Study of Lisdexamfetamine Sulfate to Treat Cognitive Dysfunction in Multiple Sclerosis

Study Overview
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Brief Summary
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Amphetamines have been shown to improve cognition but its use is limited due to its side effects. Lisdexamfetamine is an amphetamine pro-drug, minimizing these effects and has been safely used in children and adults with Attention Deficit Hyperactivity Disorder (ADHD). The investigators hypothesize that lisdexamfetamine may improve cognitive abilities in MS patients with documented cognitive dysfunction. Because lisdexamfetamine is a stimulant its positive effects should be observed primarily in the domains of processing speed and working memory. The investigators therefore propose a study in which the primary objective will be to assess the efficacy of lisdexamfetamine in improving attention and processing speed in MS. The secondary objectives will be (a) the assessment of the safety and tolerability of lisdexamfetamine in the MS population, and (b) to test for effects of the drug on other cognitive domains, depression, and self and informant reports of cognitive and executive function demanding activities and behaviors.

Official Title
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Effects of Lisdexamfetamine on Bradyphrenia in Multiple Sclerosis

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: lisdexamfetamine sulfate
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males/Females who are ≥ 18 years old and < 55 years old and are capable of understanding and complying with the protocol, including speaking and writing fluent English and having at least a 9th grade education. Have a diagnosis of either Relapsing Remitting or Secondary Progressive MS, as per revised McDonald's Criteria (68). Have not received steroids in last thirty (30) days or a relapse in the last ninety (90) days, and whose MS is considered stable. Presence of cognitive dysfunction characterized by slowed processing speed as indicated by a score of -1.5 SD below age/education matched norms on the SDMT or the PASAT. An Expanded Disability Status Scale (EDSS) of ≤ 6.5 Have given written informed consent prior to any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to his/her future medical care. Are capable of performing the requirements of a NP test battery including at least 20/70 near visual acuity by near vision chart, with correction allowed. If female, must neither be pregnant nor breast-feeding and must either (a) be > 12 months post-menopausal or surgically sterilized, or (b) agree to use an acceptable method of birth control for the duration of the study. Abstinence will not be considered an acceptable method of birth control. Exclusion Criteria: Have cognitive deficits caused by concomitant medication usage or other significant neurological/psychological disease e.g. Alzheimer's disease, Parkinson's disease, stroke, transient ischemic attack, Vascular Dementia, Huntington's disease, traumatic brain injury or chronic CNS infection Have evidence of other medical cause(s) of cognitive impairment Have evidence of major depression as determined by a positive BDIFS and clinician interview Have uncontrolled or labile hypertension, tachycardia, cardiovascular or cerebrovascular disease Have demonstrated a hypersensitivity to amphetamines in the past The following concomitant medications are not permitted to be used within 28 days of enrollment or during the study Monoamine Oxidase Inhibitors Inhaled Beta2-agonists Sympathomimetics Antipsychotic agents Modafinil Tricyclic Antidepressants Anticonvulsants other than gabapentin and pregabalin The following medications are permitted if the patient has been on a stable dose for ≥ 6 weeks: Short acting benzodiazepines, qhs administration only Gabapentin and pregabalin Cholinesterase inhibitors other than donepezil, galantamine, and rivastigmine Memantine Anti-spasmodics Selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: lisdexamfetamine sulfate<br>30mg lisdexamfetamine OD, increased to 70mg OD over 4 weeks and continued on 70mg OD for 4 weeks | Drug: lisdexamfetamine sulfate<br>* 30mg lisdexamfetamine OD, increased to 70mg OD over 4 weeks and continued on 70mg OD for 4 weeks<br>* Other names: Vyvanse;|
| Placebo Comparator: Sugar pill<br>Placebo will be administered in the same fashion as the treatment arm | Drug: placebo<br>* sugar pill<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symbol Digit Modalities Test (SDMT) | The Symbol Digit Modalities Test (SDMT) presents a series of nine symbols, each paired with a single digit in a key at the top of a stimulus page. Subjects voice the number associated with each symbol as rapidly as possible. The examiner records the total amount of responses completed. The task continues for 90 seconds with the research staff recording responses. The SDMT score ranges from 0 to 110, with higher values representing a better outcome in cognitive processing speed. | 8 weeks | 
| Paced Auditory Serial Audition Test (PASAT) | The PASAT is a test requiring attention and vigilance. In this test, the patient listens to a tape recording of digits presented one at a time. The task for the patient is to add each number to the one immediately preceding it. For example, the recording might present the numbers 1, 7, 5, 4. The patient adds the first two numbers (1 + 7) and responds with the number 8. The patient then adds the second two numbers (7 + 5) and responds with the number 12. The patient then adds the third two numbers (5 + 4) and responds with the number 9. This continues for a total of 61 numbers presented in a random order. The patients score is the total number correct out of 60 (Stebbins et al. 2007). The PASAT score ranges from 0 to 60, with higher values representing a better outcome in cognitive processing speed. | 8 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| California Verbal Learning Test - 2nd Edition | The California Verbal Learning Test Second Edition (CVLT2) begins with the examiner reading a list of 16 words. Patients listen to the list and report as many of the items as possible. After recall is recorded, the entire list is read again. Altogether, there are five learning trials, the total correct of all trials is summed together creating a total verbal learning score. The CVLT-II total verbal learning score ranges from 0 to 80, with higher values representing a better outcome in verbal learning/memory. | 8 weeks | 
| Brief Visuospatial Memory Test - Revised | The Brief Visuospatial Memory Test Revised (BVMTR) presents six abstract designs for 10 seconds. The display is removed from view and patients render the stimuli via pencil on paper manual responses. There are three learning trials in which patients attempt to replicate the stimuli previously presented. Patients are given a score for all three trials based on correct location and accuracy of the replicated stimuli. Each trial can be awarded up to 12 points, the sum of total points awarded across all three trials is the total learning score. The BVMT-R total learning score ranges from 0 to 36, with higher values representing a better outcome in visuospatial learning/memory. | 8 weeks | 
| Vitals | Heart rate | 8 weeks | 
| Vitals (Diastolic Blood Pressure) | diastolic blood pressure | 8 weeks | 
| Vitals (Systolic Blood Pressure) | systolic blood pressure | 8 weeks |