Effects of Dalfampridine on Cognition in Multiple Sclerosis
| Status: | Completed |
|---|---|
| Conditions: | Neurology, Neurology, Multiple Sclerosis |
| Therapuetic Areas: | Neurology, Other |
| Healthy: | No |
| Age Range: | 18 - 60 |
| Updated: | 4/21/2016 |
| Start Date: | December 2011 |
| End Date: | February 2016 |
Cognitive impairment is common in multiple sclerosis (MS) and has devastating impact on
functional activities. There is great demand for medications that will enhance cognitive
capacity in MS patients. To date, there is no evidence for improvement in cognition
following treatment with aminopyridines, but the few studies on the topic included
neuropsychological (NP) tests as secondary or tertiary outcomes, and were methodologically
flawed. Dalfampridine may enhance cognition by direct pharmacological mechanisms, and should
have effects on motor outcomes as in prior studies. By combining cognition and motor
outcomes in the proposed study, the investigators will evaluate if the same patients with
positive effects show beneficial responses on motor outcomes including physical activity and
if such motor outcomes mediate and/or moderate cognitive improvements with dalfampridine
functional activities. There is great demand for medications that will enhance cognitive
capacity in MS patients. To date, there is no evidence for improvement in cognition
following treatment with aminopyridines, but the few studies on the topic included
neuropsychological (NP) tests as secondary or tertiary outcomes, and were methodologically
flawed. Dalfampridine may enhance cognition by direct pharmacological mechanisms, and should
have effects on motor outcomes as in prior studies. By combining cognition and motor
outcomes in the proposed study, the investigators will evaluate if the same patients with
positive effects show beneficial responses on motor outcomes including physical activity and
if such motor outcomes mediate and/or moderate cognitive improvements with dalfampridine
3a. Patient Sample and Recruitment
Subjects will be consecutively selected from the Western New York (NY) region where the
Baird MS Center and the Jacobs Neurological Institute are located. Patients will be
interviewed and their records reviewed to assess for inclusion/exclusion. Patients will then
be approached in the clinic or contacted by telephone and invited to participate in this
clinical trial. The attached flier will also be used to directly advertise the study to
patients. Patients who initiate contact with the researcher will be interviewed to assess
eligibility.
Inclusion Criteria. Patients will be eligible for the study if they fulfill all the
inclusion criteria specified below
1. Males/Females who are ≥ 18 years old and < 65 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.
2. Have a diagnosis of MS, as per revised McDonald's Criteria.
3. Have not received steroids in last thirty (30) days or a relapse in the last ninety
(90) days, and whose MS is considered stable.
4. Impression of cognitive impairment as indicated by one of the following: (a) positive
NP testing following diagnosis of MS as determined by board certified neuropsychologist
or with z scores <-1.5 below expectation in at least one cognitive domain, or (b)
informant Multiple Sclerosis Neuropsychological Questionnaire (MSNQ) >28.
5. An Expanded Disability Status Scale (EDSS) of ≤ 6.5.
6. 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.
7. 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.
8. 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. Patients will be excluded from the study if they meet any one or more of
the exclusion criteria specified below:
1. 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 central nervous system (CNS) infection
2. Have evidence of other medical cause(s) of cognitive impairment
3. Evidence of major mental illness predating the onset of MS
4. Have evidence of major depression as determined by a positive Beck Depression
Index-Fast Screen (BDIFS) and clinician interview
5. Have report of uncontrolled or labile hypertension, tachycardia, cardiovascular or
cerebrovascular disease
6. History of seizure disorder.
7. Optic neuritis within 6 months of enrollment.
8. Trigeminal neuralgia.
9. Prior exposure to aminopyridines.
Additional Exclusion Criteria for optional speech module. Patients will not be eligible for
enrollment in the optional speech module is they meet one or more of the exclusion criteria
below:
