Effects of Dalfampridine on Cognition in Multiple Sclerosis
Condition: Multiple Sclerosis
MeSH terms: Multiple Sclerosis; Sclerosis
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      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
    

Detailed description: 
      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
    

Intervention name(s): dalfampridine; placebo
Intervention type(s): Drug; Drug
Intervention description(s): 10 mg bid; 10 mg bid
Other intervention name(s): Ampyra
Intervention MeSH terms: 4-Aminopyridine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment