Multiple Sclerosis
Conditions
Keywords
Multiple sclerosis, postural balance, walking
Brief summary
Methylphenidate is an amphetamine-like psychomotor stimulant drug currently approved for the treatment of attention-deficit hyperactivity disorder (ADHD), postural orthostasis tachycardia syndrome and narcolepsy. It is also often prescribed off label to people with MS to improve fatigue. It is proposed that methylphenidate may also improve imbalance and walking deficits in MS by improving concentration and central integration, one of the primary mechanisms thought to underlie imbalance and walking deficits in MS.
Detailed description
The proposed pilot study will examine the effects of methylphenidate on imbalance and walking in 24 subjects with MS and imbalance. The subjects will be randomly assigned to receive either an escalating does of methylphenidate, 20mg, 40mg or 60mg, divided into two doses each day, or matched placebo for 2 weeks at each dose. If a subject does not tolerate dose escalation they will be instructed to discontinue use of the drug. The maximum safely tolerated dose for each subject will be noted. Changes from baseline in subject's walking speed, balance, vestibular function, cognitive function, and fatigue will be assessed at each dose.
Interventions
DRUGMethylphenidate
Escalating dose of methylphenidate, 20mg, 40mg, 60mg/day, for 2 weeks each
DRUGPlacebo
Escalating matched dose of placebo
Sponsors
Portland VA Medical Center
Oregon Health and Science University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Age 20-65 * Able to walk at least 100m without an aide or with unilateral assistance * Poor static balance, specifically prolonged APR latencies (≥ 1 standard deviation (SD) \> mean for healthy people in this age range), OR * Reduced balance-related activity (ABC scores ≤ 85%) * Walking difficulties, specifically T25FW \> 6 seconds, OR reduced self perceived walking (MSWS-12 scores ≥ 50/60)
Exclusion criteria
* Currently taking methylphenidate, modafinil, or armodafinil.(any within the last 2 weeks) * Cause(s) of imbalance other than MS * Systolic pressure consistently greater than 150 mm Hg or diastolic pressure consistently greater than 90 mm Hg * Contraindications to methylphenidate (Anxiety, tension, agitation, thyrotoxicosis, tachyarrhythmias, severe angina pectoris or glaucoma, hypersensitivity to methylphenidate, motor tics or a family history or diagnosis of Tourette's syndrome, seizures, severe or poorly controlled hypertension, treatment with monoamine oxidase inhibitors currently or within the last 14 days, current use of guanethidine, pressors, coumarin anticoagulants, anticonvulsants, phenylbutazone, or tricyclic antidepressants, history of drug abuse or alcoholism) * Pregnancy or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Timed Up and Go (TUG) Test Time at 6 Weeks | 6 weeks | The primary outcome of this study will be the difference between mean change in TUG time between methylphenidate and placebo treated subjects at 6 weeks. Mean changes will be compared for active and placebo treated subjects using Bayesian analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Timed 25 Foot Walk (T25FW) at 6 Weeks | 6 weeks | Mean changes in Timed 25 Foot Walk (T25FW) at 6 weeks will be compared for active and placebo treated subjects using Bayesian analysis. |
| Change From Baseline in Pittsburgh Sleep Quality Assessment Questionnaire Score at 6 Weeks | 6 weeks | Mean changes in the score attained on the Pittsburgh Sleep Quality Assessment Questionnaire at 6 weeks will be compared for active and placebo treated subjects using Bayesian analysis. Scale ranges from 0-21 points, with higher numbers indicating poorer sleep quality. |
| Change From Baseline in Modified Fatigue Index Scale Score at 6 Weeks | 6 weeks | Mean changes in the score attached on the Modified Fatigue Index Scale at 6 weeks will be compared for active and placebo treated subjects using Bayesian analysis. Scale ranges from 0-84 points, with higher scores indicating greater fatigue. |
| Change From Baseline in Automatic Postural Response (APR) Latency at 6 Weeks | 6 weeks | Mean changes in APR latency at 6 weeks will be compared for active and placebo treated subjects using Bayesian analysis. |
