The utility of frequency-modulated electromagnetic neural stimulation as a third-line treatment in patients with painful diabetes-related peripheral neuropathy

ISRCTN	ISRCTN11665378
DOI	https://doi.org/10.1186/ISRCTN11665378
ClinicalTrials.gov (NCT)	Nil known
Clinical Trials Information System (CTIS)	Nil known
Integrated Research Application System (IRAS)	316524
Protocol serial number	CPMS 53965, IRAS 316524, Grant Code: NIHR133599
Sponsor	University of Birmingham
Funder	NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC)

Submission date: 10/01/2023
Registration date: 16/01/2023
Last edited: 19/05/2025

Recruitment status: Recruiting
Overall study status: Ongoing
Condition category: Nervous System Diseases

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims
Diabetes mellitus (DM) is very common in the UK and globally and is a major healthcare challenge for the NHS. Diabetes UK announced that the number of people living with DM in the UK has more than doubled over the last 20 years, reaching 4.7 million in 2018, costing the NHS at least £10 billion a year, or 10% of the total NHS budget. The number of people living with DM is expected to reach 5 million in 2025 and 5.5 million in 2030, and the cost to the NHS is likely to increase significantly with this increased prevalence. Painful diabetes-related peripheral neuropathy (PDPN, damage to the nerves caused by high blood sugar levels) is a serious complication affecting 20-26% of patients with DM. PDPN has a major impact on quality of life, mood, sleep and relationships. This study aims to evaluate the clinical and cost-effectiveness of FREMS (frequency rhythmic electrical modulated system) in adults with PDPN.

Who can participate?
Patients aged 18 years and over with diabetes mellitus and neuropathic pain affecting both feet for at least 3 months or taking pain medication for neuropathic pain for at least 3 months

What does the study involve?
Participants are randomly allocated to receive 10 sessions of either transcutaneous electrical nerve stimulation (TENS) or FREMS treatment for 35 minutes each session. Follow-up is then up until 6 months.

What are the possible benefits and risks of participating?
The researchers do not expect any safety issues or risks for the participants. The only risk associated with either intervention is in the potential for soreness at the point of application of the adhesive patches during and shortly after treatment; this risk remains the same for both arms. Offering the study to potential participants may prolong the clinic visit. The time taken for patients to receive their treatment can also be deemed as a potential burden but this additional time was felt to be within acceptable limits by patients and patient society representatives. Both treatments could give some pain relief to patients. Participants will have the potential opportunity to try a new therapy before it is generally available.

Where is the study run from?
University of Birmingham (UK)

When is the study starting and how long is it expected to run for?
January 2022 to February 2027

Who is funding the study?
National Institute for Health and Care Research (NIHR) (UK)

Who is the main contact?
Ursula Ann Bobi, u.a.w.bobi@bham.ac.uk

Contact information

Ms Ursula Ann Bobi
Scientific

Birmingham Clinical Trials Unit
Public Health Building (Y17)
University of Birmingham
Edgbaston
Birmingham
B15 2TT
United Kingdom

