The Therapeutic Effects of Forced Aerobic Exercise in Multiple Sclerosis

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04906057

Enrollment

Registered

2021-05-28

Start date

2021-07-06

Completion date

2022-11-29

Last updated

2025-03-06

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Multiple Sclerosis

Keywords

aerobic exercise, gait

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.

Interventions

BEHAVIORALForced Aerobic Exercise (FE)

High-rate aerobic exercise on a semi-recumbent custom-designed stationary cycle ergometer

BEHAVIORALVoluntary Aerobic Exercise (VE)

Voluntary-rate aerobic exercise on a semi-recumbent stationary cycle ergometer

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

SINGLE (Outcomes Assessor)

Masking description

Group allocation will be concealed to the individual obtaining all outcomes of interest

Intervention model description

rater-blind, prospective randomized trial

Eligibility

Sex/Gender

ALL

Age

18 Years to 75 Years

Healthy volunteers

Inclusion criteria

1. Confirmed diagnosis of RRMS with Expanded Disability Status Scale (EDSS) score between 1.5 and 6.5, 2. 18-75 years of age, 3. Deemed minimal risk for cardiovascular event using American College of Sports Medicine Exercise Pre-participation Criteria

Exclusion criteria

1. hospitalization for myocardial infarction, heart failure or heart surgery within 3 months, 2. serious cardiac arrhythmia, 3. hypertrophic cardiomyopathy, 4. severe aortic stenosis, 5. pulmonary embolus, 6. significant contractures, 7. dysphagia resulting in inability to sufficiently hydrate, and 8. other contraindication to exercise.

Design outcomes

Primary

Measure	Time frame	Description
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.
Exercise Duration	collected during each exercise session (twice per week for 12 weeks)	Average exercise duration
Aerobic Intensity	Collected during each exercise session (twice per week for 12 weeks)	average percent max heart rate
Exercise Cadence	collected during each exercise session (twice per week for 12 weeks)	Average Exercise Cadence (cycling 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
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.
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.
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.
Multiple Sclerosis Manual Dexterity Test	Week 0 (baseline), Week 13 (post exercise sessions)	Assessment examining cognitive and hand function for persons with MS

Secondary

Measure	Time frame	Description
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.

Countries

United States

Participant flow

Participants by arm

Arm	Count
Forced Aerobic Exercise (FE) The FE group (N=11) completed 45 minutes of FE on the custom-engineered cycle designed to augment pedaling rate to greater than 70 revolutions per minute (RPM's). Forced Aerobic Exercise (FE): High-rate aerobic exercise on a semi-recumbent custom-designed stationary cycle ergometer	11
Voluntary Aerobic Exercise (VE) The VE group (N=7) completed exercise on an identical semi-recumbent cycle ergometer for 45 minutes at their self-selected cadence without assistance. Voluntary Aerobic Exercise (VE): Voluntary-rate aerobic exercise on a semi-recumbent stationary cycle ergometer	7
Total	18

Baseline characteristics

Characteristic	Forced Aerobic Exercise (FE)	Voluntary Aerobic Exercise (VE)	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	2 Participants	0 Participants	2 Participants
Age, Categorical Between 18 and 65 years	9 Participants	7 Participants	16 Participants
Age, Continuous	53.6 years STANDARD_DEVIATION 12.2	56.9 years STANDARD_DEVIATION 7.9	54.9 years STANDARD_DEVIATION 10.6
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	10 Participants	7 Participants	17 Participants
Sex: Female, Male Female	6 Participants	4 Participants	10 Participants
Sex: Female, Male Male	5 Participants	3 Participants	8 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 12	0 / 10
other Total, other adverse events	2 / 12	4 / 10
serious Total, serious adverse events	1 / 12	0 / 10

Outcome results

Primary

Aerobic Intensity

average percent max heart rate

Time frame: Collected during each exercise session (twice per week for 12 weeks)

Population: FE + VE groups

Arm	Measure	Value (MEAN)	Dispersion
Forced Aerobic Exercise (FE)	Aerobic Intensity	0.63 % Max HR	Standard Deviation 0.07
Voluntary Exercise (VE)	Aerobic Intensity	.70 % Max HR	Standard Deviation 0.05

Primary

Exercise Cadence

Average Exercise Cadence (cycling rate)

Time frame: collected during each exercise session (twice per week for 12 weeks)

Population: Completed participants within the FE \& VE groups

Arm	Measure	Value (MEAN)	Dispersion
Forced Aerobic Exercise (FE)	Exercise Cadence	69.1 revolutions per minute	Standard Deviation 11.1
Voluntary Exercise (VE)	Exercise Cadence	64.5 revolutions per minute	Standard Deviation 16.7

Primary

Exercise Duration

Average exercise duration

Time frame: collected during each exercise session (twice per week for 12 weeks)

Population: Completed participants in the FE \& VE groups.

Arm	Measure	Value (MEAN)	Dispersion
Forced Aerobic Exercise (FE)	Exercise Duration	42.2 Minutes	Standard Deviation 2.4
Voluntary Exercise (VE)	Exercise Duration	42.2 Minutes	Standard Deviation 2.4

Primary

Gait Velocity

Spatio-temporal and kinematic parameters of gait will be obtained using 3-D motion capture and an instrumented walkway.