The utility of frequency-modulated electromagnetic neural stimulation as a third-line treatment in patients with 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 a week 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 tr CONDITION: Painful diabetes‐related peripheral neuropathy ; Nervous System Diseases PRIMARY OUTCOME: 7‐day average 24‐hour pain measured on an 11‐point NRS scale (0 = no pain and 10 = worst pain imaginable) at 3 months post‐randomisation 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 SECONDARY OUTCOME: 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 Inde X(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