Investigating whether a device that provides neuromuscular electrical stimulation can improve nerve function in the legs of people with diabetic neuropathy

ISRCTN	ISRCTN17050221
DOI	https://doi.org/10.1186/ISRCTN17050221
ClinicalTrials.gov (NCT)	NCT03767478
Clinical Trials Information System (CTIS)	Nil known
Integrated Research Application System (IRAS)	237312
Protocol serial number	18HH4610, IRAS 237312
Sponsor	Imperial College London
Funder	Actegy Ltd

Submission date: 21/06/2023
Registration date: 30/06/2023
Last edited: 02/04/2025

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Nutritional, Metabolic, Endocrine

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims
Around half of people with diabetes experience nerve damage called diabetic neuropathy. The nerve damage commonly occurs in the feet and legs and can lead to symptoms such as numbness, pain and hypersensitivity. The cause of diabetic neuropathy is thought to be due to nerves not functioning properly and poor circulation in the blood vessels that supply the nerves. A new device has become available to improve nerve function in the legs by directly stimulating nerves and increasing blood flow in the legs. This study aims to look at its effect on people with damaged nerves in the legs.

Who can participate?
Adults aged over 18 years old with diabetes-related nerve problems in their legs

What does the study involve?
Participants will receive a study device in addition to the standard of care for 12 weeks. Participants will be asked to use their 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 comfortably). If participants do not perceive any sensation or muscle contractions, they will 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. Participants will receive a telephone call at 3 weeks, 6 weeks and 9 weeks and will be invited back to the clinic for tests at 12 weeks and 26 weeks.

What are the possible benefits and risks of participating?
We know from previous studies that Revitive devices increase blood flow in healthy people. We expect it to do the same for patients with diabetic neuropathy, so there will be a direct benefit to study participants. The device has been through the national testing process and is safe to use for healthy individuals to improve circulation. This study aims to look at its effect on people with diabetic neuropathy as the device has not been tested extensively in these individuals. However, additional risks for this patient group are not anticipated.

Where is the study run from?
Imperial College London (UK)

When is the study starting and how long is it expected to run for?
October 2016 to June 2025

Who is funding the study?
Actegy Ltd, the neuromuscular electrical stimulation device manufacturer (UK)

Who is the main contact?
Miss Sasha Smith (Imperial College London), sasha.smith@imperial.ac.uk

Contact information

Miss Sasha Smith
Public

4th Floor, East Wing
Charing Cross Hospital
Fulham Palace Road
London
W6 8RF
United Kingdom

ORCID ID	0000-0001-9843-5368
Phone	+44 (0)7565123056
Email	sasha.smith@imperial.ac.uk

Miss Sasha Smith
Scientific

4th Floor, East Wing
Charing Cross Hospital
Fulham Palace Road
London
W6 8RF
United Kingdom

Phone	+44 (0)7565123056
Email	sasha.smith@imperial.ac.uk

Prof Alun Davies
Principal investigator

4th Floor, East Wing
Charing Cross Hospital
Fulham Palace Road
London
W6 8RF
United Kingdom

ORCID ID	0000-0001-5261-6913
Phone	+44 (0)20833117320
Email	a.h.davies@imperial.ac.uk

Study information

Primary study design	Interventional
Study design	Multi-centre double-blind pilot randomized sham-controlled trial
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	NeuroMuscular Electrical Stimulation for the treatment of Diabetic Neuropathy: A multi-centre, double-blind, pilot, randomised, sham-controlled trial (NMES-DN)
Study acronym	NMES-DN
Study objectives	Current study hypothesis as of 20/12/2024: Primary outcome null hypothesis (H0): There is no statistically significant difference in change in neuropathy symptoms measured using the Michigan Neuropathy Screening Instrument (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 Michigan Neuropathy Screening Instrument (MNSI) Part A questionnaire total score, between the control and intervention groups from baseline to the end of the treatment phase (12 weeks). Previous study hypothesis: Primary outcome measure hypotheses Primary outcome null hypothesis (H0): There is no statistically significant difference in change in sural nerve conductivity, specifically the conduction velocity (m/s) or the sensory nerve action potential (SNAP) amplitude (µV), between the control and intervention groups from baseline to the end of the treatment phase (6 months). Primary outcome alternative hypothesis (H1): There is a statistically significant difference in change in sural nerve conductivity, specifically the conduction velocity (m/s) or the sensory nerve action potential (SNAP) amplitude (µV), between the control and intervention groups from baseline to the end of the treatment phase (6 months).
Ethics approval(s)	Approved 23/10/2018, North East - Newcastle & North Tyneside 2 Research Ethics Committee (NHSBT Newcastle Blood Donor Centre, Holland Drive, Newcastle upon Tyne, NE2 4NQ, United Kingdom; +44 (0)2071048082; newcastlenorthtyneside2.rec@hra.nhs.uk), ref: 18/NE/0281
Health condition(s) or problem(s) studied	Patients with diabetic neuropathy
Intervention	Current interventions as of 20/12/2024: 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. For the purpose of the trial, all participants will be asked to use their study device for two 30-minute sessions per day, a minimum of five hours per week for 3 months 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 will 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. Previous interventions: 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. For the purpose of the trial, all participants will be asked to use their study device for two 30-minute sessions per day, a minimum of five hours per week for 6 months 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 will 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.
Intervention type	Device
Phase	Not Applicable
Drug / device / biological / vaccine name(s)	Revitive Medic Coach neuromuscular electrical stimulation
Primary outcome measure(s)	Current primary outcome measure as of 20/12/2024: Neuropathy symptoms measured using the Michigan Neuropathy Screening Instrument (MNSI) Part A questionnaire at 12 weeks Previous primary outcome measure: Sural nerve conductivity measured using a nerve conduction study at month 6 (Primary), and month 9. This includes conduction velocity (m/s), calculated using distance and latency (ms), and sensory nerve action potential (SNAP) amplitude (µV).
Key secondary outcome measure(s)	Current secondary outcome measures as of 20/12/2024: Feasibility outcome measures: 1. Recruitment rate measured using screening and randomisation logs at pre-screening / identification, recruitment and consent, and baseline 2. Participant retention rate measured using randomisation and withdrawal logs at recruitment and consent, baseline, week 12, week 26 3. Adherence to treatment measured using Revitive App and a patient diary at week 12 Safety outcome measures : 1. Adverse Events (AEs) collected and reported via AE form at baseline, week 3, week 6, week 9, week 12, week 26 (and any communication in between) 2. Adverse Device Effects (ADEs) collected and reported via AE form at baseline, week 3, week 6, week 9, week 12, week 26 (and any communication in between) 3. Serious Adverse Events (SAEs) collected and reported via SAE form at baseline, week 3, week 6, week 9, week 12, week 26 (and any communication in between) 4. Serious Adverse Device Effects (SADEs) collected and reported via SAE form at baseline, week 3, week 6, week 9, week 12, week 26 (and any communication in between) Secondary outcome measures 1. Sural nerve conductivity (central site only) measured using a nerve conduction study, includes conduction velocity (m/s), calculated using distance and latency (ms), and sensory nerve action potential (SNAP) amplitude (µV) at week 12 and week 26 2. Superficial peroneal nerve conductivity (central site only) measured using a nerve conduction study, includes conduction velocity (m/s), calculated using distance and latency (ms), and sensory nerve action potential (SNAP) amplitude (µV) at week 12 and week 26 3. Common peroneal nerve conductivity (central site only) measured using a nerve conduction study, 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) at week 12 and week 26 4. Tibial nerve conductivity (central site only) measured using a nerve conduction study, including conduction velocity (m/s), calculated using distance and distal latency (ms), Compound Muscle Action Potential (CMAP) amplitude (mV) and minimum F wave latency (ms) at week 12 and week 26 5. Somatosensory nerve fibre function (central site only) measured using Quantitative Sensory Testing (QST) at week 12 and week 26 6. Blood glucose measured using HbA1c at week 12 7. Mobility and balance measured using a validated Berg Balance Scale (BBS) at week 12 and week 26 8. Neuropathy signs measured using a validated screening questionnaire, Michigan Neuropathy Screening Instrument (MNSI) Part B Examination at week 12 and week 26 9. Symptoms measured using Total Symptom Score at week 6, week 12 and week 26 10. Protected sensation measured using monofilament test at week 12 and week 26 11. Neuropathic pain measured using Neuropathic Pain Symptom Inventory (NPSI) at week 12 and week 26 12. Device sensation measured using device sensory threshold and suprathreshold at week 12 and week 26 13. Device experience measured using a device experience questionnaire at week 12 14. Device credibility and expectancy measured using modified credibility and expectancy questionnaire at baseline _____ Previous secondary outcome measures as of 13/07/2023: Feasibility outcome measures 1. Recruitment rate – measured using screening and randomisation logs at pre-screening / identification, recruitment and consent, and baseline 2. Participant retention rate – measured using randomisation and withdrawal logs at recruitment and consent, baseline, month 6 3. Adherence to treatment – measured using Revitive App and a patient diary at month 6 Safety outcome measures 1. Adverse Events (AEs) – collected and reported via AE form at baseline, week 2, month 6, month 9 (and any communication in between) 2. Adverse Device Effects (ADEs) – collected and reported via AE form at baseline, week 2, month 6, month 9 (and any communication in between) 3. Serious Adverse Events (SAEs) – collected and reported via SAE form at baseline, week 2, month 6, month 9 (and any communication in between) 4. Serious Adverse Device Effects (SADEs) – collected and reported via SAE form at baseline, week 2, month 6, month 9 (and any communication in between) Secondary outcome measures 1. Superficial peroneal nerve conductivity – measured using a nerve conduction study, includes conduction velocity (m/s), calculated using distance and latency (ms), and sensory nerve action potential (SNAP) amplitude (µV) at months 6 and 9 2. Common peroneal nerve conductivity – measured using a nerve conduction study, 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) at months 6 and 9 3. Tibial nerve conductivity – measured using a nerve conduction study, including conduction velocity (m/s), calculated using distance and distal latency (ms), Compound Muscle Action Potential (CMAP) amplitude (mV) and minimum F wave latency (ms) at months 6 and 9 4. Somatosensory nerve fibre function – measured using Quantitative Sensory Testing (QST) at months 6 and 9 5. Mobility and balance – measured using validated Berg Balance Scale (BBS) at months 6 and 9 6. Quality of life – measured using a validated EQ-5D-5L questionnaire at months 6 and 9 7. Illness perceptions – measured using validated Brief Illness Perception Questionnaire (Brief IPQ) at months 6 and 9 8. Neuropathy signs and symptoms – measured using a validated screening questionnaire, Michigan Neuropathy Screening Instrument (MNSI) at months 6 and 9 9. Neuropathy symptoms – measured using validated Self-administered Neuropathy Total Symptom Score (NTSS-6-SA) at months 6 and 9 10. Protected sensation – measured using monofilament test at months 6 and 9 11. Pain – neuropathic pain measuring using Neuropathic Pain Symptom Inventory (NPSI) at months 6 and 9, and daily pain measured using an 11-point Numerical Rating Scale (NRS) collected via text message daily for the treatment phase (6 months) 12. Sleep interference – daily sleep interference measured using Daily Sleep Interference Scale (DSIS) collected via text message daily for the treatment phase (6 months) 13. Peripheral arterial perfusion – measured using Ankle Brachial Pressure Index (ABPI) at baseline 14. Device sensation – measured using device sensory threshold and suprathreshold at months 6 and 9 15. Device experience – measured using a device experience questionnaire at month 6 16. Device credibility and expectancy – measured using modified credibility and expectancy questionnaire at baseline _____ Previous secondary outcome measures: Feasibility outcome measures 1. Recruitment rate – measured using screening and randomisation logs at pre-screening / identification, recruitment and consent, and baseline 2. Participant retention rate – measured using randomisation and withdrawal logs at recruitment and consent, baseline, month 6 3. Adherence to treatment – measured using Revitive App and a patient diary at month 6 Safety outcome measures 1. Adverse Events (AEs) – collected and reported via AE form at baseline, week 2, month 6, month 9 (and any communication in between) 2. Adverse Device Effects (ADEs) – collected and reported via AE form at baseline, week 2, month 6, month 9 (and any communication in between) 3. Serious Adverse Events (SAEs) – collected and reported via SAE form at baseline, week 2, month 6, month 9 (and any communication in between) 4. Serious Adverse Device Effects (SADEs) – collected and reported via SAE form at baseline, week 2, month 6, month 9 (and any communication in between) Secondary outcome measures 1. Superficial peroneal nerve conductivity – measured using a nerve conduction study, includes conduction velocity (m/s), calculated using distance and latency (ms), and sensory nerve action potential (SNAP) amplitude (µV) at months 6 and 9 2. Common peroneal nerve conductivity – measured using a nerve conduction study, 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) at months 6 and 9 3. Tibial nerve conductivity – measured using a nerve conduction study, including conduction velocity (m/s), calculated using distance and distal latency (ms), Compound Muscle Action Potential (CMAP) amplitude (mV) and minimum F wave latency (ms) at months 6 and 9 4. Somatosensory nerve fibre function – measured using Quantitative Sensory Testing (QST) at months 6 and 9 5. Mobility and balance – measured using validated Berg Balance Scale (BBS) at months 6 and 9 6. Quality of life – measured using a validated EQ-5D-5L questionnaire at months 6 and 9 7. Illness perceptions – measured using validated Brief Illness Perception Questionnaire (Brief IPQ) at months 6 and 9 8. Neuropathy signs and symptoms – measured using a validated screening questionnaire, Michigan Neuropathy Screening Instrument (MNSI) at months 6 and 9 9. Neuropathy symptoms – measured using validated Self-administered Neuropathy Total Symptom Score (NTSS-6-SA) at months 6 and 9 10. Protected sensation – measured using monofilament test at months 6 and 9 11. Pain – neuropathic pain measuring using Neuropathic Pain Symptom Inventory (NPSI) at months 6 and 9, and daily pain measured using an 11-point Numerical Rating Scale (NRS) collected via text message daily for the treatment phase (6 months) 12. Sleep interference – daily sleep interference measured using Daily Sleep Interference Scale (DSIS) collected via text message daily for the treatment phase (6 months) 13. Peripheral arterial perfusion – measured using Ankle Brachial Pressure Index (ABPI) at months 6 and 9 14. Device sensation – measured using device sensory threshold and suprathreshold at months 6 and 9 15. Device experience – measured using a device experience questionnaire at month 6 16. Device credibility and expectancy – measured using modified credibility and expectancy questionnaire at baseline
Completion date	30/06/2025