Phone	+44 (0)121 415 9128
Email	u.a.w.bobi@bham.ac.uk

Study information

Primary study design	Interventional
Study design	Randomized; Interventional; Design type: Treatment, Device
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	The utility of frequency-modulated electromagnetic neural stimulation as a third-line treatment in patients with painful diabetes-related peripheral neuropathy: a randomised controlled trial
Study acronym	FREMS-PDPN
Study objectives	In patients with painful diabetes-related peripheral neuropathy (PDPN), frequency-modulated electromagnetic neural stimulation (FREMS) added to standard care as a third-line treatment (or higher) is superior to standard care in terms of reducing pain, improving sleep, improving quality of life (QoL) and reducing the use of medications, especially opioids.
Ethics approval(s)	Approved 28/11/2022, London-Bromley Research Ethics Committee (Temple Quay House, 2 The Square, Temple Quay, Bristol, BS1 6PN, UK; +44 (0)2071048118, +44 (0)2071048140, +44 (0)2071048016; bromley.rec@hra.nhs.uk), ref: 22/LO/0683
Health condition(s) or problem(s) studied	Painful diabetes-related peripheral neuropathy
Intervention	Design: A pragmatic, multi-centre, two-arm, parallel-group, double-blind, sham-controlled, randomised trial with an internal pilot. Target population: 356 adults with PDPN for ≥3 months with significant pain (mean pain Numerical Rating Scale [NRS] ≥4 for ≤4 weeks prior to randomisation) despite trying ≥2 different classes of PDPN medications. Setting: NHS Trusts with PDPN services and aligned primary care and podiatry services. Sub-study: Aimed at ensuring that there is no worsening sensory dysfunction with the trial interventions. The sub-study will also look for different responder rates in relation to the quantitative sensory testing (QST) phenotype. The substudy will perform QST using the validated and standardised German Research Network on Neuropathic Pain (DFNS) protocol, which also has validated age and gender normative values Treatment allocation: Participants will be individually randomised on a 1:1 basis between FREMS and transcutaneous electrical nerve stimulation (TENS) via a secure, online randomisation system based at Birmingham Clinical Trials Unit. A minimisation algorithm will be used within the randomisation system to ensure equal distribution. Screening visits: The research team will take pre-screening consent and assess partial eligibility. Participants will be asked to complete a 7-day pain diary in order to confirm trial suitability. The patient will complete a pain diary at home via their personal device. Baseline visit: If the patient is eligible to take part, the research team will take full trial informed consent, and complete outcome assessments and questionnaires with them at a baseline visit. The research team will record participants' personal details, medical history and current medication for randomisation. At randomisation trial treatment will be allocated, and started as soon as is practical for the participant. Treatment phase: 10 x 35-minute sessions over a 2-week period. Follow-up: Patients will be followed up at 3 and 6 months post-randomisation. During these visits patients will be asked to repeat some of the questionnaires and outcome assessments completed at the baseline visit. Patients will complete the daily pain diary via text message/email for the duration of the trial from pre-screening to 6-month follow-up. Statistical analysis and sample size: 356 patients will be recruited in total. Up to 100 of these patients will take part in the QST sub-study. The justification for the sample size is based on the placebo response from RCTs in PDPN which is estimated to be 1.4 (95% CI 1.2 to 1.6) points reduction in pain severity based on NRS. To detect a mean difference of 0.6 points between groups at 3 months using the standard method of difference between means using a two-sided t-test and assuming a standard deviation of 1.65 (effect size 0.36) with 90% power and a type I error rate of 5%, a total of 160 participants per group will need to be randomised, 320 in total. Assuming and adjusting for a 10% attrition rate, 356 participants will need to be recruited (178 per group).
Intervention type	Device
Phase	Not Applicable
Drug / device / biological / vaccine name(s)	Frequency-Modulated Electromagnetic Neural Stimulation (FREMS) device
Primary outcome measure(s)	7-day average 24-hour pain on an 11-point NRS scale (0 = no pain and 10 = worst pain imaginable) measured at 3 months post-randomisation
Key secondary outcome measure(s)	Current secondary outcome measures as of 15/04/2025: Clinical: 1. 7-day average 24-hour pain measured on an 11-point NRS scale at the end of treatment and 6 months 2. Disease-specific quality of Life (QoL) measured using the Neuropathic Pain Impact on Quality-of-Life Questionnaire (NePIQoL) at 3 and 6 months 3. Treatment success (measured as a 30% reduction in 7-day average 24-hour pain scores) at the end of treatment, 3 and 6 months 4. Treatment success (measured as a 50% reduction in 7-day average 24-hour pain scores) at the end of treatment, 3 and 6 months 5. Area Under the Curve (AUC) for the daily NRS pain scores over the study period (from baseline to 3 months and from baseline to 6 months) 6. Pain interference with function measured using the Brief Pain Inventory-Diabetic Peripheral Neuropathy (BPI-DPN) at 3 and 6 months 7. Depression measured using the Beck Depression Inventory at 3 and 6 months 8. Sleep quality measured using the Pittsburgh Sleep Quality Index (PSQI) at 3 and 6 months 9. Pain intensity measured using the Neuropathic Pain Symptom Inventory (NPSI) at the end of treatment, 3 and 6 months. 10. Participant ratings of overall improvement, assessed by the Patients' Global Impression of Change (PGIC) and Clinician Global Impression of Change (CGIC) with a 7-point Likert scale at the end of treatment, 3 and 6 months 11. Changes to pain medications (frequencies and dosages) measured using patient-reported outcomes/clinical examination and interview with the patient at 3 and 6 months 12. Patient perception of their treatment arm, documented on the end-of-treatment participant case report form (CRF) by the patient. The patient has the option to select if they think they received FREMS or TENS. Measured at the end of the treatment phase. Cost-effectiveness: 1. Health-related QoL assessed by the EQ-5D-5L at 6 months 2. Health resource use measured using the Health Economic Questionnaire at 3 and 6 months 3. Cost per quality-adjusted life year (QALY) gained over 6 months measured using the Health Economic Questionnaire Subgroup outcomes: Changes in overall PDPN and overall quality of life measured using the Neuropathic Pain Symptom Inventory (NPSI) questionnaire mean total score and mean subscores (burning, pressing, paroxysmal and evoked pain, paresthesia/dysesthesia) at end of treatment, 3 and 6 months Safety: 1. Frequency and proportion of adverse events documented from the start of treatment until 7 days after the last treatment dose and will be reviewed for any changes in decreased pain and overall quality of life 2. Frequency of serious adverse events documented from the first treatment dose until the 6-month follow-up, to assess the safety of treatment/patient tolerance and overall treatment success/burden Previous secondary outcome measures: Clinical: 1. 7-day average 24-hour pain measured on an 11-point NRS scale at the end of treatment and at 6 months 2. Disease-specific quality of Life (QoL) measured using the Neuropathic Pain Impact on Quality-of-Life Questionnaire (NePIQoL) at 3 and 6 months 3. Treatment success (measured as a 30% reduction in 7-day average 24-hour pain scores) at end of treatment, 3 months and 6 months 4. Treatment success (measured as a 50% reduction in 7-day average 24-hour pain scores) at end of treatment, 3 months and 6 months. 5. Area Under the Curve (AUC) for the daily NRS pain scores over the study period (from baseline to 3 months and from baseline to 6 months) 6. Pain interference with function measured using the Brief Pain Inventory-Diabetic Peripheral Neuropathy (BPI-DPN) at 3 months and 6 months 7. Depression measured using the Beck Depression Inventory at 3 and 6 months 8. Sleep quality measured using the Pittsburgh Sleep Quality Index (PSQI) at 3 and 6 months 9. Participant ratings of overall improvement, assessed by the Patients' Global Impression of Change (PGIC) and Clinician Global Impression of Change (CGIC) with a 7-point Likert scale at end of treatment, 3 months and 6 months 10. Changes to pain medications (frequencies and dosages) measured using patient-reported outcomes/clinical examination and interview with the patient at 3 and 6 months 11. Patient perception of their treatment arm, documented on the end-of-treatment participant case report form (CRF) by the patient. The patient has the option to select if they think they received FREMS or TENS. Measured at the end of the treatment phase. Cost-effectiveness: 1. Health-related QoL assessed by the EQ-5D-5L at 6 months 2. Health resource use measured using Health Economic Questionnaire at 3 and 6 months Subgroup outcomes: Changes in overall PDPN and overall quality of life measured using the Neuropathic Pain Symptom Inventory (NPSI) questionnaire mean total score and mean subscores (burning, pressing, paroxysmal and evoked pain, paresthesia/dysesthesia) at end of treatment, 3 months and 6 months Safety: 1. Frequency and proportion of adverse events documented from the start of treatment until 7 days after the last treatment dose and will be reviewed for any changes in decreased pain and overall quality of life 2. Frequency of serious adverse events documented from the first treatment dose until the 6-month follow-up, to assess the safety of treatment/patient tolerance and overall treatment success/burden
Completion date	28/02/2027