| Change From Baseline in Vestibular Ocular Reflex (VOR) Asymmetry (Percentage Asymmetric) at 6 Weeks | 6 weeks | Mean changes in VOR asymmetry, which is a measure of the strength of the eye responses in one direction compared with the other as measured by rotary chair testing at 6 weeks, will be compared for active and placebo treated subjects using t-tests, or other appropriate statistical analyses. A range of frequencies was tested from 0.04 Hz to 0.64 Hz, as is standard for rotary chair testing. The range of frequencies (i.e. chair speeds) assesses the vestibular system across a range of head movements. This helps to identify abnormality, which may manifest at different frequencies of movement. The measurement outcomes for rotary chair testing are gain, phase and asymmetry of the eye movements. |
| Change From Baseline in Vestibular Ocular Reflex (VOR) Phase (in Degrees) at 6 Weeks | 6 weeks | Mean changes in VOR phase, which is a measure of the timing (in degrees) of the eye movements relative to the chair movement, as measured by rotary chair testing at 6 weeks, will be compared for active and placebo treated subjects using t-tests, or other appropriate statistical analyses. A range of frequencies was tested from 0.04 Hz to 0.64 Hz, as is standard for rotary chair testing. The range of frequencies (i.e. chair speeds) assesses the vestibular system across a range of head movements. This helps to identify abnormality, which may manifest at different frequencies of movement. The measurement outcomes for rotary chair testing are gain, phase and asymmetry of the eye movements. |
| Change From Baseline in Vestibular-Ocular Reflex (VOR) Gain at 6 Weeks | 6 weeks | The most common rotary chair testing is a battery of subtests, each at a specific rate (Hz) of chair rotation from side to side. The participant is secured in the chair in total darkness while the eyes are monitored by infrared cameras. We completed tests from 0.04 to 0.64 Hz to assess the vestibular system across a range of head movements. The chair and participant's head move together while the cameras track the velocity of the eyes; eye velocity reveals how the vestibular system responds to head velocity. VOR gain is the ratio of average chair (i.e. head) velocity to average eye velocity, and is represented on a unitless scale from 0 to 1. VOR gain close to 1 indicates that eye velocity is nearly equal and opposite to head velocity. While there are normative ranges for VOR gain, we are most interested in is change in mean gain (6-week tests minus baseline tests) for the active and placebo groups. |
Countries
United States
Participant flow
Recruitment details
24 people with MS and imbalance from the MS clinics in the Portland, OR metropolitan area were enrolled into this study between September 2013 and March 2016 .
Participants by arm
| Arm | Count |
|---|---|
| Methylphenidate Intervention: An escalating dose of methylphenidate taken by mouth: 20mg for 2 weeks, 40mg for 2 weeks, 60mg for 2 weeks. All doses divided twice/day.
Other name: Ritalin
Methylphenidate: Escalating dose of methylphenidate, 20mg, 40mg, 60mg/day, for 2 weeks each | 12 |
| Placebo Placebo pill, bid for 6 weeks
Placebo: Escalating matched dose of placebo | 12 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 5 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Methylphenidate | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 46.4 years STANDARD_DEVIATION 7.9 | 49.0 years STANDARD_DEVIATION 8.6 | 51.7 years STANDARD_DEVIATION 8.7 |
| 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 | 2 Participants | 3 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 | 21 Participants | 11 Participants |
| Region of Enrollment United States | 12 Participants | 24 Participants | 12 Participants |
| Sex: Female, Male Female | 9 Participants | 19 Participants | 10 Participants |
| Sex: Female, Male Male | 3 Participants | 5 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 12 / 12 | 11 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 |
Outcome results
Primary
Change From Baseline in Timed Up and Go (TUG) Test Time at 6 Weeks
The primary outcome of this study will be the difference between mean change in TUG time between methylphenidate and placebo treated subjects at 6 weeks. Mean changes will be compared for active and placebo treated subjects using Bayesian analysis.
Time frame: 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methylphenidate | Change From Baseline in Timed Up and Go (TUG) Test Time at 6 Weeks | -0.7 change in seconds from basline | Standard Error 0.5 |
| Placebo | Change From Baseline in Timed Up and Go (TUG) Test Time at 6 Weeks | -1.3 change in seconds from basline | Standard Error 0.2 |
Secondary
Change From Baseline in Automatic Postural Response (APR) Latency at 6 Weeks
Mean changes in APR latency at 6 weeks will be compared for active and placebo treated subjects using Bayesian analysis.
Time frame: 6 weeks
Population: Population discrepancy: One participant in the intervention group and two participants in the placebo group contributed unusable APR data; due to their balance deficits, the machine could not get an accurate reading for this test. One participant in the intervention group declined this test. These four participants were not included in analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methylphenidate | Change From Baseline in Automatic Postural Response (APR) Latency at 6 Weeks | -9.2 change in milliseconds from baseline | Standard Error 2.2 |
| Placebo | Change From Baseline in Automatic Postural Response (APR) Latency at 6 Weeks | -5.3 change in milliseconds from baseline | Standard Error 1.8 |
Secondary
Change From Baseline in Modified Fatigue Index Scale Score at 6 Weeks
Mean changes in the score attached on the Modified Fatigue Index Scale at 6 weeks will be compared for active and placebo treated subjects using Bayesian analysis. Scale ranges from 0-84 points, with higher scores indicating greater fatigue.
Time frame: 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methylphenidate | Change From Baseline in Modified Fatigue Index Scale Score at 6 Weeks | -3.8 change in score from baseline | Standard Error 3.5 |
| Placebo | Change From Baseline in Modified Fatigue Index Scale Score at 6 Weeks | -9.8 change in score from baseline | Standard Error 4.4 |
Secondary
Change From Baseline in Pittsburgh Sleep Quality Assessment Questionnaire Score at 6 Weeks
Mean changes in the score attained on the Pittsburgh Sleep Quality Assessment Questionnaire at 6 weeks will be compared for active and placebo treated subjects using Bayesian analysis. Scale ranges from 0-21 points, with higher numbers indicating poorer sleep quality.
Time frame: 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methylphenidate | Change From Baseline in Pittsburgh Sleep Quality Assessment Questionnaire Score at 6 Weeks | 0.3 change in score from baseline | Standard Error 0.9 |
| Placebo | Change From Baseline in Pittsburgh Sleep Quality Assessment Questionnaire Score at 6 Weeks | -0.3 change in score from baseline | Standard Error 0.7 |
Secondary
Change From Baseline in Timed 25 Foot Walk (T25FW) at 6 Weeks
Mean changes in Timed 25 Foot Walk (T25FW) at 6 weeks will be compared for active and placebo treated subjects using Bayesian analysis.
Time frame: 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methylphenidate | Change From Baseline in Timed 25 Foot Walk (T25FW) at 6 Weeks | -0.3 change in seconds from baseline | Standard Error 0.7 |
| Placebo | Change From Baseline in Timed 25 Foot Walk (T25FW) at 6 Weeks | -0.6 change in seconds from baseline | Standard Error 0.2 |
Secondary
Change From Baseline in Vestibular Ocular Reflex (VOR) Asymmetry (Percentage Asymmetric) at 6 Weeks
Mean changes in VOR asymmetry, which is a measure of the strength of the eye responses in one direction compared with the other as measured by rotary chair testing at 6 weeks, will be compared for active and placebo treated subjects using t-tests, or other appropriate statistical analyses. A range of frequencies was tested from 0.04 Hz to 0.64 Hz, as is standard for rotary chair testing. The range of frequencies (i.e. chair speeds) assesses the vestibular system across a range of head movements. This helps to identify abnormality, which may manifest at different frequencies of movement. The measurement outcomes for rotary chair testing are gain, phase and asymmetry of the eye movements.
