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Exercise-based Therapy for Multiple Sclerosis Patients

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03735524
Recruitment Status : Not yet recruiting
First Posted : November 8, 2018
Last Update Posted : November 8, 2018
Sponsor:
Information provided by (Responsible Party):
Neuromed IRCCS

Brief Summary:

Exercise is reported to have significant beneficial effects in Multiple Sclerosis (MS) patients, particularly with respect to cardiovascular function, aerobic capacity, muscular strength and ambulatory performance. Inflammation-mediated synaptic alterations have been measured by means of transcranial magnetic stimulation (TMS) and found to correlate with disability level in MS. Due to their plastic nature, synapses represent a good therapeutic target that is sensitive to environmental stimulation, such as physical exercise.

The aim of this study is to evaluate the effect of exercise in reducing peripheral inflammation that drives the synaptic pathology and neurodegeneration occurring in the brain of MS patients. Recruited patients will be given a therapeutic exercise program, consisting of 3 hours of treatment per day, 6 days/week for 4 weeks. The program will be applied on hospitalised patients to ensure adherence to the program and reducing the risk of abandonment. The rehabilitation program will be planned by a physician specialised in physical and rehabilitation medicine and 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. The day of recruitment (t0) patients will undergo radiological and neurological examination. The effect of exercise will be evaluated with respect to neurologic function, mood and neurophysiological parameters, autonomic system function, and peripheral marker levels assessed at t0 and after 4 weeks (t1). A second time point will be included (t2, 8 weeks after the end of the treatment) to address long-term effects, with analysis limited to neurologic and mood measurements and peripheral marker levels.


Condition or disease Intervention/treatment Phase
Multiple Sclerosis Other: Exercise Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 35 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: The Inflammatory Synaptopathy as a Target of Exercise Therapy in the Fight Against Multiple Sclerosis
Estimated Study Start Date : May 2019
Estimated Primary Completion Date : November 2020
Estimated Study Completion Date : May 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Exercise
Conventional rehabilitation
Other: Exercise
Different exercises will be adopted including: repetition of different movements for ambulation and stair climbing, repetition of crossed patterns of movements for coordination, postural reactions while standing with eyes open and closed and oscillatory boards for balance, strengthening lower limb muscles, and low-intensity and long-duration static stretching of iliopsoas, rectus femoris, hamstrings, triceps surae, and lumbar spinal muscles for muscular flexibility and range of motion. In addition, advanced robotic therapy will be used to standardize rehabilitative treatment and to obtain more objective indexes of motor function. The Lokomat exoskeleton and the Biodex stability system will be used.
Other Name: Rehabilitation




Primary Outcome Measures :
  1. Changes in clinical disability (EDSS) [ Time Frame: Changes from baseline (time 0, t0), 4 weeks after the end of exercise protocol (time 1, t1) and 8 weeks after the end of exercise protocol (time 2, t2) ]
    Clinical severity will be measured by the expanded disability status scale (EDSS): the EDSS scale ranges from 0 to 10 in 0.5 unit increments that represent higher levels of disability.

  2. Changes in clinical disability: Multiple Sclerosis Functional Composite (MSFC) [ Time Frame: Changes from baseline (time 0, t0), 4 weeks after the end of exercise protocol (time 1, t1) and 8 weeks after the end of exercise protocol (time 2, t2) ]

    The Multiple Sclerosis Functional Composite (MSFC) is a three-part composite clinical measure. Three variables were recommended as primary measures: 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 yield 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 change over time. This is done 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.


  3. Changes in clinical disability (VA) [ Time Frame: Changes from baseline (time 0, t0), 4 weeks after the end of exercise protocol (time 1, t1) and 8 weeks after the end of exercise protocol (time 2, t2) ]
    The best corrected visual acuity (VA) that will performed in a well-lit room using Snellen and low-contrast letter acuity (LCLA) charts to assess clinical severity.


Secondary Outcome Measures :
  1. Changes in Mood-depressive trait [ Time Frame: Changes from baseline (time 0, t0) to the end of the 4-week exercise protocol (time 1, t1) and 8 weeks after the end of exercise protocol (time 2, t2) ]
    Depression will be assessed by means of the Beck Depression Inventory-Second Edition (BDI-II) (Watson et al, 2014).

