Exercise-based Therapy for Multiple Sclerosis Patients

NCT ID: NCT03735524

Last Updated: 2018-11-08

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: NA
• Total Enrollment: 35 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-05-31
• Study Completion Date: 2021-05-31

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.

Detailed Description

Clinical manifestations of Multiple Sclerosis (MS) indicate the involvement of motor, sensory, visual, and autonomic systems as well as brain circuits implicated in cognition and emotion.

Due to the complexity and the heterogeneity of the disease course and the clinical symptoms, the search for the appropriate personalized treatment and the disease management remains a challenging issue. Nowadays, it is increasingly recognized that MS treatment and care demand a multi-disciplinary approach, including non-pharmacological interventions, aimed to improve quality of life (QoL) and engagement in daily-life activities. Active-rehabilitation or exercise is currently considered as the form of non-medical interventions that best meets these requirements.

In the context of MS, there is now general agreement on the positive effects of exercise for both relapsing remitting (RR) and progressive (P) MS patients. Significant effects have been described for cardiovascular functions, aerobic capacity, muscular strength and ambulatory performance. Even if clear conclusions cannot be drawn, other outcomes, like balance and depression seem to be positively influenced by exercise. Symptoms linked to autonomic dysfunction caused by sympathovagal imbalance, like altered heart rate variability (HRV) and correlating with the load of inflammation in MS may benefit from exercise, being the physical activity an important modulator of the peripheral nervous system. However, the DMT potential of exercise is still overlooked, since only few studies have investigated the influence of exercise on inflammation and neurodegeneration, the main pathogenic events in MS with unclear and, to some extent, contrasting data.

This longitudinal study aims is designed to enrol at least 35 MS patients to perform a conventional 4 weeks rehabilitation program. Physical therapy will be performed for 6 days/week for 4 weeks and will consist of 3 hours of treatment. The rehabilitation program will be planned by a physician specialized 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. According to the patient's disability status, different therapeutic exercises will be performed by qualified physiotherapists. Moreover, intensity of exercise will be tailored to the level of patient's disability. To avoid fatigue and to increase patient's tolerance to the exercises, compensative pauses will be included. Moreover, genotype analysis from peripheral blood cells will be performed to identify single nucleotide polymorphisms (SNPs) in coding regions and/or gene regulators (microRNA or proteins) involved in MS synaptic transmission alterations, like NGF, PDGF, which might correlate to clinical parameters described as both primary and secondary outcomes.

Statistical analysis will be performed by IBM SPSS Statistics 15.0. Data will be tested for normality distribution through the Kolmogorov-Smirnov test. Differences between pre- and post-values will be analyzed using parametric Student's t-test for matched pairs, or if necessary, nonparametric Wilcoxon signed-rank test for matched pairs. Changes in categorical variables will be assessed by McNemar test. Correlation analysis will be performed by calculating Pearson or Spearman coefficients as appropriate. Data will be presented as the mean (standard deviation, sd) or median (25th- 75th percentile). The significance level is established at p<0.05.

Sample size calculation was performed according to the following criteria. Supposing that in MS patients the cytokine values in particular the TNF levels after exercise therapy decrease in a manner similar to that showed in the study by Hedegaard et al (2008), the investigators can estimate that the therapy will have a medium effect on TNF values, d=0.59, calculating a pre-mean value equal to 2611.2 (standard deviation, sd=1586.96) and post-exercise equal to 1249.1 (sd=1261.89), a correlation between pre-post values equals to -0.326. To detect as significant a moderate effect with a power of 95%, assuming a two-sided a=0.05 and applying a Wilcoxon signed-rank test for matched pairs, the investigators estimate a total number of 35 patients. The analysis was performed by G*POWER v3.1.9.2.

Conditions

Multiple Sclerosis

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Exercise

Conventional rehabilitation

Group Type: EXPERIMENTAL

Exercise

Intervention Type: OTHER

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.

Interventions

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.

Intervention Type: OTHER

Other Intervention Names

Rehabilitation

Eligibility 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).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Neuromed IRCCS

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Diego Centonze, MD

Role: PRINCIPAL_INVESTIGATOR

IRCCS Neuromed

Locations

IRCCS Neuromed

Pozzilli, Isernia, Italy

Countries

Italy

Central Contacts

Diego Centonze, MD

Role: CONTACT

centonze@uniroma2.it

+39 3934444159

Mario Stampanoni, MD

Role: CONTACT

mario_sb@hotmail.it

+39 2460181370

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Other Identifiers

NeuromedIRCCS

Identifier Type: -

Identifier Source: org_study_id