Neuromuscular Electrical Stimulation For The Treatment Of Diabetic Neuropathy: A Multicentre, Double-blind, Pilot, Randomised, Sham-controlled Trial
Phase: NA
Conditions: Diabetic Peripheral Neuropathy, Diabetic Neuropathies, Diabetic Polyneuropathy, Diabetic Complication
Sponsor: Imperial College London

 
 Research Governance and Integrity Team 
 
 
 
 
NMES-DN Protocol 
V12.0 14/01/2025 
IRAS ID 237312 
 
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Neuromuscular Electrical Stimulation For The 
Treatment Of Diabetic Neuropathy: A Multi-
centre, Double-blind, Pilot, Randomised, Sham-
controlled Trial (NMES-DN) 
 
 
 
Study Protocol 
 
Version: 
12.0 
 
 
Date:  
14 January   2025 
 
 
Main Sponsor: 
Imperial College London 
 
 
Device Manufacturer:  
Actegy Limited (Bracknell, UK) 
 
 
Funder:  
Actegy Limited (Bracknell, UK) 
 
 
Study Coordination Centre: 
Section of Vascular Surgery 
Department of Surgery and Cancer 
Imperial College London 
Charing Cross Hospital 
Fulham Palace Road 
London  
W6 8RF 

 
 Research Governance and Integrity Team 
 
 
 
 
NMES-DN Protocol 
V12.0 14/01/2025 
IRAS ID 237312 
 
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RESEARCH REFERENCE NUMBERS 
 
IRAS: 
237312 
 
 
REC Reference Number:  
18/NE/0281 
 
 
Sponsor Protocol Number: 
18HH4610 
 
 
ISRCTNregistry: 
ISRCTN17050221 
 
 
ClinicalTrials.gov Identifier: 
NCT03767478 
(https://clinicaltrials.gov/ct2/show/NCT03767478)  
 
PROTOCOL AUTHORISATIONS 
Separate protocol signature pages are provided at the end of this document 
for the Chief Investigator, Sponsor and Principal Investigator to sign. Protocol 
signature pages that have been signed will be filed in the Trial Master File 
(TMF).  
REVISION SUMMARY 
Protocol Version 
Date 
Revision Summary 
V1.0   
Draft – Not submitted 
to REC 
07 November 2017 N/A – Original protocol 
V2.0 
Draft – Not submitted 
to REC 
08 January 2018 
- Primary outcome measure 
clarifications 
- Further details on statistical 
analyses and publication policy 
- Typographical corrections and 
clarifications throughout 
V3.0 
Draft – Not submitted 
to REC 
20 March 2018 
- Addition of co-investigator 
Professor Nick Oliver 
- Updated study design to RCT 
assessing three study arms 
including a sham device arm 
- Additional secondary outcome 
measures: DU, NTSS-6, NIS-LL, 
pain VAS 
- Included power calculation  
- Updated length of study to 24 
months 

 
 Research Governance and Integrity Team 
 
 
 
 
NMES-DN Protocol 
V12.0 14/01/2025 
IRAS ID 237312 
 
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- Expanded on procedures and 
assessments 
- Typographical corrections and 
clarifications throughout 
V4.0 
Submitted to REC  
20 March 2018 
-  Updated inclusion / exclusion 
criteria 
- Addition of MNSI as secondary 
outcome measure, removal of 
NIS-LL 
- Length of study amended to 18 
months 
- Clarification of Imperial College 
data retainment policy 
- Typographical corrections and 
clarifications throughout 
V5.0 
Received REC 
favourable opinion 
03 September 
2018 
Removal of data loggers to track 
device usage 
V6.0 
Received REC 
favourable opinion 
24 September 
2018 
Name of NMES device changed 
from Revitive IX to Revitive 
Medic 
V7.0 
Received REC 
favourable opinion 
24 September 
2021 
- Amended full and short title  
- Updated Contact List details 
- Addition of study statistician Dr 
Cain Clark 
- Change in study manager to 
Miss Sasha Smith 
- Updated background section 
with additional literature  
- Included Table of Contents, 
Abbreviations Glossary, 
Reference Diagram, Key Words, 
Study Summary and updated 
Appendices  
- Study objective details added 
- Summary table of objectives 
and outcomes added 
- Changed from single-site to a 
multi-centre, double-blinded 
RCT in the UK  
- Changed from a three arm to a 
two arm study design, removing 

 
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IRAS ID 237312 
 
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Group B2  
- Updated NMES device from 
Revitive Medic to Revitive Medic 
Coach with Revitive App 
- Randomisation strategy 
expanded upon 
- Blinding process added  
- Inclusion of tibial and 
superficial peroneal nerve for 
NCSs 
- Clarified diagnostic criteria for 
diabetes and DPN 
- Clarification of use of NTSS-6-
SA (self-administered version) 
- Inclusion of monofilament test, 
cramping scale, DSIS, LDF, 
TcPO2, ABPI and NMES 
sensation (intervention group 
only) assessments 
- Power and sample size 
calculation updated based on 
new study design and proposed 
statistical analyses  
- Addition of REDCap for 
randomisation and data storage 
- Incidental findings section 
added 
- Further details on consent, 
record keeping and data 
protection   
- Length of study amended to 21 
months 
- Updated inclusion / exclusion 
criteria  
- Clarification of study visits 
including new assessments 
- Addition of text messaging 
service 
- Addition of therapy plan 
reminders before Week 10 and 
20 

 
 Research Governance and Integrity Team 
 
 
 
 
NMES-DN Protocol 
V12.0 14/01/2025 
IRAS ID 237312 
 
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- Telephone call changed from 
Week 5 to Week 2  
- Follow up visit changed from 
Month 12 to Month 9  
- Additional details on 
assessment of safety 
- Details on data sharing 
updated  
- Inclusion of TMG 
- Typographical corrections and 
clarifications throughout 
V8.0 
Submitted to MHRA 
Received REC 
favourable opinion 
03 May 2022 
- Updated short title to NMES-
DPN 
- Additional co-investigators 
- Updated Actegy Limited 
address 
- Updated Reference Diagram 
- Clarified MNSI as a separate 
outcome 
- Added Neuropathic Pain 
Symptom Inventory  
- Removed cramping 
questionnaire 
- Updated background literature 
and references 
- Changed randomisation 
service to Sealed Envelope 
- Added Quantitative Sensory 
Testing 
- Added credibility/ expectancy 
questionnaire 
- Included symptoms of DPN as 
part of inclusion criteria 
- Updated withdrawal criteria 
- Clarified timepoints for DU 
assessments 
- Added unmasking at final 
follow up visit 
- Safety reporting definitions and 
reporting updated, and to 
include MHRA 

 
 Research Governance and Integrity Team 
 
 
 
 
NMES-DN Protocol 
V12.0 14/01/2025 
IRAS ID 237312 
 
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- Provided further details on 
planned data analyses  
- Removed Coventry University 
as a data sharing collaborator 
- Patient and public involvement 
activities described 
- Typographical corrections and 
clarifications throughout 
V9.0 
Received no 
objection from MHRA 
Received REC 
favourable opinion 
07 September 
2022 
- Updated study title and design 
to include pilot and sham-
controlled trial  
- Changed diabetic peripheral 
neuropathy (DPN) to diabetic 
neuropathy (DN) throughout 
- Updated short title and study 
logo  
- Added following sections: Key 
Trial Contacts, Key 
Responsibilities, Primary 
Outcome Measure Hypotheses, 
Safety Outcome Measures, 
Study Setting, Monitoring, 
Amendments, Access To Data, 
Conflicts of Interest (to align with 
SPIRIT statement) 
- Updated Reference Diagram 
- Updated objectives and 
outcome measures to include 
assessment of feasibility and 
safety  
- Changed primary outcome 
measure to sural nerve only 
- Added Brief Illness Perception 
Questionnaire (Brief IPQ) 
- Removed DU, LDF and TcPO2 
assessments  
- Changed NMES sensation to 
device sensation as will be 
recorded for both study groups 
- Updated background and 
literature with up-to-date 
evidence 

 
 Research Governance and Integrity Team 
 
 
 
 
NMES-DN Protocol 
V12.0 14/01/2025 
IRAS ID 237312 
 
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- Included further information on 
Randomisation Strategy and 
Blinding Process   
- Changed length of study to 18 
months 
- Updated NCS criteria for 
diagnosis of DN  
- HIV test made optional 
- Clarified inclusion criteria: 
personal mobile phone required, 
and study smartphone provided 
- Amended exclusion criteria: 
used a NMES device within 1 
year of randomisation    
- Updated Withdrawal Criteria 
- Added further information on 
Recruitment and Consent e.g. 
use of advertisements  
- Added section on Equality, 
Diversity and Inclusion   
- Removed unmasking at final 
visit 
- Added qualitative sub-study 
and analysis   
- Updated Patient and Public 
Involvement (PPI) Section 
- Included further information on 
planned data analyses such as 
primary outcome measure, 
feasibility outcome measures, 
safety outcome measures, 
secondary outcome measures 
and qualitative sub-study 
analyses 
- Included further information on 
study database 
- Updated sample size to 100 
participants as a pilot study, 
provided justification 
- Included protocol signature 
pages  

 
 Research Governance and Integrity Team 
 
 
 
 
NMES-DN Protocol 
V12.0 14/01/2025 
IRAS ID 237312 
 
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- Typographical corrections and 
clarifications throughout 
V10.0 
Received no 
objection from MHRA 
Received REC 
favourable opinion 
06 December 2023 - Addition of Trial Monitor 
- Removal of EQ-5D-5L 
questionnaire, Brief Illness 
Perceptions Questionnaire, Self-
administered Neuropathy Total 
Symptom Score-6 and Ankle 
Brachial Pressure Index 
assessments  
- Addition of HBA1c blood test at 
baseline and Month 6 
- Typographical corrections and 
clarifications throughout 
 
V11.0 
Received no 
objection from MHRA 
Received REC 
favourable opinion 
 
05 August 2024 
- Change of primary outcome 
measure to MNSI Part A 
questionnaire  
- Sural nerve conductivity 
moved to a secondary outcome  
- Participant retention rate also 
measured at 26 weeks 
- Change of treatment phase to 
12 weeks and final follow up at 
26 weeks 
- Change of study length to 22 
months with 16 months 
recruitment and 6 months follow 
up 
- Removal of inclusion criterion: 
nerve conduction study of at 
least one lower limb must have 
a sural SNAP amplitude of <6 
µV or absent  
- NCS and QST only performed 
for participants recruited at the 
central site  
- NCS does not need to be 
repeated at baseline if 
performed within 3 months of 
consent 

 
 Research Governance and Integrity Team 
 
 
 
 
NMES-DN Protocol 
V12.0 14/01/2025 
IRAS ID 237312 
 
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- Week 2 visit changed to Week 
3 
- Addition of Week 6 and Week 
9 remote follow up visits 
- Addition of Total Symptom 
Score (TSS) 
- Removal of pain NRS and 
DSIS text messages  
- Removal of inclusion criterion 
to have a personal mobile 
phone to receive study text 
messages 
- Change in blinding process, 
whereby participants will be 
informed that this is a double-
blind trial with a control arm and 
sham device 
- Typographical corrections and 
clarifications throughout 
 
V12.0 
14 January 2025 
- Addition of Mr Darren Target to 
the statistical support team 
- Update to the Reference 
Diagram 
- Change of sample size to 64 
- Clarification that the TSS is a 
10-point rather than 11-point 
scale 
- Removal of control area 
assessment from QST  
- Update to the assessment of 
safety section to align with the 
current MHRA safety reporting 
procedures  
- Specification that the statistical 
software is SAS rather than R 
- Typographical corrections and 
clarifications throughout 
 
 

 
 Research Governance and Integrity Team 
 
 
 
 
NMES-DN Protocol 
V12.0 14/01/2025 
IRAS ID 237312 
 
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KEY TRIAL CONTACTS 
Chief Investigator: 
Professor Alun Davies  
Professor of Vascular Surgery and 
Honorary Consultant Vascular Surgeon 
 
Section of Vascular Surgery 
Department of Surgery and Cancer 
Imperial College London 
 
Imperial Vascular Unit 
Imperial College Healthcare NHS Trust 
Local Principal Investigators:  
 
Professor Alun Davies  
Professor of Vascular Surgery and 
Honorary Consultant Vascular Surgeon  
 
Section of Vascular Surgery 
Department of Surgery and Cancer 
Imperial College London 
 
Imperial Vascular Unit 
Imperial College Healthcare NHS Trust 
 
Mr Ankur Thapar  
Consultant Vascular Surgeon and 
Honorary Senior Lecturer  
 
Department of Vascular and 
Endovascular Surgery 
Mid and South Essex NHS Foundation 
Trust 
 
Section of Vascular Surgery 
Department of Surgery and Cancer 
Imperial College London 
Co-investigators:  
Miss Sasha Smith  
Doctoral Student and Clinical Trial 
Manager  
 
Section of Vascular Surgery 
Department of Surgery and Cancer 
Imperial College London  
 
Imperial Vascular Unit 
Imperial College Healthcare NHS Trust 
Mr Tristan Lane  
Consultant Vascular Surgeon and 
Honorary Clinical Senior Lecturer  
 
Department of Vascular Surgery 

 
 Research Governance and Integrity Team 
 
 
 
 
NMES-DN Protocol 
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Cambridge University Hospitals NHS 
Foundation Trust  
 
Section of Vascular Surgery 
Department of Surgery and Cancer 
Imperial College London 
Mr Pasha Normahani  
Academic Clinical Lecturer and 
Specialist Registrar in Vascular Surgery 
 
Section of Vascular Surgery 
Department of Surgery and Cancer 
Imperial College London  
 
Imperial Vascular Unit 
Imperial College Healthcare NHS Trust 
Dr Ian Mak 
Consultant Neurophysiologist  
 
Imperial Clinical Neurophysiology 
Department  
Imperial College Healthcare NHS Trust 
Dr Cain Clark  
Assistant Professor (Research) and 
Senior Research Fellow  
 
Centre for Intelligent Healthcare 
Coventry University  
 
Warwickshire InStitute for Diabetes, 
Endocrinology & Metabolism  
University Hospitals Coventry and 
Warwickshire NHS Trust 
Mr Ankur Thapar   
Consultant Vascular Surgeon and 
Honorary Senior Lecturer  
 
Department of Vascular and 
Endovascular Surgery 
Mid and South Essex NHS Foundation 
Trust 
 
Section of Vascular Surgery 
Department of Surgery and Cancer 
Imperial College London 
Mr David Hohenschurz-Schmidt 
Doctoral Student and Osteopath  
 
Pain Research Group 

 
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Department of Surgery and Cancer 
Imperial College London  
Professor John Norrie  
Professor of Medical Statistics and Trial 
Methodology  
 
Edinburgh Clinical Trials Unit  
Usher Institute 
University of Edinburgh 
Professor Nick Oliver 
Professor of Human Metabolism and 
Honorary Consultant in Diabetes and 
Endocrinology  
 
Section of Metabolic Medicine 
Department of Metabolism, Digestion 
and Reproduction 
Imperial College London  
 
Division of Medicine and Integrated 
Care 
Imperial College Healthcare NHS Trust 
Main Protocol Contributors:   
Professor Alun Davies  
 
Miss Sasha Smith  
 
Mr Tristan Lane  
 
Dr Ian Mak  
 
Dr Cain Clark  
 
Professor John Norrie  
 
Professor Nick Oliver  
Statistical Support: 
Miss Sasha Smith  
 
Dr Cain Clark  
 
Professor John Norrie  
 
Mr Darren Target  
Consultant Statistician 
Primoris Contract Solutions Ltd 
Trial Management:  
Miss Sasha Smith 
Trial Monitor: 
Miss Jessica Barbut Siva 
Trial Management Group: 
Professor Alun Davies (Chair)  
 

 
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Miss Sasha Smith  
 
Miss Jessica Barbut Siva 
 
Mr Tristan Lane  
 
Mr Ankur Thapar  
 
At least one member of the 
statistical support team 
 
At least one patient representative  
Patient Representatives:  
Ms Liz Piggot  
Imperial College Healthcare NHS Trust 
 
Ms Zoe Goodchild  
Imperial College Healthcare NHS Trust 
Sponsor:  
 
Imperial College London is the main 
research sponsor for this trial.   
 
For further information regarding the 
sponsorship conditions, please contact 
the Head of Regulatory Compliance at: 
 
 
 
Research Governance and Integrity 
Team (RGIT) 
 
Address: 
Imperial College London and Imperial 
College Healthcare NHS Trust 
Room 215 Level 2 Medical School 
Building 
Norfolk Place 
London W2 1PG 
 
Tel: +44(0)207 594 1862 
 
https://www.imperial.ac.uk/research-
and-innovation/research-
office/research-governance-and-
integrity/     
Funder:  
Actegy Limited (Bracknell, UK) is the 
funder for this trial.  
 
For further information regarding 
funding, please contact Director 
Roseanna Penny: 
 
Address: 

 
 Research Governance and Integrity Team 
 
 
 
 
NMES-DN Protocol 
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IRAS ID 237312 
 
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1 Westpoint Western Road 
Bracknell 
Berkshire RG12 1HJ 
 
Email: roseanna.penny@actegy.com  
Device Manufacturer:  
Actegy Limited (Bracknell, UK) is the 
manufacturer of neuromuscular 
electrical stimulation (NMES) and sham 
devices for this trial and are supplying 
them free of charge. In addition to the 
study devices, they will be providing 
participants study smartphones free of 
charge.  
 
For further information regarding 
manufacturing of study devices and 
supplying study devices and 
smartphones, please contact Director 
Roseanna Penny: 
 
Address: 
1 Westpoint Western Road 
Bracknell 
Berkshire RG12 1HJ 
 
Email: roseanna.penny@actegy.com 
Other Vendors/Suppliers: 
Sealed Envelope Limited (London, 
UK) will be providing the randomisation 
service.  
 
Tel: +44(0)203 488 5064 
 
Address: 
Sealed Envelope Limited 
501 Clerkenwell Workshops 
27-31 Clerkenwell Close 
London EC1R 0AT 
 
REDCap – Research Electronic Data 
Capture (Tennessee, US) will be 
providing the internet-based database 
system. Imperial College London is a 
REDCap partner, and the database 
system will be built by the Trial 
Manager based at Imperial College 
London. Any queries should be directed 
to Trial Manager in the first instance:  
 
Tel: +44 (0)756 512 3056 

 
 Research Governance and Integrity Team 
 
 
 
 
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Email: sasha.smith@imperial.ac.uk  
 
 
 
For general queries, supply of study documentation and data management, 
please contact: 
 
Name: 
Miss Sasha Smith 
Email: 
sasha.smith@imperial.ac.uk  
Address: 
Section of Vascular Surgery 
Room 16 4th Floor East Wing 
Charing Cross Hospital  
Fulham Palace Road 
London W6 8RF 
Telephone:  
+44 (0)756 512 3056 
 
For clinical queries, please contact: 
 
Name: 
Professor Alun Davies  
Email: 
a.h.davies@imperial.ac.uk  
Address: 
Section of Vascular Surgery 
Room 4E4 4th Floor East Wing 
Charing Cross Hospital  
Fulham Palace Road 
London W6 8RF 
Telephone:  
+44 (0)208 3311 7320 
 
 
 

 
 Research Governance and Integrity Team 
 
 
 
 
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KEY RESPONSIBILITIES 
Imperial College London are responsible for: 
• Sponsoring the trial in accordance with the Medicines for Human Use 
(Clinical Trial) Regulations 2004, UK Policy Framework for Health and 
Social Care Research principles and other regulatory requirements as 
appropriate 
• Providing insurance or indemnity arrangements for negligent and non-
negligent harm to clinical trial subjects   
• Storing study devices in appropriate conditions  
• Securing contracts for the supply of resources other than study 
devices 
• Designing and writing the protocol in compliance with Medicines for 
Human Use (Clinical Trial) Regulations 2004, Good Clinical Practice 
(GCP) principles, ISO 14155:2020 standards, and other regulatory 
requirements as appropriate, also considering the Standard Protocol 
Items: Recommendations for Interventional Trials (SPIRIT) 2013 
Statement 
• Managing and conducting the research in compliance with the 
protocol, Medicines for Human Use (Clinical Trial) Regulations 2004, 
UK Policy Framework for Health and Social Care Research principles, 
GCP principles, ISO 14155:2020 standards, Data Protection Act and 
other regulatory requirements as appropriate 
• Preparing and submitting materials for Clinical Trial Authorisation 
(together with Actegy Limited) and to relevant ethics committees and 
NHS organisations 
• Preparing and submitting proposed substantial amendments of the 
protocol to the regulatory authorities, relevant ethics committees and 
NHS organisations 
• Creating and maintaining the Trial Master File (TMF) 
• Maintaining detailed records of all Adverse Events (AEs) as specified 
in the protocol, and report AEs in accordance with legal and regulatory 
requirements 
• Ensuring that Serious Adverse Events (SAEs) are reviewed by 
appropriate committees/authorities for the monitoring of trial safety 
• Ensuring that all Suspected Unexpected Serious Adverse Reactions 
(SUSARs) are identified and fully reported to the regulatory authorities 
and relevant ethics committees within the required timelines 
• Ensuring that investigators are aware of any SUSARs occurring in 
relation to the study device 
• Analysing trial data, or ensure this is performed by an appropriate 
collaborator  

 
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• Initiating and coordinating review and submission of abstracts, posters 
and publications  
• Archiving all clinical trial records on conclusion of the clinical trial  
 
Actegy Limited are responsible for:  
• Manufacturing, packaging and labelling the study devices in 
accordance with Medicines for Human Use (Clinical Trial) Regulations 
2004, ISO 14155:2020 standards and Good Manufacturing Practice 
principles  
• Providing insurance or indemnity arrangements for manufacture of 
study devices  
• Storing study devices in appropriate conditions  
• Preparing and submitting materials for Clinical Trial Authorisation 
(together with Imperial College London)  
• Recalling of study devices  
• Providing funding for the clinical trial  
 
The Trial Management Group are responsible for: 
• Having oversight of trial set-up and day-to-day management of the trial 
• Ensuring that the trial is conducted at all times to the standards set out 
in regulatory requirements and GCP principles  
• Ensuring the rights, safety and well-being of the trial participants are 
not compromised 
• Reviewing and approving the study protocol/other study paperwork and 
subsequent amendments or administrative changes to the 
protocol/other study paperwork as applicable 
• Ensuring that the study protocol and any subsequent amendments are 
adhered to 
• Reviewing study progress and address any problems or issues that 
arise regarding the conduct of the trial 
• Promoting the trial 
• Defining the contents and schedule of the trial report 
• Interpreting the results of the trial 
• Reviewing and approving any trial publications 
 
Please see 7.2 SAFETY RESPONSIBILITIES for detailed safety 
responsibilities. 
 
This protocol describes the NMES-DN trial and provides information about 
procedures for entering participants.  Every care was taken in its drafting, but 
corrections or amendments may be necessary. These will be circulated to 

 
 Research Governance and Integrity Team 
 
 
 
 
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investigators in the study.  Problems relating to this study should be referred, 
in the first instance, to the Chief Investigator (CI).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 Research Governance and Integrity Team 
 
 
 
 
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GLOSSARY OF ABBREVIATIONS  
AC/DC 
Alternating Current / Direct Current 
ADE 
Adverse Device Effect 
AE 
Adverse Event  
ANCOVA 
Analysis of Covariance 
ASADE  
Anticipated Serious Adverse Device Effect 
BBS 
Berg Balance Scale 
CI 
Chief Investigator 
CMAP 
Compound Muscle Action Potential 
Conmeds 
Concomitant Medications  
COREQ 
Consolidated criteria for reporting qualitative 
research 
CRF 
Case Report Form 
DFNS 
German Research Network on Neuropathic Pain 
DFU 
Diabetic Foot Ulcer 
DN 
Diabetic Neuropathy 
DSIS 
Daily Sleep Interference Scale  
DU 
Duplex Ultrasonography  
DVT 
Deep Vein Thrombosis  
eCRF 
Electronic Case Report Form  
FDA 
Food and Drug Administration  
GCP 
Good Clinical Practice  
GP 
General Practitioner  
HbA1c 
Glycated haemoglobin  
HIV 
Human Immunodeficiency Virus 
HRA 
Health Research Authority 
IB 
Investigator’s Brochure  
IFU 
Instructions For Use  
ITT 
Intention To Treat 
LDF 
Laser Doppler Flowmetry  
MAR 
Missing At Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MNSI 
Michigan Neuropathy Screening Instrument 
NCS 
Nerve Conduction Study 
NHS 
National Health Service 

 
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NIS-LL 
Neuropathy Impairment Score in the Lower Limbs 
NMES  
Neuromuscular Electrical Stimulation  
NPSI 
Neuropathic Pain Symptom Inventory 
NRS 
Numerical Rating Scale  
PI 
Principal Investigator 
PIC 
Participant Identification Centre  
PP 
Per Protocol 
PPI 
Patient and Public Involvement  
QoL 
Quality of Life 
QST 
Quantitative Sensory Testing 
RCT 
Randomised Controlled Trial  
R&D 
Research and Development 
REC 
Research Ethics Committee  
REDCap 
Research Electronic Data Capture Software 
RGIT 
Research Governance and Integrity Team 
RIN 
Revitive Identification Number 
SADE 
Serious Adverse Device Effect  
SAE 
Serious Adverse Event  
SAP 
Statistical Analysis Plan  
SEP 
Supervised Exercise Programme 
SFA 
Superficial Femoral Artery 
SIV 
Site Initiation Visit 
SNAP 
Sensory Nerve Action Potential  
SOP 
Standard Operating Procedure  
SPIRIT 
Standard Protocol Items: Recommendations for 
Interventional Trials 
TAMV 
Time-Averaged Mean Velocity  
TcPO2 
Transcutaneous Pressure of Oxygen 
TMF 
Trial Master File 
TMG 
Trial Management Group 
TSS 
Total Symptom Score 
UK 
United Kingdom 
US 
United States  
USADE 
Unanticipated Serious Adverse Device Effect 
VAS 
Visual Analogue Scale  

 
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WHO 
World Health Organisation 
KEYWORDS 
Diabetes, diabetic neuropathy, distal symmetrical polyneuropathy, nerve 
conductivity, nerve conduction study, neuromuscular electrical stimulation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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REFERENCE DIAGRAM 
 
 
Figure 1: Flowchart of NMES-DN trial presenting planned recruitment 
and follow up 
 
 

 
 Research Governance and Integrity Team 
 
 
 
 
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V12.0 14/01/2025 
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STUDY SUMMARY 
TITLE 
Neuromuscular Electrical Stimulation For The Treatment Of Diabetic Neuropathy: A Multi-centre, 
Double-blind, Pilot, Randomised, Sham-controlled Trial (NMES-DN) 
DESIGN 
Multi-centre, Double-blinded, Pilot, Randomised (1:1), Sham-controlled Trial  
AIMS 
To assess the potential efficacy signal, feasibility and safety of a NMES device compared to a 
sham device as an adjunct to local standard of care in patients with DN  
OUTCOME 
MEASURES 
Primary outcome measure:  
• 
Neuropathy symptoms – measured using the Michigan Neuropathy Screening Instrument 
(MNSI) Part A questionnaire at 12 weeks  
Feasibility outcome measures:  
• 
Recruitment rate measured using screening and randomisation logs, participant retention 
rate measured using randomisation and withdrawal logs and treatment adherence rate 
measured using Revitive App and patient diary 
Safety outcome measures: 
• 
Adverse Events (AEs), Adverse Device Effects (ADEs), Serious Adverse Events (SAEs) 
and Serious Adverse Device Effects (SADEs) measured using AE and SAE forms  
Secondary outcome measures:  
• 
Sural, superficial peroneal, common peroneal and tibial nerve conductivity measured using 
a nerve conduction study (NCS)  
• 
Somatosensory nerve fibre function – measured using Quantitative Sensory Testing (QST) 
• 
Blood glucose – measured using HbA1c  
• 
Mobility and balance – measured using Berg Balance Scale (BBS) 
• 
Neuropathy signs– measured using the Michigan Neuropathy Screening Instrument 
(MNSI) Part B examination   
• 
Symptoms – measured using Total Symptom Score (TSS) covering paraesthesia, pain, 
numbness, cramp and sleep disruption on a 10-point Numerical Rating Scale (NRS) 
• 
Protected sensation – measured using monofilament test 
• 
Pain – measured using Neuropathic Pain Symptom Inventory (NPSI)  
 
• 
Device sensation – measured using device sensory threshold and suprathreshold 
• 
Device credibility and expectancy – measured using modified credibility and expectancy 
questionnaire  
• 
Device experience – measured using questionnaire 
ELIGIBILITY  Inclusion 
• 
≥18 years or older (no upper age limit) 
• 
Diagnosis of either type 1 or type 2 diabetes  
• 
Diagnosis of DN based on ≥4 MNSI questionnaire score and blood testing 
• 
Access to internet at home to use the Revitive App (study smartphone provided) 
Exclusion  
• 
Lacks capacity to provide informed consent  
• 
Pregnant 
• 
Implanted electronic, cardiac or defibrillator device 
• 
Other cause of peripheral neuropathy 
• 
Current foot ulceration 
• 
Severe vascular disease requiring invasive intervention  
• 
Being treated for, or has symptoms of Deep Vein Thrombosis (DVT) 
• 
Regularly used a NMES device within 1 year of randomisation    
LENGTH OF 
STUDY 
22 months: 16 months recruitment and 6 months follow up (end of treatment phase is at 3 months; 
end of follow up is at 6 months). 

 
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TABLE OF CONTENTS 
RESEARCH REFERENCE NUMBERS ........................................................... 2 
PROTOCOL AUTHORISATIONS ................................................................... 2 
REVISION SUMMARY .................................................................................... 2 
KEY RESPONSIBILITIES ............................................................................. 16 
GLOSSARY OF ABBREVIATIONS .............................................................. 19 
KEYWORDS .................................................................................................. 21 
REFERENCE DIAGRAM ............................................................................... 22 
1. INTRODUCTION ....................................................................................... 28 
1.1 BACKGROUND .............................................................................................................. 28 
1.1.1 DIABETES AND DIABETIC NEUROPATHY ............................................... 28 
1.1.2 NEUROMUSCULAR ELECTRICAL STIMULATION ............................... 29 
1.1.3 RISKS ............................................................................................................................... 30 
1.1.4 BENEFITS ...................................................................................................................... 30 
1.1.5 RATIONALE FOR STUDY..................................................................................... 30 
2. STUDY OBJECTIVES AND OUTCOME MEASURES .............................. 31 
2.1 PRIMARY OBJECTIVES ............................................................................................ 31 
2.2 SECONDARY OBJECTIVES ................................................................................... 32 
2.3 PRIMARY OUTCOME MEASURE ........................................................................ 32 
2.4 PRIMARY OUTCOME MEASURE HYPOTHESES ...................................... 32 
2.5 FEASIBILITY OUTCOME MEASURES .............................................................. 33 
2.6 SAFETY OUTCOME MEASURES ........................................................................ 33 
2.7 SECONDARY OUTCOME MEASURES ............................................................. 33 
3. STUDY DESIGN ........................................................................................ 36 
3.1 TREATMENT REGIMENS ......................................................................................... 36 
3.1.1 STANDARD OF CARE ............................................................................................ 36 
3.1.2 NEUROMUSCULAR ELECTRICAL STIMULATION DEVICE 
(INTERVENTION) .................................................................................................................. 36 
3.1.3 SHAM DEVICE (CONTROL) ................................................................................ 39 
3.1.4 TREATMENT PHASE .............................................................................................. 39 
3.1.5 STUDY DEVICE ACCOUNTABILITY .............................................................. 40 
3.2 RANDOMISATION STRATEGY ............................................................................. 40 
3.3 BLINDING PROCESS ................................................................................................. 40 
3.4 STUDY SETTING ........................................................................................................... 41 
3.5 LENGTH OF STUDY .................................................................................................... 42 
4. SELECTION AND WITHDRAWAL OF PARTICIPANTS .......................... 42 

 
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4.1 DIAGNOSTIC CRITERIA ........................................................................................... 42 
4.1.1 DIABETES DIAGNOSTIC CRITERIA .............................................................. 42 
4.1.2 DIABETIC NEUROPATHY DIAGNOSTIC CRITERIA ............................. 43 
4.1.3 NEUROPATHY SCREENING .............................................................................. 43 
4.2 INCLUSION CRITERIA ............................................................................................... 43 
4.3 EXCLUSION CRITERIA.............................................................................................. 43 
4.4 WITHDRAWAL CRITERIA ........................................................................................ 44 
5. PROCEDURES AND ASSESSMENTS ..................................................... 44 
5.1 IDENTIFICATION AND PRESCREENING ........................................................ 44 
5.2 VISIT 1 - RECRUITMENT AND CONSENT ...................................................... 45 
5.3 EQUALITY, DIVERSITY AND INCLUSION ...................................................... 45 
5.4 VISIT 1 – BASELINE .................................................................................................... 45 
5.5 VISIT 2 – WEEK 3, WEEK 6, WEEK 9 (TELEPHONE CALL) ................ 48 
5.6 VISIT 3 – WEEK 12 (END OF TREATMENT PHASE) ................................ 49 
5.7 VISIT 4 – WEEK 26 (FOLLOW UP) ...................................................................... 49 
5.8 INCIDENTAL FINDINGS ............................................................................................ 50 
6. RECORD KEEPING AND DATA PROTECTION ...................................... 50 
6.1 SOURCE DATA .............................................................................................................. 50 
6.2 LANGUAGE ...................................................................................................................... 50 
6.3 DATABASE ....................................................................................................................... 50 
6.4 MONITORING .................................................................................................................. 51 
7. ASSESSMENT OF SAFETY ..................................................................... 51 
7.1 DEFINITIONS ................................................................................................................... 51 
7.1.1 INVESTIGATIONAL MEDICAL DEVICE ........................................................ 51 
7.1.2 ADVERSE EVENT (AE) .......................................................................................... 52 
7.1.3 ADVERSE DEVICE EFFECT (ADE) ................................................................. 52 
7.1.4 DEVICE DEFICIENCY ............................................................................................. 52 
7.1.5 SERIOUS ADVERSE EVENT (SAE) ................................................................ 52 
7.1.6 SERIOUS ADVERSE DEVICE EFFECT (SADE) ....................................... 53 
7.1.7 UNANTICIPATED SERIOUS ADVERSE DEVICE EFFECT (USADE)
 ......................................................................................................................................................... 53 
7.2 SAFETY RESPONSIBILITIES ................................................................................. 54 
7.2.1 INVESTIGATOR’S RESPONSIBILITIES ....................................................... 54 
7.2.2 SPONSOR’S RESPONSIBILITIES ................................................................... 54 
7.3 ASSESSMENT ................................................................................................................ 55 
7.3.1 CAUSALITY .................................................................................................................. 55 

 
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7.3.2 ASSESSMENT OF EXPECTEDNESS ............................................................ 55 
7.4 REPORTING ..................................................................................................................... 55 
7.4.1 AEs/ADEs ...................................................................................................................... 56 
7.4.2 SAEs/SADEs ............................................................................................................... 56 
7.4.3 SAEs REPORTING TO THE MHRA ................................................................. 57 
7.4.4 USADEs .......................................................................................................................... 58 
7.4.5 URGENT SAFETY MEASURES ......................................................................... 58 
7.4.6 PREGNANCY ............................................................................................................... 58 
7.5 ANNUAL PROGRESS REPORTS ........................................................................ 58 
7.6 TREND ANALYSES ..................................................................................................... 58 
8. STATISTICAL ANALYSES ....................................................................... 59 
8.1 SAMPLE SIZE CONSIDERATIONS ..................................................................... 59 
8.2 PLANNED DATA ANALYSES ................................................................................ 59 
8.2.1 PRIMARY OUTCOME MEASURE ANALYSIS ........................................... 60 
8.2.2 FEASIBILITY OUTCOME MEASURES ANALYSIS ................................. 61 
8.2.3 SAFETY OUTCOME MEASURES ANALYSIS ........................................... 61 
8.2.4 SECONDARY OUTCOME MEASURES ANALYSIS ............................... 61 
9. REGULATORY ISSUES ............................................................................ 61 
9.1 ETHICS APPROVAL .................................................................................................... 61 
9.2 AMENDMENTS ............................................................................................................... 62 
9.3 CONSENT .......................................................................................................................... 62 
9.4 CONFIDENTIALITY ...................................................................................................... 62 
9.5 ACCESS TO DATA ....................................................................................................... 63 
9.6 INDEMNITY ....................................................................................................................... 63 
9.7 SPONSOR ......................................................................................................................... 63 
9.8 STUDY MANAGEMENT ............................................................................................. 63 
9.9 PATIENT AND PUBLIC INVOLVEMENT (PPI) .............................................. 64 
9.10 FUNDING ......................................................................................................................... 64 
9.11 AUDITS AND INSPECTIONS ............................................................................... 64 
9.12 CONFLICTS OF INTEREST .................................................................................. 64 
9.13 PUBLICATION POLICY ........................................................................................... 65 
10. APPENDICES .......................................................................................... 66 
10.1 VISIT SCHEDULE ....................................................................................................... 66 
10.2 SIGNATURE PAGE (CHIEF INVESTIGATOR) ............................................ 68 
10.3 SIGNATURE PAGE (SPONSOR) ....................................................................... 69 

 
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10.4 SIGNATURE PAGE (PRINCPAL INVESTIGATOR) .................................. 70 
11. REFERENCES ........................................................................................ 71 
 
 
 

 
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1. INTRODUCTION 
1.1 BACKGROUND 
1.1.1 DIABETES AND DIABETIC NEUROPATHY 
Diabetes is a major global healthcare problem. Approximately half a billion 
people are estimated to have diabetes worldwide, and this is forecasted to 
rise to 700 million by 2045 (1). In the United Kingdom (UK), an estimated 4.6 
million people have diabetes, and this is predicted to rise to 5 million people 
by 2025. In addition, it is estimated that 1 million cases of type 2 diabetes in 
the UK are currently undiagnosed (2).  
 
Diabetes is a chronic metabolic condition characterised by hyperglycaemia, 
which damages blood vessels and leads to macrovascular (coronary artery 
disease, cerebrovascular disease and peripheral arterial disease) and 
microvascular (nephropathy, retinopathy and neuropathy) complications. The 
most prevalent complication of diabetes, diabetic neuropathy (DN), affects 
more than 50% of people with diabetes (3,4). Distal symmetrical 
polyneuropathy is the most common type of DN, with symptoms ranging from 
numbness to burning, prickling, aching, tightness and hypersensitivity in the 
distal extremities. 
 
The insensate lower limb increases the risk of developing diabetic foot ulcers 
(DFUs). Up to a quarter of people with diabetes will be affected by DFUs 
(4,5). DFUs are particularly challenging to manage when the cause is 
neuropathic or neuro-ischemic, because numbness in the lower limb can 
cause patients to walk on infected wounds without realising it (4,6). DFUs are 
also associated with high mortality rates, which rise even further after major 
lower limb amputation (4,7,8). The associated economic burden of DFUs is 
also high, with the cost to the National Health Service (NHS) in the UK 
estimated at £1 billion per year (4,9).    
 
Guidelines for the management of DN emphasise improved glycaemic control, 
lifestyle modifications, footcare and pain management, however these 
strategies are sub-optimal. For example, glycaemic control significantly 
reduces the risk of DN in people with type 1 diabetes but not in people with 
type 2 diabetes (4,10). Pain management focuses on pharmacotherapies 
such as anticonvulsants and selective serotonin reuptake inhibitors, but these 
medications have a variety of side effects and are often only effective in the 
short term (11). Furthermore, only approximately 30% of people with DN 
experience pain, therefore the strategies for people who experience 
numbness are even more limited (3,4).  
  
Exercise is a promising lifestyle modification for the prevention and treatment 

 
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of DN, with a moderate level of evidence (4). A recent meta-analysis (13 
RCTs, 592 participants) concluded that exercise programmes can improve 
mobility, peripheral nerve conductivity and glycaemic control in people with 
DN (4,12). Although exercise appears to be an effective intervention, more 
robustly designed, large-scale randomised controlled trials (RCTs) are 
needed to strengthen its evidence base (4,11). Other challenges of exercise 
interventions include adherence, under-resourced services to provide 
supervised exercise programmes (SEPs) and long-term behaviour change 
(4). 
 
The pathogenesis of DN is poorly understood, which has slowed the 
development of novel disease-modifying therapies. However, it is widely 
accepted that DN is characterised by peripheral nerve fibre and microvessel 
dysfunction, which is primarily caused by hyperglycaemia and other metabolic 
factors such as hyperlipidaemia and impaired insulin signalling (13). As a 
result, it is critical to conduct research into interventions that address both 
peripheral nerve fibre and circulatory dysfunction. 
 
1.1.2 NEUROMUSCULAR ELECTRICAL STIMULATION  
Neuromuscular electrical stimulation (NMES) is the application of electrical 
impulses which are of sufficient intensity to produce artificial contraction of 
muscle tissue. NMES is commonly applied at the lower limb via 
transcutaneous electrodes to evoke calf and thigh muscle contraction. The 
muscle contraction simulates exercise and has been shown to increase blood 
flow in healthy individuals (14,15)  and in patients with vascular disease (16–
18). It has also been utilised to accelerate recovery after orthopaedic surgery, 
stroke and intensive care stay (19–21). 
 
There is a growing body of clinical evidence to support the use of NMES in 
improving circulation. An unpublished randomised, repeated measures, 
controlled study (n=16) demonstrated that peripheral blood flux was 
significantly enhanced at the foot by 8-fold and at the calf by 5-fold whilst 
using a NMES device compared to resting. Whereas the increase during 
voluntary exercise was 3-fold and 2-fold at the foot and calf, respectively 
(p<0.008). Compared to voluntary exercise, NMES also elicited a greater 
increase in tissue oxygenation at the foot (p<0.018) (14).  
 
