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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
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| 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Forced Aerobic Exercise (FE) | Behavioral | High-rate aerobic exercise on a semi-recumbent custom-designed stationary cycle ergometer |
|
| Measure | Description | Time Frame |
|---|---|---|
| Exercise Duration | Average exercise duration | collected during each exercise session (twice per week for 12 weeks) |
| Aerobic Intensity | average percent max heart rate | Collected during each exercise session (twice per week for 12 weeks) |
| Exercise Cadence | Average Exercise Cadence (cycling rate) | 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 | 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. | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Week 1 (exercise session 1), Week 12 (exercise session 24) |
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Inclusion Criteria:
Exclusion Criteria:
Participants identifying as male or female are eligible
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| Name | Affiliation | Role |
|---|---|---|
| Susan M Linder, DPT | The Cleveland Clinic | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Cleveland Clinic Main Campus | Cleveland | Ohio | 44195 | United States | ||
| Cleveland Clinic |
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| ID | Title | Description |
|---|---|---|
| FG000 | Forced Aerobic Exercise (FE) | The FE group (N=11) completed 45 minutes of forced-rate aerobic exercise on a 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 |
| FG001 | Voluntary Aerobic Exercise (VE) | The VE group (N=7) completed aerobic exercise on an identical semi-recumbent cycle ergometer at their self-selected cadence without assistance for 45 minutes. Voluntary Aerobic Exercise (VE): Voluntary-rate aerobic exercise on a semi-recumbent stationary cycle ergometer |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical |
1 Participant withdrew due to Covid-19 |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Exercise Duration | Average exercise duration | Completed participants in the FE & VE groups. | Posted | Mean | Standard Deviation | Minutes | collected during each exercise session (twice per week for 12 weeks) |
|
Adverse experiences were collected up to 19 weeks from start to completion of the study.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Forced Aerobic Exercise (FE) | This section includes data from all randomized participants in the forced exercise group The FE group (N=12) completed 45 minutes of FE on the custom-engineered cycle designed to augment the 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. Forced Aerobic Exercise (FE): High-rate aerobic exercise on a semi-recumbent custom-designed stationary cycle ergometer |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| STEMI | Cardiac disorders | Systematic Assessment | Heart attack |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Covid-19 Diagnosis | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Donayja Harris | Cleveland Clinic | 2164454125 | harrisD47@ccf.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jul 15, 2021 | Jul 18, 2023 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jul 15, 2021 | Jul 18, 2023 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D009103 | Multiple Sclerosis |
| ID | Term |
|---|---|
| D020278 | Demyelinating Autoimmune Diseases, CNS |
| D020274 | Autoimmune Diseases of the Nervous System |
| D009422 | Nervous System Diseases |
| D003711 | Demyelinating Diseases |
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rater-blind, prospective randomized trial
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Group allocation will be concealed to the individual obtaining all outcomes of interest
| Voluntary Aerobic Exercise (VE) | Behavioral | Voluntary-rate aerobic exercise on a semi-recumbent stationary cycle ergometer |
|
| 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. | Week 0 (baseline), Week 13 (post exercise sessions) |
| Multiple Sclerosis Manual Dexterity Test | Assessment examining cognitive and hand function for persons with MS | 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. | Week 0 (baseline), Week 13 (post exercise sessions) |
| Cleveland |
| Ohio |
| 44195 |
| United States |
| 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 |
| BG002 | Total | Total of all reporting groups |
| Count of Participants |
| Participants |
|
| Age, Continuous |
1 Participant withdrew due to Covid-19 | Mean | Standard Deviation | years |
|
| Sex: Female, Male |
1 Participant withdrew due to Covid-19 | Count of Participants | Participants |
|
| Race (NIH/OMB) |
1 Participant withdrew due to Covid-19 | Count of Participants | Participants |
|
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| Primary | Aerobic Intensity | average percent max heart rate | FE + VE groups | Posted | Mean | Standard Deviation | % Max HR | Collected during each exercise session (twice per week for 12 weeks) |
|
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| Primary | Exercise Cadence | Average Exercise Cadence (cycling rate) | Completed participants within the FE & VE groups | Posted | Mean | Standard Deviation | revolutions per minute | collected during each exercise session (twice per week for 12 weeks) |
|
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| Primary | Six Minute Walk Test | The distance walked over 6 minutes is measured on an oval walking track | Week (0) Baseline + EOT Week (13) | Posted | Mean | Standard Deviation | Meters | Week 0 (baseline), Week 13 (post exercise sessions) |
