<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/NCT02219932</url>
  </required_header>
  <id_info>
    <org_study_id>218MS305</org_study_id>
    <secondary_id>2013-003600-40</secondary_id>
    <nct_id>NCT02219932</nct_id>
  </id_info>
  <brief_title>Efficacy and Safety Study of Prolonged-Release Fampridine in Participants With Multiple Sclerosis</brief_title>
  <acronym>ENHANCE</acronym>
  <official_title>A Multicenter, Randomized, Double Blind, Placebo Controlled Study to Assess the Long-Term Efficacy and Safety of Prolonged Release Fampridine (BIIB041) 10 mg, Administered Twice Daily in Subjects With Multiple Sclerosis (ENHANCE)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Biogen</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Biogen</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The primary objective is to determine whether prolonged-release fampridine (10 mg twice&#xD;
      daily) has a clinically meaningful effect on participant-reported walking ability over a&#xD;
      24-week study period.&#xD;
&#xD;
      The secondary objectives are: to determine whether prolonged-release fampridine 10 mg taken&#xD;
      twice daily (BID) has a clinically meaningful effect on dynamic and static balance, physical&#xD;
      impact of multiple sclerosis (MS), and upper extremity function over a 24-week study period;&#xD;
      to evaluate criteria for early assessment of response to fampridine that can predict&#xD;
      clinically meaningful benefits in walking ability and balance; to assess the safety and&#xD;
      tolerability of prolonged-release fampridine 10 mg twice daily over a 24-week treatment&#xD;
      period.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>September 2014</start_date>
  <completion_date type="Actual">February 2016</completion_date>
  <primary_completion_date type="Actual">February 2016</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Proportion of Participants Achieving a Mean Improvement of ≥ 8 Points From Baseline on the Multiple Sclerosis Walking Scale (MSWS-12) Over 24 Weeks</measure>
    <time_frame>Baseline to 24 weeks</time_frame>
    <description>MSWS-12 is a participant self-assessment of the walking limitations due to MS during the past 2 weeks. It contains 12 items that measure the impact of MS on walking. Items are summed to generate a total score and transformed to a scale with a range of 0 to 100, where higher scores indicate greater impact on walking.&#xD;
A responder is defined as a participant with a mean improvement of at least 8 points over 24 weeks compared to baseline. Baseline is defined as the mean at Screening and Day 1 visits. If a participant has a mean MSWS-12 score of &lt; 0.5 over the double-blind period, and a baseline MSWS-12 score of &lt; 8 points, the participant is counted as a responder. A participant who indicates they cannot walk at all on MSWS-12 during any double-blind visit, and who shows severe disability and an inability to walk on other efficacy assessments is counted as a non-responder. Estimated proportion obtained from binomial proportions.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Proportion of Participants Achieving a Mean Improvement From Baseline of ≥ 15% in Timed Up and Go (TUG) Speed Over 24 Weeks</measure>
    <time_frame>Baseline to Week 24</time_frame>
    <description>TUG is a timed walking test designed to measure gait performance and balance. It measures in seconds the time taken by an individual to stand up from a standard arm chair (approximate seat height of 46 cm [18in], arm height 65 cm [25.6 in]), walk a distance of 3 meters (118 inches, approximately 10 feet), turn, walk back to the chair, and sit down.&#xD;
A responder is defined as a participant with a mean improvement of at least 15% in TUG speed over 24 weeks compared to baseline. Baseline is defined as the mean at Screening and Day 1 visits. Estimated proportion obtained from binomial proportions. There are 2 TUG tests given, and the average across the 2 tests is used to calculate average speed. Healthy participants below the age of 79 are expected to complete this task in 7-10 seconds (American College of Rheumatology). Missing data are handled using multiple imputation and baseline is defined as the mean over Screening and Day 1.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Multiple Sclerosis Impact Scale-29 (MSIS-29) Physical Score Over 24 Weeks</measure>
    <time_frame>Baseline to Week 24</time_frame>
    <description>The 29-item MSIS-29 is a participant-reported outcome measure to assess the impact of MS on day-to-day life during the past 2 weeks from a participant's perspective; it measures 20 physical items and 9 psychological items. The physical score is generated by summing individual items and then transforming to a scale with a range of 0 (no impact of MS) to 100 (extreme impact of MS); a negative change indicates an improvement in function.&#xD;
Data are based on a mixed model for repeated measures (MMRM) model using a common variance AR(1) variance-covariance matrix structure. Treatment, visit and treatment by visit interaction were included in the model as explanatory variables, adjusting for screening EDSS, baseline MSIS-29 physical score and prior aminopyridine as covariates. Missing data are handled using multiple imputation and baseline is defined as the mean over screening and Day 1.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Berg Balance Scale (BBS) Over 24 Weeks</measure>
    <time_frame>Baseline to Week 24</time_frame>
    <description>The BBS is a widely used assessment tool to identify balance impairment. Functional activities such as reaching, bending, transferring, and standing are evaluated on the test to evaluate balance. Participants are asked to complete 14 tasks that are rated from 0 (cannot perform) to 4 (normal performance) for a total of 56 points. BBS scores range from 0 (poor balance) to 56 (good balance); a positive change indicates improvement.&#xD;
Data are based on an MMRM model using a common variance AR(1) variance-covariance matrix structure. Treatment, visit and treatment by visit interaction were included in the model as explanatory variables, adjusting for screening EDSS, baseline BBS and prior aminopyridine as covariates. Missing data are handled using multiple imputation and baseline is defined as the mean over screening and Day 1.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in ABILHAND Score Over 24 Weeks</measure>
    <time_frame>Baseline to Week 24</time_frame>
    <description>The ABILHAND Questionnaire measures a participant's perceived difficulty in performing everyday manual activities in the last 3 months. The participant completes a 56-item questionnaire by estimating their own difficulty or ease in performing each of 56 activities. Items are summed to generate a total score and transformed to a scale with a range of 0 (poor manual ability) to 100 (good manual ability); a positive change indicates an improvement in manual ability.&#xD;
Data are based on an MMRM model using a common variance AR(1) variance-covariance matrix structure. Treatment, visit and treatment by visit interaction were included in the model as explanatory variables, adjusting for screening EDSS, baseline ABILHAND and prior aminopyridine as covariates. Missing data are handled using multiple imputation and baseline is defined as the Day 1 assessment.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">646</enrollment>
  <condition>Multiple Sclerosis</condition>
  <arm_group>
    <arm_group_label>Fampridine 10 mg BID</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Prolonged-release fampridine 10 mg twice daily (BID) for up to 24 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Matched placebo 10 mg BID for up to 24 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>fampridine</intervention_name>
    <arm_group_label>Fampridine 10 mg BID</arm_group_label>
    <other_name>dalfampridine</other_name>
    <other_name>Ampyra</other_name>
    <other_name>Fampyra</other_name>
    <other_name>fampridine prolonged-release tablets</other_name>
    <other_name>BIIB041</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Matched placebo</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Key Inclusion Criteria:&#xD;
&#xD;
          -  Must have a diagnosis of primary-progressive, secondary-progressive,&#xD;
             progressive-relapsing, or relapsing-remitting MS per revised McDonald Committee&#xD;
             criteria [McDonald 2001; Polman 2005] as defined by Lublin and Reingold [Lublin and&#xD;
             Reingold 1996] of at least 3 months duration&#xD;
&#xD;
          -  Must have an Expanded Disability Status Scale (EDSS) score of 4 to 7, inclusive&#xD;
&#xD;
          -  Must have walking impairment, as deemed by the Investigator&#xD;
&#xD;
        Key Exclusion Criteria:&#xD;
&#xD;
          -  History of human immunodeficiency virus (HIV)&#xD;
&#xD;
          -  Presence of acute or chronic hepatitis. Subjects who have evidence of prior hepatitis&#xD;
             infection that has been serologically confirmed as resolved are not excluded from&#xD;
             study participation&#xD;
&#xD;
          -  Known allergy to fampridine, pyridine-containing substances, or any of the inactive&#xD;
             ingredients in the prolonged-release fampridine tablet&#xD;
&#xD;
          -  Creatinine clearance (CrCl) of &lt;80 mL/min&#xD;
&#xD;
          -  History of malignant disease&#xD;
&#xD;
          -  Presence of pulmonary disease&#xD;
&#xD;
          -  A body mass index (BMI) ≥40 (BMI formula: BMI = mass [kg]/[height(m)]2)&#xD;
&#xD;
        NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Medical Director</last_name>
    <role>Study Director</role>
    <affiliation>Biogen</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>Cullman</city>
        <state>Alabama</state>
        <zip>35058</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>Phoenix</city>
        <state>Arizona</state>
        <zip>85013</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>San Diego</city>
        <state>California</state>
        <zip>92108</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>Bradenton</city>
        <state>Florida</state>
        <zip>34205</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Orlando</city>
        <state>Florida</state>
        <zip>32806</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33634</zip>
        <country>United States</country>
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    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>West Palm Beach</city>
        <state>Florida</state>
        <zip>33407</zip>
        <country>United States</country>
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  </location>
  <location>
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      <name>Research site</name>
      <address>
        <city>Lexington</city>
        <state>Kentucky</state>
        <zip>40513</zip>
        <country>United States</country>
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    <facility>
      <name>Research site</name>
      <address>
        <city>New Bedford</city>
        <state>Massachusetts</state>
        <zip>02740</zip>
        <country>United States</country>
      </address>
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  </location>
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    <facility>
      <name>Research site</name>
      <address>
        <city>Detroit</city>
        <state>Michigan</state>
        <zip>48201</zip>
        <country>United States</country>
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  </location>
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    <facility>
      <name>Research site</name>
      <address>
        <city>Chesterfield</city>
        <state>Missouri</state>
        <zip>63017</zip>
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  </location>
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      <name>Research site</name>
      <address>
        <city>Rochester</city>
        <state>New York</state>
        <zip>14642</zip>
        <country>United States</country>
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      <address>
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        <state>North Carolina</state>
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      <name>Research site</name>
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        <state>Ohio</state>
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        <country>United States</country>
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    <facility>
      <name>Research site</name>
      <address>
        <city>Helsinki</city>
        <zip>00100</zip>
        <country>Finland</country>
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      <name>Research site</name>
      <address>
        <city>Oulu</city>
        <zip>90220</zip>
        <country>Finland</country>
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    <facility>
      <name>Research site</name>
      <address>
        <city>Tampere</city>
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        <country>Finland</country>
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    <facility>
      <name>Research site</name>
      <address>
        <city>Turku</city>
        <zip>20520</zip>
        <country>Finland</country>
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    <facility>
      <name>Research Site</name>
      <address>
        <city>Gallarate</city>
        <country>Italy</country>
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  <location>
    <facility>
      <name>Research site</name>
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      <name>Research site</name>
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      <name>Research site</name>
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        <country>Poland</country>
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        <country>Poland</country>
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        <country>Poland</country>
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      <address>
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        <country>Poland</country>
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        <country>Poland</country>
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    <facility>
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      <address>
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  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>Krakow</city>
        <zip>31-637</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>Lodz</city>
        <zip>90-324</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>Olsztyn</city>
        <zip>10-561</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>Plewiska</city>
        <zip>62064</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>Rzeszow</city>
        <zip>35055</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>Warsaw</city>
        <zip>00-669</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>Warsaw</city>
        <zip>01-697</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>Warsaw</city>
        <zip>04-749</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Kazan</city>
        <zip>420021</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>Kemerovo</city>
        <zip>650066</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>Krasnoyarsk</city>
        <zip>660037</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Moscow</city>
        <zip>127015</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>Moscow</city>
        <zip>129128</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Nizhny Novgorod</city>
        <zip>60155</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>Belgrade</city>
        <zip>11000</zip>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>Kragujevac</city>
        <zip>34000</zip>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>Nis</city>
        <zip>18000</zip>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>Exeter</city>
        <state>Devon</state>
        <zip>EX2 5DW</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>Plymouth</city>
        <state>Devon</state>
        <zip>PL6 8DH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>Romford</city>
        <state>Essex</state>
        <zip>RM7 0AG</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>Salford</city>
        <state>Greater Manchester</state>
        <zip>M6 8HD</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>Norwich</city>
        <state>Norfolk</state>
        <zip>NR4 7UY</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>Glasgow</city>
        <state>Scotland</state>
        <zip>G51 4TF</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>Chertsey</city>
        <state>Surrey</state>
        <zip>KT16 0PZ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>Cardiff</city>
        <state>Swansea</state>
        <zip>SA6 6NL</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>Birmingham</city>
        <state>West Midlands</state>
        <zip>B15 2WB</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>London</city>
        <zip>E1 2AT</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>London</city>
        <zip>NW3 2QG</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>London</city>
        <zip>WC1N 3BG</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research site</name>
      <address>
        <city>Nottingham</city>
        <zip>NG7 2UH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Bulgaria</country>
    <country>Czech Republic</country>
    <country>Finland</country>
    <country>Italy</country>
    <country>Lithuania</country>
    <country>Netherlands</country>
    <country>Poland</country>
    <country>Russian Federation</country>
    <country>Serbia</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>Argentina</country>
    <country>Germany</country>
    <country>Switzerland</country>
  </removed_countries>
  <verification_date>January 2017</verification_date>
  <study_first_submitted>August 18, 2014</study_first_submitted>
  <study_first_submitted_qc>August 18, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 19, 2014</study_first_posted>
  <results_first_submitted>February 6, 2017</results_first_submitted>
  <results_first_submitted_qc>February 6, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">March 27, 2017</results_first_posted>
  <last_update_submitted>February 6, 2017</last_update_submitted>
  <last_update_submitted_qc>February 6, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">March 27, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Fampridine</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>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>4-Aminopyridine</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>A total of 646 participants were enrolled. A single site in Poland was later closed due to serious Good Clinical Practice noncompliance issues observed during the conduct of the study. There were 10 participants randomized at this site (6 to fampridine and 4 to placebo). The data from this site were excluded from all analyses.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Placebo</title>
          <description>Placebo twice daily (BID) for up to 24 weeks</description>
        </group>
        <group group_id="P2">
          <title>Fampridine 10 mg BID</title>
          <description>Prolonged-release fampridine 10 mg BID for up to 24 weeks</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="319"/>
                <participants group_id="P2" count="317"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Randomized, Not Treated</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="254"/>
                <participants group_id="P2" count="266"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="65"/>
                <participants group_id="P2" count="51"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Other</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="11"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Investigator Decision</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Consent Withdrawn</title>
              <participants_list>
                <participants group_id="P1" count="11"/>
                <participants group_id="P2" count="7"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lack of Efficacy (Subject Perception)</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Pregnancy</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="23"/>
                <participants group_id="P2" count="21"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Safety population: all participants who received at least 1 dose of study drug.</population>
      <group_list>
        <group group_id="B1">
          <title>Placebo</title>
          <description>Placebo BID for up to 24 weeks</description>
        </group>
        <group group_id="B2">
          <title>Fampridine 10 mg BID</title>
          <description>Prolonged-release fampridine 10 mg BID for up to 24 weeks</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="319"/>
            <count group_id="B2" value="316"/>