1. Have any language/dialect other than Standard American English as their first language.
2. Make use of a mechanical hearing aid.
3b. Outcome Measures
Cognition Endpoints. Psychometric testing will incorporate gold standard tests from
validated test batteries by Benedict et al and Rao et al [7-9, 47-49]. The test order is
described below:
Table 2. Cognitive Battery Test Domain Time in min California Verbal Learning Test 2 (CVLT2)
Learning Trials Auditory/Verbal Memory 15 Brief Visuospatial Memory Test Revised (BVMTR)
Learning Trials Visual/Spatial Memory 05 Paced Auditory Serial Addition Test (PASAT) 3 sec
Auditory Processing Speed 05 Symbol Digit Modalities Test (SDMT) Visual Processing speed 05
Delis Kaplan Executive Function System (DKEFS) Sorting Test Executive Function 12 California
Verbal Learning Test 2 (CVLT2) Delayed Recall Auditory/Verbal Memory 05 Brief Visuospatial
Memory Test Revised (BVMTR) Delayed Recall Visual/Spatial Memory 03 Total Time 50 min
Subjects will be consecutively selected from the Western New York (NY) region where the
Baird MS Center and the Jacobs Neurological Institute are located. Patients will be
interviewed and their records reviewed to assess for inclusion/exclusion. Patients will then
be approached in the clinic or contacted by telephone and invited to participate in this
clinical trial. The attached flier will also be used to directly advertise the study to
patients. Patients who initiate contact with the researcher will be interviewed to assess
eligibility.
Inclusion Criteria. Patients will be eligible for the study if they fulfill all the
inclusion criteria specified below
1. Males/Females who are ≥ 18 years old and < 65 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.
2. Have a diagnosis of MS, as per revised McDonald's Criteria.
3. Have not received steroids in last thirty (30) days or a relapse in the last ninety
(90) days, and whose MS is considered stable.
4. Impression of cognitive impairment as indicated by one of the following: (a) positive
NP testing following diagnosis of MS as determined by board certified neuropsychologist
or with z scores <-1.5 below expectation in at least one cognitive domain, or (b)
informant Multiple Sclerosis Neuropsychological Questionnaire (MSNQ) >28.
5. An Expanded Disability Status Scale (EDSS) of ≤ 6.5.
6. 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.
7. 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.
8. 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. Patients will be excluded from the study if they meet any one or more of
the exclusion criteria specified below:
1. 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 central nervous system (CNS) infection
2. Have evidence of other medical cause(s) of cognitive impairment
3. Evidence of major mental illness predating the onset of MS
4. Have evidence of major depression as determined by a positive Beck Depression
Index-Fast Screen (BDIFS) and clinician interview
5. Have report of uncontrolled or labile hypertension, tachycardia, cardiovascular or
cerebrovascular disease
6. History of seizure disorder.
7. Optic neuritis within 6 months of enrollment.
8. Trigeminal neuralgia.
9. Prior exposure to aminopyridines.
Additional Exclusion Criteria for optional speech module. Patients will not be eligible for
enrollment in the optional speech module is they meet one or more of the exclusion criteria
below:
1. Have any language/dialect other than Standard American English as their first language.
2. Make use of a mechanical hearing aid.
3b. Outcome Measures
Cognition Endpoints. Psychometric testing will incorporate gold standard tests from
validated test batteries by Benedict et al and Rao et al [7-9, 47-49]. The test order is
described below:
Table 2. Cognitive Battery Test Domain Time in min California Verbal Learning Test 2 (CVLT2)
Learning Trials Auditory/Verbal Memory 15 Brief Visuospatial Memory Test Revised (BVMTR)
Learning Trials Visual/Spatial Memory 05 Paced Auditory Serial Addition Test (PASAT) 3 sec
Auditory Processing Speed 05 Symbol Digit Modalities Test (SDMT) Visual Processing speed 05
Delis Kaplan Executive Function System (DKEFS) Sorting Test Executive Function 12 California
Verbal Learning Test 2 (CVLT2) Delayed Recall Auditory/Verbal Memory 05 Brief Visuospatial
Memory Test Revised (BVMTR) Delayed Recall Visual/Spatial Memory 03 Total Time 50 min
Inclusion Criteria:
Patients will be eligible for the study if they fulfill all the inclusion criteria
specified below:
1. Males/Females who are ≥ 18 years old and < 65 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.
2. Have a diagnosis of MS, as per revised McDonald's Criteria.
3. Have not received steroids in last thirty (30) days or a relapse in the last ninety
(90) days, and whose MS is considered stable.
4. Impression of cognitive impairment as indicated by one of the following: (a) positive
NP testing following diagnosis of MS as determined by board certified
neuropsychologist or with z scores <-1.5 below expectation in at least one cognitive
domain, or (b) informant MSNQ >28.
5. An Expanded Disability Status Scale (EDSS) of ≤ 6.5.
6. 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.
7. 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.
8. 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:
1. 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
2. Have evidence of other medical cause(s) of cognitive impairment
3. Evidence of major mental illness predating the onset of MS
4. Have evidence of major depression as determined by a positive BDIFS and clinician
interview
5. Have report of uncontrolled or labile hypertension, tachycardia, cardiovascular or
cerebrovascular disease
6. History of seizure disorder.
7. Optic neuritis within 6 months of enrollment.
8. Trigeminal neuralgia.
9. Prior exposure to aminopyridines within the last six months.
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