Exercise Therapy in Multiple Sclerosis

NCT04294979 | Completed DMC

• 1 other identifier: RP 19/13
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 1

Brief Summary

Exercise or active rehabilitation is a non-pharmacological approach increasingly used for people with Multiple Sclerosis (MS), in support of disease-modifying therapies (DMTs), with the aim of improving the quality of life and engagement in daily activities. Exercise improves several disease outcomes, like cardiovascular and neuromuscular functions and walking abilities. However, its disease modifying potential is poorly explored. Exercise might target two relevant disease hallmarks that are interconnected, such as the dysregulated immune system and the inflammatory synaptopathy. Exercise might act through the activation of the autonomic part of the vagus nerve, which is an important modulator of both the innate and adaptive immune system, through the so-called cholinergic anti-inflammatory pathway-CAP. This study aims to address the effect of exercise in reducing peripheral inflammation that drives the synaptic pathology and neurodegeneration occurring in the brain of MS patients. Patients will undergo a therapeutic exercise program, consisting of 3 hours of treatment per day, 6 days/week for a total of 6 weeks. The treatment will include both passive and active therapeutic exercises targeted to restore or preserve muscular flexibility, motor coordination and ambulatory function. The day of recruitment (time 0) patients will undergo neurological and mood examination and blood withdrawal to analyze peripheral markers of immune function. Moreover, transcranial magnetic stimulation (TMS) will be used to measure synaptic transmission, while the heart rate variability (HRV) test will be performed to explore vagal function. The effect of exercise will be evaluated at the end of rehabilitation (after 6 weeks-time 1), on the above parameters. A follow up will be included (time 2, 8 weeks after the end of the treatment) to address long-term effects on neurologic and mood measurements as well as peripheral marker levels.

Conditions

Multiple Sclerosis

Keywords

Rehabilitation; exercise; Multiple sclerosis; Physical therapy

Outcome Measures

Primary Outcomes (3)

• Changes in clinical disability (EDSS)

  Clinical severity will be measured by the expanded disability status scale (EDSS): this scale ranges from 0 to 10 in 0.5 unit increments that represent higher levels of disability.

  Changes from baseline (time 0, t0), to the end of the 6-week exercise protocol (time 1, t1) and 8 weeks after the end of exercise protocol (time 2, t2)

• Changes in clinical disability: Multiple Sclerosis Functional Composite (MSFC)

  The Multiple Sclerosis Functional Composite (MSFC) is a three-part composite clinical measure that includes three variables: Timed 25-Foot walk; 9-Hole Peg Test; and Paced Auditory Serial Addition Test (PASAT-3"). The results from each of these three tests are transformed into Z-scores and averaged to generate a composite score for each patient at each time point. There are 3 components: 1. the average scores from the four trials on the 9-HPT; 2. the average scores of two 25-Foot Timed Walk trials; 3. the number correct from the PASAT-3. The scores for these three dimensions are combined to create a single score that can be used to detect variations over time, by creating Z-scores for each component. MSFC Score = {Zarm, average + Zleg, average + Zcognitive} / 3.0 (Where Zxxx =Z-score). Increased scores represent deterioration in the 9-HPT and the 25-Foot Timed Walk, whereas decreased scores represent deterioration in the PASAT-3.

  Changes from baseline (time 0, t0), to the end of the 6-week exercise protocol (time 1, t1) and 8 weeks after the end of exercise protocol (time 2, t2)

• Changes in visual disability

  The visual acuity test (VA) will be performed using Snellen scales and low-contrast letter acuity (LCLA).

  Changes from baseline (time 0, t0), to the end of the 6-week exercise protocol (time 1, t1) and 8 weeks after the end of exercise protocol (time 2, t2)

Secondary Outcomes (6)

• Changes in Mood-depressive trait

  Changes from baseline (time 0, t0), to the end of the 6-week exercise protocol (time 1, t1) and 8 weeks after the end of exercise protocol (time 2, t2)

• Changes in Mood-anxiety trait

  Changes from baseline (time 0, t0), to the end of the 6-week exercise protocol (time 1, t1) and 8 weeks after the end of exercise protocol (time 2, t2)

• Neurophysiological assessment

  Changes from baseline (time 0, t0) to the end of the 6-week exercise protocol (time 1, t1)

• Changes in autonomic function

  Changes from baseline (time 0, t0) to the end of the 6-week exercise protocol (time 1, t1)

• Changes in T cell function

  Changes from baseline (time 0, t0), to the end of the 6-week exercise protocol (time 1, t1) and 8 weeks after the end of exercise protocol (time 2, t2)

Study Arms (1)

Rehabilitation

EXPERIMENTAL

Conventional Physical Therapy

Other: Physical Therapy

Interventions

Physical Therapy OTHER

The rehabilitation program will consist of both passive and active therapeutic exercises specifically aimed at restoring or maintaining muscular flexibility, range of motion, balance, coordination of movements, postural passages and transfers, and ambulation. . Furthermore, advanced robotic therapy such as Lokomat® exoskeleton (Hocoma AG, Volketswil, Switzerland), Biodex® Stability System (BSS, Biodex, Inc, Shirley, NY), G-EO System™ (Reha Technology AG, Olten, Svizzera) and Indego® Therapy (Parker USA), will be used to personalize rehabilitation treatment.