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	All
Target sample size at registration	64
Total final enrolment	65
Key inclusion criteria	Current inclusion criteria as of 20/12/2024: 1. Aged ≥18 years (no upper limit) 2. Diagnosis of type 1 or type 2 diabetes based on World Health Organisation (WHO) definition 3. Diagnosis of diabetic neuropathy based on validated screening questionnaire Michigan Neuropathy Screening Instrument score of ≥4 4. Access to the internet at home to use the Revitive App (study smartphones will be provided) Previous inclusion criteria: 1. Aged ≥18 years (no upper limit) 2. Diagnosis of type 1 or type 2 diabetes based on World Health Organisation (WHO) definition 3. Diagnosis of diabetic neuropathy based on: 3.1. Symptoms of diabetic neuropathy 3.2. Validated screening questionnaire Michigan Neuropathy Screening Instrument score of ≥4 3.3. Nerve conduction study of at least one lower limb must have a sural sensory nerve action potential (SNAP) amplitude of <6 µV or absent 4. Access to the internet at home to use the Revitive App (study smartphones will be provided) 5. Personal mobile phone to receive text messages
Key exclusion criteria	Current exclusion criteria as of 20/12/2024: 1. Lacks the capacity to provide informed consent 2. Pregnant 3. Implanted electronic, cardiac or defibrillator device 4. Other causes of peripheral neuropathy 5. Current foot ulceration 6. Severe vascular disease requiring invasive intervention 7. Being treated for, or having the symptoms of, an existing deep vein thrombosis (DVT) 8. Regularly used a neuromuscular electrical stimulation (NMES) device within 1 year of randomisation Previous exclusion criteria: 1. Lacks the capacity to provide informed consent 2. Pregnant 3. Implanted electronic, cardiac or defibrillator device 4. Other causes of peripheral neuropathy (e.g. excessive drinking, low levels of vitamin B12 or other vitamins, syphilis, HIV, underactive thyroid gland) 5. Current foot ulceration 6. Severe vascular disease requiring invasive intervention 7. Being treated for, or having the symptoms of, an existing deep vein thrombosis (DVT) 8. Used a neuromuscular electrical stimulation (NMES) device within 1 year of randomisation
Date of first enrolment	23/08/2023
Date of final enrolment	31/12/2024