A separate study, investigating the same type of NMES device, showed that 
both venous and arterial haemodynamic parameters significantly increased 
(venous blood flow p=0.014; venous time-averaged mean velocity [TAMV] 
p=0.065; arterial blood flow p<0.0001; arterial TAMV p=0.0003) in healthy 
individuals during NMES device use compared to baseline. Furthermore, 

 
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improvement was also sustained shortly after device cessation, though this 
was not significant (15).  
 
Improvement in blood flow whilst using a NMES device has been observed in 
patients with peripheral arterial disease. A pilot and subsequent RCT reported 
that participants randomised to a 6-week therapy plan of one 30-minute 
NMES session per day plus a SEP were able to walk for significantly longer 
without pain (initial claudication distance – 46% increase; p=0.014) and walk 
for significantly longer without stopping due to pain (maximum claudication 
distance – 46% increase; p<0.001) compared to those randomised to a SEP 
alone (17).  
 
A similar 6-week NMES therapy plan has also been trialled in patients with 
chronic venous insufficiency. In this study, those randomised to the control 
group received a sham device. There were significant differences in venous 
blood flow between the active NMES and sham groups after 6 weeks 
(p<0.0001) (16). A more recent study, comparing groups allocated to 30 
minutes and 60 minutes of NMES per day and no NMES (control) also 
recorded significant differences in venous haemodynamic parameters, 
microcirculatory flow and foot temperature after 6 weeks (p<0.001) (18).  
 
1.1.3 RISKS  
The risks are defined in the Instructions for Use (IFU) and Investigators 
Brochure (IB).  
 
1.1.4 BENEFITS  
The NMES device may improve neuropathy symptoms in patients with DN, 
and therefore have an adjuvant benefit when provided in addition to standard 
of care. It may also improve other clinical and subjective outcomes which 
include, but are not limited to, sural, superficial peroneal, common peroneal 
and tibial nerve conductivity, somatosensory nerve fibre function, blood 
glucose, mobility and balance, neuropathy signs and symptoms, protected 
sensation.  
 
1.1.5 RATIONALE FOR STUDY 
NMES is hypothesised to improve neuropathy symptoms in people with DN by 
directly stimulating peripheral nerves and increasing circulation in the lower 
limbs. Findings from a  proof-of-concept study of NMES in people with DN 
showed that Michigan Neuropathy Screening Instrument (MNSI) Part A 
questionnaire scores significantly improved from baseline after 10 weeks of 
daily NMES device use (p<0.028) (22). To further understand the effects of 
this intervention in people with DN, more high-quality research is needed. 

 
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Hence, this pilot, randomised, sham-controlled trial is planned to robustly 
assess the potential efficacy signal, feasibility and safety of a NMES device as 
an adjunct to standard of care in people with DN. The inclusion of a sham 
control also allows for the assessment of any sham treatment effects. 
 
If this pilot RCT demonstrates a potential efficacy signal and the NMES device 
is deemed safe, future plans are to run a statistically powered, multi-centre, 
RCT. If clinical efficacy and safety are demonstrated in larger trials, this could 
lead to an accessible, non-invasive, safe and effective treatment option for 
patients with DN and may reduce the burden to patients and healthcare 
systems. 
 
Details of the NMES device used in this study (Revitive Medic Coach, Actegy 
Ltd, Bracknell, UK) are described below in section 3.1 TREATMENT 
REGIMENS and are described in the Instructions For Use (IFU) and 
Investigator’s Brochure (IB).  
 
For further details on the justification of the trial please see the Clinical 
Investigation Decision document.  
2. STUDY OBJECTIVES AND OUTCOME MEASURES 
2.1 PRIMARY OBJECTIVES 
The primary objectives are to assess the potential efficacy signal, feasibility 
and safety of a NMES device as an adjunct to standard of care in people with 
DN.  
 
The potential efficacy signal of a NMES device as an adjunct to standard of 
care will be primarily assessed by a change in neuropathy symptoms from 
baseline to the end of the treatment phase (12 weeks), compared to a sham 
device as an adjunct to standard of care. Neuropathy symptoms will be 
measured using the MNSI and will also be evaluated at follow up 6 weeks and 
26 weeks, but the end of the treatment phase (12 weeks) will be the primary 
timepoint of interest.  
 
The feasibility of a NMES device as an adjunct to standard of care will be 
assessed through recruitment rate, which will compare number of patients 
pre-screened/identified and number of participants recruited at baseline, 
participant retention rate, which will compare number of participants 
randomised and number of participants on study at the end of the treatment 
phase (12 weeks) and follow up (26 weeks), and adherence to treatment at 
the end of the treatment phase (12 weeks), which will be measured through 
the Revitive App and a patient diary.   

 
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The safety of a NMES device as an adjunct to standard of care will be 
assessed through reporting of Adverse Events (AEs), Adverse Device Effects 
(ADEs), Serious Adverse Events (SAEs) and Serious Adverse Device Effects 
(SADEs). For further details of assessment of safety and definitions please 
see 7. ASSESSMENT OF SAFETY.  
 
2.2 SECONDARY OBJECTIVES 
The secondary objectives are to determine if there are changes in other 
clinical and subjective outcomes when using a NMES device as an adjunct to 
standard of care in people with DN. 
 
Other clinical and subjective outcomes include, but are not limited to, sural, 
superficial peroneal, common peroneal and tibial nerve conductivity, 
somatosensory nerve fibre function, mobility and balance, neuropathy signs 
and symptoms, protective sensation, neuropathic pain and device sensation. 
Changes in these outcomes from baseline to the end of the treatment phase 
(12 weeks) and follow up (26 weeks) will be compared to a sham device as an 
adjunct to standard of care. In addition, blood glucose will be compared from 
baseline to the end of the treatment phase (12 weeks). Participants’ views on 
device credibility and expectancy will be compared after their first treatment 
session at baseline and their experiences of the study device will be 
compared at the end of the treatment phase (12 weeks).  
  
2.3 PRIMARY OUTCOME MEASURE 
The primary outcome is neuropathy symptoms measured using the MNSI Part 
A questionnaire at 12 weeks. The MNSI Part A is a validated screening 
questionnaire for DN, consisting of 15 yes or no questions about lower limb 
sensation. The total score is based on 13 questions, as two questions are 
excluded from the scoring (23,24).  
 
2.4 PRIMARY OUTCOME MEASURE HYPOTHESES 
Primary outcome null hypothesis (H0): There is no statistically significant 
difference in change in neuropathy symptoms measured using the MNSI Part 
A questionnaire total score between the control and intervention groups from 
baseline to the end of the treatment phase (12 weeks). 
 
Primary outcome alternative hypothesis (H1): There is a statistically significant 
difference in change in neuropathy symptoms measured using the MNSI Part 
A questionnaire total score, between the control and intervention groups from 
baseline to the end of the treatment phase (12 weeks). 
 

 
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2.5 FEASIBILITY OUTCOME MEASURES 
• Recruitment rate – measured using screening and randomisation logs 
• Participant retention rate – measured using randomisation and 
withdrawal logs  
• Adherence to treatment – measured using Revitive App and a patient 
diary 
 
2.6 SAFETY OUTCOME MEASURES 
• Adverse Events (AEs) – collected and reported via AE form  
• Adverse Device Effects (ADEs) – collected and reported via AE form  
• Serious Adverse Events (SAEs) – collected and reported via SAE form 
• Serious Adverse Device Effects (SADEs) – collected and reported via 
SAE form  
 
2.7 SECONDARY OUTCOME MEASURES 
• Sural nerve conductivity – measured using a nerve conduction study 
(NCS), includes conduction velocity (m/s), calculated using distance 
and latency (ms), and SNAP amplitude (µV) (central site only) 
• Superficial peroneal nerve conductivity – measured using a NCS, 
includes conduction velocity (m/s), calculated using distance and 
latency (ms), and SNAP amplitude (µV) (central site only) 
• Common peroneal nerve conductivity – measured using a NCS, 
includes conduction velocity (m/s), calculated using distance and distal 
latency (ms), Compound Muscle Action Potential (CMAP) amplitude 
(mV) and minimum F wave latency (ms) (central site only) 
• Tibial nerve conductivity – measured using a NCS, includes conduction 
velocity (m/s), calculated using distance and distal latency (ms), CMAP 
amplitude (mV) and minimum F wave latency (ms) (central site only) 
• Somatosensory nerve fibre function – measured using Quantitative 
Sensory Testing (QST) (central site only) 
• Blood glucose – measured using HbA1c  
• Mobility and balance – measured using validated Berg Balance Scale 
(BBS) (25) 
• Neuropathy signs – measured using the validated MNSI Part B 
physical examination (23,24)  
• Protected sensation – measured using monofilament test 
• Symptoms – measured using Total Symptom Score (TSS) covering 
paraesthesia, pain, numbness, cramp and sleep disruption on a 10-
point Numerical Rating Scale (NRS) 
• Neuropathic pain – measured using Neuropathic Pain Symptom 
Inventory (NPSI) (26)  

 
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• Device sensation – measured using device sensory threshold and 
suprathreshold 
• Device experience – measured using device experience questionnaire  
• Device credibility and expectancy – measured using modified credibility 
and expectancy questionnaire (27)  
 
Timepoints at which primary, feasibility, safety and secondary outcome 
measures are assessed are included in Table 1.   
 
Table 1: Summary of objectives and outcomes  
Objectives Outcome measure  
Measuring tool 
Timepoint(s) of 
evaluation of 
this outcome 
Primary 
objectives 
Neuropathy symptoms 
(Primary)  
MNSI Part A 
questionnaire  
Week 6, Week 
12 (Primary), 
Week 26 
Recruitment rate 
(Feasibility) 
Screening logs 
and 
randomisation 
logs  
Pre-screening / 
Identification, 
Recruitment and 
Consent, 
Baseline 
Participant retention 
rate (Feasibility) 
Randomisation 
logs and 
withdrawal logs  
Recruitment and 
Consent, 
Baseline, Week 
12, Week 26 
Adherence to 
treatment (Feasibility) 
Revitive App 
and a patient 
diary 
Week 12 
Adverse Events 
(Safety) 
AE form  
Baseline, Week 
3, Week 6, Week 
9, Week 12, 
Week 26 (and 
any 
communication in 
between) 

 
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Adverse Device 
Effects (Safety) 
AE form 
Baseline, Week 
3, Week 6, Week 
9, Week 12, 
Week 26 (and 
any 
communication in 
between) 
Serious Adverse 
Events (Safety) 
SAE form  
Baseline, Week 
3, Week 6, Week 
9, Week 12, 
Week 26 (and 
any 
communication in 
between) 
Serious Adverse 
Device Effects 
(Safety)  
SAE form  
Baseline, Week 
3, Week 6, Week 
9, Week 12, 
Week 26 (and 
any 
communication in 
between) 
Secondary 
objectives  
Sural nerve conductivity 
(Central site only) 
NCS 
Week 12, Week 
26 
Superficial peroneal 
nerve conductivity 
(Central site only) 
NCS 
Week 12, Week 
26 
Common peroneal 
nerve conductivity 
(Central site only) 
NCS 
Week 12, Week 
26 
Tibial nerve 
conductivity (Central 
site only) 
NCS 
Week 12, Week 
26 
Somatosensory nerve 
fibre function (Central 
site only) 
QST 
Week 12, Week 
26 
Blood glucose  
HbA1c  
Week 12 
Mobility and balance  
BBS 
Week 12, Week 
26 
Neuropathy signs  
MNSI Part B 
Questionnaire 
Week 12, Week 
26 

 
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Symptoms  
TSS 
Week 6, Week 
12, Week 26 
Protected sensation  
Monofilament 
test 
Week 12, Week 
26 
Neuropathic pain 
NPSI  
Week 12, Week 
26 
Device sensation 
Device sensory 
threshold and 
suprathreshold 
Week 12, Week 
26 
Device credibility and 
expectancy 
Modified 
credibility and 
expectancy 
questionnaire 
Baseline 
Device experience  
Questionnaire 
Week 12 
  
3. STUDY DESIGN 
3.1 TREATMENT REGIMENS 
This is a multi-centre, double-blind, pilot, randomised (1:1), sham-controlled 
trial assessing two arms: 
Arm 1 (Control group): 
Sham Device + Standard of 
Care   
Arm 2 (Intervention group): 
NMES Device + Standard of 
care  
3.1.1 STANDARD OF CARE 
Standard of care is defined as the therapy for DN available locally to the 
clinical trial site. It can comprise of advice on glycaemic control, footcare, 
anticonvulsant and antidepressant medications. For pragmatism, standard of 
care will be as per local guidelines and is not standardised by the study 
protocol. A full medical and drug history will be taken at baseline and 
concomitant medications will be recorded and monitored at each study visit. 
There are no prohibited concomitant medications for this trial. 
3.1.2 NEUROMUSCULAR ELECTRICAL STIMULATION DEVICE 
(INTERVENTION) 
Revitive Medic Coach (Figure 2) is a CE Marked, Class IIa, NMES medical 
device. It is intended to deliver nerve and muscle stimulation of the legs, feet 
and ankles to actively improve circulation. It is suitable for healthy individuals 
or people with poor circulation, a sedentary lifestyle, limited mobility, following 

 
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surgery or injury and those with diabetes (including DN), osteoarthritis, 
peripheral arterial disease, chronic venous insufficiency and chronic 
obstructive pulmonary disease. The intended operator profile is based on 
users in the home environment.  
The device causes nerve and muscle stimulation by applying electrical 
stimulation to the feet via large conductive rubber footpad electrodes. It is 
accompanied by a CE Marked Class II AC/DC power adaptor (Figure 2) for 
charging and once sufficiently charged can be cordless for use. Routinely, it is 
also accompanied with electrode body pads, but these will not be provided for 
this study. The device can be activated via the power on/off button on the 
device or by the Revitive App via Bluetooth pairing, which is available for 
download from Play or App stores. For the purposes of this study, participants 
will be provided with a study smartphone to access the Revitive App. The 
device includes hydration sensors, which provide feedback to the user if they 
are required to hydrate their feet to improve conductivity. It also has an 
IsoRocker function, which allows natural heel toe raises and accentuates the 
calf muscle pump action at the ankle.  
The key device components that are intended to come into contact with the 
human body are the silicone rubber footplates. The device comes into non-
invasive contact with the user’s intact skin on the plantar surface, via the 
footplate electrodes. These are comprised of Silicone (ER-70 + Carbon 
Nanotube) rubber. Transient contact may also be made in carrying the device, 
plugging in the charging cables or in using the device display interface. 
The device is programmed with the Standard Programme, constructed from 
15 one-minute low frequency waveforms patterns that repeat twice in each 
30-minute programme. The intensity of electrical stimulus can be varied from 
level 0 to 99. When first using the NMES device at the baseline visit, baseline 
device sensory and motor thresholds will be established for participants by 
systematically increasing the stimulation intensity in increments of one whilst 
the participant provides verbal sensory feedback. The minimal intensity, at 
which the participant is able to clearly feel electrical stimulation, will be 
recorded as the sensory threshold; and that producing visible muscle twitches 
of the medial gastrocnemius will be the motor threshold. The stimulation 
intensity will be adjusted to produce visible but non-painful contraction of the 
lower limb musculature at twice the individual motor threshold or as much as 
the participant can tolerate as comfortable (suprathreshold) and this will be 
recorded. Participants may not perceive any sensation or muscle contractions 
because of their diabetic neuropathy (a disease characterised by 
sensorimotor dysfunction). In this case, participants should be encouraged to 
use the device at the highest stimulation intensity (level 99), provided there 

 
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are no other concerns with using the device at this level. Device sensory 
threshold and suprathreshold will also be recorded at Week 12 and Week 26 
to assess any change in participants’ device sensation over time. At baseline, 
an IFU will be given to all participants so they can use their study device at 
home. At Week 3, Week 6 and Week 9 participants will be contacted to see 
how they are tolerating their study device. During this visit and across the 
treatment phase, the clinical judgement of the local Principal Investigator (PI) 
will determine whether a participant is experiencing problems that require 
reducing the stimulation intensity level or stopping treatment. 
 
