Frequency Modulated Neural Stimulation (FREMS) in Symptomatic Diabetic Neuropathy

• Change in Nerve Conduction Velocity of the Deep Peroneal, Tibial, or Sural Nerve [ Time Frame: baseline and 51 weeks ] [ Designated as safety issue: No ]
  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 [ Time Frame: baseline and 51 weeks ] [ Designated as safety issue: No ]
  Change in Vibration Perception Threshold at 51 weeks (i.e., after three cycles of FREMS treatment) versus baseline
  
  
• Change in Cold Sensory Threshold [ Time Frame: baseline and 51 weeks ] [ Designated as safety issue: No ]
  Change in Cold Sensory Threshold at 51 weeks (i.e., after three cycles of FREMS treatment) versus baseline
  
  
• Change in Warm Sensory Threshold [ Time Frame: baseline and 51 weeks ] [ Designated as safety issue: No ]
  Change in Warm Sensory Threshold at 51 weeks (i.e., after three cycles of FREMS treatment) versus baseline
  
  
• Change in Day Pain Intensity (Visual Analogue Scale) [ Time Frame: baseline and week 3 ] [ Designated as safety issue: No ]
  Change in Pain Intensity (assessed using Visual Analogue Scale) during day time with the first cycle of FREMS
  
  
• Change in Day Pain Intensity (Visual Analogue Scale) [ Time Frame: week 17 and week 20 ] [ Designated as safety issue: No ]
  Change in Pain Intensity (assessed using Visual Analogue Scale) during day time with the second cycle of FREMS
  
  
• Change in Day Pain Intensity (Visual Analogue Scale) [ Time Frame: week 34 and week 37 ] [ Designated as safety issue: No ]
  Change in Pain Intensity (assessed using Visual Analogue Scale) during day time with the third cycle of FREMS
  
  
• Change in Night Pain Intensity (Visual Analogue Scale) [ Time Frame: baseline and week 3 ] [ Designated as safety issue: No ]
  Change in Pain Intensity (assessed using Visual Analogue Scale) during night time with the first cycle of FREMS
  
  
• Change in Night Pain Intensity (Visual Analogue Scale) [ Time Frame: week 17 and week 20 ] [ Designated as safety issue: No ]
  Change in Pain Intensity (assessed using Visual Analogue Scale) during night time with the second cycle of FREMS
  
  
• Change in Night Pain Intensity (Visual Analogue Scale) [ Time Frame: week 34 and week 37 ] [ Designated as safety issue: No ]
  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) [ Time Frame: baseline and 51 weeks ] [ Designated as safety issue: No ]
  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 [ Time Frame: baseline and 51 weeks ] [ Designated as safety issue: No ]
  Change in the dose and type of analgesic medications at week 51 (i.e. after three FREMS cycles) versus baseline
  
  
• Number of patients with treatment-related adverse events [ Time Frame: baseline and 51 weeks ] [ Designated as safety issue: No ]
  Change in the dose and type of analgesic medications at week 51 (i.e. after three FREMS cycles) versus baseline
  
  

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.