<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01667497</url>
  </required_header>
  <id_info>
    <org_study_id>102825</org_study_id>
    <nct_id>NCT01667497</nct_id>
  </id_info>
  <brief_title>Does Fampridine SR Improve Cognitive Fatigue in Multiple Sclerosis Patients?</brief_title>
  <official_title>Does Fampridine SR Improve Cognitive Fatigue in Multiple Sclerosis Patients? A Cross Over Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>London Health Sciences Centre</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>London Health Sciences Centre</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Multiple Sclerosis (MS) patients often complain of cognitive fatigue. There is currently no&#xD;
      treatment for this symptom. Fampridine SR is a recently approved medication that improves&#xD;
      walking ability and walking speed in MS patients. It is thought that it might have the same&#xD;
      positive effect on cognitive fatigue. This study will compare fampridine 10mg twice a day to&#xD;
      placebo in order to determine if there is any benefit of this medication for cognitive&#xD;
      fatigue in MS.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Fampridine-SR (4-aminopyridine) is a slow release oral medication that acts as a selective&#xD;
      neuronal potassium-channel blocker. It has been investigated in several multiple sclerosis&#xD;
      (MS) studies and has been shown to improve ambulation, fatigue, and endurance. The hypothesis&#xD;
      for the mode of action of fampridine in MS patients is based on the fact that demyelinated&#xD;
      axons do not effectively conduct action potentials partly due to abnormal potassium currents&#xD;
      that contribute to conduction failure by decreasing action potential duration and amplitude.&#xD;
      Thus, potassium channel blockers such as 4-aminopyridine or 3,4 diaminopyridine improve nerve&#xD;
      impulse propagation by enhancing action potential formation, improving conduction and&#xD;
      preventing conduction block. In a randomized, multicenter, double-blind, placebo controlled&#xD;
      phase III trial, 301 patients were treated with either fampridine (10 mg BID n=229) or&#xD;
      placebo (n=72). Consistent improvement on the timed 25 foot walk (T25FW) was the primary&#xD;
      outcome measure. The proportion who improved on the T25FW was higher in the fampridine than&#xD;
      placebo group (35% vs. 8%; p&lt;0.0001). This data shows that fampridine improves walking speed&#xD;
      in MS. Additionally, the study suggested there is a &quot;responder effect&quot; meaning MS subjects&#xD;
      who respond to the medication respond very well (timed walk responder), while others do not&#xD;
      show any beneficial response (timed walk non-responder). A responder was defined as an&#xD;
      increase in walking speed, compared to placebo run-in, for at least 3 of 4 assessments while&#xD;
      on treatment during the trial. However, this study demonstrated that responders could be&#xD;
      identified as early as the first and second week after the initiation of treatment, as there&#xD;
      was a significant difference between responders and non-responders at this time point. After&#xD;
      discontinuation of fampridine, T25FW scores returned to baseline within one week&#xD;
&#xD;
      MS and Cognitive Fatigue It is estimated that 43-60% of patients with MS have cognitive&#xD;
      dysfunction and studies using objective neuropsychological (NP) tests have consistently shown&#xD;
      impairment in speed of information processing and sustained attention. Further, MS patients&#xD;
      complain of &quot;cognitive fatigue&quot;, a symptom that may or may not be associated with&#xD;
      generalized/central fatigue. Cognitive fatigue has been defined as a decline in cognitive&#xD;
      performance during a task requiring sustained cognitive activity. Although generalized or&#xD;
      motor/muscle fatigue has been shown to affect the subjective assessment of cognitive&#xD;
      performance, it does not affect performance on objective cognitive measures. In contrast,&#xD;
      cognitive fatigue has been demonstrated in MS patients on objective neuropsychological tests.&#xD;
      Kujala et al (1995) examined MS patients with and without mild cognitive impairment on a task&#xD;
      of sustained attention. Both groups declined over time while healthy controls did not. Krupp&#xD;
      et al (2000) administered a verbal learning/memory task twice separated by a continuous&#xD;
      cognitively effortful task involving processing speed and attention. Normal controls&#xD;
      demonstrated an increase in number of words recalled (+2.6) on the 2nd test administration,&#xD;
      as expected due to a practice effect. In contrast, the MS subjects showed a decrease in test&#xD;
      scores (-1.8) on the 2nd test administration. This difference was found despite both groups&#xD;
      subjectively reporting an increase in mental fatigue over the testing period. Finally, Schwid&#xD;
      et al (2003) examined the decline in performance on the Paced Auditory Serial Addition Test&#xD;
      (PASAT), a measure of processing speed and sustained attention. There was a 5.3-5.8% decline&#xD;
      in correct responses when comparing the MS subjects' performance at the beginning vs. the end&#xD;
      of the test. Normal controls did not show a significant decrease in performance.&#xD;
&#xD;
      Treating MS Associated Cognitive Impairment and Cognitive Fatigue Currently approved MS&#xD;
      specific medications have been shown to affect physical disability, relapse rate and MRI&#xD;
      progression in MS subjects but cognition, fatigue and cognitive fatigue have not been the&#xD;
      main focus of any of these studies. Further, symptomatic treatments for generalized fatigue&#xD;
      have not focused on cognitive fatigue. Studies of l-amphetamine found a positive response on&#xD;
      measures of processing speed in a small sample of MS subjects, but a larger, multi-centered&#xD;
      placebo controlled trial by Morrow et al did not find any significant benefit. Cognitive&#xD;
      fatigue was not specifically addressed in this study.&#xD;
&#xD;
      Aminopyridines and Cognition in the MS Population Only two previous studies have addressed&#xD;
      the effect of aminopyridines on cognition in MS subjects. In one study, no benefit was found.&#xD;
      It is important to note that the primary aim of the study was to examine changes in&#xD;
      generalized fatigue and the cognitive outcomes were tertiary outcomes only. Further, the&#xD;
      measure of attention used has not been validated in the MS population. In the other study,&#xD;
      performance on Rao's Brief Repeatable Neuropsychological Battery (BRN-B) before and after&#xD;
      treatment with 4-aminopyridine was compared. A trend was found for improvement on measures of&#xD;
      verbal learning and on the PASAT 2.0 second version, but the findings were not statistically&#xD;
      significant. However the trial was underpowered, with only 20 subjects.&#xD;
&#xD;
      Summary Cognitive impairment and cognitive fatigue are common in MS yet there are no&#xD;
      currently effective treatments for these debilitating symptoms. Based on the proposed&#xD;
      mechanism of action of fampridine, it is probable that it will improve cognitive fatigue in&#xD;
      MS by improving nerve conduction. Using a placebo controlled cross-over study with a two week&#xD;
      washout period in between, changes on tests of attention and processing speed under the two&#xD;
      conditions can be compared. Since cognitive impairment is the leading cause of work&#xD;
      disability, as well as having an negative impact on social activities and relationships,&#xD;
      improving cognitive fatigue will contribute positively to the quality of life of MS patients.&#xD;
&#xD;
      Trial Objectives&#xD;
&#xD;
      To determine if fampridine SR 10mg BID has a beneficial effect on cognitive fatigue in MS&#xD;
      patients.&#xD;
&#xD;
      Study Design and Duration&#xD;