Also known as: Exercise

Rehabilitation

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Ability to provide written informed consent to the study;
• Diagnosis of MS definite according to 2010 revised McDonald's criteria (Polman et al., 2011);
• Age range 18-65 (included);
• EDSS range between 4,5 and 6,5 (included);
• Ability to participate to the study protocol.

You may not qualify if:

• Inability to provide written informed consent to the study;
• Altered blood count;
• Female with a positive pregnancy test at baseline or having active pregnancy plans in the following months after the beginning of the protocol;
• Contraindications to gadolinium (MRI);
• Contraindications to TMS;
• Patients with comorbidities for a neurological disease other than MS, included other neurodegenerative chronic diseases or chronic infections (i.e tuberculosis, infectious hepatitis, HIV/AIDS);
• Unstable medical condition or infections;
• Use of medications with increased risk of seizures (i.e. Fampridine, 4- Aminopyridine);
• Concomitant use of drugs that may alter synaptic transmission and plasticity (cannabinoids, L-dopa, antiepileptics, nicotine, baclofen, SSRI, botulinum toxin).

Sponsors & Collaborators

• IRCCS San Raffaele Roma: lead
• Neuromed IRCCS: collaborator

Study Sites (1)

IRCCS San Raffele Pisana

Roma, RM, 00166, Italy

Location

Related Publications (20)

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  PMID: 26585978 BACKGROUND

• Motl RW, Sandroff BM, Kwakkel G, Dalgas U, Feinstein A, Heesen C, Feys P, Thompson AJ. Exercise in patients with multiple sclerosis. Lancet Neurol. 2017 Oct;16(10):848-856. doi: 10.1016/S1474-4422(17)30281-8. Epub 2017 Sep 12.

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• Charron S, McKay KA, Tremlett H. Physical activity and disability outcomes in multiple sclerosis: A systematic review (2011-2016). Mult Scler Relat Disord. 2018 Feb;20:169-177. doi: 10.1016/j.msard.2018.01.021. Epub 2018 Feb 2.

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• Gentile A, De Vito F, Fresegna D, Rizzo FR, Bullitta S, Guadalupi L, Vanni V, Buttari F, Stampanoni Bassi M, Leuti A, Chiurchiu V, Marfia GA, Mandolesi G, Centonze D, Musella A. Peripheral T cells from multiple sclerosis patients trigger synaptotoxic alterations in central neurons. Neuropathol Appl Neurobiol. 2020 Feb;46(2):160-170. doi: 10.1111/nan.12569. Epub 2019 Jun 17.

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• Carbone F, De Rosa V, Carrieri PB, Montella S, Bruzzese D, Porcellini A, Procaccini C, La Cava A, Matarese G. Regulatory T cell proliferative potential is impaired in human autoimmune disease. Nat Med. 2014 Jan;20(1):69-74. doi: 10.1038/nm.3411. Epub 2013 Dec 8.

  PMID: 24317118 BACKGROUND

• Feys P, Giovannoni G, Dijsselbloem N, Centonze D, Eelen P, Lykke Andersen S. The importance of a multi-disciplinary perspective and patient activation programmes in MS management. Mult Scler. 2016 Aug;22(2 Suppl):34-46. doi: 10.1177/1352458516650741.

  PMID: 27465614 BACKGROUND

• Hedegaard CJ, Krakauer M, Bendtzen K, Sorensen PS, Sellebjerg F, Nielsen CH. The effect of beta-interferon therapy on myelin basic protein-elicited CD4+ T cell proliferation and cytokine production in multiple sclerosis. Clin Immunol. 2008 Oct;129(1):80-9. doi: 10.1016/j.clim.2008.06.007. Epub 2008 Jul 23.

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• Lanzillo R, Carbone F, Quarantelli M, Bruzzese D, Carotenuto A, De Rosa V, Colamatteo A, Micillo T, De Luca Picione C, Sacca F, De Rosa A, Moccia M, Brescia Morra V, Matarese G. Immunometabolic profiling of patients with multiple sclerosis identifies new biomarkers to predict disease activity during treatment with interferon beta-1a. Clin Immunol. 2017 Oct;183:249-253. doi: 10.1016/j.clim.2017.08.011. Epub 2017 Aug 18.

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• La Rocca C, Carbone F, De Rosa V, Colamatteo A, Galgani M, Perna F, Lanzillo R, Brescia Morra V, Orefice G, Cerillo I, Florio C, Maniscalco GT, Salvetti M, Centonze D, Uccelli A, Longobardi S, Visconti A, Matarese G. Immunometabolic profiling of T cells from patients with relapsing-remitting multiple sclerosis reveals an impairment in glycolysis and mitochondrial respiration. Metabolism. 2017 Dec;77:39-46. doi: 10.1016/j.metabol.2017.08.011. Epub 2017 Sep 8.

  PMID: 29132538 BACKGROUND

• Pavlov VA, Tracey KJ. Neural regulation of immunity: molecular mechanisms and clinical translation. Nat Neurosci. 2017 Feb;20(2):156-166. doi: 10.1038/nn.4477. Epub 2017 Jan 16.

  PMID: 28092663 BACKGROUND

• Studer V, Rocchi C, Motta C, Lauretti B, Perugini J, Brambilla L, Pareja-Gutierrez L, Camera G, Barbieri FR, Marfia GA, Centonze D, Rossi S. Heart rate variability is differentially altered in multiple sclerosis: implications for acute, worsening and progressive disability. Mult Scler J Exp Transl Clin. 2017 Apr 5;3(2):2055217317701317. doi: 10.1177/2055217317701317. eCollection 2017 Apr-Jun.

  PMID: 28607756 BACKGROUND

• Mori F, Kusayanagi H, Monteleone F, Moscatelli A, Nicoletti CG, Bernardi G, Centonze D. Short interval intracortical facilitation correlates with the degree of disability in multiple sclerosis. Brain Stimul. 2013 Jan;6(1):67-71. doi: 10.1016/j.brs.2012.02.001. Epub 2012 Feb 24.

  PMID: 22425067 BACKGROUND

• Mori F, Kusayanagi H, Nicoletti CG, Weiss S, Marciani MG, Centonze D. Cortical plasticity predicts recovery from relapse in multiple sclerosis. Mult Scler. 2014 Apr;20(4):451-7. doi: 10.1177/1352458513512541. Epub 2013 Nov 21.

  PMID: 24263385 BACKGROUND

• Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Montalban X, O'Connor P, Sandberg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011 Feb;69(2):292-302. doi: 10.1002/ana.22366.

  PMID: 21387374 BACKGROUND

• Sternberg Z. Promoting sympathovagal balance in multiple sclerosis; pharmacological, non-pharmacological, and surgical strategies. Autoimmun Rev. 2016 Feb;15(2):113-23. doi: 10.1016/j.autrev.2015.04.012. Epub 2015 May 3.

  PMID: 25945428 BACKGROUND

• Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human motor cortex. Neuron. 2005 Jan 20;45(2):201-6. doi: 10.1016/j.neuron.2004.12.033.

  PMID: 15664172 BACKGROUND

• Centonze D, Muzio L, Rossi S, Cavasinni F, De Chiara V, Bergami A, Musella A, D'Amelio M, Cavallucci V, Martorana A, Bergamaschi A, Cencioni MT, Diamantini A, Butti E, Comi G, Bernardi G, Cecconi F, Battistini L, Furlan R, Martino G. Inflammation triggers synaptic alteration and degeneration in experimental autoimmune encephalomyelitis. J Neurosci. 2009 Mar 18;29(11):3442-52. doi: 10.1523/JNEUROSCI.5804-08.2009.

  PMID: 19295150 BACKGROUND

• Gentile A, Musella A, De Vito F, Rizzo FR, Fresegna D, Bullitta S, Vanni V, Guadalupi L, Stampanoni Bassi M, Buttari F, Centonze D, Mandolesi G. Immunomodulatory Effects of Exercise in Experimental Multiple Sclerosis. Front Immunol. 2019 Sep 13;10:2197. doi: 10.3389/fimmu.2019.02197. eCollection 2019.

  PMID: 31572399 BACKGROUND

• Dalgas U, Stenager E, Jakobsen J, Petersen T, Hansen HJ, Knudsen C, Overgaard K, Ingemann-Hansen T. Resistance training improves muscle strength and functional capacity in multiple sclerosis. Neurology. 2009 Nov 3;73(18):1478-84. doi: 10.1212/WNL.0b013e3181bf98b4.

  PMID: 19884575 BACKGROUND

• Schulz KH, Gold SM, Witte J, Bartsch K, Lang UE, Hellweg R, Reer R, Braumann KM, Heesen C. Impact of aerobic training on immune-endocrine parameters, neurotrophic factors, quality of life and coordinative function in multiple sclerosis. J Neurol Sci. 2004 Oct 15;225(1-2):11-8. doi: 10.1016/j.jns.2004.06.009.

  PMID: 15465080 BACKGROUND

MeSH Terms

Conditions

Multiple Sclerosis; Motor Activity

Interventions

Physical Therapy Modalities; Exercise

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Behavior

Intervention Hierarchy (Ancestors)

Therapeutics; Rehabilitation; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena

Study Officials

• Antonietta Gentile, phD

  IRCCS San Raffele Pisana

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 2, 2020
• First Posted: March 4, 2020
• Study Start: February 1, 2020
• Primary Completion: December 1, 2023
• Study Completion: April 1, 2024
• Last Updated: May 13, 2025

Record last verified: 2025-05

Locations

IT (1)