Multiple SclerosisNCT04906057
The Therapeutic Effects of Forced Aerobic Exercise in Multiple Sclerosis
A study testing Forced Aerobic Exercise (FE) and Voluntary Aerobic Exercise (VE) in people with Multiple Sclerosis, run by The Cleveland Clinic at 2 sites in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Multiple Sclerosis
- What is being tested?
- Forced Aerobic Exercise (FE) and Voluntary Aerobic Exercise (VE)
- Type of treatment
- Lifestyle or therapy programme
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 22 participants
- Where
- 2 sitesUnited States
- Study dates
- 6 Jul 2021to 29 Nov 2022
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Cleveland Clinic Main Campus
Cleveland, Ohio, 44195
Cleveland Clinic
Cleveland, Ohio, 44195
About this study
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.
Read the 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.
- Conditions
- Multiple Sclerosis
- Being tested
- Forced Aerobic Exercise (FE), Voluntary Aerobic Exercise (VE)
- Keywords
- aerobic exercise, gait
- Medical subject headings
- Multiple Sclerosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Forced Aerobic Exercise (FE)Behavioural
High-rate aerobic exercise on a semi-recumbent custom-designed stationary cycle ergometer
Voluntary Aerobic Exercise (VE)Behavioural
Voluntary-rate aerobic exercise on a semi-recumbent stationary cycle ergometer
| Study group | Role | What they receive |
|---|---|---|
| Forced Aerobic Exercise (FE) | Experimental | 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. Receives: Behavioral: Forced Aerobic Exercise (FE) |
| Voluntary Aerobic Exercise (VE) | Active comparator | The VE group (N=10) will exercise on an identical semi-recumbent cycle ergometer for 45 minutes at their self-selected cadence without assistance. Receives: Behavioral: Voluntary Aerobic Exercise (VE) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Exercise Duration
Average exercise duration
Measured: collected during each exercise session (twice per week for 12 weeks)
Aerobic Intensity
average percent max heart rate
Measured: Collected during each exercise session (twice per week for 12 weeks)
Exercise Cadence
Average Exercise Cadence (cycling rate)
Measured: collected during each exercise session (twice per week for 12 weeks)
Six Minute Walk Test
The distance walked over 6 minutes is measured on an oval walking track
Measured: Week 0 (baseline), Week 13 (post exercise sessions)
Gait Velocity
Spatio-temporal and kinematic parameters of gait will be obtained using 3-D motion capture and an instrumented walkway.
Measured: Week 0 (baseline), Week 13 (post exercise sessions)
PROMIS-29
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.
Measured: Week 0 (baseline), Week 13 (post exercise sessions)
Modified Fatigue Impact Scale (MFIS)
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.
Measured: Week 0 (baseline), Week 13 (post exercise sessions)
Multiple Sclerosis Manual Dexterity Test
Assessment examining cognitive and hand function for persons with MS
Measured: Week 0 (baseline), Week 13 (post exercise sessions)
Processing Speed Test
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.
Measured: Week 0 (baseline), Week 13 (post exercise sessions)
Secondary outcomes (1)
To Investigate the Role of Klotho in Promoting Neuroprotection.
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.
Measured: Week 1 (exercise session 1), Week 12 (exercise session 24)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 May 2021
- Study start6 Jul 2021
- Primary completion29 Nov 2022
- Study completion29 Nov 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Multiple SclerosisStudies of the same condition, open and under way.
- More trials run by The Cleveland ClinicThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- rater-blind, prospective randomized trial
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 22 participants (actual)
Sponsor and investigators
- Lead sponsor
- The Cleveland Clinic
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Susan Linder, The Cleveland Clinic
- Investigators
- Susan M Linder, DPT, Principal investigator, The Cleveland Clinic
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04906057
- Sponsor's protocol ID
- 19-1003
- Status last verified
- Feb 2025
- First submitted
- 10 May 2021
- Last updated
- 6 Mar 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 6 Mar 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Therapeutic Effects of Forced Aerobic Exercise in Multiple Sclerosis
- ClinicalTrials.gov ID
- NCT04906057
- Acronym / sponsor ID
- 19-1003
- Conditions
- Multiple Sclerosis
- Keywords
- aerobic exercise, gait
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 22 participants (actual)
- Lead sponsor
- The Cleveland ClinicUniversity, hospital or other
- Study start
- 6 Jul 2021 (actual)
- Primary completion
- 29 Nov 2022 (actual)
- Study completion
- 29 Nov 2022 (actual)
- First posted
- 28 May 2021 (actual)
- Results
- Posted 11 Feb 2025
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
- Model description
- rater-blind, prospective randomized trial
| Arm | Type | Receives |
|---|---|---|
| Forced Aerobic Exercise (FE) | Experimental | Behavioral: 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) | Active comparator | Behavioral: 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. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- 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
Key exclusion criteria (8 listed)
- hospitalization for myocardial infarction, heart failure or heart surgery within 3 months,
- serious cardiac arrhythmia,
- hypertrophic cardiomyopathy,
- severe aortic stenosis,
- pulmonary embolus,
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Forced Aerobic Exercise (FE)High-rate aerobic exercise on a semi-recumbent custom-designed stationary cycle ergometer | Behavioural | Forced Aerobic Exercise (FE) |
| Voluntary Aerobic Exercise (VE)Voluntary-rate aerobic exercise on a semi-recumbent stationary cycle ergometer | Behavioural | Voluntary Aerobic Exercise (VE) |
Primary outcome
Exercise Duration
Time frame: collected during each exercise session (twice per week for 12 weeks)
Average exercise duration
Aerobic Intensity
Time frame: Collected during each exercise session (twice per week for 12 weeks)
average percent max heart rate
Exercise Cadence
Time frame: collected during each exercise session (twice per week for 12 weeks)
Average Exercise Cadence (cycling rate)
Six Minute Walk Test
Time frame: Week 0 (baseline), Week 13 (post exercise sessions)
The distance walked over 6 minutes is measured on an oval walking track
Gait Velocity
Time frame: 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
Time frame: 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)
Time frame: 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
Time frame: Week 0 (baseline), Week 13 (post exercise sessions)
Assessment examining cognitive and hand function for persons with MS
Processing Speed Test
Time frame: 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.
1 secondary outcome
To Investigate the Role of Klotho in Promoting Neuroprotection.
Time frame: Week 1 (exercise session 1), Week 12 (exercise session 24)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Mar 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Susan M Linder, DPT principal investigator
The Cleveland Clinic
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Forced Aerobic Exercise (FE) and Voluntary Aerobic Exercise (VE) in people with Multiple Sclerosis, run by The Cleveland Clinic at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Mar 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 11 Feb 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Exercise Duration (time frame: collected during each exercise session (twice per week for 12 weeks)). The study lists 9 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Mar 2025.