Further details on the NMES device can be found in in the Instructions for 
Use (IFU) and Investigator’s Brochure (IB). 
 
 
 
 
 
Figure 2: Revitive Medic Coach and power adaptor 
 
 
 

 
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3.1.3 SHAM DEVICE (CONTROL) 
A sham control device has been included for the assessment of any sham 
treatment effects. The sham device will be a modified Revitive Medic Coach 
with all external appearances the same but with a maximum voltage cap to 
provide only very low sensory stimulation. It will begin at an intensity level of 5 
for the first minute then level 2 for the second minute, then to a level zero for 
the remaining session. The numbers on the sham device and the Revitive 
App will display at the corrected intensity, similar to the display units on the 
NMES device to prevent unblinding. As the sham device still produces some 
stimulation, albeit very low, it is possible that there may be a change in sural 
nerve conductivity in the control group.  
The same procedure as for the intervention group will be followed in that 
participants will be familiarised with their allocated study device and be 
provided with a study smartphone. Device sensory and suprathresholds will 
be established at baseline and recorded at Week 12 and Week 26 to assess 
any change in participants’ device sensation over time. Participants may not 
perceive any sensation or muscle contractions because the sham device 
produces very low stimulation and/or because of their diabetic neuropathy (a 
disease characterised by sensorimotor dysfunction). In this case, participants 
should be encouraged to use the device at the highest stimulation intensity 
(level 99), provided there are no other concerns with using the device at this 
level.  
At baseline, an IFU will be given to all participants so they can use their study 
device at home. At Week 3, Week 6 and Week 9 participants will be contacted 
to see how they are tolerating their study device.  
 
Further details on the sham device can be found in in the Instructions for 
Use (IFU) and Investigator’s Brochure (IB). 
 
3.1.4 TREATMENT PHASE 
For the purpose of the trial, all participants will be asked to use their allocated 
study device for two 30-minute sessions per day, a minimum of five hours per 
week for 12 weeks at suprathreshold (twice the individual motor threshold or 
as much as the participant can tolerate as comfortable). If participants do not 
perceive any sensation or muscle contractions, they should be encouraged to 
use their study device at the highest stimulation intensity (level 99), provided 
there are no other concerns with using the device at this level. The maximum 
total treatment time of 3 hours per day will be advised to minimise the 
potential for muscle fatigue. Adherence to treatment will be recorded in a 
patient diary and collected via the Revitive App. Participants will also receive 

 
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reminders to complete their treatment sessions via the Revitive App. Study 
smartphones will be provided for participants to access the Revitive App.  
3.1.5 STUDY DEVICE ACCOUNTABILITY 
During the clinical trial, the study devices will be fully traceable due to 
individually assigned device codes. Access to study devices will be restricted 
to authorised persons only and appropriate records will be kept by the device 
manufacturer, study coordination centre and clinical trials sites to document 
the physical location of all study devices from shipment from the device 
manufacturer to the clinical trial sites, provided to participants for the clinical 
trial period (12 weeks), returned to the clinical trial site and then provided to 
participants to keep at the end of the trial. Records will be kept of who 
received, used, returned or disposed (if applicable) of the study devices. 
3.2 RANDOMISATION STRATEGY  
Participants will be randomised in a 1:1 design, intervention: control at 
baseline to the following groups: 
1.  Sham Device + Standard of Care (Control group)  
2.  NMES Device + Standard of care (Intervention group) 
 
The online computer software application Sealed Envelope (London, UK) will 
be used for randomisation, and it will be programmed with a randomisation 
schedule blocked with random block sizes. To ensure concealment, the block 
sizes will not be revealed until the analysis stage (after last patient last visit).  
 
Randomisation and study assessments must be performed by a blinded 
researcher. The blinded researcher will confirm the eligibility criteria that must 
be met to allow randomisation on the online service. Once confirmed, Sealed 
Envelope will provide a study device code rather than treatment allocation. 
The unblinded randomisation list ‘code-break’ for treatment allocation will 
remain concealed from the study team and be held by the device 
manufacturer and an unblinded researcher at the study coordination centre 
who will not interact with participants.  
 
There will be no randomisation within sites because ‘there are only two clinical 
trial sites planned, with the majority of recruitment expected to take place at 
Imperial College Healthcare NHS Trust. This is also consistent with Food and 
Drug Administration (FDA) Good Review Practice guidance, which suggests 
that stratification by centre is not feasible for multi-centre trials with small 
numbers recruited per site (28). 
 
3.3 BLINDING PROCESS 
As this is a double-blind study, both participants and researchers (including 

 
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outcome assessors) will be blinded to treatment allocation. Participants will be 
aware it is a double-blind study, in that there is a 50% chance they will be 
randomised to a sham device. At the study coordination centre, there will be 
an unblinded researcher who will not interact with patients. The unblinded 
randomisation list ‘code-break’ will only be accessible to the device 
manufacturer and unblinded researcher.  
 
Participants may not perceive any sensation or muscle contractions because 
the sham device produces very low stimulation and/or because of their 
diabetic neuropathy (a disease characterised by sensorimotor dysfunction). 
Participants in the active NMES arm may also not perceive any sensation or 
muscle contractions because of their diabetic neuropathy.  
 
During the course of a trial, unblinding should only occur if it is relevant to the 
safety and medical management of the participant. The final decision of 
unblinding will rest with the treating clinician. Ideally, where time allows, there 
should be a discussion with the Chief Investigator (CI) about the need to 
unblind; if this is not an option, the PI should notify the CI as soon as possible 
afterwards. The unblinded researcher at the study coordination centre will 
only share the treatment allocation details of the participant required to be 
unblinded, the full unblinded randomisation list ‘code-break’ will still be 
concealed from the study team. Every effort should be made to limit sharing 
treatment allocation details to the treating clinician and not to divulge this to 
the study team, PI (unless treating clinician) and CI. 
All requests for unblinding should be documented including details of who 
made the request, who performed it, how it was carried out and the reason. 
The treatment allocation should not be included on this documentation as it 
could unblind further members of the clinical trial site team. The local PI is 
responsible for ensuring that the documentation is completed, a copy is filed 
in the Investigator Site File, and a copy is sent to the Trial Manager/Monitor 
for filing in the TMF. A record should also be made in the participant’s medical 
notes, case report form (CRF) and electronic Case Report Form (eCRF) to 
document the unblinding.  
 
3.4 STUDY SETTING  
This study is open to all patients at the participating NHS sites (Table 2) 
meeting specific inclusion and exclusion criteria. 
 
 
 
 

 
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Table 2: Clinical trial sites  
Number Principal 
Investigator 
Address 
Institution  
Country 
1. 
Professor Alun 
Davies  
Charing Cross 
Hospital 
Fulham Palace 
Road 
London W6 8RF 
Imperial 
College 
Healthcare 
NHS Trust  
 
UK 
2. 
Mr Ankur Thapur  
Basildon and 
Thurrock 
University 
Hospital 
Essex SS16 5NL 
Mid and 
South Essex 
NHS 
Foundation 
Trust 
UK 
 
These clinical trial sites have been selected because the local PIs have 
indicated the trial is feasible and that they have the capacity and capability to 
conduct the trial at their site. In addition to clinical trial sites, potential 
participants will also be identified from community settings who will act as 
participant identification centres (PICs). These PICs will conduct a search of 
the patient record database and suitable participants will be contacted either 
via letter, mailout or text to inform them about the study. Interested patients 
would contact the clinical trial site team directly for more information. 
 
All delegated clinical trial site staff must be appropriately trained in order to 
carry out the study assessments and procedures, and this must be approved 
by the study coordination centre at Imperial College London who will provide 
the “green light” for participant recruitment once training has taken place and 
appropriate regulatory approvals have been received. The majority of training 
will be completed at the Site Initiation Visit (SIV). In particular, there will be 
training on data collection, responding to data queries and general information 
on obtaining high-quality research data.  
 
3.5 LENGTH OF STUDY 
The duration of the study is 22 months: 16 months recruitment and 6 months 
follow up (end of treatment phase is at 3 months; end of follow up is at 6 
months). Recruitment started on 22 August 2023. 
4. SELECTION AND WITHDRAWAL OF PARTICIPANTS 
4.1 DIAGNOSTIC CRITERIA 
4.1.1 DIABETES DIAGNOSTIC CRITERIA 
A confirmed diagnosis of diabetes, either type 1 or type 2.   

 
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4.1.2 DIABETIC NEUROPATHY DIAGNOSTIC CRITERIA 
For the purposes of the trial, a diagnosis of DN will be based on a validated 
screening questionnaire for DN using the Michigan Neuropathy Screening 
Instrument (MNSI) – a questionnaire score of ≥4, which is considered 
abnormal, and more sensitive and specific than the previously defined cut-off 
point of ≥7 (23,24) 
 
4.1.3 NEUROPATHY SCREENING 
Other causes of peripheral neuropathy will be excluded by taking a medical 
history.  
The following blood tests will be collected and processed locally: 
a. Folate  
b. Vitamin B12 
c. Thyroid function 
d. HIV (optional)  
 
Any abnormalities in blood test results will be recorded, patients will be 
excluded from the trial and receive appropriate written information. The 
patient’s General Practitioner (GP) will be informed with the consent of the 
patient. 
 
An additional HbA1c blood test will be collected at screening and Week 12, 
but this is not part of neuropathy screening.  
 
4.2 INCLUSION CRITERIA  
• Aged ≥18 (no upper limit) 
• Diagnosis of type 1 or type 2 diabetes based on World Health 
Organisation (WHO) definition Diagnosis of diabetic neuropathy based 
on the validated screening questionnaire Michigan Neuropathy 
Screening Instrument score of ≥4  
• Access to internet at home to use the Revitive App (study smartphones 
will be provided) 
 
4.3 EXCLUSION CRITERIA  
• Lacks capacity to provide informed consent 
• Pregnant  
• Implanted electronic, cardiac or defibrillator device 
• Other cause of peripheral neuropathy  
• Current foot ulceration 
• Severe vascular disease requiring invasive intervention  
• Being treated for, or have the symptoms of, an existing deep vein 
thrombosis (DVT) 

 
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• Regularly used a neuromuscular electrical stimulation (NMES) device 
within 1 year of randomisation    
 
4.4 WITHDRAWAL CRITERIA  
Once a participant has been enrolled, the clinical trial site will make every 
reasonable effort to keep in touch with the participant for the duration of the 
study (26 weeks). However, it is expected that approximately 10% of 
participants will be lost to follow up. Participants will be free to withdraw from 
any part of the study at any time without any effect on their usual medical 
care.  
 
The local PI may withdraw participants from the study (after consultation with 
the CI) in order to protect their safety and/or if participants are unwilling to 
follow the protocol. All randomised participants who withdraw or are 
discontinued from the study will be considered off study device/on study and 
will be followed up until the study end (26 weeks), unless they specifically 
withdraw their consent to further follow up. The reason for their change of 
status and the study procedures and assessments they have withdrawn from 
will be recorded in the CRF/eCRF and medical records if offered by the 
participant.  
5. PROCEDURES AND ASSESSMENTS 
5.1 IDENTIFICATION AND PRESCREENING 
Patients presenting with DN at the participating clinical trial sites will be 
considered for this study. They will be pre-screened by a member of the 
direct care team and invited to speak to a member of the clinical trial site 
team. In addition to clinical trial sites, potential participants will also be 
identified from community settings who will act as participant identification 
centres (PICs). These PICs will conduct a search of the patient record 
database and suitable participants will be contacted either via letter, mailout 
or text to inform them about the study. Interested patients would contact the 
clinical trial site team directly for more information. Advertisements for the trial 
will be placed in clinical trial sites, PICs and posted online and will include 
clinical trial site contact information.  
 
Interested patients will be given a patient information sheet to read and will be 
given at least 24 hours before attending an appointment for written informed 
consent. A pseudonymised pre-screening log will identify all approached 
patients, with a minimum dataset of age, sex and reason for exclusion (if 
applicable).  
 

 
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5.2 VISIT 1 - RECRUITMENT AND CONSENT 
Patients will be recruited from participating clinical trial sites in the UK. 
Consent to enter the study will be sought from each participant only after a full 
verbal explanation has been given, and a patient information sheet is offered 
at least 24 hours beforehand. Written informed consent will be obtained 
before the subject is enrolled in the study. Consent is a continuous process 
which will be assessed during the study.  
 
If there are substantial changes to the protocol that require re-consent, the 
same process will be followed. An associated updated patient information 
sheet will be provided to participants prior to written informed re-consent.  
 
5.3 EQUALITY, DIVERSITY AND INCLUSION 
It is important that medical devices are trialled in diverse samples of 
participants. To address any potential bias in trial recruitment, the following 
will be in place:  
• Data relating to equality and diversity (age, gender, disability, ethnicity, 
sexual orientation recruitment site) will be collected from study 
participants at the initial visit. Data will be monitored on a monthly basis 
by the Trial Management Group (TMG) to ensure that our research 
sample is representative of the diabetic population. Factors limiting 
equality and diversity in recruitment will be reviewed and addressed. 
• Ms Liz Pigott, our patient representative from an ethnic minority 
background, can help ensure that our study remains inclusive and 
assist with building rapport with other members of the community.   
• The inclusion criteria are broad so that certain demographics are not 
excluded. 
• The study will be advertised online to improve accessibility for all 
potential participants.  
• Translations of patient information sheets and consent forms (and 
other patient-facing documents) will be provided to improve 
accessibility to non-English speaking potential participants. 
 
5.4 VISIT 1 – BASELINE 
All study assessments will be performed by a blinded researcher. These 
assessments can be carried out over several days to reduce participant 
burden. After a participant has consented into the study, they will be formally 
assessed against the inclusion/exclusion criteria, and the following eligibility 
assessments will be completed: 

 
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• Demographic information and vital signs – Age, sex, ethnicity, date 
of birth, lifestyle, socioeconomic status, weight, height, blood pressure 
and pulse will be collected.  
• Clinical assessment – Medical and drug history and other inclusion 
and exclusion criteria will be reviewed (i.e. whether the patient has 
other causes of peripheral neuropathy, severe vascular disease 
requiring invasive intervention, current foot ulceration prohibiting NMES 
device use, any implanted electronic, cardiac or defibrillator device 
prohibiting NMES device use, symptoms consistent with, or being 
treated for DVT, regularly used a NMES device within 1 year of 
randomisation). There are no prohibited concomitant medications for 
this trial.   
• Pregnancy test – A pregnancy test will be performed for participants 
of childbearing potential. Participants must either be of non-
childbearing potential OR be using adequate contraception for the 
duration of the study period and have a negative urine pregnancy test 
result. The urine from the point of care pregnancy test will be discarded 
immediately after the test is performed.  
• Blood tests – Blood samples will be taken to exclude any other 
causes of DN (as mentioned in 4.1.3 NEUROPATHY SCREENING). 
Blood tests will be collected and processed locally at sites.  
• Michigan Neuropathy Screening Instrument (MNSI) – The MNSI is 
a validated screening system for distal symmetrical polyneuropathies 
(23,24). It comprises of a patient questionnaire and a separate clinical 
examination of the feet. Participants must be positively screened for 
DN, as demonstrated by a questionnaire score of ≥4 (24) 
Once eligibility is confirmed, the following further assessments will take place: 
• Nerve conduction study (NCS) (central site only) – The sural, 
common peroneal, tibial and superficial peroneal nerves will be 
bilaterally tested. All NCSs will be performed by a single, blinded 
researcher (a highly trained neurophysiologist) at the core lab at 
Imperial College Healthcare NHS Trust to reduce inter-operator 
variability. A separate Nerve Conduction Study (NCS) Protocol will 
outline how NCSs for this trial are conducted. If a NCS has been 
performed within 3 months of consent by the blinded researcher (a 
highly trained neurophysiologist) as part of standard of care, this NCS 
can be used instead, and it does not need to be repeated as part of the 
baseline visit. 
• Quantitative Sensory Testing (QST) (central site only) – 
Somatosensory nerve fibre function will be assessed using the German 
Research Network on Neuropathic Pain (DFNS) QST protocol (29). 

 
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The battery of tests includes measures of cold and warm detection 
thresholds, paradoxical heat sensations, cold and heat pain thresholds, 
mechanical detection threshold, mechanical pain threshold, mechanical 
pain sensitivity, dynamic mechanical allodynia, temporal pain 
summation, vibration detection threshold and pressure pain threshold. 
Testing will take place on the worst affected limb. 
• Berg Balance Scale (BBS) – Mobility and balance will be assessed 
using the validated measure (25).  
• Neuropathic Pain Symptom Inventory (NPSI) – Neuropathic pain will 
be assessed using the validated measure (26).  
• Total Symptom Score (TSS) – Symptoms (paraesthesia, pain, 
numbness, cramp and sleep disruption) will be assessed on a 10-point 
Numerical Rating Scale (NRS) and scores will be combined to give a 
TSS out of 50.  
• Monofilament test – Protected sensation will be objectively assessed 
using a monofilament test. A 10g monofilament will be perpendicularly 
applied to five sites (1st, 3rd, and 5th metatarsal heads and plantar 
surface of the hallux and 3rd toe) of both feet for approximately two 
seconds each to cause the filament to bend. The participant will be 
asked if they felt the pressure applied or not at each site.  
• Patient diary – Clinical trial site staff will provide a patient diary to 
participants to collect daily device usage for the 12-week treatment 
phase (i.e. adherence to treatment). Timed used and intensity level 
setting will be recorded. Although device usage will be collected via the 
Revitive App, a diary will also be provided to verify the Revitive App 
data collected.  
• Randomisation – Once eligibility has been confirmed and additional 
baseline assessments completed, participants will be randomised to 
either the control group or intervention group by being allocated a study 
device code. They will also be assigned a pseudonymised study 
number unique to each individual enrolled on the trial using Sealed 
Envelope. 
• Device set-up and device sensory and suprathreshold – Clinical 
trial site staff will assist in setting up the allocated study device for the 
participant and familiarise the participant with their device. Device set-
up will include creating an account for the Revitive App and setting up 
the therapy plan on the participants study smartphone, which will be 
provided. The IFU will be provided for participants to take home for 
home device use. 
 
Participants will be familiarised with their allocated study device by 
being asked to place the soles of both feet onto the respective 

 
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footpads. Baseline device sensory and motor thresholds will be 
established by systematically increasing the stimulation intensity in 
increments of one whilst the participant provides verbal sensory 
feedback. The minimal intensity, at which the participant is able to 
clearly feel electrical stimulation, will be recorded as the sensory 
threshold; and that producing visible muscle twitches of the medial 
gastrocnemius will be the motor threshold. The stimulation intensity will 
be adjusted to produce visible but non-painful contraction of the lower 
limb musculature at twice the individual motor threshold or as much as 
the participant can tolerate as comfortable (suprathreshold) and this 
will be recorded. Participants will be instructed to use the device at the 
suprathreshold level (twice the individual motor threshold or as much 
as the participant can tolerate as comfortable). If participants do not 
perceive any sensation or muscle contractions, they should be 
encouraged to use their study device at the highest stimulation 
intensity (level 99), provided there are no other concerns with using the 
device at this level. Participants will complete their first treatment at the 
clinical trial site and will be advised to complete two 30-minute 
sessions a day, a minimum of five hours a week for 12 weeks at home. 
Usage will be recorded in a patient diary and Revitive App. Treatment 
session reminders will be issued via the Revitive App.  
 
Device credibility and expectancy questionnaire – After completing 
their first treatment session, participants will be asked to complete a 
modified treatment credibility and expectancy questionnaire. This is a 
simple questionnaire to assess participants’ treatment expectancy and 
rationale credibility as these factors may contribute to observed 
differences in outcomes (27).  
5.5 VISIT 2 – WEEK 3, WEEK 6, WEEK 9 (TELEPHONE CALL) 
At Week 3, Week 6 and Week 9, participants will be telephoned to see if they 
are tolerating the device. They will be asked to continue with treatment until 
the end of the treatment phase (12 weeks) and to increase the stimulation 
intensity of the device if they feel comfortable to do so, unless they are 
experiencing problems which require reducing the stimulation intensity level or 
stopping treatment, which will be based on clinical judgement of the local PI. If 
there are any concerns with safety, this will be escalated to the PI who will 
make a final decision on if unblinding is necessary (see 3.3 BLINDING 
PROCESS).  
 
At these follow up visits, participants will be told to inform the clinical trial site 
staff of any change in their medication or health. These AE (safety reporting) 
and concomitant medication checks are important as any changes may affect 

 
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their participation in the trial, although there are no prohibited concomitant 
medications for the trial.  
 
At Week 6, the MNSI Part A questionnaire and TSS will also be completed 
over the telephone.  
 
At Week 9, participants will be reminded to restart their therapy plan the 
following week on the Revitive App. A therapy plan will be set-up for 
participants at baseline by clinical trial site staff on the Revitive App, however, 
therapy plans in the Revitive App last for 10 weeks as standard. These will 
need to be restarted by participants at 10 weeks to complete the 3-month 
treatment phase. Re-starting therapy plans are also important to ensure 
participants continue to receive reminders to complete their treatment 
sessions.  
 
5.6 VISIT 3 – WEEK 12 (END OF TREATMENT PHASE) 
After 12 weeks of treatment, participants will be invited to return to hospital. 
This will mark the end of their treatment phase and they will return their 
allocated study device. Assessment and data collection will be collected as 
follows:  
• Blood test (HbA1c only) 
• Michigan Neuropathy Screening Instrument (MNSI) 
• Nerve conduction study (NCS – bilateral testing of sural, common 
peroneal, tibial and superficial peroneal nerves) (central site only) 
• Quantitative Sensory Testing (QST) (central site only) 
• Berg Balance Scale (BBS) 
• Neuropathic Pain Symptom Inventory (NPSI) 
• Total Symptom Score (TSS) 
• Monofilament test 
• Device sensory threshold and suprathreshold 
• Device experience questionnaire – A simple device use questionnaire 
will be taken to report ease of device use and suggest any 
developments 
• Collection of patient diary 
• AE (safety reporting) and concomitant medication check  
 
5.7 VISIT 4 – WEEK 26 (FOLLOW UP) 
At 26 weeks, participants will be invited to return to hospital. This will mark 
their final trial visit and completion of the study. Assessment and data 
collection will be collected as follows:  
• Michigan Neuropathy Screening Instrument (MNSI) 

 
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• Nerve conduction study (bilateral testing of sural, common peroneal, 
tibial and superficial peroneal nerves) (central site only) 
• Quantitative Sensory Testing (QST) (central site only) 
• Mobility/Balance test (Berg Balance Scale) 
• Neuropathic Pain Symptom Inventory (NPSI) 
• Total Symptom Score (TSS) 
• Monofilament test 
• Device sensory threshold and suprathreshold 
• AE (safety reporting) and concomitant medication check  
 
 
5.8 INCIDENTAL FINDINGS 
Incidental findings may potentially be identified during study assessments, 
such as blood and pregnancy tests. These will be reported to the  GP with the 
consent of the patient. 
.  
6. RECORD KEEPING AND DATA PROTECTION 
6.1 SOURCE DATA 
Participants in the study will be identified using a unique study number, which 
will be used to label all documentation. A list of patient details will be kept in a 
locked filing cabinet at the local clinical trial site. Data will be written directly 
into the CRF and then transcribed into the eCRF (REDCap). The Medical 
Dictionary for Regulatory Activities (MedDRA) dictionary will be used as the 
coding system for the study. Source documents include original documents 
related to the trial, medical treatment and history of the participant, and 
adequate source documentation will be maintained to allow reliable 
verification and validation of the trial data. 
 
6.2 LANGUAGE 
CRFs will be in English. All written material to be used by participants will use 
vocabulary that is clearly understood and be in the language appropriate for 
the study site. 
 
6.3 DATABASE 
The principal means of data collection and storage will be the eCRF, provided 
by the internet-based REDCap database system. Data will be entered into the 
eCRF system by clinical trial site staff and will be viewable through data entry 
access. The type of activity site staff may undertake on the database will be 
regulated by authorisations set up by the Trial Manager/Monitor. Where 
applicable, the option to select a value from a list of valid options will be 

 
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available. Valid rules and range checks, for example, will be set up on the 
database to ensure data integrity and queries will be generated by 
programmes designed to detect missing or erroneous data. The Trial Monitor 
will also be able to create data queries on missing or erroneous data identified 
through remote monitoring or source data verification. Clinical trial site staff 
will need to respond to these queries in a timely manner to ensure data 
integrity. Any data changes will also need to be updated on the source 
documentation and signed and dated by the clinical trial site staff to provide a 
paper trail. Regular reports will be sent to sites from the Trial Monitor detailing 
outstanding queries. All source data recorded in the CRF and data recorded 
in the eCRF will be signed by the local PI or delegate. All changes made 
following the electronic signing will have an electronic audit trail with a 
signature and date.  
 
It is the policy of Imperial College London to retain all trial data for 10 years 
after a study has ended. All data, whether held electronically or manually, will 
be kept securely, backed up regularly (if electronic) and not disclosed 
unlawfully. The data custodian is Imperial College London. Actegy Limited will 
process the Revitive App data on behalf of Imperial College London and are 
therefore a data processor for this study.  
 
6.4 MONITORING 
The study will be monitored periodically to assess the progress of the study, 
verify adherence to the protocol, GCP guidelines and other 
national/international requirements and to review the completeness, accuracy 
and consistency of the data. Monitoring will be undertaken by the Trial Monitor 
and self-compliance checklists will be performed by site staff. 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. 
7. ASSESSMENT OF SAFETY 
7.1 DEFINITIONS  
7.1.1 INVESTIGATIONAL MEDICAL DEVICE   
The medical device being assessed for safety or performance in a clinical 
investigation. This includes medical devices already on the market that are 
being evaluated for new intended uses, new populations, new materials or 
design changes. 
 
The medical device being investigated for this trial is the Revitive Medic 
Coach. The device is suitable for healthy individuals or people with poor 
circulation, a sedentary lifestyle, limited mobility, following surgery or injury 

 
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and those with diabetes (including DN), osteoarthritis, peripheral arterial 
disease, chronic venous insufficiency and chronic obstructive pulmonary 
disease. The device is safe to use in patients and there are very few clinical 
risks associated with the use of NMES devices. There is no expected risk in 
patients with DN, if the exclusion criteria are adhered to. 
 
