Ignite Creation Date:
2024-05-06 @ 2:21 PM
Last Modification Date:
2024-10-26 @ 1:29 PM
Study NCT ID:
NCT04294979
Status:
UNKNOWN
Last Update Posted:
2020-03-11
First Post:
2020-03-02
Brief Title:
Exercise Therapy in Multiple Sclerosis
Sponsor:
IRCCS San Raffaele
Organization:
IRCCS San Raffaele
Study Overview
Official Title:
Study on the Interaction Between Immune Autonomic and Central Nervous Systems as a Target of Exercise Therapy in Multiple Sclerosis
Status:
UNKNOWN
Status Verified Date:
2020-03
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
RehaMS
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 daysweek 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
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 daysweek 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
Detailed Description:
Clinical manifestations of Multiple Sclerosis MS indicate the involvement of motor sensory visual systems cognition and emotion as well as peripheral autonomic system PAS Disease modifying therapies DMTs are immunomodulatory drugs designed to dampen the immune reaction occurring in MS Indeed MS pathogenesis is supposed to rely on the break of immunological tolerance against myelin epitopes which trigger an inflammatory cascade that leads to chronic inflammation axonal loss and neurodegeneration T cell population in MS presents several metabolic dysfunctions such as glycolysis alterations that can be attenuated by DMTs Studies of synaptic transmission conducted on both MS patients via transcranial magnetic stimulation TMS and EAE mice via electrophysiological recordings of single neurons showed an early synaptopathy characterized by an impairment of glutamatergic and GABAergic transmissions Such synaptopathy is independent of demyelination and caused by inflammation Importantly TMS cortical excitability measures positively correlate with disability in MS patients Moreover chimeric experiments obtained incubating MS T cells and murine brain slices clearly indicate that T cells drive synaptic damage during MS suggesting that interfering with T cell-neuron crosstalk could be a possible therapeutic target
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 It is increasingly recognized that a multi-disciplinary approach in MS treatment including non-pharmacological interventions is required to treat MS Active-rehabilitation or exercise has been proven effective in the improvement of cardiovascular functions aerobic capacity muscular strength and ambulatory performance while some data indicate that other outcomes like balance and depression can be positively influenced by exercise Symptoms of sympathovagal imbalance like altered heart rate variability HRV previously shown to depend on inflammatory bulk in MS may be positively modulated by exercise which is known to regulate both the peripheral nervous system and the immune system However the mechanisms involved in exercise-beneficial effects as well as the impact of exercise on MS pathophysiological hallmarks especially those regarding the immune-synaptic axis are still poorly elucidated
This longitudinal interventional non-pharmacological study is designed to enrol 44 MS patients and 30 healthy controls matched by gender and age to the MS group The MS patient group will undergo a conventional 6-week rehabilitation program Physical therapy will be performed for 6 daysweek for 6 weeks and will consist of 3 hours of treatment per day 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 patients disability status different therapeutic exercises will be performed by qualified physiotherapists Intensity of exercise will be tailored to the level of patients disability 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 standardize rehabilitation treatment and obtain more objective indices of motor function and will be applied according to clinical indications Three time-points t of evaluations are included in the study t0 before starting the rehabilitation period t1 soon after rehabilitation and t2 follow-up after 8 weeks by the end of rehabilitation Therapeutic efficacy will be evaluated at the end of the exercise program t1 by repeating evaluations performed at t0 which include neurological and psychological assessments together with measures of brain synaptic activity and vagal function and immune function At t2 analysis will be limited to neurological and psychological assessments and immune function Thus blood samples will be collected at t0 t1 and t2 to study changes in immune function that might correlate with clinical parameters described as primary and secondary outcomes at the different time-points
Statistical analysis will be performed by IBM SPSS Statistics 150 Data will be tested for normality distribution through the Kolmogorov-Smirnov test Differences between pre- and post-values will be analyzed using parametric Students 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 Changes in categorical variables will be evaluated by the test McNemar Data will be presented as the mean standard deviation sd or median 25th- 75th percentile The significance level is established at p005
