Award Title: The Utility Of Frequency-Modulated Electromagnetic Neural Stimulation (FREMS) As A Third Line Treatment In Patients With Painful Diabetes-Related Peripheral Neuropathy: A Randomised Controlled Trial (FREMS-PDPN)
Funder: Department of Health and Social Care

Abstract: Aims: To evaluate the efficacy of FREMS (Frequency Rhythmic Electrical Modulated System) in patients with painful diabetic peripheral neuropathy (PDPN, painful feet from nerve damages caused by diabetes) who have not responded to the NICE (National Institute for Health and Care Excellence) recommended treatments. FREMS delivers electrical pulses via stickers that are placed on the feet and legs; these pulses can reduce the pain in patients with PDPN._x000D_
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Background: PDPN affects a quarter of people with diabetes and 70% of sufferers have moderate-to-severe foot pain. This pain results in in sleep disruption, poor quality of life (QoL), unemployment and depression. The average health care cost for each patient with PDPN in the UK was estimated to be £2,511 per year, which increases with greater pain severity. The burden of PDPN is likely to increase as diabetes becomes more common. NICE guidance 173 recommended certain medications as initial treatments for PDPN. However, using these medications results in 50% reduction in pain in one third of patients at best. These medications also have multiple side effects such as nausea, sedation, dizziness, dry mouth, weight gain, falls, constipation and more. Beyond these drugs, there are no NICE recommended treatments. As a result, many patients receive opioids (43%), which has many unwanted side effects including addiction.  _x000D_
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Hence, there is a clear need to identify an effective, safe, well-tolerated, non-invasive intervention that is good value for money in those who fail to respond to NICE recommended treatments. This could reduce medications and opioid use & improve QoL._x000D_
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Design and methods: We propose a randomised controlled trial to assess the efficacy of FREMS in patients with PDPN who have significant pain despite trying the NICE recommended treatments. Randomised means that the patients will receive a treatment chosen by chance (like flipping a coin). Participants will be randomised to FREMS or TENS (Transcutaneous Electrical Nerve Stimulation). Both FREMS and TENS give electrical pulses delivered through stickers on the skin. The nature of these pulses is different between FREMS and TENS, resulting in different biological effects on pain and different responses (short term pain reductions for TENS, usually days, and 3-4 months for FREMS). In this study, both FREMS and TENS will be delivered using the same device and stickers on the skin, but treatment will be chosen by a keycard with a pre-programmed randomly chosen treatment allocation. This will ensure that neither participants nor researchers can tell which treatment is given, and this will improve the quality of the study results._x000D_
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After randomisation, participants will receive 35-minute treatment sessions for 10 consecutive weekdays at the research centre. The main study outcome will be at 3 months with a total follow up of 6 months. During the study, routine care will continue and participants’ medications can be adjusted by their doctors as needed. The main study outcome is pain severity collected by text message from the participants. Other outcomes include QoL, sleep quality, medication changes & value for money._x000D_
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Patient and public involvement: Patients have been involved in defining the research question and writing the lay summary. Patients will be involved in the study conduct and oversight, producing patient information, and dissemination._x000D_
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Dissemination: The findings will be shared widely, including conferences, patient groups, NICE and local commissioning groups.

Lay Abstract: Research question: Is Frequency Rhythmic Electrical Modulated System (FREMS) an effective treatment in patients with persistent painful diabetic peripheral neuropathy (PDPN) despite trying at least two PDPN medications?_x000D_
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Background: PDPN affects 25% of people with diabetes and 70% of sufferers have moderate-to-severe pain. PDPN is associated with sleep disruption, poor quality of life (QoL), unemployment & depression. The average health care cost of PDPN in the UK is £2,511 per patient per year, which increases with greater pain severity. The burden of PDPN is likely to increase with increasing diabetes prevalence. National Institute for Health and Care Excellence (NICE) guidance 173 recommended certain medications as initial treatments for PDPN. However, using these medications only results in 50% reduction in pain in 33% of patients at best. These medications also have multiple significant side effects (such as weight gain, falls, urinary retention, constipation). Beyond these drugs, there are no NICE recommended treatments. As a result, many patients (43%) receive opioids, which have many unwanted side effects including dependency. There is a clear need to identify an effective, safe, well-tolerated, non-invasive, and cost-effective intervention in those who fail to respond to NICE recommended treatments. This could reduce medication and opioid use and improve QoL._x000D_
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Aims and objectives: Efficacy objectives: 1. To evaluate the efficacy of FREMS using 11-point numerical rating scale (NRS) 24-hour pain scores (0 to 10) averaged over the last 7 days (primary outcome). 2. Other outcomes: sleep quality, QoL & medication use amongst others. 3. To evaluate the cost effectiveness of FREMS in PDPN. Safety objectives: To describe Adverse Events and Serious Adverse Events data. Exploratory objectives: To investigate if patient phenotypes predict response to treatment._x000D_
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Methods:_x000D_
Design: A multi-centre 2-arm parallel group double blind sham-controlle RCT. The RCT will include an internal pilot with stop/go criteria. _x000D_
Setting: Patients will be recruited from 10 NHS Trusts that have PDPN services and the aligned primary care and podiatry services, as well as social media and Diabetes UK local patient groups. The study device will be placed in the Trusts._x000D_
Population: Adults with PDPN for >=3 months with significant pain (a mean total pain NRS >=4 for the week before randomisation) despite trying at least 2 different classes of medication._x000D_
Intervention: FREMS + standard care. Comparator: TENS (Transcutaneous Electrical Nerve Stimulation) + standard care_x000D_
Outcomes: As above. The primary outcome is at 3 months & study end at 6 months._x000D_
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Timelines: Protocol, database & CRFs: months 1-8; HRA, REC, MHRA approvals: 5-9; Site set-up: 8-13; Recruitment: 10-29; Follow-up: 13-35, Data Cleaning: 35-38; Analysis & dissemination: 36-41; Health economic analysis: 36-41; Final report: 41_x000D_
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Anticipated impact: The trial is designed to address gaps identified by NICE multiple technology appraisal (MTA) of FREMS in 2017. Hence the outcome of the trial is likely to lead to a NICE technology appraisal_x000D_
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Dissemination: Via peer-reviewed articles, national/international presentations, Diabetes UK patients groups and social media. The investigators will liaise with the manufacturer & NICE. Study participants will be informed of the findings.

Research Activity Codes: 6.3 MEDICAL DEVICES
Health Categories: METABOLIC AND ENDOCRINE;NEUROLOGICAL