Locations

Countries of recruitment

United Kingdom
England

Study participating centres

Imperial College Healthcare NHS Trust

Charing Cross Hospital
Fulham Palace Road
London
W6 8RF
United Kingdom

Mid and South Essex NHS Foundation Trust

Basildon University Hospital
Nethermayne
Basildon
Essex
SS16 5NL
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
IPD sharing plan	The datasets generated during and/or analysed during the current study are/will be available upon request from Miss Sasha Smith (Imperial College London), sasha.smith@imperial.ac.uk. Data-sharing requests may be made outside the sponsor organisation and will be made under an appropriate data-sharing agreement.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes
Protocol file	version 12.0	14/01/2025	02/04/2025	No	No

Additional files

ISRCTN17050221_PROTOCOL_V12.0_14Jan25.pdf: Protocol file

Editorial Notes

02/04/2025: Protocol uploaded. The target number of participants was changed from 100 to 64. Total final enrolment added.
20/12/2024: The study hypothesis, interventions, primary and secondary outcome measures, inclusion and exclusion criteria and plain English summary were updated.
19/12/2024: The following changes were made to the study record:
1. The overall end date was changed from 30/09/2025 to 30/06/2025.
2. The intention to publish date was changed from 30/03/2026 to 31/12/2026.
19/03/2024: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/03/2024 to 31/12/2024.
2. The overall end date was changed from 31/12/2024 to 30/09/2025.
3. The intention to publish date was changed from 30/06/2025 to 30/03/2026.
4. The plain English summary was updated to reflect these changes.
11/08/2023: The recruitment start date was changed from 01/08/2023 to 23/08/2023.
13/07/2023: The following changes were made to the trial record:
1. The secondary outcome measures were changed.
2. The recruitment start date was changed from 01/07/2023 to 01/08/2023.
22/06/2023: Trial's existence confirmed by the Health Research Authority (HRA) (UK).