&#xD;
      The design is a cross-over, placebo controlled, double-blind study with four weeks of&#xD;
      treatment for drug (fampridine 10mg BID) and placebo separated by a one week washout period.&#xD;
      For each visit subsequent to visit 1, we will encourage subjects to ensure similar&#xD;
      environmental and behavioural compartment as the first assessment (i.e. amount of sleep,&#xD;
      caffeine intake etc.) to try to ensure similar testing settings. Additionally, the&#xD;
      assessments will occur at similar times of day as visit 1.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>September 2012</start_date>
  <completion_date type="Actual">August 2015</completion_date>
  <primary_completion_date type="Actual">July 2015</primary_completion_date>
  <phase>Phase 2/Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Paced Auditory Serial Addition Test (PASAT) Cognitive Fatigue scores</measure>
    <time_frame>Day 1, day 29 and Day 37, Day 64</time_frame>
    <description>Measure of cognitive fatigue</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">60</enrollment>
  <condition>Cognitive Fatigue</condition>
  <arm_group>
    <arm_group_label>Fampridine SR</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Fampridine SR 10mg BID</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>non-drug</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fampridine SR</intervention_name>
    <arm_group_label>Fampridine SR</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Males/Females who are ≥ 18 years old and &lt; 65 years old&#xD;
&#xD;
          -  Capable of understanding and complying with the protocol, including speaking and&#xD;
             writing fluent English and having at least a 9th grade education&#xD;
&#xD;
          -  Have a diagnosis of Relapsing Remitting, Secondary Progressive or Primary Progressive&#xD;
             MS, as per revised McDonald's Criteria&#xD;
&#xD;
          -  Have not received steroids in last thirty (30) days or a relapse in the last sixty&#xD;
             (60) days, and whose MS is considered stable&#xD;
&#xD;
          -  Have a PASAT CF z-score that is worse than 1.5 SD below the mean (&lt;-1.5 SD).&#xD;
&#xD;
          -  Have an Expanded Disability Status Scale (EDSS) of ≤ 7.0&#xD;
&#xD;
          -  Have given written informed consent prior to any study-related procedure not part of&#xD;
             normal medical care, with the understanding that consent may be withdrawn by the&#xD;
             subject at any time without prejudice to his/her future medical care&#xD;
&#xD;
          -  Are capable of performing the requirements of a NP test battery including at least&#xD;
             20/70 near visual acuity by near vision chart, with correction allowed&#xD;
&#xD;
          -  If female, must neither be pregnant nor breast-feeding&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Have cognitive deficits caused by concomitant medication usage or other significant&#xD;
             neurological/psychological disease e.g. Alzheimer's disease, Parkinson's disease,&#xD;
             stroke, transient ischemic attack, Vascular Dementia, Huntington's disease, traumatic&#xD;
             brain injury or chronic CNS infection&#xD;
&#xD;
          -  Have evidence of other medical cause(s) of cognitive impairment&#xD;
&#xD;
          -  Have evidence of major depression as determined by a positive BDIFS and clinician&#xD;
             interview&#xD;
&#xD;
          -  Have a history of uncontrolled hypertension, tachycardia or cardiovascular or disease&#xD;
&#xD;
          -  Have a history or current presentation of seizure&#xD;
&#xD;
          -  Are currently taking compounded 4-aminopyridine or another form of fampridine&#xD;
&#xD;
          -  Have a known hypersensitivity to any medical or non-medical ingredient of the&#xD;
             medication tablet.&#xD;
&#xD;
          -  Have evidence of renal impairment (creatinine clearance ≤ 80 mL/min)&#xD;
&#xD;
          -  Are taking medications that are inhibitors of the renal organic cation transporter 2&#xD;
             (OCT2)&#xD;
&#xD;
          -  Have a diagnosis of colour blindness&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>64 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>London Health Sciences Center and St. Joseph's Heathcare Center (Parkwood)</name>
      <address>
        <city>London</city>
        <state>Ontario</state>
        <zip>N6G 1W8</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>September 2015</verification_date>
  <study_first_submitted>August 13, 2012</study_first_submitted>
  <study_first_submitted_qc>August 16, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 17, 2012</study_first_posted>
  <last_update_submitted>September 1, 2015</last_update_submitted>
  <last_update_submitted_qc>September 1, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">September 2, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>London Health Sciences Centre</investigator_affiliation>
    <investigator_full_name>Sarah Morrow</investigator_full_name>
    <investigator_title>Assistant Professor of Neurology</investigator_title>
  </responsible_party>
  <keyword>Cognitive fatigue</keyword>
  <keyword>multiple sclerosis</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Multiple Sclerosis</mesh_term>
    <mesh_term>Sclerosis</mesh_term>
    <mesh_term>Fatigue</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>4-Aminopyridine</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01667497
org study id: 102825
nct id: NCT01667497
lead sponsor: 
has dmc: No
Multiple Sclerosis (MS) patients often complain of cognitive fatigue. There is currently no
      treatment for this symptom. Fampridine SR is a recently approved medication that improves
      walking ability and walking speed in MS patients. It is thought that it might have the same
      positive effect on cognitive fatigue. This study will compare fampridine 10mg twice a day to
      placebo in order to determine if there is any benefit of this medication for cognitive
      fatigue in MS.
Fampridine-SR (4-aminopyridine) is a slow release oral medication that acts as a selective
      neuronal potassium-channel blocker. It has been investigated in several multiple sclerosis
      (MS) studies and has been shown to improve ambulation, fatigue, and endurance. The hypothesis
      for the mode of action of fampridine in MS patients is based on the fact that demyelinated
      axons do not effectively conduct action potentials partly due to abnormal potassium currents
      that contribute to conduction failure by decreasing action potential duration and amplitude.
      Thus, potassium channel blockers such as 4-aminopyridine or 3,4 diaminopyridine improve nerve
      impulse propagation by enhancing action potential formation, improving conduction and
      preventing conduction block. In a randomized, multicenter, double-blind, placebo controlled
      phase III trial, 301 patients were treated with either fampridine (10 mg BID n=229) or
      placebo (n=72). Consistent improvement on the timed 25 foot walk (T25FW) was the primary
      outcome measure. The proportion who improved on the T25FW was higher in the fampridine than
      placebo group (35% vs. 8%; p<0.0001). This data shows that fampridine improves walking speed
      in MS. Additionally, the study suggested there is a "responder effect" meaning MS subjects
      who respond to the medication respond very well (timed walk responder), while others do not
      show any beneficial response (timed walk non-responder). A responder was defined as an
      increase in walking speed, compared to placebo run-in, for at least 3 of 4 assessments while
      on treatment during the trial. However, this study demonstrated that responders could be
      identified as early as the first and second week after the initiation of treatment, as there
      was a significant difference between responders and non-responders at this time point. After
      discontinuation of fampridine, T25FW scores returned to baseline within one week

      MS and Cognitive Fatigue It is estimated that 43-60% of patients with MS have cognitive
      dysfunction and studies using objective neuropsychological (NP) tests have consistently shown
      impairment in speed of information processing and sustained attention. Further, MS patients
      complain of "cognitive fatigue", a symptom that may or may not be associated with
      generalized/central fatigue. Cognitive fatigue has been defined as a decline in cognitive
      performance during a task requiring sustained cognitive activity. Although generalized or
      motor/muscle fatigue has been shown to affect the subjective assessment of cognitive
      performance, it does not affect performance on objective cognitive measures. In contrast,
      cognitive fatigue has been demonstrated in MS patients on objective neuropsychological tests.
      Kujala et al (1995) examined MS patients with and without mild cognitive impairment on a task
      of sustained attention. Both groups declined over time while healthy controls did not. Krupp
      et al (2000) administered a verbal learning/memory task twice separated by a continuous
      cognitively effortful task involving processing speed and attention. Normal controls
      demonstrated an increase in number of words recalled (+2.6) on the 2nd test administration,
      as expected due to a practice effect. In contrast, the MS subjects showed a decrease in test
      scores (-1.8) on the 2nd test administration. This difference was found despite both groups
      subjectively reporting an increase in mental fatigue over the testing period. Finally, Schwid
      et al (2003) examined the decline in performance on the Paced Auditory Serial Addition Test
      (PASAT), a measure of processing speed and sustained attention. There was a 5.3-5.8% decline
      in correct responses when comparing the MS subjects' performance at the beginning vs. the end
      of the test. Normal controls did not show a significant decrease in performance.

