Frequency Modulated Neural Stimulation (FREMS) in Symptomatic Diabetic Neuropathy

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

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.

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.

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.

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.

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

Change in Vibration Perception Threshold at 51 weeks (i.e., after three cycles of FREMS treatment) versus baseline

Change in Cold Sensory Threshold at 51 weeks (i.e., after three cycles of FREMS treatment) versus baseline

Change in Warm Sensory Threshold at 51 weeks (i.e., after three cycles of FREMS treatment) versus baseline

Change in Pain Intensity (assessed using Visual Analogue Scale) during day time with the first cycle of FREMS

Change in Pain Intensity (assessed using Visual Analogue Scale) during day time with the second cycle of FREMS

Change in Pain Intensity (assessed using Visual Analogue Scale) during day time with the third cycle of FREMS

Change in Pain Intensity (assessed using Visual Analogue Scale) during night time with the first cycle of FREMS

Change in Pain Intensity (assessed using Visual Analogue Scale) during night time with the second cycle of FREMS

Change in Pain Intensity (assessed using Visual Analogue Scale) during night time with the third cycle of FREMS

Change in the Michigan Diabetic Neuropathy Score (MDNS) at 51 weeks (i.e. after three FREMS cycles) versus baseline

Change in the dose and type of analgesic medications at week 51 (i.e. after three FREMS cycles) versus baseline

Change in the dose and type of analgesic medications at week 51 (i.e. after three FREMS cycles) versus baseline

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

Conti M, Peretti E, Cazzetta G, Galimberti G, Vermigli C, Pola R, Scionti L, Bosi E. Frequency-modulated electromagnetic neural stimulation enhances cutaneous microvascular flow in patients with diabetic neuropathy. J Diabetes Complications. 2009 Jan-Feb;23(1):46-8. doi: 10.1016/j.jdiacomp.2008.02.004. Epub 2008 Apr 10.

Bosi E, Conti M, Vermigli C, Cazzetta G, Peretti E, Cordoni MC, Galimberti G, Scionti L. Effectiveness of frequency-modulated electromagnetic neural stimulation in the treatment of painful diabetic neuropathy. Diabetologia. 2005 May;48(5):817-23. doi: 10.1007/s00125-005-1734-2. Epub 2005 Apr 15.

Bosi E, Bax G, Scionti L, Spallone V, Tesfaye S, Valensi P, Ziegler D; FREMS European Trial Study Group. Frequency-modulated electromagnetic neural stimulation (FREMS) as a treatment for symptomatic diabetic neuropathy: results from a double-blind, randomised, multicentre, long-term, placebo-controlled clinical trial. Diabetologia. 2013 Mar;56(3):467-75. doi: 10.1007/s00125-012-2795-7. Epub 2012 Dec 13.