Multiple Sclerosis
Conditions
Brief summary
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.
Interventions
DRUGlisdexamfetamine sulfate
30mg lisdexamfetamine OD, increased to 70mg OD over 4 weeks and continued on 70mg OD for 4 weeks
DRUGplacebo
sugar pill
Sponsors
State University of New York at Buffalo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
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prior to any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to his/her future medical care.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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Symbol Digit Modalities Test (SDMT) | 8 weeks | 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. |
| Paced Auditory Serial Audition Test (PASAT) | 8 Weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Vitals | 8 weeks | Heart rate |
| California Verbal Learning Test - 2nd Edition | 8 weeks | 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. |
| Vitals (Systolic Blood Pressure) | 8 weeks | systolic blood pressure |
| Vitals (Diastolic Blood Pressure) | 8 weeks | diastolic blood pressure |
| Brief Visuospatial Memory Test - Revised | 8 weeks | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Lisdexamfetamine Sulfate 30mg lisdexamfetamine OD, increased to 70mg OD over 4 weeks and continued on 70mg OD for 4 weeks
lisdexamfetamine sulfate: 30mg lisdexamfetamine OD, increased to 70mg OD over 4 weeks and continued on 70mg OD for 4 weeks | 29 |
| Sugar Pill Placebo will be administered in the same fashion as the treatment arm
placebo: sugar pill | 19 |
| Total | 48 |
Baseline characteristics
| Characteristic | Lisdexamfetamine Sulfate | Total | Sugar Pill |
|---|---|---|---|
| Age, Continuous | 48.7 years STANDARD_DEVIATION 8 | 47.7 years STANDARD_DEVIATION 8.25 | 46.7 years STANDARD_DEVIATION 8.5 |
| 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 | 3 Participants | 4 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 | 26 Participants | 44 Participants | 18 Participants |
| Region of Enrollment United States | 29 participants | 48 participants | 19 participants |
| Sex: Female, Male Female | 23 Participants | 35 Participants | 12 Participants |
| Sex: Female, Male Male | 6 Participants | 13 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 23 / 41 | 12 / 22 |
| serious Total, serious adverse events | 0 / 41 | 0 / 22 |
Outcome results
Primary
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.
Time frame: 8 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lisdexamfetamine Sulfate | Paced Auditory Serial Audition Test (PASAT) | 32.0 score on a scale | Standard Deviation 12.5 |
| Sugar Pill | Paced Auditory Serial Audition Test (PASAT) | 37.4 score on a scale | Standard Deviation 12.1 |
Primary
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.
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lisdexamfetamine Sulfate | Symbol Digit Modalities Test (SDMT) | 36.9 score on a scale | Standard Deviation 8.7 |
| Sugar Pill | Symbol Digit Modalities Test (SDMT) | 46.8 score on a scale | Standard Deviation 7.5 |
Secondary
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.
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lisdexamfetamine Sulfate | Brief Visuospatial Memory Test - Revised | 15.2 score on a scale | Standard Deviation 6.1 |
| Sugar Pill | Brief Visuospatial Memory Test - Revised | 18.7 score on a scale | Standard Deviation 5.5 |
Secondary
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.
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lisdexamfetamine Sulfate | California Verbal Learning Test - 2nd Edition | 44.9 score on a scale | Standard Deviation 11.5 |
| Sugar Pill | California Verbal Learning Test - 2nd Edition | 49.2 score on a scale | Standard Deviation 10.2 |
Secondary
Vitals
Heart rate
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lisdexamfetamine Sulfate | Vitals | 72.3 beats/min | Standard Deviation 11.7 |
| Sugar Pill | Vitals | 76.9 beats/min | Standard Deviation 10.6 |
Secondary
Vitals (Diastolic Blood Pressure)
diastolic blood pressure
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lisdexamfetamine Sulfate | Vitals (Diastolic Blood Pressure) | 75.1 mm hg (millimeters of mercury) | Standard Deviation 11.3 |
| Sugar Pill | Vitals (Diastolic Blood Pressure) | 77.7 mm hg (millimeters of mercury) | Standard Deviation 7.7 |
Secondary
Vitals (Systolic Blood Pressure)
systolic blood pressure
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lisdexamfetamine Sulfate | Vitals (Systolic Blood Pressure) | 127.3 mm hg (millimeters of mercury) | Standard Deviation 15.9 |
| Sugar Pill | Vitals (Systolic Blood Pressure) | 121.6 mm hg (millimeters of mercury) | Standard Deviation 13.1 |