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	All
Target sample size at registration	356
Key inclusion criteria	Current inclusion criteria as of 15/04/2025: 1. Aged ≥18 years 2. Neuropathic pain affecting both feet for ≥3 months or taking pain medication for neuropathic pain for ≥3 months 3. Mean pain score ≥4 on the daily NRS ≤4 weeks prior to randomisation 4. Douleur Neuropathique 4 (DN-4) questionnaire score ≥4/10 at screening to confirm the diagnosis of bilateral distal symmetrical neuropathic pain [70] 5. Diabetes-related neuropathy based on the Michigan Neuropathy Screening Instrument (MNSI) (MNSI questionnaire scored ≥7 or examination scored >2) [71, 72] 6. HbA1c <108 mmol/mol or 12% taken (within last 2 months). 7. Have tried at least two anti-neuropathic drugs from two different classes for PDPN 8. Willing and able to comply with the study schedule and be available for the treatment duration 9. Able to give written informed consent Previous inclusion criteria: 1. Aged ≥18 years 2. Neuropathic pain affecting both feet for ≥3 months or taking pain medication for neuropathic pain for ≥3 months 3. Mean pain score ≥4 on the daily NRS for 1 week prior to randomisation 4. Douleur Neuropathique 4 (DN-4) questionnaire score ≥4/10 at screening to confirm the diagnosis of bilateral distal symmetrical neuropathic pain 5. Diabetes-related neuropathy based on the Michigan Neuropathy Screening Instrument (MNSI) (MNSI questionnaire scored ≥7 or examination scored >2) 6. HbA1c <108 mmol/mol or 12% (within the last 2 months) 7. Have tried at least two drugs from two different classes for PDPN 8. Willing and able to comply with the study schedule and be available for the treatment duration 9. Able to give written informed consent
Key exclusion criteria	Current exclusion criteria as of 15/04/2025: 1. Non-diabetic neuropathies 2. Currently using TENS for PDPN 3. History of epilepsy 4. Other painful medical conditions where the pain is significantly more severe than their PDPN pain (patients will not be excluded if the pain is transient in nature) 5. Major amputations of the lower limbs 6. Active diabetic foot ulcers 7. Active malignancy 8. Patient has a pacemaker, defibrillator or neurostimulator 9. Pregnancy Previous exclusion criteria: 1. Non-diabetic neuropathies 2. Currently using TENS for PDPN 3. History of epilepsy 4. Other painful medical conditions where the pain is significantly more severe than their PDPN pain (patients will not be excluded if the pain is transient in nature) 5. Major amputations of the lower limbs 6. Active diabetic foot ulcers 7. Diagnosed malignancy 8. Pacemakers, defibrillator or neurostimulator 9. Pregnancy
Date of first enrolment	31/01/2023
Date of final enrolment	28/02/2026