Sample size calculation was performed according to the following criteria Assuming that in MS patients the cytokine values in particular the TNF level after exercise therapy decrease in a manner similar to that showed in the study by Hedegaard et al 2008 Based on these results calculating an average difference between pre and post exercise values of TNF equal to 13651 pg ml sd 2570 d 053 in order to appreciate a moderate effect with a statistical capacity of 95 and assuming a two-tailed a 005 and applying a Wilcoxon rank test for paired values the investigators estimate a total number of patients equal to 40 Analysis was performed with the G POWER v3192 program Considering possible drop-outs the investigators estimate to increase the number of patients recruited by one percentage equal to 10 meaning 4 subjects Moreover using Power Analysis d061 it has been calculated that the number of healthy volunteer subjects needed to be recruited for the study of the immunophenotype and secretoma will be 30 subjects per experimental group in order to be able to refuse the null hypothesis that the two groups are equal with a test power of 95 and appreciate a difference of 16009 pg ml between the means of the experimental groups healthy control vs MS standard deviation equal to 2599 d 061 The probability of Type I error associated with this test for this hypothesis is 5
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 It is increasingly recognized that a multi-disciplinary approach in MS treatment including non-pharmacological interventions is required to treat MS Active-rehabilitation or exercise has been proven effective in the improvement of cardiovascular functions aerobic capacity muscular strength and ambulatory performance while some data indicate that other outcomes like balance and depression can be positively influenced by exercise Symptoms of sympathovagal imbalance like altered heart rate variability HRV previously shown to depend on inflammatory bulk in MS may be positively modulated by exercise which is known to regulate both the peripheral nervous system and the immune system However the mechanisms involved in exercise-beneficial effects as well as the impact of exercise on MS pathophysiological hallmarks especially those regarding the immune-synaptic axis are still poorly elucidated
This longitudinal interventional non-pharmacological study is designed to enrol 44 MS patients and 30 healthy controls matched by gender and age to the MS group The MS patient group will undergo a conventional 6-week rehabilitation program Physical therapy will be performed for 6 daysweek for 6 weeks and will consist of 3 hours of treatment per day 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 patients disability status different therapeutic exercises will be performed by qualified physiotherapists Intensity of exercise will be tailored to the level of patients disability 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 standardize rehabilitation treatment and obtain more objective indices of motor function and will be applied according to clinical indications Three time-points t of evaluations are included in the study t0 before starting the rehabilitation period t1 soon after rehabilitation and t2 follow-up after 8 weeks by the end of rehabilitation Therapeutic efficacy will be evaluated at the end of the exercise program t1 by repeating evaluations performed at t0 which include neurological and psychological assessments together with measures of brain synaptic activity and vagal function and immune function At t2 analysis will be limited to neurological and psychological assessments and immune function Thus blood samples will be collected at t0 t1 and t2 to study changes in immune function that might correlate with clinical parameters described as primary and secondary outcomes at the different time-points
Statistical analysis will be performed by IBM SPSS Statistics 150 Data will be tested for normality distribution through the Kolmogorov-Smirnov test Differences between pre- and post-values will be analyzed using parametric Students 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 Changes in categorical variables will be evaluated by the test McNemar Data will be presented as the mean standard deviation sd or median 25th- 75th percentile The significance level is established at p005
Sample size calculation was performed according to the following criteria Assuming that in MS patients the cytokine values in particular the TNF level after exercise therapy decrease in a manner similar to that showed in the study by Hedegaard et al 2008 Based on these results calculating an average difference between pre and post exercise values of TNF equal to 13651 pg ml sd 2570 d 053 in order to appreciate a moderate effect with a statistical capacity of 95 and assuming a two-tailed a 005 and applying a Wilcoxon rank test for paired values the investigators estimate a total number of patients equal to 40 Analysis was performed with the G POWER v3192 program Considering possible drop-outs the investigators estimate to increase the number of patients recruited by one percentage equal to 10 meaning 4 subjects Moreover using Power Analysis d061 it has been calculated that the number of healthy volunteer subjects needed to be recruited for the study of the immunophenotype and secretoma will be 30 subjects per experimental group in order to be able to refuse the null hypothesis that the two groups are equal with a test power of 95 and appreciate a difference of 16009 pg ml between the means of the experimental groups healthy control vs MS standard deviation equal to 2599 d 061 The probability of Type I error associated with this test for this hypothesis is 5
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None