The Therapeutic Effects of Forced Aerobic Exercise in Multiple Sclerosis

Not Applicable

Completed

Conditions: Multiple Sclerosis

Interventions: Behavioral: Forced Aerobic Exercise (FE)
Behavioral: Voluntary Aerobic Exercise (VE)

Registration Number: NCT04906057

Lead Sponsor: The Cleveland Clinic

Brief Summary: This project will investigate the feasibility and initial efficacy of two aerobic exercise training approaches, forced and voluntary, to improve motor function in persons with multiple sclerosis (MS). We hypothesize that intensive aerobic exercise training elicits a neurorepairative and neurorestorative response on the central nervous system, which may improve motor function as it relates to gait and mobility. Should aerobic cycling, forced or voluntary, improve gait and functional mobility in persons with MS, it would serve as a new model to restoring function, rather than current models that focus on compensation.

Detailed Description: Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system characterized by progressive loss of motor function, cognitive function, in addition to symptoms of fatigue and depression. These motor and non-motor symptoms negatively affect the individuals' walking ability, functional mobility, quality of life, ability to maintain gainful employment, and social engagement. Identifying rehabilitation approaches that may delay disease progression or restore lost neurologic function would have considerable impact in the field. The goal of this project is to investigate the feasibility and initial efficacy of forced or voluntary aerobic exercise training to improve gait, functional mobility, fatigue and quality of life in persons with multiple sclerosis (PwMS). Current rehabilitative approaches for PwMS focus on training compensatory strategies rather than restoring neurological function. Substantial evidence indicates that aerobic exercise (AE) training has the potential to enhance neurological function by restoring and repairing damaged cells, leading to improvements in gait, balance, and cognitive function in PwMS. Despite evidence of the potential disease-modifying properties of AE, numerous physical, behavioral, and logistical barriers prevent PwMS from achieving and maintaining AE of sufficient intensity and duration to capitalize on the neurophysiologic benefits of training. Forced exercise (FE) is a novel approach to AE training that has been successfully applied to individuals with Parkinson's disease and stroke, in which the voluntary efforts of the individual are augmented, allowing for disease-altering effects of intensive exercise training. During FE, pedaling cadence on a stationary cycle is augmented by a motor to assist, but not replace, the voluntary efforts of the individual. It is hypothesized that PwMS cannot sustain high rates of voluntary exercise necessary to elicit neural repair; therefore, FE is necessary to overcome physical, behavioral and logistical barriers to enhance neuroplasticity to improve gait, QOL, and the ability to participate in life activities. Positive results from our FE trials in Parkinson's disease and stroke have guided us in designing the scientific methodology for the proposed trial in PwMS. Twenty adults with relapsing-remitting MS and mild to moderate gait impairment will be randomized to undergo 1) FE or 2) voluntary aerobic exercise (VE). Both groups will attend 2X/week for 12 weeks. Exercise variables will be collected for each session as a measure of feasibility to determine how PwMS respond to each exercise approach. Clinical, biomechanical, and self-reported outcomes will be gathered prior to, after, and 4-weeks after the intervention to determine the effects of both modes of exercise on spatiotemporal and kinematic characteristics of gait, functional mobility, balance, fatigue, physical activity levels, and quality of life. Should our findings confirm our hypothesis that intensive exercise training can have disease-altering effects, a new direction for MS rehabilitation approaches would ensue, empowering PwMS to take control of their disease to improve function and reduce disability.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 22

Inclusion Criteria

Confirmed diagnosis of RRMS with Expanded Disability Status Scale (EDSS) score between 1.5 and 6.5,
18-75 years of age,
Deemed minimal risk for cardiovascular event using American College of Sports Medicine Exercise Pre-participation Criteria

Exclusion Criteria

hospitalization for myocardial infarction, heart failure or heart surgery within 3 months,
serious cardiac arrhythmia,
hypertrophic cardiomyopathy,
severe aortic stenosis,
pulmonary embolus,
significant contractures,
dysphagia resulting in inability to sufficiently hydrate, and
other contraindication to exercise.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Forced Aerobic Exercise (FE)	Forced Aerobic Exercise (FE)	The FE group (N=10) will complete 45 minutes of FE on the custom-engineered cycle designed to augment pedaling rate to greater than 70 revolutions per minute (RPM's). The VE group (N=10) will exercise on an identical semi-recumbent cycle ergometer at their self-selected cadence without assistance.
Voluntary Aerobic Exercise (VE)	Voluntary Aerobic Exercise (VE)	The VE group (N=10) will exercise on an identical semi-recumbent cycle ergometer for 45 minutes at their self-selected cadence without assistance.

Primary Outcome Measures

Name	Time	Method
Multiple Sclerosis Manual Dexterity Test	Week 0 (baseline), Week 13 (post exercise sessions)	Assessment examining cognitive and hand function for persons with MS
Exercise Duration	collected during each exercise session (twice per week for 12 weeks)	Average exercise duration
Gait Velocity	Week 0 (baseline), Week 13 (post exercise sessions)	Spatio-temporal and kinematic parameters of gait will be obtained using 3-D motion capture and an instrumented walkway.
Aerobic Intensity	Collected during each exercise session (twice per week for 12 weeks)	average percent max heart rate
Six Minute Walk Test	Week 0 (baseline), Week 13 (post exercise sessions)	The distance walked over 6 minutes is measured on an oval walking track
Exercise Cadence	collected during each exercise session (twice per week for 12 weeks)	Average Exercise Cadence (cycling rate)
PROMIS-29	Week 0 (baseline), Week 13 (post exercise sessions)	The Patient-Reported Outcomes Measurement Information System (PROMIS) is a set of person-centered measures that evaluates and monitors physical, mental, and social health in the general population and with individuals living with chronic conditions. Raw scores were converted to T-scores (using an adult referent population) ranging from 0-100 with a mean of 50 and standard deviation (SD) of 10 in the referent population. For the PROMIS-29 symptom-related domains (anxiety, depression, fatigue, sleep disturbance, and pain interference), higher scores represent greater symptom burden (worse function). For the physical and participation domains, higher scores represent greater levels of function. Pain intensity is scored separately using a 0-10 scaler with higher scores representing greater pain.
Processing Speed Test	Week 0 (baseline), Week 13 (post exercise sessions)	Assessment examining processing speed using an tablet-based measure developed to closely resemble the symbol digit modalities test. Participants match symbols to digits over a 2-minute trial. The number of correct matches represents the score, with higher correct matches indicative of better processing speed performance. The low range of possible scoring is 0 with no upper range limit. In a study by Rao and colleagues (2017), persons with MS scored and average of 51.1 (+/- 11.9) on the first trial and 52.8 (+/- 2.0) on the second trial. One trial was conducted in this study.
Modified Fatigue Impact Scale (MFIS)	Week 0 (baseline), Week 13 (post exercise sessions)	The MFIS is a 21-item self-reported measure of how fatigue impacts the lives of persons with multiple sclerosis. This instrument provides an assessment of the effects of fatigue as it relates to physical, cognitive, and psychosocial functioning. Participants rate on a 5-point Likert scale, with 0 = 'Never' to 4 = 'Almost always' their agreement with 21 statements. Total score (0-84) and subscales for physical (0-36), cognitive (0-40) and psychosocial functioning (0-8). Higher numbers indicate greater fatigue in all domains.

Secondary Outcome Measures

Name	Time	Method
To Investigate the Role of Klotho in Promoting Neuroprotection.	Week 1 (exercise session 1), Week 12 (exercise session 24)	Laboratory Assessment: Blood draws will be conducted at 4 different points in time to determine the acute and long-term change in serum Klotho; at week one session one, pre- and post-exercise, and at the last session12-week exercise intervention, pre- and post-exercise.