 
PAD 
Peripheral Arterial Disease 
QA 
Quality Assurance 
QALY 
Quality-adjusted-life-year 
QC 
Quality Control  
SAE 
Serious Adverse Event 
SADE 
Serious Adverse Device Effect 
SAP 
Statistical Analysis Plan 
SET 
Supervised Exercise Therapy 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SSAR 
Suspected Serious Adverse Reaction 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TMG 
Trial Management Group  
TSC 
Trial Steering Committee 
USADE 
Unanticipated Serious Adverse Device Effect 
 
 

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Table of Contents 
RESEARCH REFERENCE NUMBERS 
2 
REVISION SUMMARY 
2 
CONTACT LIST 
4 
ABBREVIATIONS 
8 
TRIAL SUMMARY 
12 
1. 
BACKGROUND 
14 
1.1 
Peripheral Arterial Disease .................................................................................. 14 
1.2 
Intermittent Claudication ...................................................................................... 14 
1.3 
Treatment options for Intermittent Claudication .................................................... 14 
1.4 
Summary of current research .............................................................................. 14 
1.5 
Neuromuscular electrical stimulation .................................................................... 16 
1.6 
Mechanistic evaluation of the device ................................................................... 16 
1.7 
Technological Basis of the Product ...................................................................... 19 
1.8 
Clinical evaluation of NMES techniques and similar devices ................................ 19 
1.9 
Rationale for the study ......................................................................................... 23 
1.10 Risk / Benefit Assessment ................................................................................... 25 
2. 
OBJECTIVES AND ENDPOINTS 
25 
2.1 
Primary Objective ................................................................................................ 25 
2.2 
Secondary Objective............................................................................................ 25 
2.3 
Primary Endpoint ................................................................................................. 26 
2.4 
Secondary Endpoints ........................................................................................... 26 
3. 
STUDY DESIGN 
27 
3.1 
Design ................................................................................................................. 27 
3.2 
Treatment regimens............................................................................................. 27 
4. 
PARTICIPANT ENTRY 
29 
4.1 
Study setting and population ................................................................................ 29 
5. 
PROCEDURES AND MEASUREMENTS 
31 
5.1 
Identification and recruitment of patients .............................................................. 31 
5.2 
Screening and pre-randomisation evaluations ..................................................... 31 
5.3 
Randomisation..................................................................................................... 32 
5.4 
Other baseline investigations ............................................................................... 33 
5.5 
Treatment ............................................................................................................ 35 
5.6 
Follow-up ............................................................................................................. 37 
5.7 
Summary of Visit Schedule .................................................................................. 41 
6. 
TREATMENTS 
43 
6.1 
Investigational Medical Device Details ................................................................. 43 
6.2 
Labelling and Packaging ...................................................................................... 48 
6.3 
Storage ................................................................................................................ 48 
6.4 
Permanent Discontinuation of Study Treatment and Withdrawal from Study ....... 48 
7. 
SAFETY REPORTING 
49 
7.1 
Adverse Events ................................................................................................... 49 
7.2 
Adverse Event Definition ..................................................................................... 49 
7.3 
Adverse Event Recording .................................................................................... 50 
7.4 
Severity of Adverse Events .................................................................................. 50 
7.5 
Causality of Adverse Events ................................................................................ 50 
7.6 
Serious Adverse Event (SAE) .............................................................................. 51 
7.7 
Adverse Device Effect (ADE) ............................................................................... 53 

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7.8 
Serious Adverse Device Effects (SADE) .............................................................. 54 
7.9 
Anticipated Serious Adverse Device Effects (ASADE) ......................................... 54 
7.10 Unanticipated Serious Adverse Device Effects (USADE) ..................................... 55 
7.11 Developmental Safety Update Reports / Annual Safety Reports .......................... 55 
7.12 Pregnancy ........................................................................................................... 55 
7.13 Reporting urgent safety measures ....................................................................... 56 
8. 
STATISTICAL ANALYSES 
56 
8.1 
. Sample size and power considerations .............................................................. 56 
8.2 
. Planned recruitment rate ................................................................................... 57 
8.3 
Statistical analysis ............................................................................................... 57 
9. 
REGULATORY, ETHICAL AND LEGAL ISSUES 
60 
9.1 
Declaration of Helsinki ......................................................................................... 60 
9.2 
Good Clinical Practice ......................................................................................... 61 
9.3 
Independent Ethics Committee Approval ............................................................. 61 
9.4 
Regulatory Authority Approval ............................................................................. 62 
9.5 
HRA approval ...................................................................................................... 62 
9.6 
Non-Compliance and Serious Breaches .............................................................. 62 
9.7 
Insurance and Indemnity ..................................................................................... 63 
9.8 
Trial Registration ................................................................................................. 63 
9.9 
Informed Consent ................................................................................................ 63 
9.10 Contact with General Practitioner ........................................................................ 64 
9.11 Subject Confidentiality ......................................................................................... 65 
9.12 Data Protection and Patient Confidentiality .......................................................... 65 
9.13 End of Trial .......................................................................................................... 65 
9.14 Study Documentation and Data Storage .............................................................. 65 
10. 
DATA MANAGEMENT 
66 
10.1 Source Data ........................................................................................................ 66 
10.2 Language ............................................................................................................ 66 
10.3 Database ............................................................................................................. 66 
10.4 Data Collection .................................................................................................... 67 
10.5 Archiving .............................................................................................................. 67 
11. 
STUDY MANAGEMENT STRUCTURE 
67 
11.1 Trial Steering Committee ..................................................................................... 67 
11.2 Trial Management Group ..................................................................................... 67 
11.3 Data Monitoring Committee ................................................................................. 68 
11.4 Early Discontinuation of the Study ....................................................................... 68 
11.5 Risk Assessment ................................................................................................. 68 
11.6 Monitoring ............................................................................................................ 68 
11.7 Quality Control and Quality Assurance ................................................................ 69 
11.8 Peer review ......................................................................................................... 69 
11.9 Patient and Public Involvement ............................................................................ 69 
11.10 Publication and Dissemination policy .................................................................. 70 
12. 
REFERENCES 
73 
SIGNATURE PAGE 1 (CHIEF INVESTIGATOR) 
76 
SIGNATURE PAGE 2 (SPONSOR) 
77 
SIGNATURE PAGE 3 (STATISTICIAN) 
78 
SIGNATURE PAGE 4 (PRINCIPAL INVESTIGATOR) 
79 
 

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TRIAL SUMMARY 
TITLE: Does Neuromuscular Electrical Stimulation Improve the Absolute Walking 
Distance in Patients with Intermittent Claudication (NESIC) Compared to Best 
Available Treatment?  
 
OBJECTIVE: To assess the benefit of using a neuromuscular electrical stimulation 
device as an adjunct to the local standard care available at the study sites compared 
to local standard care alone. 
 
DESIGN: This is a 1:1 multicenter randomised trial stratified by centre.  
 
SAMPLE SIZE: A total of 192 participants: 96 in each arm 
 
INCLUSION/EXCLUSION CRITERIA 
Inclusion Criteria: 
 Capacity to provide informed consent  
 Aged 18 or above 
 Positive Edinburgh Claudication Questionnaire   
 ABPI <0.9 OR positive stress test (fall in ankle pressure >30mmHg, 40 
secs post 1 min treadmill at 10% gradient, 4 km/h)   
 
Exclusion Criteria: 
 Severe IC requiring invasive intervention as determined by the treating clinician 
 Critical limb Ischaemia as defined by the European Consensus Document  
 Co-morbid disease prohibiting walking on a treadmill or taking part in supervised 
exercise therapy.  
 Able to walk for longer than 15 minutes on the study treadmill assessment 
 Have attended supervised exercise therapy classes in the previous 6 months 
 Popliteal entrapment syndrome 
 Commenced vascular symptom specific medication in previous 6 months e.g. 
naftidrofuryl oxalate, cilostazol 
 Pregnancy  
 Any implanted electronic, cardiac or defibrillator device 
 Acute deep vein thrombosis  
 Broken or bleeding skin including leg ulceration 
 Peripheral neuropathy 
 Recent lower limb injury or lower back pain 
 Already using a neuromuscular electrical stimulation device  
 
 

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TREATMENT/MAIN STUDY PROCEDURES 
Treatment duration: 3 months of device use 
Follow-Up duration: 12 months (follow-up visits at 3, 6, and 12 months) 
SET Centre  
 Control Group 1:      Exercise Advice + Supervised  Exercise Therapy 
 Treatment Group 1: Exercise Advice + Supervised Exercise Therapy and 
Neuromuscular electrical stimulation (NMES) 
 
When recruitment is completed at SET centres, authorised SET centres will be 
permitted to randomise patients using a randomisation list that will allocate 
participants to Exercise Advice + NMES  or Exercise Advice alone.  
Patients at SET centres will first be offered the opportunity to attend the SET 
classes, and only if they do not wish to attend these classes will they be offered the 
opportunity to participate in the trial as a nonSET patient. 
  
Non-SET Centre   
 Control Group 2:       Exercise Advice 
 Treatment Group 2:  Exercise Advice + NMES    
 
 
PRIMARY ENDPOINT: Absolute walking distance (AWD) measured by treadmill 
testing at 3 months (the end of the intervention period). 
 
SECONDARY ENDPOINT(S): 
 
Initial claudication distance (ICD) 
 
Quality of life – Intermittent Claudication Questionnaire (ICQ), EuroQoL 5D 
(EQ5D), Short Form 36 (SF-36) 
 
Haemodynamic assessment - Duplex ultrasonography, Laser Doppler 
Flowmetry (LDF), Ankle Brachial Pressure Index (ABPI) 
 
Health economic assessment 
 
Compliance with interventions 
 
Device experience questionnaire 
 
DEVICE: Revitive IX (supplied by Actegy Ltd) 
 

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1. BACKGROUND 
 
Peripheral arterial disease (PAD) has a significant global health burden with over 
202 million individuals suffering from a manifestation of this disease worldwide (1). 
Risk factors include smoking, advancing age, diabetes, dietary factors, high blood 
pressure, dyslipidaemia, lack of exercise and male gender (2). The impact of this 
burden is highly important as patients suffering from PAD are more likely to suffer 
co-morbid conditions related to an underlying atherosclerotic disease process, 
where-by narrowing or blockages of arteries supplying organs and limbs increase 
the risk of heart attacks and stroke (2). 
 
 
Intermittent claudication (IC) is the commonest manifestation of PAD, presenting 
as pain in the lower limbs on exertion, which settles after a period of rest. This has 
a significant impact on exercise tolerance and quality of life (QoL). Approximately 
5-10% of the UK population are estimated to be suffering from IC (3). 
 
 
National guidelines from the National Institute for Health and Care Excellence 
(NICE) (4) recommend that all patients suffering from IC should receive first line 
treatment of best medical therapy (BMT) to control cardiovascular risk factors 
(which includes exercise advice), and supervised exercise therapy (SET). SET 
involves a number of lower limb related physical activities that are undertaken for 
a set period and duration under the supervision of a healthcare professional. 
 
 
SETs are known to significantly improve the absolute walking distances in patients 
suffering from IC.  
A Cochrane systematic review of the impact of SET on walking distances was 
carried out by Bendermacher et al in 2006 (5), and was repeated with updated 

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study data in 2013 by Fokkenrood et al (6). The latter review included randomised 
controlled trial (RCT) data comparing SET to non- SET management in patients 
with IC. Fourteen studies with a total of 1002 participants were randomised and 
followed up for a duration between 6 weeks and 12 months, with the primary 
outcome measure being absolute walking distance (AWD) measured by treadmill 
testing. There was a significant improvement of AWD with a size effect of 0.69 
(95% Confidence Interval (CI) 0.51-0.86) and 0.48 (95% CI 0.32-0.64) at 3 months 
and 6 months respectively. On average, there was an improvement in AWD of 
approximately 180 metres in the SET group (6). 
There is a strong evidence base in favour of SET, contributing to the NICE 
recommended first line therapy strategy in all IC patients. Despite these benefits, 
SET remains underutilised in the UK. A postal audit published by Shalhoub et al 
in 2009 (7) showed that only 24% of 84 responding UK vascular surgeons had 
access to a SET for their IC patients.  
An online survey audit was repeated in 2014 by Babber et al (8) as the first audit 
of SET access following the publication of the 2012 NICE guidance and was open 
to vascular surgeons in the UK and Ireland, as well as to members of a 
physiotherapy organisation as the main SET providers. This audit showed only 
35% of 118 respondents had access to a SET. Where these programmes exist, 
the majority are run by qualified physiotherapists (85%) or specialist nurses 
(13%). The main reasons for lack of access were attributed to a lack of funding, 
staff and infrastructure. Where SET was available, compliance was a major 
concern with reasons including patient difficulties with travelling to the SET class, 
travel expenditure and time being cited. Therefore, the actual standard of care for 
65% of the survey respondents reflecting generic practice in UK and Ireland is 
best medical therapy and exercise advice only. The cost of attending 2 hours of 
SET per week for a 3-month duration in a class of 10 patients is approximately 
£288 per patient, excluding the cost of travel and absence from work or other 
activities (9). 
 

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Electrical therapy for medical use has been practiced since the 18th century. Only 
in the last 30-40 years has there been an improvement in understanding of the 
optimal electrical parameters that can maximise clinical effect, however mass use 
of electrical therapy was largely limited by the ability to produce small, portable and 
affordable units. Within the last 20 years, advances in design technology have 
overcome this problem, making small, portable, affordable, safe and effective 
electrical therapy units readily available. 
Neuromuscular electrical stimulation (NMES) is an emerging technology. A proof 
of concept pilot study of 20 patients with IC showed a significant improvement in 
AWD (102.3m vs. 187.2m, p<0.01), and both ‘disease specific’ and ‘generic’ QoL 
measures after using a commercially available NMES device for 6 weeks (10). 
Compliance as assessed by patient recorded diaries was 98.5% NMES device 
usage in the 6-week follow-up period. 
A systematic review by Williams et al included 5 studies employing a number of 
different NMES devices used as a treatment strategy for patients with IC (11). 
Ninety-six patients with IC were compared between control and NMES groups in 
the 5 included studies showing up to 150% improvement in AWD at 4 weeks of 
intervention and 34% at 8 weeks. 
 
 
In addition to a robust assessment of the clinical efficacy of NMES in vascular disease, 
there is a lack of understanding of potential mechanisms of effective change that may 
be attributed to this form of intervention. Studies using intermittent pneumatic 
compression (IPC) on the calf and feet of patients suffering with IC have attempted to 
explain likely mechanisms for symptomatic improvement post intervention, and these 
may be similar for NMES. Delis et al suggest that the post compressive state of the 
calf muscle following IPC decreases the venous pressure therefore increasing the 
arterio-venous pressure gradient. This would then favour an increased arterial flow in 
order to stabilise the gradient mis-match (12). Measuring blood flow haemodynamics 

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by duplex ultrasound (DU) has been utilised to evaluate the response of lower limb 
arteries to various interventions. Bemmelen et al (13) showed increased  popliteal 
artery blood flow up to 8 times on releasing a pneumatic cuff applied around the calf 
for 2 seconds in the seated position in healthy individuals. In patients with arterial 
disease, there was a mean 3-fold increase in blood flow. The suggested mechanism 
was an increase in the veno-arterial pressure gradient upon release of the cuff. In 10 
healthy individuals using a Geko NMES device there was a significant increase in 
superficial femoral artery flow of 84% (P<0.005) (14). We intend to use DU to analyse 
the blood flow (cc/min) and time-averaged mean velocity (cm/s) in the superficial 
femoral artery of control patients at rest, in a seated position, as well as patients 
receiving the NMES device at rest, 15 minutes into use, 30 minutes into use, 1 minute 
after cessation and 5 minutes after cessation. A point 5 cm distal to the mid-inguinal 
point will be utilised and marked for accurate repeat measurements of the time-
averaged mean velocity (TAMV) and blood flow at the same site at different time-
points. 
Laser Doppler flow (LDF) is an optical measurement technique using disruption of 
laser wavelengths delivered through skin-applied probes to measure skin 
microcirculation. In the study above, LDF significantly improved in 10 healthy patients 
using the Geko NMES device for 20 minutes (14). The same was not seen when using 
IPC. Continuous LDF will be used to assess change in perfusion at rest for the control 
group and throughout the device use, up to 5 minutes post cessation, in the 
intervention group. 
 
The Revitive IX is a CE marked class IIa device that has the following pre-set ranges 
of electrical output parameters: Frequency 1 Hz – 50 Hz, Output current maximum 13 
mA. The electrical intensity is variable and set by the user from 1 - 99 units. 
Therapeutic levels of intensity are dependent on an intensity sufficient to cause motor 
neurostimulation causing calf muscle contraction, whilst remaining comfortable for the 
user. Intensity level varies from person to person and may be dependent on factors 
including foot plantar surface skin hydration and comfort. 

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This footplate device provides a 30-minute pre-programmed session of electrical 
stimulation to the plantar aspect of the feet to activate the venous foot and calf muscles 
pumps. The user controls the intensity of the impulses, and therapeutic benefit is 
deemed to occur when impulses are sufficient to cause ankle flexion thereby activating 
the calf muscle and pump increasing venous return to the heart.  
The device is designed to be used whilst the user is in a seated position, with the 
device placed on the floor.  The user places bare feet, one on each foot pad; the device 
requires both feet to be on their respective foot pads in order to complete the electrical 
circuit and deliver the required energy to effect stimulation. 
The default starting setting of the device is for a 30 minutes duration with intensity set 
at zero.  The user is required to increase the intensity using the interface controls until 
the stimulation can be felt or the muscles in the feet and calves can be seen to contract 
and relax.  The device will continue to provide stimulation until the timer reaches zero 
at which point the device will automatically switch off. 
The user may stop the stimulation at any point by pressing the power button and 
turning the device off or when using the foot pads by lifting one foot from off the device 
to break the circuit.  
The device is recommended to be used for 30 minutes per treatment session with a 
maximum total treatment time of 3 hours per day as required to minimise the potential 
for muscle fatigue. 
Revitive IX is intended for use in the home setting without the need for involvement of 
a clinical professional and can be used for up to 3 hours daily in 30 minute sessions. 
The retail cost of the device is approximately £160. 
The Revitive IX devices have been designed for use with home users in mind and so 
have been designed to provide simple operation with minimal instruction and without 
the need for involvement or supervision by a health care professional.  The range of 
capabilities for typical home users can vary by a large degree and so it is highly 
desirable for the devices to be relatively simple and physically easy to use. 
 

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Revitive IX uses the principle of electrical muscle stimulation (EMS) to elicit its effect. 
The products deliver energy to the user in the form of an electrical current applied to 
the skin surface, which stimulates the sensory and motor nerves, producing muscle 
contraction.  
The electrical current causes a temporary and local change of state of the nerve 
membrane polarisation resulting in the initiation of an action potential (impulse), which 
travels the length of the nerve to the innervated muscle fibres. In response a muscle 
action potential is generated and conducted along the muscle fibres causing the 
muscle to contract1  
To be effective, stimulation has to be sufficiently large, of sufficient duration and of 
suitable shape to overcome the threshold for depolarisation of the membrane, 
otherwise no action potential will occur.  
Successful nerve stimulation and muscle recruitment therefore depends on the 
intensity of current and the duration and the frequency of energy applied. However 
sufficient time is needed for membrane repolarisation (the recovery of the resting 
membrane potential after each action potential) and to allow muscle relaxation, 
metabolic recovery and to prevent premature accelerated fatigue. As such sufficient 
rest intervals also need to be incorporated within the stimulation pattern.   
The manner in which the Revitive generates stimulation is described in detail in the 
current version of the Investigator’s Brochure. 
 
 
Clinical evaluation of NMES techniques and similar devices resulted in the following: 
28 papers (n=913) were identified that investigated the use of electrical stimulation 
(ES) to improve blood flow, circulation and swelling. These studies were conducted in 
a range of populations including; 
 17 studies in healthy individuals  

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 4 in patients with diabetes  
 2 patients following knee surgery 
 1 study in each of the following; patients with amputation, investigating blood 
flow in patients with wounds, patients who had undergone hip / knee 
arthroplasty, patients with peripheral vascular disease and ankle sprain.  
There were two studies (one in patients with diabetes and one in patients with wound 
healing) which used a healthy population as a control. 
Please refer to Clinical Evaluation Report for full details of these studies. 
Of the 28 studies (n=676) reporting a significant improvement in blood flow due to 
electrical stimulation, 19 (n=582) were deemed to be clinically significant.  A range of 
electrical stimulation devices were used in the studies which showed that ES produced 
a clinically significant improvement in blood flow, with Revitive IX investigated in three 
studies and Duo-STIM and Health fit P4-Microstim devices all being used in two 
studies each.   
In the 17 studies which investigated the effect of ES on blood flow in healthy 
population, the results of 13 studies were determined to be clinically significant 
(n=261). One study investigated the use of ES to reduce swelling during motionless 
standing. Post-test foot and ankle volume was significantly greater than pre-test 
volume after 30 minutes of motionless standing (t= -7.093, p<0.001), but there were 
no significant differences after 30 minutes of standing with NMES (t = -1.374, 
p<0.185). The mean volume changes from pre-test to post-test in the conditions 
without NMES and with NMES were significantly different (51 ±32 mL and 12 ±39 mL, 
respectively; t=3.905, p=0.001), and therefore NMES in healthy individuals appears to 
limit fluid accumulation in the lower limb. In a similar healthy volunteer study (n=49), 
there was a significant increase in calf blood flow following 4 hours NMES stimulation 
whilst seated, compared to the contralateral unstimulated control leg. 
Three unpublished studies investigate the use of Revitive IX to improve blood flow and 
reduce swelling in healthy subjects as a means for comparison. The first study 

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investigated electrical stimulation with different pulse widths on the peripheral tissue 
perfusion, comparing both wide pulse (1 ms, WPS) and narrow pulse (0.5 ms, NPS) 
stimulation. Both WPS and NPS enhanced tissue perfusion in calf and foot above 
resting baseline. At a current intensity of 20 mA both WPS and NPS enhanced 
perfusion in calf and foot tissues (calf p=0.001; foot p=0.014).  A significantly higher 
intensity was needed with NPS compared to WPS to enhance and retain peripheral 
blood flow similar to exercise.  Furthermore, WPS at current intensities of >15mA 
(RMS at 500Ω) produced larger joint movement amplitudes compared to NPS. The 
authors concluded that WPS requires smaller current intensity than conventional NPS 
to produce beneficial effects on peripheral tissue perfusion.  
A second study with Revitive IX investigated the use of ES or exercise to alleviate 
lower limb swelling induced by a 40-minute session of prolonged inactivity. The 
authors report that 20 minutes of ES led to a significant (p=0.005) reduction in limb 
swelling, significant (p=0.003) increase in temperature of the foot, but not calf surface 
and significantly enhanced (p<0.0001) blood flux in both foot and calf. ES was shown 
to be at least or even more efficient as voluntary exercise in resolving circulation 
insufficiencies induced by prolonged inactivity.  
The Revitive IX device was investigated (n=16) for its effects on foot and calf blood 
flow and tissue oxygenation compared to a voluntary exercise control. The data 
demonstrated that ES produced a 10-fold increase in blood flux above baseline in the 
foot (p<0.001) and 7-fold increase in the calf (p<0.001). In comparison, voluntary 
exercise produced 3-fold (p=0.008) and 2-fold (p=0.002) for foot and calf respectively. 
Furthermore, tissue oxygenation in the foot and calf significantly increased in the ES 
group compared to voluntary exercise (p<0.018). 
The use of ES to increase the blood flow in patients with vascular disease (n=36) was 
investigated by Clover et al. They reported that the use of localised subcontractile 
electrical stimulation (3 h/day for 6 weeks) on the feet of patients with peripheral 
vascular disease led to a significant (p<0.05) increase in micro vessel density and 
tissue perfusion.  

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Of the 27 studies (n=897) which reported the use of ES in blood flow, circulation and 
swelling, only two commented on adverse events. One reported that there were no 
adverse events in the study, while the second reported local skin irritation at the 
electrode site which resolved after cleaning the electrode site 3 days post-operatively 
and changing the electrode.  
The papers include a heterogeneous population with both healthy subjects (16/27) 
and a range of clinical presentations, some of whom would be expected to present 
with vascular impairment or a reason for lower limb swelling.  
 
This includes three papers with data specific to the Revitive IX device demonstrating 
statistically and clinically significant outcomes in a healthy population. The papers 
have not been published, but this is in relation to commercial sensitivity and is normal 
in such circumstances. The effect of the stimulation (which was clearly significant) in 
these reports is predominantly achieved during the stimulation period. 
Clinically, electrical stimulation is employed as a means to stimulate a local circulatory 
response for patients with peripheral vascular disease, persistent swelling of the limb, 
wounds and other similar conditions. The literature cited is a reasonable reflection of 
the range of available material, and the selection of papers represents a full non-
biased reflection of outcomes. 
The conclusion that electrical stimulation can have a significant effect on local 
circulation is generally supported by the literature. This effect is clearly most 
pronounced when the application is made at a motor level, though there is some 
evidence for circulatory changes even with sensory level stimulation (e.g. Wilkstrom 
et al 1999). This sensory level circulatory response appears to be 'real' and is a 
phenomenon which is under current investigation (Anzelmo and Watson, in process). 
There are fewer papers presented which relate directly to an evaluation of swelling, 
though this is a fair reflection of the available evidence. Of the 4 cited papers, all 
appear to demonstrate a statistically and clinically significant change. 
In terms of safety and adverse events reporting, not all papers make a specific 
comment in this regard (though this is now an essential reporting component of a 

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modern publication). Two papers have made specific reference to adverse outcomes, 
though in fact only one (Jensen et al, 1985) reports an incident which was minor (skin 
irritation) and resolved within a short time frame. This would be consistent with the 
electrical stimulation literature across the whole range of applications. Thousands of 
stimulation procedures are routinely carried out in clinical practice and as a home 
treatment and the incidence of adverse effects reported (formally or otherwise) is very 
low. Assuming that those trials which make no comment with regards adverse events 
actually did not witness anything untoward, this means that of the 913 patients, only a 
limited number (not actually reported in the Jensen paper) reported minor skin 
irritation. This may well have actually been linked to the Betadine employed at the time 
of the surgery, though it cannot be ruled out as an irritation due to the stimulating 
electrodes. Even so, this is a very low incidence of a very minor 'adverse' effect which 
was easily resolved. 
In Summary: 
The claims made in relation to the effects of electrical stimulation on local circulation 
are supported by the cited literature.  
 The cited literature is a fair reflection of the available material.  
 The support for circulatory effects is stronger than the support for swelling 
effects, but this is largely due to the difference in the volume of published 
material covering these topics.  
 The adverse effects reported are at a low incidence and are very minor in 
nature.  
 
 
Although some evidence of the efficacy of NMES in the management of patients with 
IC exists, there is a significant paucity of high quality research conducted in a powered 
and controlled fashion. The proposed study is vital to robustly identify the contribution 
of clinical change using NMES, compared to the current gold standard recommended 
practice of SET and, actual standard of care offered in the majority of the UK and 
Ireland, which is BMT (including exercise advice). 

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In addition, compliance with NMES is likely to be better as devices can be used in the 
patient’s own environment, at a time convenient to them for a variable duration 
unlimited by a SET programmed duration. The unit price of an NMES device is 
significantly less than SET and therefore if proven efficacious, this study may provide 
the necessary evidence required to effect a change in recommendations and policy for 
the benefit of patients. 
Another aspect to the study is evaluating the potential underlying mechanism by which 
NMES may improve lower limb IC symptoms. A number of studies evaluating IPC have 
shown functional and symptomatic benefit in patients suffering from IC (11). Potential 
mechanisms include enhanced activation of the calf muscle pump increasing the 
venoarterial pressure gradient, thereby increasing the blood flow in the lower limbs. 
The drawback of IPC is expensive and bulky equipment, long duration of treatment 
required (3-4 hours daily) and discomfort of the pressures required to increase venous 
return. Lower limb NMES may mimic the effect of IPC by causing sufficient calf 
contraction to activate the calf muscle pump. Haemodynamic assessment whilst using 
the Revitive IX device has shown significant increases in lower limb arterial blood flow 
measured by ultrasonography in healthy individuals (16). Further haemodynamic 
assessment in a robust clinical trial of NMES in IC patients will help in advancing our 
understanding and assist in developing future technology to optimise the use of this 
mechanism for patient benefit. 
Under the remit of the NIHR EME programme, this study will enable robust research 
to determine definitive clinical efficacy, mechanistic evaluation and cost effectiveness 
of a novel intervention that will significantly impact care provision and outcomes for 
patients with PAD. 
If effective, NMES has the potential to improve flexibility and compliance to treatment 
with non-invasive therapies, reducing the burden of advancing disease on the NHS 
as fewer patients will require specialist care input or more invasive management. 
Adding a more accessible, safe and effective modality to the non-invasive 
management strategy for patients with intermittent claudication is of vital current 

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importance with implementation of a readily available and clinically effective 
modernised tool providing a 21st century solution to an age old problem. 
 
 
The device is expected to increase the walking distance in patients with intermittent 
claudication, and therefore have an adjuvant benefit on the same when provided in 
addition to supervised exercise programmes. It is also expected to cause a reduction 
in pain symptoms and reduced likelihood of major intervention in late stage PAD 
(critical limb ischaemia). 
 
The risks as defined in the Instructions for Use (IFU) and Investigators Brochure (IB). 
 
2. OBJECTIVES AND ENDPOINTS 
 
The research objective is to assess the clinical efficacy of a NMES device as an 
adjunct to the local standard care available at the study randomisation sites to 
improve walking distance in patients with IC. The number of sites is equally 
distributed between those that provide the NICE recommended gold standard of 
care for IC patients, including SET compared to real-world management as 
practiced by the majority of centres across the UK, including exercise advice only. 
The clinical efficacy will primarily be measured by a change in the Absolute 
Walking Distance (AWD) over the study protocol period, measured by a 
standardised treadmill test 
 
In addition, secondary outcomes including validated QoL questionnaires and 
compliance data will assist in modelling for economic evaluation of this intervention 
compared to standard treatment practice in order to assess cost effectiveness. 

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Evaluation will also be undertaken with the objective to understand the underlying 
mechanisms for change in clinical and subjective outcomes in the form of lower 
limb gross and superficial haemodynamic assessment. This will be undertaken by 
using DU and LDF, respectively. 
 
 Absolute walking distance (AWD) at 3 months– standardised treadmill 
test   
 
 
 Initial claudication distance (ICD) 
 Quality of Life  - Intermittent Claudication Questionnaire (ICQ), 
EuroQoL 5D (EQ5D-5L), Short Form 36 (SF-36) 
 Haemodynamic assessment - Duplex ultrasonography, Laser Doppler 
Flowmetry (LDF), Ankle Brachial Pressure Index (ABPI) 
 Health economic assessment 
 Compliance with interventions 
 Device experience questionnaire 
 
 
 
 
 
 
 

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3. STUDY DESIGN   
 
This is a multicentre randomised controlled study including 11 participating 
centres in England, equally distributed according to local therapy provision 
between supervised exercise therapy (SET) (6 centres) and exercise advice only 
(6 centres) with one centre, St George’s Hospital, acting as a dual site. Subject 
to any patient specific restrictions, all patients will also be provided with best 
medical therapy (BMT) in order to control for any cardiovascular risk factors. 
 
 
Subjects will be randomised to one of 2 treatments, depending on whether they are 
treated in a centre providing SET or not as shown below in Table 1.  
 
 
 
 
Non-SET Centre Treatment  
Number of subjects 
Treatment  
Control 2 
48 
EA 
Treatment 2 
48 
EA + NMES 
Total number of subjects non SET 
centre 
96 
 
Total number of trial subjects 
192 
 
 
 
 
SET Centre Treatment* 
Number of subjects 
Treatment 
Control 1 
48 
EA + SET 
Treatment 1 
48 
EA + SET + NMES 
Total number of subjects SET centre 
96 
Table 1. Summary of treatment allocation  
All patients will be expected to receive BMT as per local guidelines which includes exercise 
advice 
* Authorised SET centres will be permitted to randomise patients who do not wish to attend SET 
classes using a randomisation list that will allocate participants to Exercise Advice + NMES or 
Exercise Advice alone.  
 

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Figure 1: Study flow chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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4. PARTICIPANT ENTRY 
 
 
 
This study is open to all patients at the participating NHS sites with a diagnosis of IC 
meeting specific inclusion and exclusion criteria. 
The sites have been selected with their respect to their ability or not to provide SET. 
 
The following six able to provide a SET programme^: 
1. Imperial College Healthcare NHS Trust 
2. North Bristol NHS Trust 
3. Hull and East Yorkshire Hospitals NHS Foundation Trust 
4. University Hospital Southampton NHS Foundation Trust 
5. Dorset County Hospital NHS Foundation Trust   
6. St George’s University Hospitals NHS Foundation Trust* 
^Authorised SET centres will be permitted to recruit patients who do not wish to attend SET classes using 
a randomisation list that will allocate participants to Exercise Advice + NMES or Exercise Advice 
alone.  
 
The following six are not able to provide a SET programme: 
7. Cambridge University Hospitals NHS Foundation Trust 
8. The Newcastle Upon Tyne Hospitals NHS Foundation Trust  
9 .Taunton and Somerset NHS Foundation Trust 
10. Nottingham University Hospitals NHS Trust 
11. The Royal Bournemouth & Christchurch Hospitals NHS Foundation Trust 
*a dual centre; a SET programme is only recommended in patients residing in the 
Wandsworth catchment area  

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 Capacity to provide informed consent  
 Aged 18 or above 
 Positive Edinburgh Claudication Questionnaire   
 ABPI <0.9 OR positive stress test (fall in ankle pressure >30mmHg, 40 
secs post 1 min treadmill at 10% gradient, 4 km/h)   
 
 
 Severe IC requiring invasive intervention as determined by the treating clinician 
 Critical limb ischaemia as defined by the European Consensus Document  
 Co-morbid disease prohibiting walking on a treadmill or taking part in supervised 
exercise therapy.  
 Able to walk for longer than 15 minutes on the study treadmill assessment 
 Have attended supervised exercise therapy classes in the previous 6 months 
 Popliteal Entrapment Syndrome 
 Commenced vascular symptom specific medication in previous 6 months e.g. 
naftidrofuryl oxalate, cilostazol 
 Pregnancy. Participants must be of non-childbearing potential* OR using 
adequate contraception for the duration of the study period and have a negative 
urine pregnancy test result   
 Any implanted electronic, cardiac or defibrillator device 
 Acute Deep Vein Thrombosis  
 Broken or bleeding skin including leg ulceration 
 Peripheral neuropathy 
 Recent lower limb injury or lower back pain 
 Already using a neuromuscular electrical stimulation device  
* defined as those who have no uterus, ligation of the fallopian tubes, or permanent cessation of 
ovarian function due to ovarian failure or surgical removal of the ovaries. A woman is also 
presumed to be infertile due to natural causes if she has been amenorrheic for greater than 12 
months and has an FSH greater than 40 IU/L 

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5. PROCEDURES AND MEASUREMENTS  
 
 
 
Patients presenting with IC at the recruiting site vascular clinic will be identified by 
the direct healthcare team who will notify the research nurse or delegated individual 
to approach the participant with an information leaflet. This may be in person in the 
clinic, or by a patient invitation letter sent by mail / email or by telephone contact. 
Posters placed in participating research centres will support recruitment by 
signposting patients to the relevant research teams. 
 
 
 
Adults with IC presenting to vascular outpatient departments will be pre- screened by 
a member of the direct care team and invited to speak to a research nurse.  With 
permission of the participant the reasons for non-inclusion will be logged anonymously 
along with a minimum data set of age, sex & ABPI and reason for exclusion. The 
anonymised pre-screening logs will be transferred to the Trial Coordinating Centre for 
the purposes of monitoring recruitment.  Written informed consent will be obtained 
before the subject is enrolled in the study.   
 
 
 
ABPI measurement  <0.9: The brachial blood pressure from the right arm using a 
manual blood pressure monitor cuff and Doppler will be recorded after 5 minutes of 
resting supine on a couch. The systolic blood pressure of the anterior tibial artery and 
posterior tibial artery at the ankle will also be recorded using the cuff and Doppler 

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method. The ratio of the systolic brachial and ankle pressures will form the ABPI 
measurement. 
OR 
Positive stress test: (fall in ankle pressure >30mmHg, 40 secs post 1 min treadmill 
at 10% gradient, 4 km/h)  
 
Positive Edinburgh Claudication Questionnaire: This defines a claudicant as 
someone who indicates pain in the calf, regardless of whether pain is also marked in 
other sites; a diagnosis of atypical claudication is made if pain is indicated in the thigh 
or buttock, in the absence of any calf pain. Subjects should not be considered to have 
claudication if pain is indicated in the hamstrings, feet, shins, joints or appears to 
radiate, in the absence of any pain in the calf. 
 
Medical & drug history & other criteria: Review of inclusion and exclusion criteria 
including whether the patient has severe IC requiring invasive intervention, critical 
limb ischaemic, co-morbid disease prohibiting walking on a treadmill or taking part in 
SET. popliteal entrapment syndrome, commenced vascular symptom specific 
medication in previous 6 months e.g. naftidrofuryl oxalate, cilostazol, any implanted 
electronic, cardiac or defibrillator device, acute deep vein thrombosis, broken or 
bleeding skin including leg ulceration, peripheral neuropathy, recent lower limb injury 
or lower back pain 
 
Pregnancy test: Participants must be of non-childbearing potential* (page 29) OR 
using adequate contraception for the duration of the study period and have a negative 
urine pregnancy test result 
  
 
 
Randomisation will take place via the InForm system (the electronic case report 
form database for the study), which will be programmed with a randomisation 

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schedule provided by an independent statistician. Randomisation will be blocked 
with random block size and stratified by centres. 
Once eligibility has been confirmed, subjects will be randomised to one of the two 
arms of the study and assigned a pseudononymised study number unique to each 
individual enrolled on the trial: 
 
 
SET Centre randomisation: 
 
 Best medical therapy including exercise advice and supervised exercised 
(control 1) 
OR 
 Best medical therapy including exercise advice, supervised exercised and 
neuromuscular electrical stimulation (treatment 1) 
Authorised SET centres will be permitted to randomise patients who do not wish to 
attend SET classes (i.e. nonSET patients). Therefore, the authorised SET sites will 
act, for the purposes of these participants, as nonSET sites. In doing so they are still 
following the basic protocol instructions in that they are providing best medical 
therapy, as agreed between patient and clinicians, which in this case is not to 
participate in the SET classes. 
At these centres, the InForm database will be linked to a SET and nonSET 
randomisation list. The appropriate randomisation list will be used by sites 
dependent on whether the patient is attending / not to attending the SET programme.  
Non SET Centre randomisation: 
 
 Best medical therapy including exercise advice (control 2) 
OR 
 Best medical therapy, including exercise advice and neuromuscular electrical 
stimulation (treatment 2) 
 
 
 

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 Demographic information & vital signs: age, ethnicity, date of birth, lifestyle, 
socioeconomic status, weight, height, blood pressure, pulse 
 
 Treadmill: The Gardner-Skinner graded treadmill test will be used (15). The 
treadmill will start at 3.2 km/h at a 0% incline. Every 2 minutes, the gradient of 
the treadmill will increase by 2%. Patients will indicate the start of their 
claudication pain, which will be recorded as the Initial Claudication Distance 
(ICD) and finally stop the test at the point the patient does not want to continue 
due to lower limb pain; this is the Absolute Walking Distance (AWD). The 
patient will not be given a final score to prevent bias. If patients are able to walk 
for longer than 15 minutes on the treadmill, they will be excluded from the trial. 
 
 Quality of Life questionnaires: The validated EuroQoL (EQ-5D-5L) 
questionnaire and Short Form-36 (SF-36) questionnaire will be used to assess 
the generic QoL and will allow economic assessment based on intervention and 
score improvement. The validated Intermittent Claudication Questionnaire 
(ICQ) will be used to assess change in disease-specific QoL. These should be 
completed prior to informing the participant of the treatment allocation to 
prevent bias. 
 
 Haemodynamic assessment 
- 
Duplex ultrasonography: Using the appropriate arterial ultrasound probe 
and pre-set volume flow algorithms on a duplex ultrasound machine, flow 
within the common femoral artery (CFA), preferably of the most affected 
limb, will be measured, approximately 5cm below the mid-inguinal point at 
the groin. Measures include volume flow (VF, cc/min) and time-averaged 
mean velocity (TAMV, cm/s). 
o In the control group: only resting values will be undertaken over a 
3-minute period. 

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o The intervention group will have these parameters measured at 
rest, at 15 and 30 minutes into device use and then at 1 and 5 
minutes after device cessation (16). 
- 
Laser Doppler flowmetry - The single fibre laser optical probe of the LDF 
machine will be positioned on the dorsal aspect of the foot using single use 
adhesive pads. The LDF device measures skin surface temperature and 
superficial skin perfusion or blood flux, as a measure of superficial skin 
blood flow. Once the probe is placed, measurement is continuously 
collected via the LDF software.  
o In the control group: this will be at rest for a 3 minutes duration 
o The intervention group: data will be collected at rest until 5 minute 
after device cessation.  
 
 
There will be no change to the local site standard of care for patients with IC 
attributed to participation in this trial. Those sites with SET will continue to provide this 
intervention as per their normal standard of care and locally agreed protocol. The 
treatment period will last for 3 months. 
 
 
Best medical therapy for PAD (comprising of smoking cessation, antiplatelet agent 
use, cholesterol reduction, exercise therapy, and the diagnosis and treatment of 
hypertension and diabetes mellitus) will be as per standard care and local guidelines 
and it not standardised by this protocol.  
 
 
 
 

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The participants will be given standard advice on exercise as per local guidelines. 
Participants will be provided with a diary to note the frequency and duration of their 
exercise activity. 
 
 
The supervised exercise programme will be as per standard care and local guidelines 
and is not standardised by this protocol but usually involves at least 30 minutes of 
physical activity made up of rotating through various low impact exercises (treadmill 
walking, steps, stretching etc.) under the supervision of the programme leader as per 
the NICE Guidance 147: Lower limb peripheral arterial disease. August 2012. 
http://guidance.nice.org.uk/CG147 . 
 
The SET will be carried out under the supervision of a healthcare professional 
and entail a circuit of lower limb specific exercises for a minimum of 30 minutes 
per week usually over 3 months duration but as per local policy and attendance 
at SET classes will be recorded. This programme should occur at least once per 
week, however patients will be advised to continue 30 minutes of daily exercise 
to similar intensity between these sessions in line with the Department of Health 
and Chief Medical Officer's guidance on daily physical activity to promote a 
healthier lifestyle and prevent disease.  
 
 
Revitive IX is a disc shaped, footplate device used in a seated position with the 
soles of both feet in contact with the conductive footpads. The user is able to alter 
the stimulation intensity until there are visible strong yet comfortable calf muscle 
contractions and associated heel-toe raises.  
 

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The groups randomised to the NMES device, will be familiarised with the device by 
asking them to place the soles of both feet onto the respective footpads. The 
IsoRocker will be enabled throughout the study period. Baseline sensory and motor 
thresholds will be established and noted. The sensory (perception) and motor 
thresholds will be established by systematically varying the stimulation intensity with 
steps of ±1% maximal output whilst the participant provides verbal sensory feedback. 
The minimal intensity, which the participant is able to clearly feel, will be recorded as 
the perception threshold, and that producing visible muscle twitches as the motor 
threshold. The stimulation intensity for the main interventions will be adjusted to 
produce visible strong but non-painful contraction of the lower limb musculature based 
on the individual suprathreshold. Participants will be instructed to use the device to as 
close a stimulation intensity to this suprathreshold level without the experience being 
uncomfortable. Participants will be made aware that they may need to increase the 
intensity over time to compensate for habituation (familiarisation with the electrical 
muscle stimulation). 
 
Patients will be advised to complete at least one pre-programmed 30-minute 
session of NMES daily, to a maximum of 6 sessions and record usage in the 
compliance diary. Where patients are also diagnosed with diabetes, a minimum 
usage of two (2) x 30 minute sessions per day is recommended. In addition, 
some devices will be fitted with a voltage/current data logger which will connect 
between the mains supply and the device, recording usage each time. This 
information will be recorded on the data logger memory and uploaded following the 
3 months intervention period in order to cross reference against the compliance 
diary. This will act as a further robust mechanism to capture adherence to device 
use, with measurement of frequency of device use. 
 
 
 
Follow-up data will be collected at 3 months, 6 months and 12 months. These visits 
should be performed at the study site to allow the treadmill test, ABPI / Peripheral 

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pulse, haemodynamic assessments to take place, however, in the event that the 
participant is unable to attend in clinic or the site is unable to accommodate the on-
site visit these visits may take place remotely (i.e. over the telephone completely or in 
combination with postal questionnaires). These visits should only take place remotely 
if this has been previously discussed and agreed with the Trial Coordinating Centre. 
Missed assessments as a result of a remote visit should be re-scheduled at a later 
date as a separate on-site visit, where possible.  
Sites should clearly document the mode of follow-up that takes place, such as face to 
face or over the telephone.   
 
 
Assessments and data collection will be collected as follows: 
 
 Treadmill test as per baseline 
 ABPI / Peripheral pulse as per baseline 
 Drug history review 
 Safety reporting 
 Quality of Life questionnaires as per baseline 
 Haemodynamic assessment as per baseline 
- 
Duplex ultrasonography:  
o In the control group: only resting values will be undertaken over a 
3-minute period. 
o The intervention group will have these parameters measured at 
rest, at 15 and 30-minutes into device use and then at 1 and 5 
minutes after device cessation. 
- 
Laser Doppler flowmetry: 
o In the control group: this will be at rest for a 3 -minute duration 
o The intervention group: data will be collected at rest until 5 minutes 
after device cessation.  
 Compliance and resource diaries  

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1) Exercise compliance - Participants will be given a compliance diary 
to complete attendances at the SET (if SET centre), and record the 
type and frequency of exercise undertaken in their own time during 
the study period. 
2) Resource diary - Participants will be given a resource diary to 
complete health care resource use during the study period. 
3) Device compliance & experience (device arm only) - Participants 
randomised to use the NMES device will be provided with a 
compliance diary to record device use details. In addition, information 
from the data logger (if applicable) will be assessed in order to cross 
reference with the compliance diary. At 3 months, a simple device 
use questionnaire will be taken to report ease of device use and 
suggest any developments. 
 
Patients will receive weekly text messages during the treatment phase to remind them 
to complete their diaries, and attend SET or follow exercise advice.  
 
In the event that the participant is unable to attend in clinic or the site is unable to 
accommodate the on-site visit, this visit may take place remotely (i.e. over the 
telephone completely or in combination with postal questionnaires). This visit should 
only take place remotely if this has been previously discussed and agreed with the 
Trial Coordinating Centre. Missed assessments as a result of a remote visit should be 
re-scheduled at a later date as a separate on-site visit, where possible. 
 
Sites should clearly document the mode of follow-up that takes place, such as face to 
face or over the telephone.   
 
 
Assessments and data collection will be collected as follows: 
 

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 Treadmill test as per baseline 
 ABPI / Peripheral pulse as per baseline 
 Drug history review 
 Safety reporting 
 Quality of Life questionnaires as per baseline 
 Haemodynamic assessment  
- 
Laser Doppler flowmetry only (no duplex): this will be at rest for a 3-
minute duration in the most affected leg. 
 Compliance and resource diaries  
1. Exercise compliance - Participants will be given a compliance diary to complete 
attendances at the SET if it runs past the 3-month visit (if SET centre), and 
record the type and frequency of exercise undertaken in their own time during 
the study period. 
2. Resource diary - Participants will be given a resource diary to complete health 
care resource use during the study period. 
 
In the event that the participant is unable to attend in clinic or the site is unable to 
accommodate the on-site visit, this visit may take place remotely (i.e. over the 
telephone completely or in combination with postal questionnaires). This visit should 
only take place remotely if this has been previously discussed and agreed with the 
Trial Coordinating Centre. Missed assessments as a result of a remote visit should be 
re-scheduled at a later date as a separate on-site visit, where possible. 
 
Sites should clearly document the mode of follow-up that takes place, such as face to 
face or over the telephone.   
 
 
Assessments and data collection will be collected as follows: 
 
 Treadmill test as per baseline 

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 ABPI / Peripheral pulse as per baseline 
 Drug history review 
 Safety reporting 
 Quality of Life questionnaires as per baseline 
 Haemodynamic assessment  
- 
Laser Doppler flowmetry only (no duplex): this will be at rest for a 
3minute duration in the most affected leg. 
 Compliance and resource diaries  
4) Exercise compliance - Participants will be given a compliance diary 
to complete attendances at the SET if it runs past the 3-month visit 
(if SET centre), and record the type and frequency of exercise 
undertaken in their own time during the study period. 
5) Resource diary - Participants will be given a resource diary to 
complete health care resource use during the study period. 
 
In the event that the participant is unable to attend in clinic or the site is unable to 
accommodate the on-site visit, this visit may take place remotely (i.e. over the 
telephone completely or in combination with postal questionnaires). This visit should 
only take place remotely if this has been previously discussed and agreed with the 
Trial Coordinating Centre. Missed assessments as a result of a remote visit should be 
re-scheduled at a later date as a separate on-site visit, where possible. 
 
Sites should clearly document the mode of follow-up that takes place, such as face to 
face or over the telephone.   
 
The 12-month follow up appointment will mark the end of the study participation.  
 
 
 
 

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Screening 
Baseline* 
Treatment 
Phase 
Follow-up (months)† 
Visit 
1 
2 
 
3 
4 
5 
 
 
 
0 to 3 months 
3 months 
6 months 
12 months 
Informed consent 
X 
 
 
 
 
 
Pregnancy test1 
X 
 
 
 
 
 
Ankle Brachial Pressure Index (ABPI) 
/ positive stress test 
X 
 
 
X 
X 
X 
Edinburgh Claudication Questionnaire  
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Drug history 
X 
 
 
X 
X 
X 
Peripheral pulse examination 
X 
 
 
X 
X 
X 
Other exclusion criteria 
X 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
Demography 
 
X 
 
 
 
 
Vital signs 
 
X 
 
 
 
 
EQ-5D-5L / SF-36 / ICQ 
 
X 
 
X 
X 
X 
Treadmill test (ICD/ AWD) 
 
X 
 
X 
X 
X 
Duplex Ultrasonography 
 
X2 
 
X2 
 
 
Laser Doppler Flowmetry 
 
X2 
 
X2 
X 
X 
NMES training3 
 
X 
 
 
 
 
SET booking4 
 
X 
 
 
 
 
Compliance Diary (SET / device / EA) 
 
X 
 
X 
X 
X 
Resource use diary 
 
X 
X 
X 
X 
X 
Weekly text messages 
 
 
X 
 
 
 
Data logger 
 
X 
X 
 
 
 
Device experience questionnaire 
 
 
 
X 
 
 
Safety reporting 
 
 
X 
X 
X 
X 
*baseline and screening visit occur on the same day if both the researcher and participant agree that informed consent has been 
adequately considered with time to ask questions  
† These visits may take place remotely In the event that the participant is unable to attend in clinic or the site is unable to 
accommodate the on-site visit 
1women of child bearing potential a required to take a urine pregnancy test  
2 At rest and during device use in device arm 
3 NMES treatment groups only 
4SET centres only where applicable  
 

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6. TREATMENTS 
 
 
 
This trial is being carried out under a MHRA Devices (Notice of No Objection). The 
device is therefore only to be used by the named investigators, for the participants 
specified in this protocol, and within the trial. 
 
 
The Revitive IX System comprises of the following Components: 
 
EMS Device:   REVITIVE IX:  
  
 
 
 
 
 
 
C: Foot Pads 
D: LED Display Panel 
E: Time Setting Controls 
F: Foot pad Intensity Controls 
G: Electrode Pad Intensity Controls 
H: Power Button 
I: Location of Accessory and Power 
Sockets 
J: IsoRocker  

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AC Power Adaptor: 
 
Remote Control:  
 
 
The Revitive IX system consists of an electrical muscle stimulation (EMS) device, 
AC/DC power adaptor and optional electrode pads. EMS is the application of electrical 
impulses that are of sufficient intensity to produce an artificial contraction of the muscle 
tissue. Revitive IX is indicated for electrical stimulation of the lower leg to: 
 
 Reduce swelling in the legs/ankles/feet - caused by being immobile due to 
osteoarthritis or an injury 
 Improve circulation to reduce or prevent blood-pooling (stasis) - caused by 
diabetes or by being immobile following surgery 
 Reduce pain and discomfort in the legs/ankles/feet - caused by diabetic 
peripheral neuropathy or swelling (oedema) due to osteoarthritis or following 
surgery 
 Increase muscle strength to help regain mobility in the legs affected by being 
immobile due to COPD, osteoarthritis or following surgery 
The AC/DC Power adaptor is a CE Marked 
Class II Portable AC Adaptor with a rated input 
of 100-240VAC, 50-60Hz, 0.18A and a Rated 
Output of 5.0VDC, Max 1.0A.  The adaptor is 
certified to EN60601-1:2006 by TUV SUD 
Product Service GmbH.  The AC adaptor is 
designed and manufactured in accordance with 
a Quality Management Systems certified to ISO 
9001:2008. 
The IR remote control is operated by 2 x 1.5v AAA 
batteries (supplied, not installed) and interacts with 
the digital display located on the main unit of 
Revitive Medic where the receiver is located.  The 
remote control provides duplicate functions to the 
user interface on the Revitive Medic device.  The 
Remote Control is designed and manufactured in 
accordance with a Quality Management System 
certified to ISO 9001:2015.  
 

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 Help maintain leg vein health - by increasing circulation, delivering more 
oxygenated-blood and reducing swelling (oedema) in the legs/feet/ankles. 
  
In addition to the medical indications the Revitive family of devices are intended to 
provide electrical muscle stimulation for the following:  Healthy individuals who have 
a sedentary lifestyle or spend long periods inactive, Revitive may help to: 
 Reduce swollen feet and ankles 
 Alleviate tired, aching & heavy legs, including cramp 
 Improve circulation 
 Help maintain leg vein health 
 Increase muscle strength in the legs 
 
The device is intended for home use for a recommended a minimum of 30 minutes 
treatment, up to a maximum of 3 hours treatment time per day as required. The device 
delivers electrical stimulation to the lower limb muscles through foot pads and/or 
through electrode pads which may be positioned on the lower limb. 
The Revitive IX provides user control of intensity and duration of stimulation.  It also 
has an additional IsoRocker feature that allows ankle movement during stimulation.  
When enabled, the IsoRocker allows Revitive IX to tilt back and forth as the muscles 
contract and relax.  The user is able to choose whether to enable the IsoRocker feature 
on the device.  Revitive IX also includes a remote control in addition to the controls on 
the device, and Revitive IX is reusable. It is supplied non-sterile with an AC adaptor, 
remote control (including 2 x 1.5v AAA batteries) and electrode pads as standard. 
The technical characteristics of the Revitive IX device is summarised in the current 
version of the current version of the Investigator’s Brochure.  
All of the manufacturing operations for the routine production of Revitive IX devices 
are subcontracted through an approved supplier comprising: 
Mirae Medi & Tech Co. Limited 

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Full details are provided in Revitive IX Technical File Section Principal Subcontractors. 
The manufacture of Revitive IX is carried out in line with documented production and 
inspection procedures. 
An overview of the manufacturing process and details of the quality assurance checks 
are provided in the in the current version of the Investigators’ Brochure. 
 
1.6.3. Name or number of the model/type, including software version and 
accessories, if any to permit full identification: 
Name: 
Revitive IX 
 Model:  RIX Ref: 1379   
Software Version: 2.0 
 
1.6.4. Description as to how traceability shall be achieved during and after the 
clinical investigation: 
Traceability is achieved by assignment of device serial numbers to patient identifiers.  
 
1.6.5. Intended purpose of the investigational device in the proposed clinical 
investigation 
Revitive IX devices are intended for electrical stimulation of the lower leg.  
 
1.6.6. Populations and indications for which the investigational device is 
intended 
The Revitive IX device is intended for electrical stimulation of the lower leg in healthy 
individuals. 
The device is intended for home use for one 30 minutes treatment per day, up to no 
more than 3 hours per day 
 
1.6.7. Summary of necessary training and experience needed to use the 
investigational device 

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Revitive IX has been designed for use with home users in mind. The range of 
capabilities for typical home users can vary by a large degree and so it is highly 
desirable for the device to be relatively simple and physically easy to use. As such the 
device has been designed to provide simple operation with minimal instructions as 
provided in the instruction sheet accompanying the device.  
The research team conducting the study, and study participants, will be instructed in 
the use of the device as follows: 
 How to switch on and off 
 How to place feet on the footpads and set intensity and duration 
 How to clean the device 
 How to use the remote control 
 How to operate the IsoRocker feature 
 
 
The investigational device will be fitted with a data logger which will monitor the device 
power input at the connection to the mains power adaptor and will provide a trace of 
usage during the study period.  This data will be utilised to assess patient compliance 
to the treatment regime.  Patients will also be required to maintain a diary throughout 
the duration of the trial, and they will be sent text message reminders to do so. 
 
1.6.9. Principle of Operation  
NMES22 is the application of electrical impulses, which are of sufficient intensity to 
produce an artificial contraction of the muscle tissue.  Through the introduction of 
electrical stimulation to the muscles of the feet and legs, the muscles are made to 
repeatedly contract and relax, restoring the pumping action and thereby helping to 
counteract stasis, increase blood flow and reduce swelling. 
 
Revitive IX is a Class IIa active medical device intended for transient use, in 
accordance with AnnexIX, Rule 9 of EC Council Directive 93/42/EEC concerning 

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medical devices as amended by Directive 2007/47/EC: “All active therapeutic devices 
intended to administer or exchange energy are in Class IIa” 
 
 
 
In accordance with Medical Devices Directive: 93/42/EEC (as amended by Directive 
2007/47/EC) all Revitive IX devices intended for clinical investigation must bear the 
wording "exclusively for clinical investigation".  
It is recognised that such wording may cause confusion to clinical staff in that it may 
be thought that the clinical investigation being referred to is of a patient rather than the 
device. Local Principal Investigators should ensure that the meaning of this wording is 
clearly understood by all staff using or coming into contact with the device being 
investigated and that the device under investigation is segregated, where possible, 
from any similar devices in routine use.  
 
 
The device should be stored as per the instructions for use.  
 
 
 
 
Subjects may discontinue study treatment for the following reasons: 
 At the request of the subject. 
 Serious Adverse Event  
 If the investigator considers that a subject's health will be compromised due to 
adverse event or concomitant illness that develop after entering the study. 
 

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Withdrawal from the study refers to discontinuation of study treatment and study 
procedures and can occur for the following reasons: 
 Subject decision 
 Loss to follow-up 
 Subject loss of capacity  
 
 
There are no criteria for withdrawal from the study. Patients will be free to withdraw 
from the study without any effect on their usual medical care. The reason for their 
withdrawal will be recorded in the CRF/eCRF and medical records if offered. All 
randomised will be followed up to 12 months unless they specifically asked to be 
withdrawn as per intention to treat. In line with this analysis patients lost to follow up 
or withdrawn from the study will not be replaced. 
 
If a patient loses capacity after consenting to take part in the study, the local Principle 
Investigator may decide it is in the patient’s best interests to be withdrawn. Any 
identifiable data already collected with consent will be retained and may be analysed, 
but no further data will be collected or any other research procedures carried out on 
or in relation to the patient.  
 
7. SAFETY REPORTING 
 
 
 
 
 
Adverse Event (AE) An AE is any untoward medical occurrence, unintended 
disease or injury or any untoward clinical signs (including an abnormal laboratory 

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finding) in subjects, users or other persons whether or not related to the 
investigational medical device.  
 
 
This includes: events related to the investigational device or the 
comparator 
 
Includes, events related to the procedures involved (any procedure in 
the protocol) 
 
For users or other persons this is restricted to events related to the 
investigational medical device 
 
 
 
For the purposes of the study, all AEs will be followed up according to local practice 
until the event has stabilised or resolved, whichever the sooner is. It is essential that 
all AEs that occur during the course of the study are appropriately reported in order 
to ensure the participants continuing safety. Of particular importance is the 
assessment of any event for causality and expectedness in relation to the device.  
 
 
 
Mild: Awareness of event but easily tolerated 
Moderate: Discomfort enough to cause some interference with usual activity 
Severe: Inability to carry out usual activity 
 
 
 
 Unrelated: No evidence of any causal relationship between the use of the 
device and the AE. 
 
 Unlikely: There is little evidence to suggest there is a causal relationship with 
the use of the device (e.g. the event did not occur within a reasonable time after 
study treatment). There is another reasonable explanation for the event (e.g. 
the patient’s clinical condition, other concomitant treatment). 

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 Possible: There is some evidence to suggest a causal relationship between the 
use of the device and the AE (e.g. because the event occurs within a 
reasonable time after study treatment). However, the influence of other factors 
may have contributed to the event (e.g. the patient’s clinical condition, other 
concomitant treatments). 
 
 Probable: There is evidence to suggest a causal relationship between the use 
of the device and the AE and the influence of other factors is unlikely. 
 
 Definite: There is clear evidence to suggest a causal relationship between the 
use of the device and the AE and other possible contributing factors can be 
ruled out. 
 
 
 
 
7.6.1 Serious Adverse Event Definition 
 
Serious Adverse Event (SAE) is any adverse event that has 
a) Led to a death 
b) Led to a serious deterioration in health that either: 
i) 
Resulted in a life-threatening illness or injury, or 
ii) 
Resulted in a permanent impairment of a body structure or a body 
function, or 
iii) 
Required in-patient hospitalisation or prolongation of existing 
hospitalisation, or 
iv) 
Resulted in medical or surgical intervention to prevent life threatening 
illness or injury or permanent impairment to a body structure or a body 
function 
c) Led to foetal distress, foetal death or a congenital abnormality or birth defect 

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This includes device deficiencies that might have led to a serious adverse event if a) 
suitable action had not been taken or b) intervention had not been made or c) if 
circumstances had been less fortunate. These are handled under the SAE reporting 
system. 
A planned hospitalisation for pre-existing condition, or a procedure required by the 
protocol, without a serious deterioration in health, is not considered to be a serious 
adverse event. 
 
 
If an AE is assessed as serious, the PI or designated site staff member will complete 
the SAE form on the InForm database immediately or within 24 hours of being made 
aware of the event. In cases where the InForm system is unavailable, sites will email 
the completed paper SAE form to the coordinating centre via nesictrial@imperial.ac.uk 
immediately or within 24 hours of being made aware of the event. All SAEs will be 
reported to the JRCO as soon as possible after becoming aware of the event.  
SAEs which indicate an imminent risk of death, serious injury or serious illness and 
require prompt remedial action for other patients, users or other persons or a new 
finding to it, must be reported to the MHRA by the Sponsor immediately but no later 
than 2 calendar days following the date the Sponsor is made aware. 
Any other reportable events should be reported immediately but no later than 7 
calendar days following the date the Sponsor is made aware. 
The device manufacturer should also be informed within 24 hours of the SAE or device 
deficiency (if indicated in the study’s communication agreement). 
http://www.mhra.gov.uk/Safetyinformation/Reportingsafetyproblems/Devices/index.ht
m.   
 
 
 

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Adverse Device Effect is an adverse event related to the use of an 
investigational medical device. 
 
Includes any adverse event resulting from insufficiencies or inadequacies in the 
instructions for use, the deployment, the implantation, the installation, the operation, 
or any malfunction of the investigational medical device 
 
Includes any event that is a result of a use error or intentional misuse 
 
(Note: All AEs judged by either the reporting investigator or the Sponsor as having a 
reasonable causal relationship to the device qualify as adverse effects) 
 
 
 Full details of risks and anticipated adverse device effects (ADEs) for REVITIVE are 
contained within the Risk Management Report for REVITIVE® Electronic Muscle 
Stimulators (EMS), report reference: RMR/RIX/007 (document title “7. RMR_RIX_v7.0 
Combined Signed”). 
 
 
 
An adverse event defined by the PI as an adverse device effect should follow the same 
recording procedures as AEs (defined in section 7.3). ADEs form part of the ongoing 
safety review for the study and are not classified as reportable to either the MHRA or 
manufacturer, unless specified in the communication agreement. 
 
 
 

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7.8.1 Serious Adverse Device Effect Definition 
An adverse device effect that has resulted in any of the consequences characteristic 
of a serious adverse event or that might have led to any of these consequences if 
suitable action had not been taken or intervention had not been made or if 
circumstances had been less opportune. SADEs can be classified into either 
Anticipated Serious adverse effects (ASADE) or unanticipated serious device effects 
(USADE) 
 
 
 
 
 
A serious adverse device effect which by its nature, incidence, severity or outcome 
has been previously identified in the risk analysis report or Clinical Investigation 
Brochure. 
 
 
The PI or designated site staff member will complete the SAE form on the InForm 
database immediately or within 24 hours of being made aware of the event. In cases 
where the InForm system is unavailable, sites will email the completed paper SAE 
form to the coordinating centre via nesictrial@imperial.ac.uk immediately or within 24 
hours of being made aware of the event. 
SAEs which indicate an imminent risk of death, serious injury or serious illness and 
require prompt remedial action for other patients, users or other persons or a new 
finding to it, must be reported to the MHRA by the Sponsor immediately but no later 
than 2 calendar days following the date the Sponsor is made aware. 

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Any other reportable events should be reported immediately but no later than 7 
calendar days following the date the Sponsor is made aware. 
The device manufacturer should also be informed within 24 hours of the SAE or device 
deficiency (if indicated in the study’s communication agreement). 
 
 
 
A serious adverse device effect which by its nature, incidence, severity or outcome 
has not been identified in the current version of the risk analysis report, Instructions 
For Use or Clinical Investigation Brochure. 
 
 
In addition to reporting to the MHRA (as detailed in the SAE section), the Sponsor will 
report the USADE to the REC within 15 days. The Sponsor will also notify the Device 
Manufacturer and Investigators at all sites of the USADE. 
 
Follow up of patients who have experienced a USADE should continue until recovery 
is complete or the condition has stabilised. 
 
 
Annual Safety reports will be submitted to the Sponsor, the Ethics Committee and 
Regulatory Authority in accordance with regulatory requirements. 
 
 
Where relevant, any pregnancy occurring during the clinical study and the outcome of 
the pregnancy should be recorded on a pregnancy notification form patients will be 
asked to consent to be followed up for congenital abnormality or birth defect. 
Pregnancy is considered an SAE, the patient will be asked to stop using the device, 
followed up according to the protocol and the results analysed as per intention to treat. 

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If any urgent safety measures are taken the CI/Sponsor shall immediately and in any 
event no later than 3 days from the date the measures are taken, give written notice 
to the MHRA and the relevant REC of the measures taken and the circumstances 
giving rise to those measures. 
   
8. STATISTICAL ANALYSES 
 
This will be a two-arm randomised controlled trial, where the control is locally available 
therapy, which includes Best Medical Therapy AND either exercise advice or SET 
depending on the centre. The intervention, in addition to the locally available therapy, 
is NMES.  
Four studies have reported on improvement in absolute walking distance (AWD) for 
the same population of patients (17-20). Three studies report AWD at 3 months, and 
for these improvement varied between 75-90 metres (18-20). The MIMIC trial does not 
report the effect size at 3 months (17). The improvement detected at 6 months varied 
from 41m (17) to 170m (18) across all studies. None of the studies clearly reported the 
standard deviation associated with the treatment effect measurement. The MIMIC trial 
(17) assumed a standard deviation (SD) of 120m for an effect size of 60m in their 
sample size calculation. 
From pilot work and clinical judgement, using NMES together with best locally available 
therapy should at least result in an improvement of 60m after 3 months in the 
intervention group mean AWD. This improvement is deemed as clinically important. 
Therefore, we have adopted the same assumptions of effect size and standard 
deviation for the sample size calculation for our study. These parameters are deemed 
as providing significant clinical benefit in the IC population translating in improvement 
of lifestyle factors as measured by the QoL questionnaires. 
Assuming that the mean AWD in the control group is 200m at 3 months (18) and a 
common equal standard deviation of 120m (17), without considering the dropout rate, 

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it is estimated that a sample size of 172 participants (86 per group) will have 90% 
power with a two sided alpha = 0.05 to detect a difference of 60m in the mean absolute 
walking distance at 3 months between the intervention and the control group.  
Assuming a 10% dropout rate, the sample size required for this study is 192 
participants. The sample size was computed for a two-sample means test using Stata 
13. 
 
To recruit sufficient subjects 11 centres will participate in the study: six centres 
with exercise advice only as locally available therapy with the remainder 
providing supervised exercise therapy. 
Through feasibility data collected from each centre, in total, 24 patients with IC 
could theoretically meet inclusion criteria for randomisation per month.  
Accounting for 4 centres, which also undertake other studies with the same 
patient population, we anticipate randomising 13 patients per month; this would 
provide an adequate number of subjects. Therefore, a recruitment period of 15 
months would be required to reach the target recruitment of 192 patients for 
this study. 
Due to a variation in size of site, numbers of patients with Intermittent 
Claudication seen and involvement in other studies, the recruitment targets per 
site will be varied but we will ask sites to aim to recruit 24 patients in total (2 per 
month) for 15 months.  
 
 
 
The primary analysis will estimate the mean difference in AWD between the two 
intervention arms using a linear regression model which will include intervention 
arm, baseline AWD, and the randomisation stratification variable ‘centre’  as 
covariates. A repeated measure analysis will be undertaken, including patient as 
a random effect, to investigate the relationship between AWD and independent 

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baseline variables such as body mass index (BMI) with the model including 
adjustment for centre and baseline AWD. Multiple imputation will be undertaken 
for all participants who are missing values or drop out by three months.   Causal 
inference methods will be used to estimate treatment effects that account for 
compliance with the allocated intervention (NMES, SET, EA). Where necessary, 
data will be transformed to meet normality assumptions. All statistical tests will 
be two-tailed with a 5% significance level.  
Patient characteristics will be summarised. Summaries of continuous variables 
will be presented as means and standard deviations if normally distributed, and 
as medians and inter-quartile ranges for skewed data; categorical variables will 
be presented as frequencies and percentages. Data on the socioeconomic 
status of patients will be summarised by centre.  
 
8.3.1. Subgroup analyses 
 
Subgroup analysis will investigate the effect of the intervention among subgroups and 
most importantly the cost effectiveness of the intervention. The subgroups that will be 
considered are NMES + SET, NMES + EA, SET and EA. We will estimate the 
treatment effect in the six SET sites vs the six non-SET sites (NMES+SET & SET vs 
NMES +EA & EA). We will also estimate the treatment effect of NMES in the SET and 
non-SET sites (NMES+SET vs SET and NMES+EA vs EA).  
 
We will also investigate if NMES + EA has a similar effect as SET alone and if NMES 
+ EA is more cost effective than SET alone when accounting for compliance and using 
causal inference methods. Also we will aim at determining if NMES + SET is more 
effective than NMES + EA or SET alone. The subgroup effects will be based on the 
interaction between subgroup and treatment arm. 
 