            <count group_id="B3" value="635"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="48.8" spread="10.50"/>
                    <measurement group_id="B2" value="49.0" spread="9.82"/>
                    <measurement group_id="B3" value="48.9" spread="10.16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="181"/>
                    <measurement group_id="B2" value="187"/>
                    <measurement group_id="B3" value="368"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="138"/>
                    <measurement group_id="B2" value="129"/>
                    <measurement group_id="B3" value="267"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Proportion of Participants Achieving a Mean Improvement of ≥ 8 Points From Baseline on the Multiple Sclerosis Walking Scale (MSWS-12) Over 24 Weeks</title>
        <description>MSWS-12 is a participant self-assessment of the walking limitations due to MS during the past 2 weeks. It contains 12 items that measure the impact of MS on walking. Items are summed to generate a total score and transformed to a scale with a range of 0 to 100, where higher scores indicate greater impact on walking.&#xD;
A responder is defined as a participant with a mean improvement of at least 8 points over 24 weeks compared to baseline. Baseline is defined as the mean at Screening and Day 1 visits. If a participant has a mean MSWS-12 score of &lt; 0.5 over the double-blind period, and a baseline MSWS-12 score of &lt; 8 points, the participant is counted as a responder. A participant who indicates they cannot walk at all on MSWS-12 during any double-blind visit, and who shows severe disability and an inability to walk on other efficacy assessments is counted as a non-responder. Estimated proportion obtained from binomial proportions.</description>
        <time_frame>Baseline to 24 weeks</time_frame>
        <population>Intent-to-treat population: participants who received at least 1 dose of study drug and had at least 1 postbaseline efficacy assessment.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Placebo BID for up to 24 weeks</description>
          </group>
          <group group_id="O2">
            <title>Fampridine 10 mg BID</title>
            <description>Prolonged-release fampridine 10 mg BID for up to 24 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Proportion of Participants Achieving a Mean Improvement of ≥ 8 Points From Baseline on the Multiple Sclerosis Walking Scale (MSWS-12) Over 24 Weeks</title>
          <description>MSWS-12 is a participant self-assessment of the walking limitations due to MS during the past 2 weeks. It contains 12 items that measure the impact of MS on walking. Items are summed to generate a total score and transformed to a scale with a range of 0 to 100, where higher scores indicate greater impact on walking.&#xD;
A responder is defined as a participant with a mean improvement of at least 8 points over 24 weeks compared to baseline. Baseline is defined as the mean at Screening and Day 1 visits. If a participant has a mean MSWS-12 score of &lt; 0.5 over the double-blind period, and a baseline MSWS-12 score of &lt; 8 points, the participant is counted as a responder. A participant who indicates they cannot walk at all on MSWS-12 during any double-blind visit, and who shows severe disability and an inability to walk on other efficacy assessments is counted as a non-responder. Estimated proportion obtained from binomial proportions.</description>
          <population>Intent-to-treat population: participants who received at least 1 dose of study drug and had at least 1 postbaseline efficacy assessment.</population>
          <units>proportion of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="318"/>
                <count group_id="O2" value="315"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.336"/>
                    <measurement group_id="O2" value="0.432"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Based on logistic regression, adjusting for baseline MSWS-12 score, baseline TUG speed, age, screening Expanded Disability Status Scale (EDSS) score and prior aminopyridine. Missing data handled by multiple imputation. Hypothesis testing was performed at the 2-sided 5% significance level overall, with adjustment for testing multiple secondary endpoints.</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.006</p_value>
            <method>Regression, Logistic</method>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>1.61</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.15</ci_lower_limit>
            <ci_upper_limit>2.26</ci_upper_limit>
            <estimate_desc>fampridine vs. placebo</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Based on logistic regression, adjusting for baseline MSWS-12 score, baseline TUG speed, age, screening Expanded Disability Status Scale (EDSS) score and prior aminopyridine. Missing data handled by multiple imputation. Hypothesis testing was performed at the 2-sided 5% significance level overall, with adjustment for testing multiple secondary endpoints.</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Risk Difference for Adjusted Proportions</param_type>
            <param_value>0.104</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.030</ci_lower_limit>
            <ci_upper_limit>0.178</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Based on logistic regression, adjusting for baseline MSWS-12 score, baseline TUG speed, age, screening Expanded Disability Status Scale (EDSS) score and prior aminopyridine. Missing data handled by multiple imputation. Hypothesis testing was performed at the 2-sided 5% significance level overall, with adjustment for testing multiple secondary endpoints.</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Relative Risk</param_type>
            <param_value>1.38</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.06</ci_lower_limit>
            <ci_upper_limit>1.70</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Proportion of Participants Achieving a Mean Improvement From Baseline of ≥ 15% in Timed Up and Go (TUG) Speed Over 24 Weeks</title>
        <description>TUG is a timed walking test designed to measure gait performance and balance. It measures in seconds the time taken by an individual to stand up from a standard arm chair (approximate seat height of 46 cm [18in], arm height 65 cm [25.6 in]), walk a distance of 3 meters (118 inches, approximately 10 feet), turn, walk back to the chair, and sit down.&#xD;
A responder is defined as a participant with a mean improvement of at least 15% in TUG speed over 24 weeks compared to baseline. Baseline is defined as the mean at Screening and Day 1 visits. Estimated proportion obtained from binomial proportions. There are 2 TUG tests given, and the average across the 2 tests is used to calculate average speed. Healthy participants below the age of 79 are expected to complete this task in 7-10 seconds (American College of Rheumatology). Missing data are handled using multiple imputation and baseline is defined as the mean over Screening and Day 1.</description>
        <time_frame>Baseline to Week 24</time_frame>
        <population>Intent-to-treat population: participants who received at least 1 dose of study drug and had at least 1 postbaseline efficacy assessment.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Placebo BID for up to 24 weeks</description>
          </group>
          <group group_id="O2">
            <title>Fampridine 10 mg BID</title>
            <description>Prolonged-release fampridine 10 mg BID for up to 24 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Proportion of Participants Achieving a Mean Improvement From Baseline of ≥ 15% in Timed Up and Go (TUG) Speed Over 24 Weeks</title>
          <description>TUG is a timed walking test designed to measure gait performance and balance. It measures in seconds the time taken by an individual to stand up from a standard arm chair (approximate seat height of 46 cm [18in], arm height 65 cm [25.6 in]), walk a distance of 3 meters (118 inches, approximately 10 feet), turn, walk back to the chair, and sit down.&#xD;
A responder is defined as a participant with a mean improvement of at least 15% in TUG speed over 24 weeks compared to baseline. Baseline is defined as the mean at Screening and Day 1 visits. Estimated proportion obtained from binomial proportions. There are 2 TUG tests given, and the average across the 2 tests is used to calculate average speed. Healthy participants below the age of 79 are expected to complete this task in 7-10 seconds (American College of Rheumatology). Missing data are handled using multiple imputation and baseline is defined as the mean over Screening and Day 1.</description>
          <population>Intent-to-treat population: participants who received at least 1 dose of study drug and had at least 1 postbaseline efficacy assessment.</population>
          <units>proportion of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="318"/>
                <count group_id="O2" value="315"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.347"/>
                    <measurement group_id="O2" value="0.434"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Based on logistic regression, adjusting for baseline TUG speed, screening EDSS score and prior aminopyridine. Missing data were handled using multiple imputation.</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.030</p_value>
            <method>Regression, Logistic</method>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>1.46</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.04</ci_lower_limit>
            <ci_upper_limit>2.07</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Based on logistic regression, adjusting for baseline TUG speed, screening EDSS score and prior aminopyridine. Missing data were handled using multiple imputation.</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Risk Difference for Adjusted Proportions</param_type>
            <param_value>0.092</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.009</ci_lower_limit>
            <ci_upper_limit>0.175</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Based on logistic regression, adjusting for baseline TUG speed, screening EDSS score and prior aminopyridine. Missing data were handled using multiple imputation.</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Relative Risk</param_type>
            <param_value>1.25</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.99</ci_lower_limit>
            <ci_upper_limit>1.51</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Multiple Sclerosis Impact Scale-29 (MSIS-29) Physical Score Over 24 Weeks</title>
        <description>The 29-item MSIS-29 is a participant-reported outcome measure to assess the impact of MS on day-to-day life during the past 2 weeks from a participant's perspective; it measures 20 physical items and 9 psychological items. The physical score is generated by summing individual items and then transforming to a scale with a range of 0 (no impact of MS) to 100 (extreme impact of MS); a negative change indicates an improvement in function.&#xD;
Data are based on a mixed model for repeated measures (MMRM) model using a common variance AR(1) variance-covariance matrix structure. Treatment, visit and treatment by visit interaction were included in the model as explanatory variables, adjusting for screening EDSS, baseline MSIS-29 physical score and prior aminopyridine as covariates. Missing data are handled using multiple imputation and baseline is defined as the mean over screening and Day 1.</description>
        <time_frame>Baseline to Week 24</time_frame>
        <population>Intent-to-treat population: participants who received at least 1 dose of study drug and had at least 1 postbaseline efficacy assessment.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Placebo BID for up to 24 weeks</description>
          </group>
          <group group_id="O2">
            <title>Fampridine 10 mg BID</title>
            <description>Prolonged-release fampridine 10 mg BID for up to 24 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Multiple Sclerosis Impact Scale-29 (MSIS-29) Physical Score Over 24 Weeks</title>
          <description>The 29-item MSIS-29 is a participant-reported outcome measure to assess the impact of MS on day-to-day life during the past 2 weeks from a participant's perspective; it measures 20 physical items and 9 psychological items. The physical score is generated by summing individual items and then transforming to a scale with a range of 0 (no impact of MS) to 100 (extreme impact of MS); a negative change indicates an improvement in function.&#xD;
Data are based on a mixed model for repeated measures (MMRM) model using a common variance AR(1) variance-covariance matrix structure. Treatment, visit and treatment by visit interaction were included in the model as explanatory variables, adjusting for screening EDSS, baseline MSIS-29 physical score and prior aminopyridine as covariates. Missing data are handled using multiple imputation and baseline is defined as the mean over screening and Day 1.</description>
          <population>Intent-to-treat population: participants who received at least 1 dose of study drug and had at least 1 postbaseline efficacy assessment.</population>
          <units>units on a scale</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="318"/>
                <count group_id="O2" value="315"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-4.68" spread="0.936"/>
                    <measurement group_id="O2" value="-8.00" spread="0.911"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>&lt; 0.001</p_value>
            <method>mixed model for repeated measures</method>
            <param_type>LS Mean Difference</param_type>
            <param_value>-3.31</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.925</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-5.13</ci_lower_limit>
            <ci_upper_limit>-1.50</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Berg Balance Scale (BBS) Over 24 Weeks</title>
        <description>The BBS is a widely used assessment tool to identify balance impairment. Functional activities such as reaching, bending, transferring, and standing are evaluated on the test to evaluate balance. Participants are asked to complete 14 tasks that are rated from 0 (cannot perform) to 4 (normal performance) for a total of 56 points. BBS scores range from 0 (poor balance) to 56 (good balance); a positive change indicates improvement.&#xD;
Data are based on an MMRM model using a common variance AR(1) variance-covariance matrix structure. Treatment, visit and treatment by visit interaction were included in the model as explanatory variables, adjusting for screening EDSS, baseline BBS and prior aminopyridine as covariates. Missing data are handled using multiple imputation and baseline is defined as the mean over screening and Day 1.</description>
        <time_frame>Baseline to Week 24</time_frame>
        <population>Intent-to-treat population: participants who received at least 1 dose of study drug and had at least 1 postbaseline efficacy assessment.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Placebo BID for up to 24 weeks</description>
          </group>
          <group group_id="O2">
            <title>Fampridine 10 mg BID</title>
            <description>Prolonged-release fampridine 10 mg BID for up to 24 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Berg Balance Scale (BBS) Over 24 Weeks</title>
          <description>The BBS is a widely used assessment tool to identify balance impairment. Functional activities such as reaching, bending, transferring, and standing are evaluated on the test to evaluate balance. Participants are asked to complete 14 tasks that are rated from 0 (cannot perform) to 4 (normal performance) for a total of 56 points. BBS scores range from 0 (poor balance) to 56 (good balance); a positive change indicates improvement.&#xD;
Data are based on an MMRM model using a common variance AR(1) variance-covariance matrix structure. Treatment, visit and treatment by visit interaction were included in the model as explanatory variables, adjusting for screening EDSS, baseline BBS and prior aminopyridine as covariates. Missing data are handled using multiple imputation and baseline is defined as the mean over screening and Day 1.</description>
          <population>Intent-to-treat population: participants who received at least 1 dose of study drug and had at least 1 postbaseline efficacy assessment.</population>
          <units>units on a scale</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="318"/>
                <count group_id="O2" value="315"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.34" spread="0.284"/>
                    <measurement group_id="O2" value="1.75" spread="0.278"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.141</p_value>
            <method>mixed model for repeated measures</method>
            <param_type>LS Mean Difference</param_type>
            <param_value>0.41</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.277</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.13</ci_lower_limit>
            <ci_upper_limit>0.95</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in ABILHAND Score Over 24 Weeks</title>
        <description>The ABILHAND Questionnaire measures a participant's perceived difficulty in performing everyday manual activities in the last 3 months. The participant completes a 56-item questionnaire by estimating their own difficulty or ease in performing each of 56 activities. Items are summed to generate a total score and transformed to a scale with a range of 0 (poor manual ability) to 100 (good manual ability); a positive change indicates an improvement in manual ability.&#xD;
Data are based on an MMRM model using a common variance AR(1) variance-covariance matrix structure. Treatment, visit and treatment by visit interaction were included in the model as explanatory variables, adjusting for screening EDSS, baseline ABILHAND and prior aminopyridine as covariates. Missing data are handled using multiple imputation and baseline is defined as the Day 1 assessment.</description>
        <time_frame>Baseline to Week 24</time_frame>
        <population>Intent-to-treat population: participants who received at least 1 dose of study drug and had at least 1 postbaseline efficacy assessment and available data.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Placebo BID for up to 24 weeks</description>
          </group>
          <group group_id="O2">
            <title>Fampridine 10 mg BID</title>
            <description>Prolonged-release fampridine 10 mg BID for up to 24 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in ABILHAND Score Over 24 Weeks</title>
          <description>The ABILHAND Questionnaire measures a participant's perceived difficulty in performing everyday manual activities in the last 3 months. The participant completes a 56-item questionnaire by estimating their own difficulty or ease in performing each of 56 activities. Items are summed to generate a total score and transformed to a scale with a range of 0 (poor manual ability) to 100 (good manual ability); a positive change indicates an improvement in manual ability.&#xD;
Data are based on an MMRM model using a common variance AR(1) variance-covariance matrix structure. Treatment, visit and treatment by visit interaction were included in the model as explanatory variables, adjusting for screening EDSS, baseline ABILHAND and prior aminopyridine as covariates. Missing data are handled using multiple imputation and baseline is defined as the Day 1 assessment.</description>
          <population>Intent-to-treat population: participants who received at least 1 dose of study drug and had at least 1 postbaseline efficacy assessment and available data.</population>
          <units>units on a scale</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="315"/>
                <count group_id="O2" value="312"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.75" spread="0.593"/>
                    <measurement group_id="O2" value="1.49" spread="0.574"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.197</p_value>
            <method>mixed model for repeated measures</method>
            <param_type>LS Mean Difference</param_type>
            <param_value>0.74</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.573</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.38</ci_lower_limit>
            <ci_upper_limit>1.86</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Collected through follow-up (14 [±3] days following Week 24/Early Termination). Serious adverse events collected from signing of informed consent; adverse events collected from first dose of study treatment.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Placebo</title>
          <description>Placebo twice daily (BID) for up to 24 weeks</description>
        </group>
        <group group_id="E2">
          <title>Fampridine 10mg BID</title>
          <description>Prolonged-release fampridine 10 mg BID for up to 24 weeks</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA 18.1</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="21" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="25" subjects_at_risk="316"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Acute myocardial infarction</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="316"/>
              </event>
              <event>
                <sub_title>Atrioventricular block second degree</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="316"/>
              </event>
              <event>
                <sub_title>Coronary artery stenosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="316"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Vertigo positional</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="316"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chest pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="316"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Diverticulitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="316"/>
              </event>
              <event>
                <sub_title>Gallbladder empyema</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="316"/>
              </event>
              <event>
                <sub_title>Injection site infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="316"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="316"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Ankle fracture</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="316"/>
              </event>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="316"/>
              </event>
              <event>
                <sub_title>Femur fracture</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="316"/>
              </event>
              <event>
                <sub_title>Humerus fracture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="316"/>
              </event>
              <event>
                <sub_title>Joint dislocation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="316"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Intervertebral disc disorder</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="316"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Bladder cancer</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="316"/>
              </event>
              <event>
                <sub_title>Breast cancer</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="316"/>
              </event>
              <event>
                <sub_title>Ovarian endometrioid carcinoma</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="316"/>
              </event>
              <event>
                <sub_title>Uterine leiomyoma</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="316"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="316"/>
              </event>
              <event>
                <sub_title>Multiple sclerosis relapse</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="14" subjects_at_risk="316"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Pregnancy, puerperium and perinatal conditions</title>
            <event_list>
              <event>
                <sub_title>Abortion spontaneous</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="316"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="316"/>
              </event>
              <event>
                <sub_title>Mental disorder</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="316"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Endometrial atrophy</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="316"/>
              </event>
              <event>
                <sub_title>Metrorrhagia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="316"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Peripheral ischaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="316"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA 18.1</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="93" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="100" subjects_at_risk="316"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="18" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="15" subjects_at_risk="316"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="29" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="40" subjects_at_risk="316"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" subjects_affected="17" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="22" subjects_at_risk="316"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="16" subjects_at_risk="316"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Multiple sclerosis relapse</sub_title>
                <counts group_id="E1" subjects_affected="31" subjects_at_risk="319"/>
                <counts group_id="E2" subjects_affected="31" subjects_at_risk="316"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>Our agreement is subject to confidentiality but generally the PI can publish, for noncommercial purposes only, results and methods of the trial, but no other Sponsor Confidential Information. PI must give Sponsor no less than 60 days to review any manuscript for a proposed publication and must delay publication for up to an additional 90 days thereafter if Sponsor needs to file any patent application to protect any of Sponsor's intellectual property contained in the proposed publication.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Biogen Study Medical Director</name_or_title>
      <organization>Biogen</organization>
      <email>clinicaltrials@biogen.com</email>
    </point_of_contact>
  </clinical_results>
</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/NCT02219932
org study id: 218MS305
secondary id: 2013-003600-40
nct id: NCT02219932
lead sponsor: 
has dmc: Yes
The primary objective is to determine whether prolonged-release fampridine (10 mg twice
      daily) has a clinically meaningful effect on participant-reported walking ability over a
      24-week study period.

      The secondary objectives are: to determine whether prolonged-release fampridine 10 mg taken
      twice daily (BID) has a clinically meaningful effect on dynamic and static balance, physical
      impact of multiple sclerosis (MS), and upper extremity function over a 24-week study period;
      to evaluate criteria for early assessment of response to fampridine that can predict
      clinically meaningful benefits in walking ability and balance; to assess the safety and
      tolerability of prolonged-release fampridine 10 mg twice daily over a 24-week treatment
      period.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Proportion of Participants Achieving a Mean Improvement of ≥ 8 Points From Baseline on the Multiple Sclerosis Walking Scale (MSWS-12) Over 24 Weeks
time frame: Baseline to 24 weeks
description: MSWS-12 is a participant self-assessment of the walking limitations due to MS during the past 2 weeks. It contains 12 items that measure the impact of MS on walking. Items are summed to generate a total score and transformed to a scale with a range of 0 to 100, where higher scores indicate greater impact on walking.
A responder is defined as a participant with a mean improvement of at least 8 points over 24 weeks compared to baseline. Baseline is defined as the mean at Screening and Day 1 visits. If a participant has a mean MSWS-12 score of < 0.5 over the double-blind period, and a baseline MSWS-12 score of < 8 points, the participant is counted as a responder. A participant who indicates they cannot walk at all on MSWS-12 during any double-blind visit, and who shows severe disability and an inability to walk on other efficacy assessments is counted as a non-responder. Estimated proportion obtained from binomial proportions.
measure: Proportion of Participants Achieving a Mean Improvement From Baseline of ≥ 15% in Timed Up and Go (TUG) Speed Over 24 Weeks
time frame: Baseline to Week 24
description: TUG is a timed walking test designed to measure gait performance and balance. It measures in seconds the time taken by an individual to stand up from a standard arm chair (approximate seat height of 46 cm [18in], arm height 65 cm [25.6 in]), walk a distance of 3 meters (118 inches, approximately 10 feet), turn, walk back to the chair, and sit down.
A responder is defined as a participant with a mean improvement of at least 15% in TUG speed over 24 weeks compared to baseline. Baseline is defined as the mean at Screening and Day 1 visits. Estimated proportion obtained from binomial proportions. There are 2 TUG tests given, and the average across the 2 tests is used to calculate average speed. Healthy participants below the age of 79 are expected to complete this task in 7-10 seconds (American College of Rheumatology). Missing data are handled using multiple imputation and baseline is defined as the mean over Screening and Day 1.
measure: Change From Baseline in Multiple Sclerosis Impact Scale-29 (MSIS-29) Physical Score Over 24 Weeks
time frame: Baseline to Week 24
description: The 29-item MSIS-29 is a participant-reported outcome measure to assess the impact of MS on day-to-day life during the past 2 weeks from a participant's perspective; it measures 20 physical items and 9 psychological items. The physical score is generated by summing individual items and then transforming to a scale with a range of 0 (no impact of MS) to 100 (extreme impact of MS); a negative change indicates an improvement in function.
Data are based on a mixed model for repeated measures (MMRM) model using a common variance AR(1) variance-covariance matrix structure. Treatment, visit and treatment by visit interaction were included in the model as explanatory variables, adjusting for screening EDSS, baseline MSIS-29 physical score and prior aminopyridine as covariates. Missing data are handled using multiple imputation and baseline is defined as the mean over screening and Day 1.
measure: Change From Baseline in Berg Balance Scale (BBS) Over 24 Weeks
time frame: Baseline to Week 24
description: The BBS is a widely used assessment tool to identify balance impairment. Functional activities such as reaching, bending, transferring, and standing are evaluated on the test to evaluate balance. Participants are asked to complete 14 tasks that are rated from 0 (cannot perform) to 4 (normal performance) for a total of 56 points. BBS scores range from 0 (poor balance) to 56 (good balance); a positive change indicates improvement.
Data are based on an MMRM model using a common variance AR(1) variance-covariance matrix structure. Treatment, visit and treatment by visit interaction were included in the model as explanatory variables, adjusting for screening EDSS, baseline BBS and prior aminopyridine as covariates. Missing data are handled using multiple imputation and baseline is defined as the mean over screening and Day 1.
measure: Change From Baseline in ABILHAND Score Over 24 Weeks
time frame: Baseline to Week 24
description: The ABILHAND Questionnaire measures a participant's perceived difficulty in performing everyday manual activities in the last 3 months. The participant completes a 56-item questionnaire by estimating their own difficulty or ease in performing each of 56 activities. Items are summed to generate a total score and transformed to a scale with a range of 0 (poor manual ability) to 100 (good manual ability); a positive change indicates an improvement in manual ability.
Data are based on an MMRM model using a common variance AR(1) variance-covariance matrix structure. Treatment, visit and treatment by visit interaction were included in the model as explanatory variables, adjusting for screening EDSS, baseline ABILHAND and prior aminopyridine as covariates. Missing data are handled using multiple imputation and baseline is defined as the Day 1 assessment.
arm group label: Fampridine 10 mg BID
arm group type: Experimental
description: Prolonged-release fampridine 10 mg twice daily (BID) for up to 24 weeks
arm group label: Placebo
arm group type: Placebo Comparator
description: Matched placebo 10 mg BID for up to 24 weeks
intervention type: Drug
intervention name: fampridine
arm group label: Fampridine 10 mg BID
other name: dalfampridine
other name: Ampyra
other name: Fampyra
other name: fampridine prolonged-release tablets
other name: BIIB041
intervention type: Drug
intervention name: Placebo
description: Matched placebo
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Medical Director
role: Study Director
affiliation: Biogen
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country: Bulgaria
country: Czech Republic
country: Finland
country: Italy
country: Lithuania
country: Netherlands
country: Poland
country: Russian Federation
country: Serbia
country: United Kingdom
country: United States
country: Argentina
country: Germany
country: Switzerland
responsible party type: Sponsor
mesh term: Multiple Sclerosis
mesh term: Sclerosis
mesh term: 4-Aminopyridine
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 