Time frame: 6 weeks
Population: Explanation of population discrepancy: One participant in the active group declined this test, so was not analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Methylphenidate | Change From Baseline in Vestibular Ocular Reflex (VOR) Asymmetry (Percentage Asymmetric) at 6 Weeks | VOR Asymmetry at 0.04 Hz | 0.9927 change in % of asymmetry from baseline | Standard Deviation 5.6664 |
| Methylphenidate | Change From Baseline in Vestibular Ocular Reflex (VOR) Asymmetry (Percentage Asymmetric) at 6 Weeks | VOR Asymmetry at 0.32 Hz | 1.9157 change in % of asymmetry from baseline | Standard Deviation 5.1153 |
| Methylphenidate | Change From Baseline in Vestibular Ocular Reflex (VOR) Asymmetry (Percentage Asymmetric) at 6 Weeks | VOR Asymmetry at 0.08 Hz | -0.0572 change in % of asymmetry from baseline | Standard Deviation 5.6678 |
| Methylphenidate | Change From Baseline in Vestibular Ocular Reflex (VOR) Asymmetry (Percentage Asymmetric) at 6 Weeks | VOR Asymmetry at 0.64 Hz | 0.3104 change in % of asymmetry from baseline | Standard Deviation 4.0893 |
| Methylphenidate | Change From Baseline in Vestibular Ocular Reflex (VOR) Asymmetry (Percentage Asymmetric) at 6 Weeks | VOR Asymmetry at 0.16 Hz | 2.5833 change in % of asymmetry from baseline | Standard Deviation 3.1565 |
| Placebo | Change From Baseline in Vestibular Ocular Reflex (VOR) Asymmetry (Percentage Asymmetric) at 6 Weeks | VOR Asymmetry at 0.64 Hz | -1.5111 change in % of asymmetry from baseline | Standard Deviation 3.7015 |
| Placebo | Change From Baseline in Vestibular Ocular Reflex (VOR) Asymmetry (Percentage Asymmetric) at 6 Weeks | VOR Asymmetry at 0.04 Hz | -1.7291 change in % of asymmetry from baseline | Standard Deviation 2.3367 |
| Placebo | Change From Baseline in Vestibular Ocular Reflex (VOR) Asymmetry (Percentage Asymmetric) at 6 Weeks | VOR Asymmetry at 0.16 Hz | -5.2852 change in % of asymmetry from baseline | Standard Deviation 4.9239 |
| Placebo | Change From Baseline in Vestibular Ocular Reflex (VOR) Asymmetry (Percentage Asymmetric) at 6 Weeks | VOR Asymmetry at 0.32 Hz | -4.1203 change in % of asymmetry from baseline | Standard Deviation 5.4695 |
| Placebo | Change From Baseline in Vestibular Ocular Reflex (VOR) Asymmetry (Percentage Asymmetric) at 6 Weeks | VOR Asymmetry at 0.08 Hz | -6.5209 change in % of asymmetry from baseline | Standard Deviation 1.9883 |
Secondary
Change From Baseline in Vestibular-Ocular Reflex (VOR) Gain at 6 Weeks
The most common rotary chair testing is a battery of subtests, each at a specific rate (Hz) of chair rotation from side to side. The participant is secured in the chair in total darkness while the eyes are monitored by infrared cameras. We completed tests from 0.04 to 0.64 Hz to assess the vestibular system across a range of head movements. The chair and participant's head move together while the cameras track the velocity of the eyes; eye velocity reveals how the vestibular system responds to head velocity. VOR gain is the ratio of average chair (i.e. head) velocity to average eye velocity, and is represented on a unitless scale from 0 to 1. VOR gain close to 1 indicates that eye velocity is nearly equal and opposite to head velocity. While there are normative ranges for VOR gain, we are most interested in is change in mean gain (6-week tests minus baseline tests) for the active and placebo groups.
Time frame: 6 weeks
Population: Explanation of population discrepancy: One participant in the active group declined this test, so was not analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Methylphenidate | Change From Baseline in Vestibular-Ocular Reflex (VOR) Gain at 6 Weeks | VOR Gain at 0.16 Hz | -0.0151 ratio | Standard Deviation 0.0949 |
| Methylphenidate | Change From Baseline in Vestibular-Ocular Reflex (VOR) Gain at 6 Weeks | VOR Gain at 0.08 Hz | -0.0061 ratio | Standard Deviation 0.0759 |
| Methylphenidate | Change From Baseline in Vestibular-Ocular Reflex (VOR) Gain at 6 Weeks | VOR Gain at 0.32 Hz | -0.0422 ratio | Standard Deviation 0.1154 |