      Treating MS Associated Cognitive Impairment and Cognitive Fatigue Currently approved MS
      specific medications have been shown to affect physical disability, relapse rate and MRI
      progression in MS subjects but cognition, fatigue and cognitive fatigue have not been the
      main focus of any of these studies. Further, symptomatic treatments for generalized fatigue
      have not focused on cognitive fatigue. Studies of l-amphetamine found a positive response on
      measures of processing speed in a small sample of MS subjects, but a larger, multi-centered
      placebo controlled trial by Morrow et al did not find any significant benefit. Cognitive
      fatigue was not specifically addressed in this study.

      Aminopyridines and Cognition in the MS Population Only two previous studies have addressed
      the effect of aminopyridines on cognition in MS subjects. In one study, no benefit was found.
      It is important to note that the primary aim of the study was to examine changes in
      generalized fatigue and the cognitive outcomes were tertiary outcomes only. Further, the
      measure of attention used has not been validated in the MS population. In the other study,
      performance on Rao's Brief Repeatable Neuropsychological Battery (BRN-B) before and after
      treatment with 4-aminopyridine was compared. A trend was found for improvement on measures of
      verbal learning and on the PASAT 2.0 second version, but the findings were not statistically
      significant. However the trial was underpowered, with only 20 subjects.

      Summary Cognitive impairment and cognitive fatigue are common in MS yet there are no
      currently effective treatments for these debilitating symptoms. Based on the proposed
      mechanism of action of fampridine, it is probable that it will improve cognitive fatigue in
      MS by improving nerve conduction. Using a placebo controlled cross-over study with a two week
      washout period in between, changes on tests of attention and processing speed under the two
      conditions can be compared. Since cognitive impairment is the leading cause of work
      disability, as well as having an negative impact on social activities and relationships,
      improving cognitive fatigue will contribute positively to the quality of life of MS patients.

      Trial Objectives

      To determine if fampridine SR 10mg BID has a beneficial effect on cognitive fatigue in MS
      patients.

      Study Design and Duration

      The design is a cross-over, placebo controlled, double-blind study with four weeks of
      treatment for drug (fampridine 10mg BID) and placebo separated by a one week washout period.
      For each visit subsequent to visit 1, we will encourage subjects to ensure similar
      environmental and behavioural compartment as the first assessment (i.e. amount of sleep,
      caffeine intake etc.) to try to ensure similar testing settings. Additionally, the
      assessments will occur at similar times of day as visit 1.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Change in Paced Auditory Serial Addition Test (PASAT) Cognitive Fatigue scores
time frame: Day 1, day 29 and Day 37, Day 64
description: Measure of cognitive fatigue
arm group label: Fampridine SR
arm group type: Experimental
description: Fampridine SR 10mg BID
arm group label: Placebo
arm group type: Placebo Comparator
description: non-drug
intervention type: Drug
intervention name: Fampridine SR
arm group label: Fampridine SR
intervention type: Drug
intervention name: Placebo
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 64 Years
healthy volunteers: No
facility: 
country: Canada
responsible party type: Principal Investigator
investigator affiliation: London Health Sciences Centre
investigator full name: Sarah Morrow
investigator title: Assistant Professor of Neurology
mesh term: Multiple Sclerosis
mesh term: Sclerosis
mesh term: Fatigue
mesh term: 4-Aminopyridine