Frequency Modulated Neural Stimulation (FREMS) in Symptomatic Diabetic Neuropathy

Study Overview
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Brief Summary
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Aim of this study is to evaluate safety and efficacy of transcutaneous frequency modulated electromagnetic neural stimulation (FREMS) to treat symptomatic peripheral neuropathy in patients with diabetes mellitus.

Detailed Description
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Diabetic neuropathy is a common and potentially disabling complication of patients with type 1 or type 2 diabetes due to the damage of peripheral nerves caused by chronic hyperglycemia. The most common clinical signs and symptoms of diabetic neuropathy include numbness, diminished sensation and painful symptoms, such as burning, pins and needles, intolerable pain and hyperaesthesia of the lower extremities. Different classes of drugs, such as analgesics, antidepressants and anti-epileptics are variably efficacious in pain relief, but are unfortunately unable to revert the natural history of the disease. A wide range of electrotherapies have been proposed for the non-pharmacological treatment of diabetic neuropathy. The rationale of using electric or magnetic stimulation is the potential enhancement of microcirculation and endoneural blood flow, possibly counteracting the nerve ischemic damage, together with other yet poorly understood mechanisms, such as masking pain by interfering with pain gate control. A number of studies have reported the efficacy of different electrotherapies, such as transcutaneous electrical nerve stimulation (TENS), pulsed-dose electrical stimulation, peripheral nerve, nerve root, spinal cord, deep brain and epidural motor cortex stimulations, pulsed (electro-)magnetic fields and static magnetic fields, high-frequency external muscle stimulation, high-tone external muscle stimulation and external muscle stimulation. However, of all these electrotherapies, only TENS is currently recommended as a treatment for painful diabetic neuropathy by the American Academy of Neurology. Recently, a novel transcutaneous frequency-modulated electromagnetic neural stimulation (also named as Frequency Rhythmic Electrical Modulation System, FREMS), has been developed. FREMS consists of a sequence of modulated electrical stimuli that varies automatically in terms of pulse frequency, duration and voltage amplitude. FREMS was tested in a pilot randomized, cross-over study, and reduced diabetic neuropathy pain and ameliorated the sensory tactile and vibration perception threshold and motor nerve conduction velocity compared to a sham treatment. The aim of this study was to test the efficacy and safety of FREMS in a multicentre, randomized, double-blind, placebo-controlled study enrolling a large population with symptomatic diabetic polyneuropathy, with repeated treatment sessions and a post-treatment follow-up of adequate length.

Official Title
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Long Term, Double Blind, Randomized, Placebo Controlled Multi-center Study of FRE.M.S.- Frequency Modulated Neural Stimulation Lorenz Therapy™ in Symptomatic Diabetic Neuropathy

Conditions
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Diabetic Neuropathy, Painful

Intervention / Treatment
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* Device: Frequency Modulated Neural Stimulation (FREMS) (Aptiva)
* Device: sham treatment (Aptiva)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 1 or Type 2 diabetes Diabetes duration of > 1 year Age: 18 to 75 years Symptomatic neuropathy Abnormal amplitude, latency or conduction velocity in at least one motor nerve (Tibial or Peroneal) or in the Sural Nerve A measurable Sural Nerve conduction velocity Stable glycemic control in the last 3 months, HbA1C < 11% MDNS score > 7 Stable dose of analgesic medications, if any, in the month prior enrollment Exclusion Criteria: Previous treatment with TENS or other electrotherapy Motor or Sensitive nerve conduction velocity < 30 non recordable/evocable Unstable glycemic control during last 3 months Pregnancy Implanted pacemaker or defibrillator or neurostimulator Cancer diagnosed in the last 5 years Psychological or psychiatric disorders that in the Investigator's opinion may interfere with patient's compliance to study procedures Active foot ulcer and/or major lower limb amputation Diabetic mononeuropathy Severe peripheral artery disease (Leriche Fontaine scale grade 3 and 4) Ankle-brachial index (ABI) < 0.7 Uremic neuropathy or end-stage renal disease Toxic neuropathies Severe hepatic disease Alcohol consumption ≥ 40 g/day or 30 units/week

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FREMS<br>Frequency Modulated Neural Stimulation (FREMS) | Device: Frequency Modulated Neural Stimulation (FREMS) (Aptiva)<br>* FREMS consisted of sequences of biphasic (negative and positive), asymmetric and electrically balanced pulses, composed of: 1) an active phase of high negative voltage spike (variable, max -300 V) and extra short duration (variable, 10-100 μsec, mostly  40 μsec); followed by: 2) a recharging phase of low voltage and long duration (0.9 - 999 msec); pulse frequency was variable, ranging 1 to 1,000 Hz, mainly in the low range 1-50 Hz. Three cycles of 10 consecutive (one a day for 5 days/week) applications to both lower limbs were delivered.<br>* Other names: Aptiva device (Lorenz Biotech, Medolla, Italy);|
| Sham Comparator: Control<br> | Device: sham treatment (Aptiva)<br>* The sham treatment consisted of no electrical pulses delivered by the same device used to deliver the FREMS treatment and with the same treatment procedure and schedule.<br>* Other names: Aptiva device (Lorenz Biotech, Medolla, Italy);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Nerve Conduction Velocity of the Deep Peroneal, Tibial, or Sural Nerve | Change in Nerve Conduction Velocity of the Deep Peroneal , Tibial, or Sural Nerve at 51 weeks (i.e., after three cycles of FREMS treatment) versus baseline | baseline and 51 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Vibration Perception Threshold | Change in Vibration Perception Threshold at 51 weeks (i.e., after three cycles of FREMS treatment) versus baseline | baseline and 51 weeks | 
| Change in Cold Sensory Threshold | Change in Cold Sensory Threshold at 51 weeks (i.e., after three cycles of FREMS treatment) versus baseline | baseline and 51 weeks | 
| Change in Warm Sensory Threshold | Change in Warm Sensory Threshold at 51 weeks (i.e., after three cycles of FREMS treatment) versus baseline | baseline and 51 weeks | 
| Change in Day Pain Intensity (Visual Analogue Scale) | Change in Pain Intensity (assessed using Visual Analogue Scale) during day time with the first cycle of FREMS | baseline and week 3 | 
| Change in Day Pain Intensity (Visual Analogue Scale) | Change in Pain Intensity (assessed using Visual Analogue Scale) during day time with the second cycle of FREMS | week 17 and week 20 | 
| Change in Day Pain Intensity (Visual Analogue Scale) | Change in Pain Intensity (assessed using Visual Analogue Scale) during day time with the third cycle of FREMS | week 34 and week 37 | 
| Change in Night Pain Intensity (Visual Analogue Scale) | Change in Pain Intensity (assessed using Visual Analogue Scale) during night time with the first cycle of FREMS | baseline and week 3 | 
| Change in Night Pain Intensity (Visual Analogue Scale) | Change in Pain Intensity (assessed using Visual Analogue Scale) during night time with the second cycle of FREMS | week 17 and week 20 | 
| Change in Night Pain Intensity (Visual Analogue Scale) | Change in Pain Intensity (assessed using Visual Analogue Scale) during night time with the third cycle of FREMS | week 34 and week 37 | 
| Change in the Michigan Diabetic Neuropathy Score (MDNS) | Change in the Michigan Diabetic Neuropathy Score (MDNS) at 51 weeks (i.e. after three FREMS cycles) versus baseline | baseline and 51 weeks | 
| Change in the dose and type of analgesic medications | Change in the dose and type of analgesic medications at week 51 (i.e. after three FREMS cycles) versus baseline | baseline and 51 weeks | 
| Number of patients with treatment-related adverse events | Change in the dose and type of analgesic medications at week 51 (i.e. after three FREMS cycles) versus baseline | baseline and 51 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetic Neuropathy, Painful