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All analyses will be on an intention-to-treat basis where all participants will be analysed 
in the groups to which they were allocated regardless of the treatment they received. 
Per-protocol analyses will also be performed. 
 
A statistical analysis plan including a detailed description of all the planned analysis 
will be prepared, finalised and signed off before the database lock. There is no planned 
interim analysis. 
 
8.3.2. Mechanistic Evaluation 
The mechanistic evaluation of the interventions will involve haemodynamic 
measurements of femoral artery blood flow including time averaged mean velocity 
(TAMV, cm/s) and blood flow (cc/min) by DU and skin microcirculation (blood flux) by 
LDF. 
These are both continuous measurements; haemodynamic measurements via LDF 
will be taken several times during the trial assessment time points (baseline, 3 months, 
6 months, 12 months) DU will be conducted at baseline and  months only. The main 
analysis will involve comparing arterial flow and skin microcirculation at 3 months for 
the intervention and control group using multi-level regression to take into account the 
repeated measurements. 
A secondary analysis will investigate the effect of compliance and drop out by 
calculating the complier average causal effect. 
 
8.3.3. Cost-effectiveness analysis 
 
The economic analyses will compare local therapy (supervised exercise therapy, SET 
or exercise advice, EA only) versus the intervention (local therapy + Neuromuscular 
Electrical Stimulation, NMES) in patients with Intermittent Claudication. The price year 
will be 2017/2018. The analyses will be performed from the perspective of the NHS. 
Secondary analyses will consider the societal perspective. As a preliminary step, a 

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literature review will be conducted to identify other economic analyses in these or 
similar patients. The analyses will be based on a (i) patient level in-trial cost-
effectiveness analysis, (ii) a decision model and (iii) budget impact assessment. The 
in-trial analysis will calculate costs and quality-adjusted life years (QALYs) over the 
one year time horizon of the trial. Appropriate methods will be used to handle missing 
data. Costs will be estimated from healthcare resource use in the trial. Unit costs will 
be taken from the literature and manufacturers’ list prices. QALYs will be measured 
from EQ-5D-5L collected in the trial adjusting for baseline differences in utility. 
Subgroup analyses will be carried out by pre-defined groups as described in the 
statistical analysis plan. The decision model will use the information from the trial and 
other sources to project costs and QALYs over the lifetime of the patients, by 
estimating the effect of IC on mortality, quality of life and resource use, and the impact 
of the intervention on these endpoints. As Intermittent Claudication is a chronic 
disease, a Markov structure is likely to be appropriate. Costs and QALYs will be 
discounted. Univariate sensitivity analyses will be used to test the robustness of the 
model to alternative input parameters. Probabilistic sensitivity analyses will be 
undertaken using Monte-Carlo simulation. The budget impact assessment will 
estimate the annual cost to the NHS taking into account projected take-up of the 
treatment, should it be demonstrated to be cost-effective, and expected cost savings 
to the NHS. Pseudonymised data will be transferred to the University of Granada in 
accordance with a data sharing agreement, collaboration agreement, and ICTU SOPs 
 
9. REGULATORY, ETHICAL AND LEGAL ISSUES 
 
The investigator will ensure that this study is conducted in full conformity with the 7th 
revision (2013) of the 1964 Declaration of Helsinki. 
 

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The study will be conducted in accordance with the guidelines laid down by the 
International Conference on Harmonisation for Good Clinical Practice (ICH GCP E6 
R2 guidelines).  
 
 
 
 
Prior to the shipment of device and the enrolment of subjects, the REC and HRA must 
provide written approval of the conduct of the study at named sites, the protocol and 
any amendments, the Subject Information Sheet and Consent Form, any other written 
information that will be provided to the subjects, any advertisements that will be used 
and details of any subject compensation.  
 
 
Amendments to the protocol will only be made with the approval of the Chief 
Investigator and will be subject to review and approval by the Sponsor who will decide 
whether the changes are substantial or non-substantial. 
Proposed amendments to the protocol and aforementioned documents must be 
submitted to the REC for approval as instructed by the Sponsor. Amendments 
requiring REC approval may be implemented only after a copy of the REC’s approval 
letter has been obtained.  
Amendments that are intended to eliminate an apparent immediate hazard to subjects 
may be implemented prior to receiving Sponsor or REC and HRA’s approval. 
However, in this case, approval must be obtained as soon as possible after 
implementation. 
 

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The REC will be sent annual progress reports in accordance with national 
requirements. 
 
The REC will be sent annual safety updates in order to facilitate their continuing review 
of the study (reference. ICH GCP E6 Section 3.1.4) and will also be informed about 
the end of the trial, within the required timelines. 
 
 
The study will be performed in compliance with UK regulatory requirements. A notice 
of no objection from the appropriate Regulatory Authority must be obtained prior to the 
start of the study. In addition, the Regulatory Authority must approve amendments 
prior to their implementation (as instructed by the Sponsor), receive SUSAR reports 
and annual safety updates, and be notified of the end of the trial. 
 
Health Research Authority (HRA) approval will be obtained prior to starting the study. 
Each participating site will confirm capacity and capability prior to commencing. 
The HRA and all participating sites also need to be notified of all protocol amendments 
to assess whether the amendment affects the institutional approval for each site.  
 
 
 
All protocol deviations and protocol violations will be reported via the eCRF/CRF and 
reviewed by the Chief Investigator and reported to the ICTU QA Manager on a monthly 
basis. Protocol violations will be reported to the Sponsor. 
An assessment of whether the protocol deviation/violation constitutes a serious 
breach will be made.  

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A serious breach is defined as: 
A breach of the conditions and principles of GCP in connection with a trial or the trial 
protocol, which is likely to affect to a significant degree:  
 The safety or physical or mental integrity of the UK trial subjects; or 
 The overall scientific value of the trial 
 
The Sponsor will be notified within 24 hours of identifying a likely serious breach. If a 
decision is made that the incident constitutes a Serious Breach, this will be reported 
to the MHRA and REC within 7 days of becoming aware of the serious breach. 
 
 
Imperial College London holds negligent harm and non-negligent harm insurance 
policies which apply to this study. Imperial College London will act as the main Sponsor 
for this study.  Delegated responsibilities will be assigned to the NHS trusts taking part 
in this study.  
  
 
The study will be registered on a trial database (ISRCTN and clinicaltrials.gov) in 
accordance with requirements of the International Committee of Medical Journal 
Editors (ICMJE) regulations. 
 
 
Consent to enter the study will be sought from each participant only after a full verbal 
explanation has been given, and an information leaflet offered. The consent will be 
informed, voluntary and participants will be given an appropriate amount of time to 
consider participation and to ask questions. There will be no set minimum time to 
consider the trial as this will be determined on a case by case basis, this is usually 24 

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hours but could be less if there is agreement from both the researcher and participant 
that the consent is fully informed. 
  
Signed participant consent will be obtained and participants will be asked to consent 
for their data to be linked with appropriate databases including Hospital Episode 
Statistics (HES), and the National Vascular Database as well as for longer term follow-
up in the event the trial is extended.  A copy of the signed Participant Information 
Sheet/Informed Consent Form document will be provided to the patient and the 
original Informed Consent Form should be retained with the source documents 
 
The right of the participant to refuse to participate without giving reasons will be 
respected, although if the participate is willing a reason for declining will be recorded. 
After the participant has entered the trial the clinician remains free to give alternative 
treatment to that specified in the protocol at any stage if he/she feels it is in the 
participant’s best interest, but the reasons for doing so should be recorded. In these 
cases, the participants remain within the study for the purposes of follow-up and data 
analysis. All participants are free to withdraw at any time from the protocol treatment 
without giving reasons and without prejudicing further treatment. Participants will be 
asked to consent to long term follow up to allow for linkage to routine datasets including 
Hospital Episode Statistics (HES) and the National Vascular Database.  
 
 
 
It is the investigator’s responsibility to inform the subject’s General Practitioner (where 
applicable) by letter that the subject is taking part in the study provided the subject 
agrees to this, and information to this effect is included in the Subject Information 
Sheet and Informed Consent.  A copy of the letter should be filed in the Investigator 
Site File. 
 

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The investigator must ensure that the subject’s confidentiality is maintained. On the 
CRF or other documents submitted to the Sponsor, or on anonymised safety 
information provided to the device manufacturer, subjects will be identified by a subject 
ID number only.  
Documents that are held by the coordinating centre (e.g., signed informed consent 
form) should be kept in a lockable office in a strictly confidential file by the investigator. 
 
The investigator shall permit direct access to subjects’ records and source documents 
for the purposes of monitoring, auditing, or inspection by the Sponsor, authorised 
representatives of the Sponsor, NHS and Regulatory Authorities.  
 
Subject’s mobile phone numbers will be entered into a secure database hosted by a 
company called The 3rd Degree who will send weekly text message reminders. This 
company is regularly used by the NHS and will keep subjects’ phone numbers 
confidential. Subjects will only receive reminder messages for the duration of the study 
or up until the point of withdrawal, loss to follow up or at the patient’s request.    
 
 
The investigator will preserve the confidentiality of all participants taking part in the 
study, which will be conducted in accordance with the Data Protection Act. 
 
 
The end of the trial is defined as last patient last visit.  
 
 
The investigator must retain essential documents until notified by the Sponsor, and for 
at least ten years after study completion. Subject files and other source data (including 
copies of protocols, CRFs, original reports of test results, correspondence, records of 

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informed consent, and other documents pertaining to the conduct of the study) must 
be retained. Documents should be stored in such a way that they can be 
accessed/data retrieved at a later date. Consideration should be given to security and 
environmental risks. 
 
No study document will be destroyed without prior written agreement between the 
Sponsor and the investigator. Should the investigator wish to assign the study records 
to another party or move them to another location, written agreement must be obtained 
from the Sponsor. 
 
10.  DATA MANAGEMENT 
 
Data will be written directly into the CRF and then transcribed into the eCRF. Source 
documents include original documents related to the trial, to medical treatment and to 
the history of the participant, and adequate source documentation must be maintained 
to allow reliable verification and validation of the trial data.  
 
 
CRFs will be in English. Generic names for concomitant medications should be 
recorded in the CRF wherever possible. All written material to be used by subjects 
must use vocabulary that is clearly understood, and be in the language appropriate for 
the study site. 
 
 
The principal means of data collection from participant visits will be Electronic Data 
Capture (EDC) in the InForm database system via the internet. Data is entered into 
the EDC system via site personnel. All source data recorded in the CRF will be signed 
by the Investigator or his/her appropriate designee. All changes made following the 

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electronic signing will have an electronic audit trail with a signature and date. Specific 
instructions and further details will be outlined in SOPs and/or manuals.  
 
 
Details of procedures for eCRF/CRF completion will be provided in a study manual. 
 
 
All trial documentation, including that held at participating sites and the trial 
coordinating centre, will be archived for a minimum of 10 years following the end of 
the study.  
11. STUDY MANAGEMENT STRUCTURE  
 
 
In line with current NIHR recommendations a Trial Steering Committee (TSC) will be 
convened and will include as a minimum an independent Chair, independent clinician, 
the Chief Investigator and Trial Manager. A lay member will be invited to join the 
committee.  
 
The role of the TSC is to provide overall supervision of trial conduct and progress. 
Details of membership, responsibilities and frequency of meetings will be conducted 
as per the EME research governance guidelines and are defined in a separate TSC 
Charter.  A TSC meeting will be held at the start of the trial prior to patient recruitment, 
and then annually as a minimum.  
 
 
 
A Trial Management Group (TMG) will be convened including the Chief Investigator, 
co-investigators and key collaborators, trial statistician and trial manager. The TMG 
will be responsible for day-to-day conduct of the trial and operational issues. Details 

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of membership, responsibilities and frequency of meetings will be defined in separate 
terms of Reference. A lay person should be included wherever possible. A lay member 
will be invited to join the group.  
TMG meetings will be held monthly throughout the set up and recruitment phase and 
then at least every other month until trial closure. 
 
In line with current NIHR recommendations a Data Monitoring Committee (DMC) will 
be convened and will include as a minimum a clinician with experience in the relevant 
area and expert trial statistician. 
 
The role of the DMC is to monitor patient safety and treatment efficacy data. Details 
of membership, responsibilities and frequency of meetings will be conducted as per 
the EME research governance guidelines and are defined in a separate DMC Charter. 
A DMC meeting will be held prior to first patient first visit, following completion of an 
internal pilot study and will then be held one month prior to each TSC meeting. 
 
There are no formal stopping rules but safety will be reviewed periodically by the DMC 
who could recommend early discontinuation of the study. 
 
 
A study-specific risk assessment will be performed prior to the start of the study to 
assign a risk category of ‘low’, ‘medium’ or ‘high’ to the trial. Risk assessment will be 
carried out by the ICTU QA Manager in collaboration with the Study Manager and the 
result will be used to guide the monitoring plan. The risk assessment will consider all 
aspects of the study and will be updated as required during the course of the study. 
 
 
The study will be monitored periodically by trial monitors to assess the progress of the 
study, verify adherence to the protocol, ICH GCP E6 guidelines and other 

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national/international requirements and to review the completeness, accuracy and 
consistency of the data. 
Monitoring procedures and requirements will be documented in a Monitoring Plan, 
developed in accordance with the risk assessment and will follow a risk based 
approach when determining the level of onsite and remote monitoring.  
 
 
Quality Control will be performed according to ICTU internal procedures. The study 
may be audited by a Quality Assurance representative of the Sponsor and/or ICTU. 
All necessary data and documents will be made available for inspection. 
The study may be subject to inspection and audit by regulatory bodies to ensure 
adherence to GCP and the NHS Research Governance Framework for Health and 
Social Care (2nd Edition).  
 
The study design was peer reviewed by NIHR funding panel which includes at least 7 
different reviewers, including expert clinicians, lay representatives and statisticians. 
 
Participation, involvement and engagement are key principles to running an 
effective study in order to obtain the right balance between academic development 
and user satisfaction. PPI will be incorporated to the following areas of the research 
project: 
 Design of the research: An experienced patient representative is a co-
applicant of this study and has played a key advisory role in providing an 
understandable plain English summary as detailed in the outline submission 
and, as part of a number of patient representatives, provided a key patient 
perspective on achieving our project aims, having been a participant in a similar 
trial. 
 Management of the research: This patient co-applicant has expressed a 
keenness to continue on-going active involvement including from an advisory 

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perspective at various time points in this study and will be invited to be an active 
member of the TSC and be involved in TMG discussions. 
 Undertaking the research: Activities will include the development of patient 
participation information sheets and associated documents in addition to vital 
end-user input throughout the study period. 
 Analysis of results: The patient representative will also be invited to take part 
in the analysis discussions. 
 Dissemination of findings: The patient representative will also be invited to 
provide perspective during dissemination of study findings including how best 
to communicate these to study participants and other patient groups. 
 
 
This research will be beneficial for health care professionals, patients, NHS policy 
makers and commissioners. Dissemination of the study findings will be undertaken on 
an ongoing basis, appropriate for these groups and publications will be written in 
accordance with the Consort guidelines. 
 
Briefing papers will summarise the key findings relevant to this study and executive 
summaries of main reports will be beneficial for NHS policy makers. The study protocol 
and results will be written up and submitted for publication in a high impact factor 
medical journal. In order to reach a wider audience, open access publication has been 
factored into the costings of this trial. 
 
Regular presentation of study findings will be made to nurses, doctors and allied health 
professionals through local, regional, national and international meetings of the 
research network. Study findings will also be disseminated through important national 
professional organisations including the Vascular Society of Great Britain and Ireland, 
The Royal Society of Medicine and The Circulation Foundation. Study findings will also 
be made available via online media through a study website and social media including 
Twitter, Facebook and LinkedIn. The trial management group will draft reports and 

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each centre involved in the study will be provided with copies of manuscripts for review 
of all lead investigators and collaborators prior to publication. 
Workshops will be held with key stakeholders including patient and public groups, 
allied health professionals and policy makers to discuss the study findings and 
methods of implementation in more detail. 
 
Information concerning the study, patent applications, processes, scientific data or 
other pertinent information is confidential and remains the property of the Sponsor. 
The investigator may use this information for the purposes of the study only. 
 
It is understood by the investigator that the manufacturer may use information 
developed in this clinical study in connection with the development of the device and, 
therefore, may disclose it as required to other clinical investigators and to Regulatory 
Authorities. In order to allow the use of the information derived from this clinical study, 
the investigator understands that he/she has an obligation to provide complete test 
results and all data developed during this study to the Sponsor. 
 
Verbal or written discussion of results prior to study completion and full reporting 
should only be undertaken with written consent from the Sponsor. Therefore, all 
information obtained as a result of the study will be regarded as CONFIDENTIAL, at 
least until appropriate analysis and review by the investigator(s) are completed.  
 
Permission from the Executive/Writing Committee is necessary prior to disclosing any 
information relative to this study outside of the Trial Steering. Any request by site 
investigators or other collaborators to access the study dataset must be formally 
reviewed by the TSC.    
 
The results may be published or presented by the investigator(s), but the Funder will 
be given the opportunity to review and comment on any such results for up to 1 month 
before any presentations or publications are produced.  
 

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A Clinical Study Report summarising the study results will be prepared and submitted 
to the REC and MHRA within a year of the end of study. The results will also be 
submitted to the EudraCT results database in accordance with regulatory 
requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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12.  REFERENCES 
 
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Lancet.382(9901):1329-40. 
2. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FGR. 
Inter-Society Consensus for the Management of Peripheral Arterial 
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3. Fowkes FG, Housley E, Cawood EH, Macintyre CC, Ruckley CV, Prescott 
RJ. Edinburgh Artery Study: prevalence of asymptomatic and symptomatic 
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4. National Institute of Health and Care Excellence (NICE). Lower Limb 
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Guideline 147. 2012;gudance.nice.org.uk/cg147:1-30. 
5. Bendermacher BL, Willigendael EM, Teijink JA, Prins MH. Supervised 
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7. Shalhoub J, Hamish M, Davies AH. Supervised exercise for intermittent 
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14. Williams KJ MH, Davies AH. Haemodynamic changes with the use of 
compression. Phlebology / Venous Forum of the Royal Society of Medicine 
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16. Varatharajan L, Williams K, Moore H, Davies AH. The effect of footplate 
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17. Greenhalgh RM, Belch JJ, Brown LC, Gaines PA, Gao L, Reise JA, et al. The 
adjuvant benefit of angioplasty in patients with mild to moderate intermittent 
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advice and best medical therapy: results from two randomised trials for stenotic 

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femoropopliteal and aortoiliac arterial disease. European Journal of Vascular 
& Endovascular Surgery.36(6):680-8. 
18. Cheetham DR, Burgess L, Ellis M, Williams A, Greenhalgh RM, Davies AH. 
Does supervised exercise offer adjuvant benefit over exercise advice alone for 
the treatment of intermittent claudication? A randomised trial. European 
Journal of Vascular and Endovascular Surgery. 2004;27(1):17-23. 
19. Perkins JMT, Collin J, Creasy TS, Fletcher EWL, Morris PJ. Exercise training 
versus angioplasty for stable claudication. Long and medium term results of 
a prospective, randomised trial. European Journal of Vascular and 
Endovascular Surgery. 1996;11(4):409-13. 
20. Mazari FAK, Khan JA, Carradice D, Samuel N, Abdul Rahman MNA, Gulati S, 
et al. Randomized clinical trial of percutaneous transluminal angioplasty, 
supervised exercise and combined treatment for intermittent claudication due 
to femoropopliteal arterial disease. British Journal of Surgery. 2012;99(1):39-
48. 
21. Watson T. Electrotherapy: Evidence-Based Practice. 12th Edition edn. 
22. Corley GJ, Breen PP, Grace PA, G OL. The effect of surface neuromuscular 
electrical stimulation and compression hosiery applied to the lower limb, on 
the comfort and blood flow of healthy subjects. Conf Proc IEEE Eng Med Biol 
Soc 2008;2008:703-6. http://dx.doi.org/10.1109/IEMBS.2008.4649249 
 
 
 
 
 

Imperial Clinical Trials 
Unit 
NESIC Clinical Study Protocol V6.0 24/03/2020 
Form Number 
CR001A-T 
 
 
C001A-T v4.0 Effective 5th April 2017 
 
 
 
 
 
Page 76 of 79 
 
 
 
SIGNATURE PAGE 1 (CHIEF INVESTIGATOR) 
 
The signature below constitutes approval of this protocol by the signatory and provides 
the necessary assurances that this study will be conducted according to all stipulations 
of the protocol including all statements regarding confidentiality. 
 
 
Study Title: A Multicentre Randomised Controlled Study: Does Neuromuscular 
Electrical Stimulation Improve the Absolute Walking Distance in Patients with 
Intermittent Claudication (NESIC) compared to best available treatment?  
 
Protocol Number:  
6.0 
 
 
Signed: 
 
___________________________________________ 
 
 
 
 
Alun H Davies  
 
 
 
Professor 
 
 
 
 
 
Date:  
 
_____________________ 
  

Imperial Clinical Trials 
Unit 
NESIC Clinical Study Protocol V6.0 24/03/2020 
Form Number 
CR001A-T 
 
 
C001A-T v4.0 Effective 5th April 2017 
 
 
 
 
 
Page 77 of 79 
 
 
 
SIGNATURE PAGE 2 (SPONSOR) 
 
The signatures below constitute approval of this protocol by the signatory.  
 
 
Study Title: A Multicentre Randomised Controlled Study: Does Neuromuscular 
Electrical Stimulation Improve the Absolute Walking Distance in Patients with 
Intermittent Claudication (NESIC) compared to best available treatment? 
 
Protocol Number:  
6.0 
 
 
 
 
Signed: 
 
___________________________________________ 
 
 
 
 
Becky Ward 
 
 
 
Ms 
 
 
 
Imperial College London 
 
 
 
 
 
 
Date:  
 
_____________________ 

Imperial Clinical Trials 
Unit 
NESIC Clinical Study Protocol V6.0 24/03/2020 
Form Number 
CR001A-T 
 
 
C001A-T v4.0 Effective 5th April 2017 
 
 
 
 
 
Page 78 of 79 
 
 
 
SIGNATURE PAGE 3 (STATISTICIAN) 
 
The signatures below constitute approval of this protocol by the signatory.  
 
 
Study Title:  
 
A Multicentre Randomised Controlled Study: Does 
Neuromuscular Electrical Stimulation Improve the Absolute Walking Distance in 
Patients with Intermittent Claudication (NESIC) compared to best available treatment? 
 
Protocol Number:  
6.0 
 
 
 
 
Signed: 
 
___________________________________________ 
 
 
 
 
Francesca Fiorentino 
 
 
 
Dr. 
 
 
 
Imperial College London 
 
 
Date:  
 
_____________________ 
 
 

Imperial Clinical Trials 
Unit 
NESIC Clinical Study Protocol V6.0 24/03/2020 
Form Number 
CR001A-T 
 
 
C001A-T v4.0 Effective 5th April 2017 
 
 
 
 
 
Page 79 of 79 
 
 
 
SIGNATURE PAGE 4 (PRINCIPAL INVESTIGATOR) 
 
The signature of the below constitutes agreement of this protocol by the signatory and 
provides the necessary assurance that this study will be conducted at his/her 
investigational site according to all stipulations of the protocol including all statements 
regarding confidentiality. 
 
 
Study Title:  
 
A Multicentre Randomised Controlled Study: Does 
Neuromuscular Electrical Stimulation Improve the Absolute Walking Distance in 
Patients with Intermittent Claudication (NESIC) compared to best available treatment?
 
 
 
Protocol Number:  
6.0 
 
 
Address of Institution:  
____________________________________________ 
 
 
 
 
           
 
 
 
 
____________________________________________ 
 
 
 
Signed: 
 
 
____________________________________________ 
 
 
Print Name and Title: 
____________________________________________ 
 
 
Date:  
 
 
____________________________________________