Clinical trial NCT01628627: Frequency Modulated Neural Stimulation (FREMS) in Symptomatic Diabetic Neuropathy
Official title: Long Term, Double Blind, Randomized, Placebo Controlled Multi-center Study of FRE.M.S.- Frequency Modulated Neural Stimulation Lorenz Therapy™ in Symptomatic Diabetic Neuropathy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Diabetic Neuropathy, Painful
Keywords: Diabetic Neuropathy, Painful
Lead sponsor: Lorenz Biotech S.p.A.
Sponsor class: INDUSTRY
First posted: 2012-06-27
Enrollment: 164
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in Nerve Conduction Velocity of the Deep Peroneal, Tibial, or Sural Nerve
timeFrame: baseline and 51 weeks
Secondary outcomes:
measure: Change in Vibration Perception Threshold
timeFrame: baseline and 51 weeks
measure: Change in Cold Sensory Threshold
timeFrame: baseline and 51 weeks
measure: Change in Warm Sensory Threshold
timeFrame: baseline and 51 weeks
measure: Change in Day Pain Intensity (Visual Analogue Scale)
timeFrame: baseline and week 3
measure: Change in Day Pain Intensity (Visual Analogue Scale)
timeFrame: week 17 and week 20
measure: Change in Day Pain Intensity (Visual Analogue Scale)
timeFrame: week 34 and week 37
measure: Change in Night Pain Intensity (Visual Analogue Scale)
timeFrame: baseline and week 3
measure: Change in Night Pain Intensity (Visual Analogue Scale)
timeFrame: week 17 and week 20
measure: Change in Night Pain Intensity (Visual Analogue Scale)
timeFrame: week 34 and week 37
measure: Change in the Michigan Diabetic Neuropathy Score (MDNS)
timeFrame: baseline and 51 weeks
measure: Change in the dose and type of analgesic medications
timeFrame: baseline and 51 weeks
measure: Number of patients with treatment-related adverse events
timeFrame: baseline and 51 weeks
Other outcomes:
Locations:
city: Bondy
country: France
facility: Paris-Nord University
state: Ile del France
city: Düsseldorf
country: Germany
facility: Heinrich Heine University
city: Milano
country: Italy
facility: San Raffaele Hospital & Scientific Institute
state: MI
city: Padua
country: Italy
facility: University of Padua
state: PD
city: Perugia
country: Italy
facility: University of Perugia
state: PG
city: Rome
country: Italy
facility: Tor Vergata University
state: RM
Study officials:
affiliation: San Raffaele Hospital & Scientific Institute
name: Emanuele Bosi, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.