Methylphenidate to Improve Balance and Walking in MS

Study Overview
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Brief Summary
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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
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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.

Official Title
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Methylphenidate to Improve Balance and Walking in MS

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: Methylphenidate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Methylphenidate<br>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 | Drug: Methylphenidate<br>* Escalating dose of methylphenidate, 20mg, 40mg, 60mg/day, for 2 weeks each<br>* Other names: Ritalin;|
| Placebo Comparator: Placebo<br>Placebo pill, bid for 6 weeks | Drug: Placebo<br>* Escalating matched dose of placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 6 weeks | 
| 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. | 6 weeks | 
| 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. | 6 weeks | 
| 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. | 6 weeks | 
| 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. | 6 weeks | 
| 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. | 6 weeks | 
| 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. | 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple sclerosis, postural balance, walking