| Methylphenidate | Change From Baseline in Vestibular-Ocular Reflex (VOR) Gain at 6 Weeks | VOR Gain at 0.64 Hz | 0.0221 ratio | Standard Deviation 0.0894 |
| Methylphenidate | Change From Baseline in Vestibular-Ocular Reflex (VOR) Gain at 6 Weeks | VOR Gain at 0.04 Hz | -0.0107 ratio | Standard Deviation 0.0868 |
| Placebo | Change From Baseline in Vestibular-Ocular Reflex (VOR) Gain at 6 Weeks | VOR Gain at 0.64 Hz | 0.0151 ratio | Standard Deviation 0.0614 |
| Placebo | Change From Baseline in Vestibular-Ocular Reflex (VOR) Gain at 6 Weeks | VOR Gain at 0.04 Hz | -0.0229 ratio | Standard Deviation 0.0521 |
| Placebo | Change From Baseline in Vestibular-Ocular Reflex (VOR) Gain at 6 Weeks | VOR Gain at 0.08 Hz | -0.283 ratio | Standard Deviation 0.034 |
| Placebo | Change From Baseline in Vestibular-Ocular Reflex (VOR) Gain at 6 Weeks | VOR Gain at 0.16 Hz | 0.0871 ratio | Standard Deviation 0.0702 |
| Placebo | Change From Baseline in Vestibular-Ocular Reflex (VOR) Gain at 6 Weeks | VOR Gain at 0.32 Hz | 0.0322 ratio | Standard Deviation 0.068 |
Secondary
Change From Baseline in Vestibular Ocular Reflex (VOR) Phase (in Degrees) at 6 Weeks
Mean changes in VOR phase, which is a measure of the timing (in degrees) of the eye movements relative to the chair movement, as measured by rotary chair testing at 6 weeks, will be compared for active and placebo treated subjects using t-tests, or other appropriate statistical analyses. A range of frequencies was tested from 0.04 Hz to 0.64 Hz, as is standard for rotary chair testing. The range of frequencies (i.e. chair speeds) assesses the vestibular system across a range of head movements. This helps to identify abnormality, which may manifest at different frequencies of movement. The measurement outcomes for rotary chair testing are gain, phase and asymmetry of the eye movements.
Time frame: 6 weeks
Population: Explanation of population discrepancy: One participant in the active group declined this test, so was not analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Methylphenidate | Change From Baseline in Vestibular Ocular Reflex (VOR) Phase (in Degrees) at 6 Weeks | VOR Phase at 0.08 Hz | 1.8914 change in degrees from baseline | Standard Deviation 4.2548 |
| Methylphenidate | Change From Baseline in Vestibular Ocular Reflex (VOR) Phase (in Degrees) at 6 Weeks | VOR Phase at 0.16 Hz | 0.9449 change in degrees from baseline | Standard Deviation 2.24 |
| Methylphenidate | Change From Baseline in Vestibular Ocular Reflex (VOR) Phase (in Degrees) at 6 Weeks | VOR Phase at 0.32 Hz | -1.3564 change in degrees from baseline | Standard Deviation 7.0617 |
| Methylphenidate | Change From Baseline in Vestibular Ocular Reflex (VOR) Phase (in Degrees) at 6 Weeks | VOR Phase at 0.04 Hz | 2.2790 change in degrees from baseline | Standard Deviation 5.2622 |
| Methylphenidate | Change From Baseline in Vestibular Ocular Reflex (VOR) Phase (in Degrees) at 6 Weeks | VOR Phase at 0.64 Hz | -2.7082 change in degrees from baseline | Standard Deviation 3.601 |
| Placebo | Change From Baseline in Vestibular Ocular Reflex (VOR) Phase (in Degrees) at 6 Weeks | VOR Phase at 0.64 Hz | 0.2833 change in degrees from baseline | Standard Deviation 1.78 |
| Placebo | Change From Baseline in Vestibular Ocular Reflex (VOR) Phase (in Degrees) at 6 Weeks | VOR Phase at 0.16 Hz | -0.3342 change in degrees from baseline | Standard Deviation 3.6845 |
| Placebo | Change From Baseline in Vestibular Ocular Reflex (VOR) Phase (in Degrees) at 6 Weeks | VOR Phase at 0.04 Hz | 1.9535 change in degrees from baseline | Standard Deviation 4.2274 |
| Placebo | Change From Baseline in Vestibular Ocular Reflex (VOR) Phase (in Degrees) at 6 Weeks | VOR Phase at 0.32 Hz | 0.5981 change in degrees from baseline | Standard Deviation 3.6808 |
| Placebo | Change From Baseline in Vestibular Ocular Reflex (VOR) Phase (in Degrees) at 6 Weeks | VOR Phase at 0.08 Hz | -1.4716 change in degrees from baseline | Standard Deviation 2.5754 |