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| Primary | Gait Velocity | Spatio-temporal and kinematic parameters of gait will be obtained using 3-D motion capture and an instrumented walkway. | Data was obtained using a ZENO & Caren walking pad; however, one participant was unable to complete this outcome measure due to unsteady gait. | Posted | Mean | Standard Deviation | Meters per second | Week 0 (baseline), Week 13 (post exercise sessions) |
|
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|
| Primary | 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. | Each participant completed the PROMIS-29 assessment at baseline. Some participants chose not to complete the EOT questionnaire, hence the overall number of participants for the EOT testing is fewer than the baseline. | Posted | Mean | Standard Deviation | Units on a scale | Week 0 (baseline), Week 13 (post exercise sessions) |
|
|
|
| Primary | 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. | Each participant completed the Modified Fatigue Impact Scale (MFIS) assessment at baseline. Some participants chose not to complete the EOT questionnaire, hence the overall number of participants for the EOT testing is fewer than the baseline. | Posted | Mean | Standard Deviation | score on Likert scale | Week 0 (baseline), Week 13 (post exercise sessions) |
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| Primary | Multiple Sclerosis Manual Dexterity Test | Assessment examining cognitive and hand function for persons with MS | One forced exercise participant was unable to complete the Manual Dexterity test on the left side at baseline. | Posted | Mean | Standard Deviation | Time in Seconds | Week 0 (baseline), Week 13 (post exercise sessions) |
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|
| Primary | 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. | One participant from the VE group could not complete the processing speed test. | Posted | Mean | Standard Deviation | number correct | Week 0 (baseline), Week 13 (post exercise sessions) |
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| Secondary | 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. | Participants in this data set have completed the entire 12 weeks of the prescribed exercise session. | Posted | Mean | Standard Deviation | pg/mL | Week 1 (exercise session 1), Week 12 (exercise session 24) |
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| 0 |
| 12 |
| 1 |
| 12 |
| 2 |
| 12 |
| EG001 | Voluntary Aerobic Exercise (VE) | This section includes data from all randomized participants in the the voluntary exercise group The VE group (N=10) completed the 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 | 0 | 10 | 0 | 10 | 4 | 10 |
| Fall | Injury, poisoning and procedural complications | Systematic Assessment |
|
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| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| CAREN Walking Speed Baseline (Average) |
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| PROMIS Physical at EOT |
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| PROMIS Anxiety at baseline |
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| PROMIS Anxiety at EOT |
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| PROMIS Depression at baseline |
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| PROMIS Depression at EOT |
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| PROMIS Fatigue at baseline |
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| PROMIS Fatigue at EOT |
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| PROMIS Sleep Disturbance at baseline |
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| PROMIS Sleep Disturbance at EOT |
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| PROMIS Participation at baseline |
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| PROMIS Participation at EOT |
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| PROMIS Pain Interference at baseline |
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| PROMIS Pain Interference at EOT |
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| PROMIS Pain Intensity at baseline |
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| PROMIS Pain Intensity at EOT |
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| MFIS total score at EOT |
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| MFIS Physical Subscale at baseline |
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| MFIS Physical Subscale at EOT |
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| MFIS Cognitive Subscale at baseline |
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| MFIS Cognitive Subscale at EOT |
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| MFIS Psychosocial Subscale at baseline |
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| MFIS Psychosocial Subscale at EOT |
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| Manual Dexterity Test (right) at EOT |
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| Manual Dexterity Test (Left) at baseline |
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| Manual Dexterity Test (left) at EOT |
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| Klotho (Baseline Post-Exercise) |
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| Klotho (Final Session pre-exercise) |
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| Klotho (Final Session post-exercise) |
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| Neurofilament light (Baseline) |
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| Neurofilament light (Final Session) |
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