Locations

Countries of recruitment

United Kingdom
England
Wales

Study participating centres

The Walton Centre

Lower Lane
Fazakerley
Liverpool
L9 7LJ
United Kingdom

Heartlands Hospital

Bordesley Green East
Bordesley Green
Birmingham
B9 5ST
United Kingdom

Ipswich Hospital

Heath Road
Ipswich
IP4 5PD
United Kingdom

Royal Hallamshire Hospital

Glossop Road
Sheffield
S10 2JF
United Kingdom

George Eliot Hospital

College Street
Nuneaton
CV10 7DJ
United Kingdom

Kings College Hospital

Mapother House
De Crespigny Park
Denmark Hill
London
SE5 8AB
United Kingdom

Manchester Diabetes, Endocrine and Metabolism Centre

Manchester Royal Infirmary
Cobbett House
Oxford Road
Manchester
M13 9WL
United Kingdom

Minerva Health Centre

Lancashire and South Cumbria NHS Foundation Trust
Sceptre Way
Walton Summit
Preston
PR5 6AW
United Kingdom

University Hospital of Wales

Cardiff and Vale University Local Health Board
Woodland House
Cardiff
CF14 4HH
United Kingdom

Hywel Dda University Lhb

Corporate Offices, Ystwyth Building
Hafan Derwen
St Davids Park, Jobswell Road
Carmarthen
SA31 3BB
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
IPD sharing plan	The final dataset will be available to members of the TMG and co-applicant group who need access to the data to undertake the final analyses. Requests for data generated during this study will be considered by BCTU. Data will typically be available 6 months after the primary publication unless it is not possible to share the data. Only scientifically sound proposals from appropriately qualified Research Groups will be considered for data sharing. The request will be reviewed by the BCTU Data Sharing Committee in discussion with the CI and, where appropriate (or in absence of the CI) any of the following: the Trial Sponsor, the TMG, and the TSC. A formal Data Sharing Agreement may be required between respective organisations once the release of the data is approved and before data can be released. Data will be fully de-identified (anonymised) unless the Data Sharing Agreement covers the transfer of participant-identifiable information. Any data transfer will use a secure and encrypted method.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
HRA research summary			26/07/2023	No	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes
Study website	Study website	11/11/2025	11/11/2025	No	Yes

Editorial Notes

19/05/2025: The following changes were made to the study record:
1. The recruitment end date was changed from 30/09/2025 to 28/02/2026.
2. The overall study end date was changed from 31/03/2026 to 28/02/2027.
15/04/2025: The following changes were made to the study record:
1. The secondary outcome measures, inclusion and exclusion criteria, and contact details were updated.
2. Study website added.
3. The recruitment end date was changed from 31/05/2024 to 30/09/2025.
4. The overall study end date was changed from 30/04/2025 to 31/03/2026.
5. The study participating centres were updated to remove Queens Medical Centre and Warwick Hospital and add Minerva Health Centre, University Hospital of Wales and Hywel Dda University Lhb.
11/01/2023: Trial's existence confirmed by the NIHR.