Further details on the NMES device can be found in in the Instructions for 
Use (IFU) and Investigator’s Brochure (IB). 
 
7.1.2 ADVERSE EVENT (AE)   
An Adverse Event (AE) is any untoward medical occurrence, unintended 
disease or injury, or any untoward clinical signs (including an abnormal 
laboratory finding) in participants, users or other persons concerned with the 
medical device. These may, or may not be, considered related to the 
investigational device, device related procedure or comparator. If the AE  
is considered to have a reasonable causal relationship with the device, then it 
is considered to be an Adverse Device Effect (ADE). 
 
7.1.3 ADVERSE DEVICE EFFECT (ADE)   
An Adverse Event (AE) related to the use of an investigational medical device. 
This includes any AE resulting from insufficiencies or inadequacies in the 
instructions for use, the deployment, implantation or operation of the medical 
device or any malfunction. This also includes any AE that is a result of an 
error in use or intentional misuse of the medical device. 
 
7.1.4 DEVICE DEFICIENCY   
Inadequacy of a medical device with respect to its identity, quality, durability, 
reliability, safety or performance. Device deficiencies include malfunctions, 
misuse or use errors and inadequate labelling. 
 
7.1.5 SERIOUS ADVERSE EVENT (SAE)   
An Adverse Event (AE) that results in: 
• Death. 
• Life threatening illness or injury. 
• Permanent impairment of a body structure or body function. 
• Hospitalisation or prolongation of existing hospitalisation. 
• Medical or surgical intervention to prevent life threatening illness, injury 
or impairment to a body structure or body function. 
• Foetal distress, foetal death or congenital anomaly or birth defect. 
• Is otherwise considered medically significant by the Investigator.  
 

 
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This includes potential SAEs which were avoided as result of action or 
intervention. A planned hospitalisation for a pre-existing condition, or a 
procedure required in the protocol, without a serious deterioration in health, is 
not considered an SAE.  
 
NOTE: Device deficiencies that might have led to a SAE where a suitable 
action had not been taken or an intervention had not been made or if 
circumstances had been less fortunate are handled under the serious adverse 
event reporting system.  
 
Such AEs should be reported as soon as possible.  
 
Medical judgement should be exercised in deciding whether an adverse event 
is serious in other situations. Important adverse events that are not 
immediately life-threatening or do not result in death or hospitalisation but 
may jeopardise the subject or may require intervention to prevent one of the 
other outcomes listed in the definition above, should also be considered 
serious.  
 
Severity: The term “severe” is often used to describe the intensity (severity) 
of a specific event. This is not the same as “serious”, which is based on 
patient/event outcome or action criteria. 
 
7.1.6 SERIOUS ADVERSE DEVICE EFFECT (SADE) 
An Adverse Device Effect (ADE) that results in: 
• 
Death. 
• 
Life threatening illness or injury. 
• 
Hospitalisation, or prolongation of existing hospitalisation. 
• 
Persistent or significant disability or incapacity. 
• 
Foetal distress, foetal death or congenital anomaly or birth defect. 
• 
Is otherwise considered medically significant by the Investigator.  
 
But has previously been identified in the Study Protocol and/or Investigator 
Brochure (IB).  
 
Any hospitalisation planned prior to enrolment is not a SADE. 
 
7.1.7 UNANTICIPATED SERIOUS ADVERSE DEVICE EFFECT (USADE) 
Serious adverse device effect (SADE) which by its nature, incidence, severity 
or outcome has not been identified in the current version of the risk analysis 
report. 
 

 
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7.2 SAFETY RESPONSIBILITIES  
There are a number of responsibilities when managing adverse events (AEs).  
 
The CI has overall responsibility for the conduct of the study. The CI has co-
ordinating responsibility for reporting adverse events (AEs) to the Medicines 
and Healthcare products Regulatory Agency (MHRA) and to the relevant 
Research Ethics Committee (REC). 
 
The Principal Investigator (PI) has responsibility for the research at a local 
clinical trial site where the study involves specified procedures requiring site-
specific assessment. There should be one PI for each research site. In the 
case of a single-site study, the CI and the PI should be the same person. The 
PI is responsible for informing the CI, or the coordinating research team, of all 
adverse events that occur at their site following the guidelines below. 
 
7.2.1 INVESTIGATOR’S RESPONSIBILITIES  
1. PI to report all SAEs within agreed timelines to the CI.  
2. CI to report all SAEs within agreed timelines to Sponsor.  
3. CI to report SAEs within agreed timelines to Sponsor, MHRA, REC and 
relevant NHS Trust Research and Development (R&D) Office. Only 
Unanticipated Serious Adverse Device Effects (USADEs) will be 
reported to the REC.  
4. Provide the Sponsor with details of all AEs identified in the protocol as 
critical to the evaluation of safety within the agreed timeframes 
specified in the protocol.  
5. Review SAE reports from Investigators and perform an evaluation with 
respect to seriousness, causality and expectedness.  
6. Supply the Sponsor, MHRA, REC and relevant NHS Trust R&D with 
any supplementary information they request.  
 
7.2.2 SPONSOR’S RESPONSIBILITIES  
1. In collaboration with the Device Manufacturer, perform ongoing safety 
evaluation of the trial device and report any findings that may affect the 
health of subjects to the Device Manufacturer.  
2. Promptly notify all Investigators, REC and MHRA, of any findings that 
may affect the health of subjects.  
3. Keep detailed written reports of all AEs reported by PIs and performing 
an evaluation with respect to seriousness, causality and expectedness. 
4. Report all relevant safety information and SAEs to the relevant REC 
and MHRA within the relevant timelines. 
5. Break treatment codes before submitting expedited reports to MHRA 
and REC for specific subjects, even if the Investigator has not broken 
the code.  

 
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6. Submit the annual report to Sponsor and REC (if required).  
7. Submit summary reports as required to the MHRA.  
 
As this study is an Imperial College sponsored study, the above sponsor 
responsibilities will be delegated to the CI. 
 
7.3 ASSESSMENT  
7.3.1 CAUSALITY 
Adverse reactions should be assessed for causality. The definitions below can 
be used. 
 
Table 3: Definitions for causality assessment   
Relationship 
Description  
Unrelated 
There is no evidence of any causal 
relationship to the medical device 
Unlikely 
The relationship with the use of the 
investigational medical device 
seems not relevant and/or the event 
can be reasonably explained by 
another cause 
Possible 
The relationship with the use of the 
device is weak but cannot be ruled 
out completely 
Probable 
The relationship with the 
investigational medical device 
seems relevant and/or the event 
cannot be reasonably be explained 
by another cause 
Causal Relationship 
The serious event is associated with 
the investigational medical device 
beyond reasonable doubt 
 
7.3.2 ASSESSMENT OF EXPECTEDNESS  
Anticipated: The reaction is consistent with the effects of the device listed in 
the Investigator Brochure (IB) or Study Protocol.   
 
Unanticipated: the reaction is not consistent with the effects of the device 
listed in the Investigator Brochure (IB) or Study Protocol.   
 
7.4 REPORTING 
Once the CI/PI has evaluated the AE in terms of seriousness, causality and 
expectedness, the following guidelines should be followed. 
 

 
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7.4.1 AEs/ADEs  
For the purposes of the study, all AEs will be followed up until resolution or 
death of the participant. 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. 
 
7.4.2 SAEs/SADEs  
If the AE is assessed as serious, the PI must report the event to the CI 
immediately or within 24 hours of being made aware of the event. The 
initial report can be made via email but must be promptly followed with a 
detailed, written report. The PI must record the event with their assessment of 
seriousness, (along with causality, expectedness and severity) on a trial SAE 
form provided by the CI. The PI should ensure that follow up information is 
provided when available. Where supporting documents are sent with this 
form, these must be pseudonymised. Where the information available is 
incomplete at that time, as much information as can be ascertained should be 
sent to ensure timely reporting, with additional information provided as soon 
as it is known. Additional information received for an event (follow up or 
corrections to the original event data) needs to be detailed on a new SAE 
form.  
 
In cases where the REDCap system is unavailable and the electronic SAE 
form cannot be completed, clinical trial sites will email the completed paper 
SAE form to the study coordination centre immediately or within 24 hours of 
being made aware of the event.  
 
Study Coordination Centre Contact Details 
Please send SAE forms via email to: 
Sasha Smith 
sasha.smith@imperial.ac.uk  
 
or via post to:  
Sasha Smith,  
Section of Vascular Surgery 
Room 16 4th Floor East Wing 
Charing Cross Hospital  
Fulham Palace Road 
London W6 8RF 
Tel: +44 (0)756 512 3056 (Mon to Fri 09.00 – 17.00) 
 

 
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7.4.3 SAEs REPORTING TO THE MHRA  
The following must be reported to the MHRA by the delegated study 
coordination centre staff using the appropriate tabular reporting form.  
a) Any SAE (whether initially considered to be device related or not) 
b) Any Investigational Medical Device Deficiency that might have led to a 
SAE if,  
1. Suitable action had not been taken or 
2. Intervention had not been made or  
3. If circumstances had been less fortunate 
c) New findings/updates in relation to already reported events  
 
The CI should ensure that these are reported to the Imperial College 
Research Governance and Integrity Team (RGIT) within 24 hours. The tabular 
reporting form will give a cumulative overview of the reportable events per 
clinical investigation and will be updated and transmitted to the MHRA each 
time a new reportable event or a new finding to an already reported event is to 
be reported. More detailed information must be provided on request of the 
MHRA.  
 
The study coordinating centre staff delegate will submit the completed 
MEDDEV 2/7/3 reporting spreadsheet to the MHRA’s MORE portal quoting 
the MHRA’s CI reference number. 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 CI immediately but not later than 2 calendar days 
following the date the Sponsor is made aware, using the summary tabulation 
form.   
 
Any other reportable events should be reported immediately but not later 
than 7 calendar days following the date the Sponsor is made aware, using the 
same summary tabulation. The device manufacturer should also be informed 
within 24 hours of the SAE or device deficiency if indicated in the study’s 
communication agreement.   
 
The PI/CI must send all SAE reports to the Research Governance and 
Integrity Team, Imperial College AHSC immediately or within 24 hours 
after becoming aware of the event at the below address: 
RGIT@imperial.ac.uk 
 
Local research governance procedures at each site, e.g. NHS Trust, should 
also be followed. 
 

 
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7.4.4 USADEs  
If an SAE is determined to be unanticipated (not previously described in the 
Investigator Brochure (IB) or Study Protocol) and related to the study 
device then it is considered an USADE. For USADEs, in addition to reporting 
to the MHRA as described in the sections above, the CI must also report the 
event to the REC in the UK and make sure the event is reported to Ethics 
Committees in participating countries as required. Reports should be made to 
the REC within 15 days according to HRA website using the non-CTIMP SAE 
form. The Device Manufacturer and Investigators at all sites should be notified 
of the USADE.  
 
Unblinding might have to be considered in the event of a USADE, although 
unblinding should be avoided where possible. 
 
7.4.5 URGENT SAFETY MEASURES  
The CI and PIs have the authority to deviate from the protocol if doing so 
relates to the immediate safety of a participant, where continuing to follow 
protocol would put that participant at risk. This is classed as an urgent safety 
measure and must be reported to the RGIT, MHRA and REC within three 
calendar days of the occurrence. This may be reported verbally in the first 
instance but must be supported by a written report as soon as information is 
available.  
 
7.4.6 PREGNANCY  
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. 
 
7.5 ANNUAL PROGRESS REPORTS 
An annual progress report should be submitted to the REC which gave the 
favourable opinion 12 months after the date of the favourable opinion letter. 
The annual progress report should be emailed to REC within 30 days of this 
reporting period. The requirement to submit annual progress reports to the 
REC ceased on 01 August 2024.  
 
7.6 TREND ANALYSES 
The CI in conjunction with the manufacturer should undertake trend analysis 
regarding the safety of the device. 

 
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8. STATISTICAL ANALYSES 
8.1 SAMPLE SIZE CONSIDERATIONS 
The target sample size is 64 participants (32 participants per group), which 
includes an expected 10% loss to follow up rate at 6 months. Therefore, the 
final number of participants with primary outcome measure data is expected 
to be 57.  
 
As the previous research in this area has been limited, and the treatment 
effect of NMES on DN is unclear, a sample size could not be determined 
using a power calculation. A previous proof-of-concept study found a mean 
reduction of 1.75 points in the total score of the MNSI Part A questionnaire 
after 10 weeks of NMES therapy (22). For the defined objectives, the chosen 
target is realistic to achieve in this clinical setting and provide sufficient pilot 
data to assess the potential efficacy signal, feasibility and safety of a NMES 
device. This study will serve as the foundation for future powered RCTs 
investigating NMES in DN. 
 
Further details on sample size and minimal clinically important difference 
considerations will be included in the Statistical Analysis Plan (SAP), 
authored by members of the statistical support team and agreed by the Trial 
Management Group (TMG). The SAP will be finalised prior to database lock.  
 
8.2 PLANNED DATA ANALYSES 
The primary and safety analyses will be performed based on the intention-to-
treat (ITT) principle. This is defined as all participants confirmed as eligible at 
screening and randomised, regardless of treatment adherence. The follow up 
phase for these participants will be 26 weeks in total (with primary outcome 
measured at 12 weeks). These analyses will exclude all those who specifically 
asked to be withdrawn and requested for their data not to be used for the trial. 
 
There are no planned interim analyses. Sensitivity analyses will be conducted 
to assess the robustness of the conclusions. Non-compliance will be 
assessed through per protocol (PP) analyses, including participants with no 
protocol violations or major deviations.  The two populations of interest: the 
intention to treat (ITT) population and the per-protocol (PP) population for 
potential clinical efficacy will be determined prior to database lock and release 
of the randomisation.  
 
The impact of missing data will also be investigated. Prior to data analysis, the 
level and pattern of missing data will be established by creating appropriate 
tables. There will be a summary table with reasons for missing data, in 
particular primary outcome data measured at 12 weeks. For the main 

 
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analysis, missing data will be assumed to be missing at random (MAR) and 
multiple imputation will be used. To assess the impact of any bias due to 
missing data, a sensitivity analysis on the primary endpoint will be performed, 
where missing data will assumed to be missing not at random (MNAR). This 
may include copy-reference imputation, where the missing data are assumed 
to have a profile that is the same as that of the control group.  
 
Subgroup analyses will investigate the effect of the intervention among 
subgroups, such as those with different severities of DN and those with 
different types of diabetes.  
 
Quantitative data will be analysed using SAS statistical software. Following 
tests for normality, standard descriptive parameters for each study outcome 
will be calculated, either for parametric (e.g. mean, standard deviation) and 
non-parametric (e.g. medium, interquartile range) data. This will be calculated 
for the actual value at each timepoint and the change from baseline. Data will 
also be presented graphically.  
 
Further details on the planned data analyses, including the primary outcome 
measure, feasibility outcome measures, safety outcome measures and 
secondary outcome measures, will be included in the SAP, authored by 
members of the statistical support team and agreed by the Trial Management 
Group (TMG). The SAP will be finalised prior to database lock. 
 
8.2.1 PRIMARY OUTCOME MEASURE ANALYSIS  
The primary outcome measure is the MNSI Part A questionnaire total score, 
which measures neuropathy symptoms using at 12 weeks. The difference in 
change in the MNSI Part A questionnaire total score, between the two 
treatment groups at 6 weeks, 12 weeks and 26 weeks will be analysed using 
Analysis of Covariance (ANCOVA) models. The primary timepoint of interest 
is at 12 weeks, but neuropathy symptoms at 6 weeks and 26 weeks will also 
be evaluated. Each model will include a term for treatment and baseline MNSI 
Part A questionnaire total score as a covariate. The ANCOVA will be applied 
to each of the multiply imputed datasets and then combined using Rubin’s 
method. If the assumptions underlying the ANCOVA are violated, alternative 
non-parametric methods, such as a rank ANCOVA will be considered. A p 
value of ≤ 0.05 is to be considered significant. Full details of the multiple 
imputation process will be provided in the SAP. 
 
 

 
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8.2.2 FEASIBILITY OUTCOME MEASURES ANALYSIS  
Feasibility outcome measures include recruitment rate measured using 
screening and randomisation logs, participant retention rate measured using 
randomisation and withdrawal logs and treatment adherence rate measured 
using Revitive App and a patient diary. The data for these parameters will be 
summarised descriptively. Since this is the first time the Revitive App is being 
used to collect treatment adherence data in this patient population, the data 
collected from the Revitive App and patient diary will be compared to see if 
there is agreement between these two data collection methods.   
 
8.2.3 SAFETY OUTCOME MEASURES ANALYSIS  
All safety variables will be summarised by treatment in the form of frequency 
tables for categorical variables or descriptive statistics for continuous 
variables. The MedDRA dictionary will be used as the coding system for the 
study. An AE will be considered treatment emergent if it started after the first 
use of the device (NMES or sham device). Adverse events will be categorised 
by MedDRA System Organ Class and Preferred Term. Treatment emergent 
AEs will also be summarised (incidence and frequency) by severity and 
relationship to treatment.  
 
8.2.4 SECONDARY OUTCOME MEASURES ANALYSIS  
Secondary outcomes include, but are not limited to, sural, superficial 
peroneal, common peroneal and tibial nerve conductivity, somatosensory 
nerve fibre function, mobility and balance, quality of life, neuropathy signs and 
symptoms, protective sensation, neuropathic pain and device sensation. 
Secondary outcome measures will be analysed using appropriate statistical 
models with appropriate adjustments to investigate the difference in outcomes 
between the two treatment groups at baseline, 12 weeks and 26 weeks. Other 
outcomes such as device experience (patient questionnaire recorded at Week 
12) will be summarised descriptively. 
 
Intergroup comparisons of categorical variables will be analysed using chi-
squared test.  
 
9. REGULATORY ISSUES 
9.1 ETHICS APPROVAL  
The Study Coordination Centre has obtained approval from the North East -
Newcastle & North Tyneside 2 Research Ethics Committee (REC) and Health 
Research Authority (HRA). The study must also receive confirmation of 
capacity and capability (or applicable approval) from each participating NHS 
site before accepting participants into the study or any research activity is 

 
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carried out. The study will be conducted in accordance with the study protocol 
and GCP guidelines.  
 
9.2 AMENDMENTS  
Any changes to the protocol which will impact the conduct of the study, 
potential benefit to the patient or may affect patient safety, including changes 
of study objectives, study design, patient population, sample sizes, study 
procedures or significant administrative aspects will require a formal 
amendment to the protocol, which will need to be submitted and approved by 
regulatory authorities.  
 
Minor administration changes and clarifications that have no effect on the way 
the study is conducted will be submitted to the Sponsor and may require 
further regulatory approvals.  
 
9.3 CONSENT  
Consent to enter the study will be sought from each participant only after a full 
explanation has been given, a patient information leaflet is offered, and 
adequate time allowed (at least 24 hours) for consideration. Signed participant 
consent will be obtained. The right of the participant to refuse to participate 
without giving reasons will be respected. After the participant has entered the 
trial, the clinician remains free to give alternative treatment to that specified in 
the protocol at any stage if 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. A 
participant’s GP will be notified via letter of study inclusion if the participant 
consents to this communication.  
 
 
9.4 CONFIDENTIALITY  
The investigator must ensure that the subject’s confidentiality is maintained on 
the CRF/eCRF or other documents submitted to the Sponsor, or on 
anonymised safety information provided to the device manufacturer, subjects 
will be identified by a unique study number only. Documents that are held by 
the study coordination centre or clinical trial sites (e.g., signed informed 
consent form) should be kept in a lockable office in a strictly confidential file 
by the researchers.   
 
The local PI shall permit direct access to subjects’ records and source 
documents for the purposes of monitoring, auditing or inspection by the 

 
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Sponsor, authorised representatives of the Sponsor, NHS and regulatory 
authorities. The site will preserve the confidentiality of participants taking part 
in the study and is registered under the Data Protection Act. 
 
9.5 ACCESS TO DATA 
This study has planned data sharing activities with Actegy Limited.  
Anonymised data will be shared with the device manufacturer and study 
funder Actegy Limited in accordance with a data sharing agreement at the 
end of the trial (after last patient last visit).  
Other data sharing requests may be made outside the sponsor organisation 
and will be made under a data sharing agreement that provides the following: 
1. A commitment to using the data only for research purposes and not to 
identify any individual participant;  
2. A commitment to securing the data using appropriate computer 
technology; 
3. A commitment to destroying or returning the data after analyses are 
completed.   
 
All data sharing requests will be assessed, accepted and approved by the CI. 
A record of all access to data will be maintained by the Trial Manager. 
 
9.6 INDEMNITY  
Imperial College London holds negligent harm and non-negligent harm 
insurance policies which apply to this trial. 
 
9.7 SPONSOR 
Imperial College London will act as the main Sponsor for this study.  
Delegated responsibilities will be assigned to the centres taking part in this 
study. 
 
9.8 STUDY MANAGEMENT 
A Trial Management Group (TMG) will be convened including the Chief 
Investigator, co-investigators, statistician, trial manager, trial monitor and key 
collaborators. The TMG will be responsible for day-to-day conduct of the trial 
and operational issues. Details of membership, responsibilities and frequency 
of meetings will be defined in separate Terms of Reference. 
 
Any disruptions to the trial due to COVID-19, or similar circumstances, will be 
discussed with the TMG. Remote follow up visits (with physical assessments 
performed later) may be suggested if it is not appropriate for participants to 
attend on-site.  
 

 
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Due to the minimal risks of NMES interventions applied at the lower limb, a 
Data Monitoring Committee (DMC) will not be convened for this study.  
 
9.9 PATIENT AND PUBLIC INVOLVEMENT (PPI) 
Patients and the public have been involved in the design of the trial and will 
continue to be involved in further trial stages. The following PPI activities have 
taken place / are planned:  
• Design of the research: Patients have identified this research as a 
priority. The research team have spoken with patients suffering from 
DN, who have told them that current management strategies for DN 
are inadequate and that new treatments must be researched. Patient 
representatives have reviewed the patient-facing materials to check 
they are easy to understand and have provided patient perspectives on 
the inclusion of a sham device and masking this from participants. 
Furthermore, interviews have taken place with patients suffering from 
DN to identify the barriers and facilitators of NMES as a potential 
treatment, which has informed the design of the study. In sum, barriers 
were perception of safety and potential lack of sensation. Facilitators 
included device usability, independence, health motivators and 
following a routine. Based on these findings, we have added a period 
of device familiarisation into the study protocol and included regular 
contact and engagement with participants during their treatment period. 
This aims to promote independence, education, establishing 
motivations early and promoting these behaviours throughout.  
• Management of the research: Two patient representatives have 
expressed interest in remaining active in the study as advisors at 
various points throughout the study. 
• Dissemination of results: Patient representatives will also be invited to 
provide perspectives on the dissemination of the study findings 
including how best to communicate these to study participants and 
other patient groups.  
 
9.10 FUNDING 
This trial is funded by Actegy Limited. The study coordination centre will 
provide regular study progress reports to Actegy Limited.  
 
9.11 AUDITS AND INSPECTIONS 
The study will be subject to inspection and audit by Imperial College London 
under their remit as Sponsor, the study coordination centre and other 
regulatory authorities to ensure adherence to GCP. 
 
9.12 CONFLICTS OF INTEREST 

 
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Professor Alun Davies and Miss Sasha Smith are supported by research 
grants from Actegy Limited, the funder and device manufacturer for this study.  
 
9.13 PUBLICATION POLICY  
All publications and presentations relating to the study will be authorised by 
the CI. Terms of authorship will be agreed with all contributors. Authorship of 
parallel studies initiated will be according to the individuals involved in the 
project but must acknowledge the contribution of the study. The study will be 
published in a peer reviewed journal, and available from the researchers on 
request. A lay summary of the results will be provided to participants.  
 
 
 

 
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10. APPENDICES 
10.1 VISIT SCHEDULE   
PROCEDURES AND 
ASSESSMENTS 
PRESCREENING / 
IDENTIFICATION 
VISIT 1  
BASELINE1 
VISIT 2  
WEEK 3 
VISIT 3 
WEEK 6 
VISIT 4 
WEEK 9 
VISIT 5  
WEEK 12 
VISIT 6 
WEEK 26 
Pre-screening 
X 
 
 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
 
Demographics  
 
X 
 
 
 
 
 
Vital signs  
 
X 
 
 
 
 
 
Clinical assessment (Medical and 
drug history etc.) 
 
X 
 
 
 
 
 
Pregnancy test 
 
X 
 
 
 
 
 
Blood tests  
 
X 
 
 
 
X 
 
Nerve conduction study (NCS)2 
 
X 
 
 
 
X 
X 
Quantitative Sensory Testing 
(QST)2 
 
X 
 
 
 
X 
X 
Michigan Neuropathy Screening 
Instrument (MNSI) 
 
X 
 
X 
 
X 
X 
Berg Balance Scale (BBS) 
 
X 
 
 
 
X 
X 
Neuropathic Pain Symptom 
Inventory (NPSI) 
 
X 
 
 
 
X 
X 
Total Symptom Score (TSS) 
 
X 
 
X 
 
X 
X 
Monofilament test  
 
X 
 
 
 
X 
X 
Issue patient diary 
 
X 
 
 
 
 
 
Randomisation  
 
X 
 
 
 
 
 
Device set-up 
 
X 
 
 
 
 
 

 
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Device sensory and 
suprathreshold 
 
X 
 
 
 
X 
X 
Device credibility and expectancy 
questionnaire  
 
X 
 
 
 
 
 
Collect patient diary   
 
 
 
 
 
X 
 
Device experience questionnaire 
 
 
 
 
 
X 
 
AE (safety reporting) and 
concomitant medications check 
 
 
X 
X 
X 
X 
X 
Device toleration  
 
 
X 
X 
X 
X 
X 
1. Baseline (Visit 2): Allowed be performed across multiple days.  
 
2. Performed at Imperial College Healthcare NHS Trust (central site) only.  
 
 
 
 

 
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V12.0 14/01/2025 
IRAS ID 237312 
 
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10.2 SIGNATURE PAGE (CHIEF 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: 
Neuromuscular Electrical Stimulation For The 
Treatment Of Diabetic Neuropathy: A Multi-
centre, Double-blind, Pilot, Randomised, Sham-
controlled Trial (NMES-DN) 
Protocol Version: 
12.0 
Address of Institution: 
 
 
 
Signed: 
 
 
 
Print Name and Title:  
 
 
 
Date:  
 
 
 
 
 
 
 
 
 
 
 

 
 Research Governance and Integrity Team 
 
 
 
 
NMES-DN Protocol 
V12.0 14/01/2025 
IRAS ID 237312 
 
69
10.3 SIGNATURE PAGE (SPONSOR) 
 
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: 
Neuromuscular Electrical Stimulation For The 
Treatment Of Diabetic Neuropathy: A Multi-
centre, Double-blind, Pilot, Randomised, Sham-
controlled Trial (NMES-DN) 
Protocol Version: 
12.0 
Address of Institution: 
 
 
 
Signed: 
 
 
 
Print Name and Title:  
 
 
 
Date:  
 
 
 
 
 
 
 
 
 
 
 

 
 Research Governance and Integrity Team 
 
 
 
 
NMES-DN Protocol 
V12.0 14/01/2025 
IRAS ID 237312 
 
70
10.4 SIGNATURE PAGE (PRINCPAL 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: 
Neuromuscular Electrical Stimulation For The 
Treatment Of Diabetic Neuropathy: A Multi-
centre, Double-blind, Pilot, Randomised, Sham-
controlled Trial (NMES-DN) 
Protocol Version: 
12.0 
Address of Institution: 
 
 
 
Signed: 
 
 
 
Print Name and Title:  
 
 
 
Date:  
 
 
 
 
 
 
 
 
 
 

 
 Research Governance and Integrity Team 
 
 
 
 
NMES-DN Protocol 
V12.0 14/01/2025 
IRAS ID 237312 
 
71
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