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Neuromuscular Magnetic Stimulation in ALS Patients (NMS-ALS)

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ClinicalTrials.gov Identifier: NCT03618966
Recruitment Status : Completed
First Posted : August 7, 2018
Last Update Posted : August 7, 2018
Sponsor:
Information provided by (Responsible Party):
Maurizio Inghilleri, University of Roma La Sapienza

Brief Summary:
Aim of the study is to verify whether neuromuscular magnetic stimulation can improve muscle function in spinal-onset Amyotrophic Lateral Sclerosis (ALS) patients.

Condition or disease Intervention/treatment Phase
Amyotrophic Lateral Sclerosis Device: Neuromuscular magnetic stimulation (NMMS) Phase 2

Detailed Description:

Background: Amyotrophic lateral sclerosis (ALS) is a multi-factorial and multi-systemic pathology associated with motor neuron degeneration, muscle atrophy and paralysis. Mounting evidence suggests that the earliest presymptomatic functional and pathological changes are occurring distally in axons and at the neuromuscular junction (NMJ). These changes precede, and can be independent of the loss of cell bodies or alterations in other cell types already linked to the ALS disease process. In line with these studies, we found that in human ALS muscles the acetylcholine receptors (AChRs) are less sensitive to ACh than denervated non-ALS muscles. It has been also reported that muscle specific expression of mutant superoxide dismutase (SOD1) gene induces muscle atrophy, significant reduction in muscle strength, mitochondrial dysfunction, microgliosis, and neuronal degeneration, suggesting that retrograde signals from muscle to nerve may contribute to synapse and axon damage. This suggests that skeletal muscle is an important target for therapeutic intervention. Neuromuscular system may be artificially stimulated either by an electrical stimulation (ES) or by time-varying electromagnetic fields. Neuromuscular magnetic stimulation (NMMS) has been proposed as an alternative, non-invasive, stimulation technique.

Objective: aim of the study is to verify whether neuromuscular magnetic stimulation can improve muscle function in spinal-onset Amyotrophic Lateral Sclerosis (ALS) patients. We will study if neuromuscular magnetic stimulation can counteract muscle atrophy by promoting the modulation of factors associated with muscle catabolism and/or increasing the efficacy of nicotinic acetylcholine receptors.

Methods: At the baseline visit, ALS patients will be randomized in two groups to receive daily real neuromuscular magnetic stimulation in one arm and sham neuromuscular magnetic stimulation in the opposite arm for two weeks. All patients will undergo median nerve conduction study and a clinical examination, including handgrip strength test and evaluation of upper limbs muscle strength by Medical Research Council Muscle Scale. At the end of the stimulation procedures, a needle muscle biopsy will be performed bilaterally from flexor carpi radialis muscle. Muscle samples will be used to perform histomorphometric and molecular analysis and electrophysiological recordings of acetylcholine evoked currents.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 22 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Patients will be randomized in two groups by receiving a sequential number according to a from a computer-generated random list. A first group will receive a real stimulation (rNMMS) of the right arm and a sham stimulation (sNMMS) of the left arm; a second group received a rNMMS of the left arm and a sNMMS of the right arm. Every cycle of stimulation will last two weeks. All patients will undergo a medial nerve conduction study (NCS) and a clinical evaluation before and at the end of the treatment and another evaluation after two weeks after the end of treatment. Clinical examination will include i) handgrip strength test for the measure of maximal isometric strength of hand and flexor forearm muscles; ii) MRC Muscle Scale for manual muscular testing of the upper limbs. At the end of the stimulation procedure, a needle muscle biopsy under a local anesthetic will be performed bilaterally from flexor carpi radialis muscle for histological, physiological and molecular studies.
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: All the electrophysiological experiments will be performed in double-blind fashion.
Primary Purpose: Treatment
Official Title: Neuromuscular Magnetic Stimulation Counteracts Muscle Decline in ALS Patients
Actual Study Start Date : November 1, 2014
Actual Primary Completion Date : May 1, 2016
Actual Study Completion Date : November 1, 2017


Arm Intervention/treatment
Experimental: Right-real NMMS Group
It will receive a real stimulation (rNMMS) of the right arm and a sham stimulation (sNMMS) of the left arm
Device: Neuromuscular magnetic stimulation (NMMS)
It is a non-invasive, stimulation technique that does not induce high-intensity cutaneous electric fields and does not activate skin nociceptors, thus resulting in a painless and better-tolerated procedure. rNMMS is delivered through a high-frequency magnetic stimulator connected to a conventional circular cooled coil. Magnetic stimulator is placed above the flexor muscles of the forearm. rNMMS is delivered at a 5-Hz frequency and with a 100% stimulation intensity of 100% of the maximum intensity in 140 trains of 50 stimuli. sNMMS is delivered with a sham coil producing similar acoustic sensations and mechanical skin perceptions.

Active Comparator: Left-real NMMS Group
It will receive a rNMMS of the left arm and a sNMMS of the right arm
Device: Neuromuscular magnetic stimulation (NMMS)
It is a non-invasive, stimulation technique that does not induce high-intensity cutaneous electric fields and does not activate skin nociceptors, thus resulting in a painless and better-tolerated procedure. rNMMS is delivered through a high-frequency magnetic stimulator connected to a conventional circular cooled coil. Magnetic stimulator is placed above the flexor muscles of the forearm. rNMMS is delivered at a 5-Hz frequency and with a 100% stimulation intensity of 100% of the maximum intensity in 140 trains of 50 stimuli. sNMMS is delivered with a sham coil producing similar acoustic sensations and mechanical skin perceptions.




Primary Outcome Measures :
  1. Change from baseline to Week 2 in the muscle strength measured by Medical Research Council Muscle Scale (MRC). [ Time Frame: Baseline to Week 2 ]
    Evaluation of the efficacy of NMMS in improving the muscular strength in ALS patients as measured by MRC-score (numeric scale, normal value: 35 for upper limbs, 40 for lower limbs).


Secondary Outcome Measures :
  1. Change from baseline to Week 2 in the muscle strength measured by handgrip dynamometry [ Time Frame: Baseline to Week 2 ]
    Evaluation of the efficacy of NMMS in improving the muscular strength in ALS patients as measured by handgrip dynamometry (numeric scale, normal value: >35 for female, >45 for male)

  2. Change from baseline to Week 2 in the Compound Muscle Action Potential (CMAP) amplitude from flexor carpi radialis [ Time Frame: Baseline to Week 2 ]
    Evaluation of the effect of NMMS on the electrophysiological parameter (CMAP) to analyse the physiological mechanisms of the applied neurophysiological technique (milliVolt, mV, normal value 10.2 mV).

  3. Change from baseline to Week 2 in the amplitude of the ACh-evoked currents (IACh) for nicotinic acetylcholine receptors [ Time Frame: Baseline to Week 2 ]
    Evaluation of the effect of NMMS on the nicotinic acetylcholine receptor in patients with ALS (nanoAmpere, nA)

  4. Change from baseline to Week 2 on levels of insulin-like growth factor-1 (IGF-1) and Myostatin [ Time Frame: Baseline to Week 2 ]
    Evaluation of the effect of NMMS on the adaptation changes of gene expression due to rNMMS quantifying shifts in messenger ribonucleic acid (mRNA) levels of a selected panel of genes involved in muscle growth (numeric value)

  5. Change from baseline to Week 2 on the diameter size of muscle fibers [ Time Frame: Baseline to Week 2 ]
    Evaluation of the effect of NMMS on histomorphometric analysis in ALS muscle fibers (micrometer, μm).

  6. Change from baseline to Week 2 on levels of Muscle Atrophy F-box (MAFbx)/Atrogin-1 and Muscle Ring-Finger Protein 1 (MuRF-1) [ Time Frame: Baseline to Week 2 ]
    Evaluation of the effect of NMMS on the adaptation changes of gene expression due to rNMMS quantifying shifts in mRNA levels of a selected panel of genes involved in downregulation of atrophy-related genes (numeric value)



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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • diagnosis of probable or definite ALS with spinal-onset
  • right-handed patients
  • a bilateral symmetric muscular deficit in flexor carpi radialis muscle or flexor digitorum profundus muscle (defined by a MRC Muscle Scale score of 3-4/5)

Exclusion Criteria:

  • history of epilepsy or severe headaches,
  • pregnancy or breast-feeding
  • patients with implanted cardiac pacemaker, neurostimulators, surgical clips or medical pumps
  • presenting any other comorbid condition affecting the possibility of completing the study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03618966


Sponsors and Collaborators
University of Roma La Sapienza
Investigators
Principal Investigator: Maurizio Inghilleri, Prof Department of Human Neuroscience, Umberto I Hospital-University of Rome Sapienza

Publications:

Responsible Party: Maurizio Inghilleri, Associate Professor, University of Roma La Sapienza
ClinicalTrials.gov Identifier: NCT03618966     History of Changes
Other Study ID Numbers: 2174
First Posted: August 7, 2018    Key Record Dates
Last Update Posted: August 7, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Maurizio Inghilleri, University of Roma La Sapienza:
Amyotrophic lateral sclerosis
Muscle disease
Neuromuscular magnetic stimulation

Additional relevant MeSH terms:
Sclerosis
Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Pathologic Processes
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases