Multiple Sclerosis Clinical Trial
— RehaMSOfficial title:
Study on the Interaction Between Immune, Autonomic and Central Nervous Systems as a Target of Exercise Therapy in Multiple Sclerosis
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.
Status | Recruiting |
Enrollment | 44 |
Est. completion date | February 1, 2023 |
Est. primary completion date | September 1, 2021 |
Accepts healthy volunteers | Accepts Healthy Volunteers |
Gender | All |
Age group | 18 Years to 65 Years |
Eligibility |
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 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). |
Country | Name | City | State |
---|---|---|---|
Italy | IRCCS San Raffele Pisana | Roma | RM |
Lead Sponsor | Collaborator |
---|---|
IRCCS San Raffaele | Neuromed IRCCS |
Italy,
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* Note: There are 20 references in all — Click here to view all references
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | 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) | |
Primary | 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) | |
Primary | 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 | Changes in Mood-depressive trait | Depression level will be assessed by the Beck Depression Inventory-Second Edition (BDI-II) (Watson et al, 2014), a self-administered questionnaire of 21 items. | 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 | Changes in Mood-anxiety trait | The level of 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 propensity to anxious mood). | 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 | Neurophysiological assessment | Cortical excitability will be measured with TMS using Magstim stimulators (Magstim Company, UK) to an eight-shaped coil placed tangentially on the scalp to elicit motor evoked potentials (MEP) in the first dorsal interosseous muscle of the dominant hand. The motor thresholds will be calculated at rest (RMT) as the lowest stimulus intensity capable of evoking a MEP of about 50 uV in five out of ten stimuli, and during a slight voluntary contraction of the target muscle as the minimum intensity capable of evoking MEP> 100 uV in five out of ten stimuli. To test the interhemispheric inhibition (IHI) a double pulse TMS paradigm will be applied. Long term potentiation (LTP) will be evaluated using the intermittent theta-burst stimulation protocol (iTBS). iTBS consists of a three pulses train delivered at the frequency of 50 Hz and repeated every 200 ms for a total of 600 stimuli, with an intensity equal to 80% of the AMT at the M1 of the dominant hemisphere. | Changes from baseline (time 0, t0) to the end of the 6-week exercise protocol (time 1, t1) | |
Secondary | Changes in autonomic function | Heart rate variability (HRV) will be measured through standard procedures. The analysis of ECG (ET Medical Devices SpA) will be performed in the frequency domain using dedicated software (Light-SNV software). The periods heart rate (HR) lasting 5 minutes will be chosen from the last 6 minutes of supine rest lasting 30 minutes. The spectral power analysis will consider an ad component high frequency (HF) (0.16-0.4 Hz), which mainly reflects vagal activity, and a low component frequency (LF) (0.04-0.15 Hz), which mainly reflects sympathetic activity. The will be considered spectral components in normalized units (LFnu, HFnu). The LF / HF ratio will be used as an index of sympathetic-vagal balance. | Changes from baseline (time 0, t0) to the end of the 6-week exercise protocol (time 1, t1) | |
Secondary | Changes in T cell function | Immediately after collection in Vacutainer tubes containing anticoagulant, peripheral blood samples, will be processed for isolation of T lymphocytes by centrifugation according to standardized techniques, and frozen at -80 in the shortest possible time. T cells isolated will be analyzed at flow cytometer to analyze the phenotype and cell subpopulations, after staining for surface antigens (CD3, CD4, CD8, CD25, CD28, CD45RA, CD69, CD71, CCR7) and intracellular labelling for specific cytokines (IFN-g, TNFa, IL-2, IL-17, IL-4). A portion of these cells will be cultured to evaluate their secretome (cytokines) via ELISA / Luminex assay and cellular metabolism via SeaHorse assay. Data will be expressed as picograms per milliliter (pg/ml) (ELISA/Lumiex assay) and extracellular acidification rate-ECAR- in mpH/min (Seahorse assay). | 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 | Electrophysiological evaluation | T lymphocytes will be used for performing chimeric experiments based on T cell incubation with murine corticostriatal and hippocampal slices to measure glutamatergic transmission and LTP, respectively, using techniques of single neuron electrophysiology on murine brain slices. | 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) |
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