  2. Changes in Mood-anxiety trait [ Time Frame: Changes from baseline (time 0, t0) to the end of the 4-week exercise protocol (time 1, t1) and 8 weeks after the end of exercise protocol (time 2, t2) ]
    Anxiety will be assessed by State-Trait Anxiety Inventory (STAI) form Y (STAI-Y), a 40-item self-administered questionnaire measuring anxiety as a state (situational anxiety) or trait (long-standing proneness to anxious situations).

  3. Neurophysiological assessment [ Time Frame: Changes from baseline (time 0, t0) to the end of the 4-week exercise protocol (time 1, t1) ]
    Cortical excitability will be probed with transcranial magnetic stimulation (TMS) using Magstim devices (The Magstim Company, Whitland, Dyfed, UK). One stimulator will be connected to a figure-of-eight coil (external wing diameter 70 mm) placed tangentially over the scalp in the optimal position for eliciting motor evoked potentials (MEPs) in the first dorsal interosseous (FDI) muscle of the dominant hand. To test the interhemispheric inhibition (IHI) we will apply a paired-pulse (conditioning-test) TMS paradigm. Paired pulses will be given with interstimulus intervals (ISIs) of 10 and 40 ms. LTP will be assessed by the intermittent theta-burst stimulation (iTBS) protocol. iTBS consists of three-pulse bursts given at 80% AMT and 50 Hz frequency, repeated every 200 ms (i.e. at 5 Hz) and delivered over the FDI muscle hot spot, for a total number of 600 stimuli. We will record and average fifteen MEPs of about 1 mV peak-to-peak in amplitude at baseline before iTBS.

  4. Changes in autonomic function [ Time Frame: Changes from baseline (time 0, t0) to the end of the 4-week exercise protocol (time 1, t1) ]
    Heart rate variability (HRV) will be assessed under standardized environmental conditions. ECG will be recorded by standard methods. The analysis will be performed in the frequency domain using a dedicated software. Stable heart rate (HR) periods of 5 minutes duration will be chosen in the last 6 minutes of a 30-minute supine rest. Power spectral analysis will consider a high frequency (HF) component, reflecting mostly vagal activity, and a low frequency (LF) component, reflecting mostly sympathetic activity. Spectral components in normalized units (LFnu, HFnu) will be considered. As an index of sympathovagal balance, we will use the LF/HF ratio.

  5. Changes in peripheral cytokine levels [ Time Frame: Changes from baseline (time 0, t0) to the end of 4 week-exercise protocol (time 1, t1) and 8 weeks after the end of exercise protocol (time 2, t2) ]

    Within few hours after the withdrawal, the peripheral blood will be processed to isolate plasma, serum and cells.

    Peripheral Blood Mononuclear Cells (PBMCs) will be isolated by Ficoll hystopaque gradient centrifugation, according to standard techniques and soon frozen in -80 and next processed to isolate T cells by magnetic immunosorting with FITC-CD3 antibody and microbeads-conjugated anti-FITC antibody (Miltenyi, Biotec). TNF and IL-1b released by T cells in culture medium will be measured by using commercial ELISA kit. Data will be expressed as picograms per milliliter (pg/ml).




Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • Inability to provide written informed consent to the study;
  • Altered blood count;
  • Female with 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 neurological disease other than MS, included other neurodegenerative chronic diseases or chronic infections (i.e tubercolosis, 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, antiepiletics, nicotine, baclofen, SSRI, botulinum toxin).

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): NCT03735524


Contacts
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Contact: Diego Centonze, MD +39 3934444159 centonze@uniroma2.it
Contact: Mario Stampanoni, MD +39 2460181370 mario_sb@hotmail.it

Locations
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Italy
IRCCS Neuromed
Pozzilli, Isernia, Italy, 86077
Sponsors and Collaborators
Neuromed IRCCS
Investigators
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Principal Investigator: Diego Centonze, MD IRCCS Neuromed
Publications:

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Responsible Party: Neuromed IRCCS
ClinicalTrials.gov Identifier: NCT03735524    
Other Study ID Numbers: NeuromedIRCCS
First Posted: November 8, 2018    Key Record Dates
Last Update Posted: November 8, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Neuromed IRCCS:
exercise, synaptopathy, inflammation
Additional relevant MeSH terms:
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Multiple Sclerosis
Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases