Neuromuscular Magnetic Stimulation in ALS Patients

Amyotrophic Lateral Sclerosis Clinical Trial

— NMS-ALS  

Official title:

Neuromuscular Magnetic Stimulation Counteracts Muscle Decline in ALS Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03618966
• Other study ID #: 2174
• Status: Completed
• Phase: Phase 2
• Start date: November 1, 2014
• Est. completion date: November 1, 2017

Study information

• Verified date: August 2018
• Source: University of Roma La Sapienza
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 22
• Est. completion date: November 1, 2017
• Est. primary completion date: May 1, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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

Related Conditions & MeSH terms

• Amyotrophic Lateral Sclerosis
• Motor Neuron Disease
• Sclerosis

Intervention

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.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
University of Roma La Sapienza

References & Publications (13)

Dadon-Nachum M, Melamed E, Offen D. The "dying-back" phenomenon of motor neurons in ALS. J Mol Neurosci. 2011 Mar;43(3):470-7. doi: 10.1007/s12031-010-9467-1. Epub 2010 Nov 7. Review. — View Citation

Dobrowolny G, Aucello M, Rizzuto E, Beccafico S, Mammucari C, Boncompagni S, Belia S, Wannenes F, Nicoletti C, Del Prete Z, Rosenthal N, Molinaro M, Protasi F, Fanò G, Sandri M, Musarò A. Skeletal muscle is a primary target of SOD1G93A-mediated toxicity. Cell Metab. 2008 Nov;8(5):425-36. doi: 10.1016/j.cmet.2008.09.002. Erratum in: Cell Metab. 2009 Jan;9(1):110. Bonconpagni, Simona [corrected to Boncompagni, Simona]. — View Citation

Dupuis L, Loeffler JP. Neuromuscular junction destruction during amyotrophic lateral sclerosis: insights from transgenic models. Curr Opin Pharmacol. 2009 Jun;9(3):341-6. doi: 10.1016/j.coph.2009.03.007. Epub 2009 Apr 20. Review. — View Citation

Eusebi F, Palma E, Amici M, Miledi R. Microtransplantation of ligand-gated receptor-channels from fresh or frozen nervous tissue into Xenopus oocytes: a potent tool for expanding functional information. Prog Neurobiol. 2009 May;88(1):32-40. doi: 10.1016/j.pneurobio.2009.01.008. Epub 2009 Feb 7. — View Citation

Kern H, Barberi L, Löfler S, Sbardella S, Burggraf S, Fruhmann H, Carraro U, Mosole S, Sarabon N, Vogelauer M, Mayr W, Krenn M, Cvecka J, Romanello V, Pietrangelo L, Protasi F, Sandri M, Zampieri S, Musaro A. Electrical stimulation counteracts muscle decline in seniors. Front Aging Neurosci. 2014 Jul 24;6:189. doi: 10.3389/fnagi.2014.00189. eCollection 2014. — View Citation

Loeffler JP, Picchiarelli G, Dupuis L, Gonzalez De Aguilar JL. The Role of Skeletal Muscle in Amyotrophic Lateral Sclerosis. Brain Pathol. 2016 Mar;26(2):227-36. doi: 10.1111/bpa.12350. Review. — View Citation

Musarò A, McCullagh K, Paul A, Houghton L, Dobrowolny G, Molinaro M, Barton ER, Sweeney HL, Rosenthal N. Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle. Nat Genet. 2001 Feb;27(2):195-200. — View Citation

Musarò A. Understanding ALS: new therapeutic approaches. FEBS J. 2013 Sep;280(17):4315-22. doi: 10.1111/febs.12087. Epub 2013 Jan 3. Review. — View Citation

Palma E, Inghilleri M, Conti L, Deflorio C, Frasca V, Manteca A, Pichiorri F, Roseti C, Torchia G, Limatola C, Grassi F, Miledi R. Physiological characterization of human muscle acetylcholine receptors from ALS patients. Proc Natl Acad Sci U S A. 2011 Dec 13;108(50):20184-8. doi: 10.1073/pnas.1117975108. Epub 2011 Nov 29. — View Citation

Palma E, Reyes-Ruiz JM, Lopergolo D, Roseti C, Bertollini C, Ruffolo G, Cifelli P, Onesti E, Limatola C, Miledi R, Inghilleri M. Acetylcholine receptors from human muscle as pharmacological targets for ALS therapy. Proc Natl Acad Sci U S A. 2016 Mar 15;113(11):3060-5. doi: 10.1073/pnas.1600251113. Epub 2016 Feb 29. — View Citation

Scicchitano BM, Rizzuto E, Musarò A. Counteracting muscle wasting in aging and neuromuscular diseases: the critical role of IGF-1. Aging (Albany NY). 2009 May 13;1(5):451-7. — View Citation

Taylor JP, Brown RH Jr, Cleveland DW. Decoding ALS: from genes to mechanism. Nature. 2016 Nov 10;539(7628):197-206. doi: 10.1038/nature20413. Review. — View Citation

Trendelenburg AU, Meyer A, Rohner D, Boyle J, Hatakeyama S, Glass DJ. Myostatin reduces Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and myotube size. Am J Physiol Cell Physiol. 2009 Jun;296(6):C1258-70. doi: 10.1152/ajpcell.00105.2009. Epub 2009 Apr 8. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change from baseline to Week 2 in the muscle strength measured by Medical Research Council Muscle Scale (MRC).	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).	Baseline to Week 2
Secondary	Change from baseline to Week 2 in the muscle strength measured by handgrip dynamometry	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)	Baseline to Week 2
Secondary	Change from baseline to Week 2 in the Compound Muscle Action Potential (CMAP) amplitude from flexor carpi radialis	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).	Baseline to Week 2
Secondary	Change from baseline to Week 2 in the amplitude of the ACh-evoked currents (IACh) for nicotinic acetylcholine receptors	Evaluation of the effect of NMMS on the nicotinic acetylcholine receptor in patients with ALS (nanoAmpere, nA)	Baseline to Week 2
Secondary	Change from baseline to Week 2 on levels of insulin-like growth factor-1 (IGF-1) and Myostatin	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)	Baseline to Week 2
Secondary	Change from baseline to Week 2 on the diameter size of muscle fibers	Evaluation of the effect of NMMS on histomorphometric analysis in ALS muscle fibers (micrometer, µm).	Baseline to Week 2
Secondary	Change from baseline to Week 2 on levels of Muscle Atrophy F-box (MAFbx)/Atrogin-1 and Muscle Ring-Finger Protein 1 (MuRF-1)	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)	Baseline to Week 2