<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/NCT02241785</url>
  </required_header>
  <id_info>
    <org_study_id>101MS409</org_study_id>
    <secondary_id>2013-005586-39</secondary_id>
    <nct_id>NCT02241785</nct_id>
  </id_info>
  <brief_title>Natalizumab as an Efficacy Switch in Participants With Relapsing Multiple Sclerosis After Failure on Other Therapies</brief_title>
  <acronym>ESCALATE</acronym>
  <official_title>A Phase 4 Multicenter, Open-Label, Single Arm Study to Evaluate Switching From BRACET/Gilenya® to Natalizumab in Subjects With Relapsing Forms of Multiple Sclerosis (MS)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Biogen</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Biogen</source>
  <brief_summary>
    <textblock>
      The primary objective of the study is to determine the efficacy of natalizumab (Tysabri,&#xD;
      BG00002) in participants with relapsing forms of multiple sclerosis (MS) who have failed&#xD;
      Gilenya or BRACET (Betaseron, Rebif, Avonex, Copaxone, Extavia, Tecfidera) as measured by the&#xD;
      proportion of participants with no evidence of disease activity (NEDA) at Year 1. The&#xD;
      secondary objectives in this study population are: change in total T1 hypointense and total&#xD;
      T2 hyperintense lesion volume; proportion of participants with NEDA at Year 2; evaluation of&#xD;
      the impact of natalizumab on annualized relapse rate (ARR); and change in Multiple Sclerosis&#xD;
      Impact Scale-29 (MSIS-29) physical impact score.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Business Decision&#xD;
  </why_stopped>
  <start_date type="Actual">September 30, 2014</start_date>
  <completion_date type="Actual">May 2, 2016</completion_date>
  <primary_completion_date type="Actual">May 2, 2016</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Proportion of Participants With No Evidence of Disease Activity (NEDA) From Reset Baseline (Week 8) to Week 56</measure>
    <time_frame>Reset Baseline (Week 8) to Week 56</time_frame>
    <description>The proportion of participants with NEDA, defined as follows: no Expanded Disability Status Scale (EDSS) progression (12-week sustained); no relapses; no gadolinium enhancing (Gd+) lesions; no new or enlarging T2 hyperintense lesions over 48 weeks after resetting the Baseline at Week 8 to remove contribution of combined unique active (CUA) lesions that occurred prior to Week 8, when natalizumab was not yet active. The EDSS quantifies disability in 8 functional systems. The final EDSS score is an ordinal clinical rating scale ranging from 0 (normal neurologic examination) to 10 (death due to MS) in half-point increments.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in T1 Unenhancing Lesion Volume and T2 Lesion Volume From Baseline (Day -1) to Reset Baseline (Week 8)</measure>
    <time_frame>Baseline (Day -1) to Reset Baseline (Week 8)</time_frame>
    <description>As measured by magnetic resonance imaging.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of Participants With NEDA From Week 8 (Reset Baseline) to Week 104</measure>
    <time_frame>from Week 8 (Reset Baseline) to Week 104</time_frame>
    <description>Proportion of participants with NEDA from Week 8 (Reset Baseline) to Week 104 (with no 12-week confirmed EDSS progression determined at Week 116). NEDA was defined as follows: no EDSS progression (12-week sustained); no relapses; no Gd+ lesions; no new or enlarging T2 hyperintense lesions over 48 weeks after resetting the Baseline at Week 8 to remove contribution of CUA lesions that occurred prior to Week 8, when natalizumab was not yet active. The EDSS quantifies disability in 8 functional systems. The final EDSS score is an ordinal clinical rating scale ranging from 0 (normal neurologic examination) to 10 (death due to MS) in half-point increments.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pre- and Post-Natalizumab Infusion Annualized Relapse Rate (ARR) Comparison at Month 12</measure>
    <time_frame>From 12 months prior to natalizumab infusion and 12 months post-natalizumab infusion</time_frame>
    <description>An MS relapse was defined as the onset of new or recurrent neurological symptoms lasting at least 24 hours, accompanied by new objective abnormalities on a neurological examination, and not explained solely by non-MS processes such as fever, infection, severe stress, or drug toxicity. 95% confidence interval is based on a Poisson regression model.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in MSIS-29 Physical Impact Scores From Baseline (Day -1) to Reset Baseline (Week 8)</measure>
    <time_frame>Baseline (Day -1) to Reset Baseline (Week 8)</time_frame>
    <description>The MSIS-29 is a brief self-administered MS-specific instrument measuring physical (20 items) and mental/psychological (9 items) impact of MS. The physical score is generated by summing individual items and then transforming to a scale with a range of 0 to 100, where high scores indicate worse health.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">47</enrollment>
  <condition>Relapsing Multiple Sclerosis</condition>
  <arm_group>
    <arm_group_label>natalizumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>natalizumab 300 mg intravenously (IV) every 4 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>natalizumab</intervention_name>
    <description>Administered as specified in the treatment arm</description>
    <arm_group_label>natalizumab</arm_group_label>
    <other_name>BG00002</other_name>
    <other_name>Tysabri</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Key Inclusion Criteria:&#xD;
&#xD;
          -  Subjects of childbearing potential must practice effective contraception from Day -1&#xD;
             and be willing and able to continue contraception for duration of the study.&#xD;
&#xD;
          -  Must have documented diagnosis of relapsing MS (McDonald 2010 Criteria [Polman 2011])&#xD;
             at Screening.&#xD;
&#xD;
          -  Must have been treated with Gilenya or Betaseron, Rebif, Avonex, Copaxone, Extavia,&#xD;
             Tecfidera (BRACET) for at least the 12 months prior to Screening with no interruption&#xD;
             of treatment greater than 1 month. Prior treatment with natalizumab is allowed;&#xD;
             however, there must be a minimum 1 year since last natalizumab infusion and the&#xD;
             Screening visit of this study, and if discontinuation of natalizumab in the past was&#xD;
             not due to intolerance, anti-natalizumab antibodies, or efficacy loss.&#xD;
&#xD;
          -  Must have had disease activity in the 6 months prior to Screening while on Gilenya or&#xD;
             BRACET (as defined by at least 1 gadolinium enhancing lesion OR at least 2 new T2&#xD;
             lesions compared with magnetic resonance imaging done within 12 months of screening OR&#xD;
             clinical relapse, or Expanded Disability Status Scale [EDSS] progression of 1 point)&#xD;
&#xD;
          -  Must have an EDSS score from 0 to 5.5 inclusive at Screening.&#xD;
&#xD;
          -  Must have lymphocyte count that is documented as at or above the lower limit of normal&#xD;
             (LLN) by the day before the first Tysabri infusion. If lymphocytes have not returned&#xD;
             to LLN or above the day before the first Tysabri infusion (day 0), the subject has&#xD;
             screen failed. The subject who screen fails is eligible to undergo Rescreening once;&#xD;
             if additional Rescreening is considered, please contact the study medical monitor.&#xD;
&#xD;
        Key Exclusion Criteria:&#xD;
&#xD;
          -  History or positive test result at Screening for human immunodeficiency virus.&#xD;
&#xD;
          -  History or positive test result at Screening for hepatitis C virus antibody or current&#xD;
             hepatitis B infection (defined as positive for hepatitis B surface antigen and/or&#xD;
             hepatitis core antibody).&#xD;
&#xD;
          -  Prior treatment with natalizumab (either commercially or through a clinical study)&#xD;
             within 1 year of Day -1.&#xD;
&#xD;
          -  Contraindications to treatment with natalizumab as described in the Prescribing&#xD;
             Information for each of the participating countries.&#xD;
&#xD;
          -  Known allergy to natalizumab or any of its ingredients, or known to be&#xD;
             anti-natalizumab antibody positive.&#xD;
&#xD;
          -  Diagnosis of primary progressive MS, secondary progressive MS, and/or&#xD;
             progressive-relapsing MS.&#xD;
&#xD;
          -  An MS relapse that has occurred within the 30 days prior to Day -1 and/or the subject&#xD;
             has not stabilized from a previous relapse prior to Day -1.&#xD;
&#xD;
          -  Known active malignancies (subjects with cutaneous basal cell carcinoma that has been&#xD;
             completely excised prior to study entry remain eligible).&#xD;
&#xD;
          -  History of severe opportunistic infections (including progressive multifocal&#xD;
             leukoencephalopathy) or any clinically significant cardiac, endocrinologic,&#xD;
             hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic,&#xD;
             dermatologic, psychiatric, and renal, or other major disease, as determined by the&#xD;
             Investigator&#xD;
&#xD;
          -  Clinically severe active infection within 1 month prior to Screening.&#xD;
&#xD;
          -  Females breastfeeding, pregnant, or planning to become pregnant; women who are not&#xD;
             post-menopausal or surgically sterile who are unwilling to practice contraception;&#xD;
             women who have a positive pregnancy test result at Day -1.&#xD;
&#xD;
          -  Prior history of immunosuppressant use (e.g., mitoxantrone, azathioprine,&#xD;
             methotrexate, cyclophosphamide, mycophenolate, cladribine, rituximab) in the last 12&#xD;
             months prior to Screening. Prior history of alemtuzumab use at any point in the past.&#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>60 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>Fullerton</city>
        <state>California</state>
        <zip>92835</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Aurora</city>
        <state>Colorado</state>
        <zip>80045</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Des Moines</city>
        <state>Iowa</state>
        <zip>50314</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Plainview</city>
        <state>New York</state>
        <zip>11803</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Raleigh</city>
        <state>North Carolina</state>
        <zip>27607-6010</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Akron</city>
        <state>Ohio</state>
        <zip>44320</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44195</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Knoxville</city>
        <state>Tennessee</state>
        <zip>37922</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Round Rock</city>
        <state>Texas</state>
        <zip>78681</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Tacoma</city>
        <state>Washington</state>
        <zip>98405</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>Germany</country>
  </removed_countries>
  <verification_date>April 2017</verification_date>
  <study_first_submitted>September 12, 2014</study_first_submitted>
  <study_first_submitted_qc>September 12, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 16, 2014</study_first_posted>
  <results_first_submitted>April 24, 2017</results_first_submitted>
  <results_first_submitted_qc>April 24, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">June 5, 2017</results_first_posted>
  <last_update_submitted>April 24, 2017</last_update_submitted>
  <last_update_submitted_qc>April 24, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">June 5, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <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>Natalizumab</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Natalizumab</title>
          <description>natalizumab 300 mg intravenously (IV) every 4 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="47"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="47"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Sponsor Termination</title>
              <participants_list>
                <participants group_id="P1" count="43"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Natalizumab</title>
          <description>natalizumab 300 mg IV every 4 weeks</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="47"/>
          </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="41.9" spread="10.43"/>
                  </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="34"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Proportion of Participants With No Evidence of Disease Activity (NEDA) From Reset Baseline (Week 8) to Week 56</title>
        <description>The proportion of participants with NEDA, defined as follows: no Expanded Disability Status Scale (EDSS) progression (12-week sustained); no relapses; no gadolinium enhancing (Gd+) lesions; no new or enlarging T2 hyperintense lesions over 48 weeks after resetting the Baseline at Week 8 to remove contribution of combined unique active (CUA) lesions that occurred prior to Week 8, when natalizumab was not yet active. The EDSS quantifies disability in 8 functional systems. The final EDSS score is an ordinal clinical rating scale ranging from 0 (normal neurologic examination) to 10 (death due to MS) in half-point increments.</description>
        <time_frame>Reset Baseline (Week 8) to Week 56</time_frame>
        <population>The limited number of participants enrolled and the early termination of the study resulted in efficacy data not collected, and efficacy outcomes not analyzed, as per the pre-specified plan of analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Natalizumab</title>
            <description>natalizumab 300 mg IV every 4 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Proportion of Participants With No Evidence of Disease Activity (NEDA) From Reset Baseline (Week 8) to Week 56</title>
          <description>The proportion of participants with NEDA, defined as follows: no Expanded Disability Status Scale (EDSS) progression (12-week sustained); no relapses; no gadolinium enhancing (Gd+) lesions; no new or enlarging T2 hyperintense lesions over 48 weeks after resetting the Baseline at Week 8 to remove contribution of combined unique active (CUA) lesions that occurred prior to Week 8, when natalizumab was not yet active. The EDSS quantifies disability in 8 functional systems. The final EDSS score is an ordinal clinical rating scale ranging from 0 (normal neurologic examination) to 10 (death due to MS) in half-point increments.</description>
          <population>The limited number of participants enrolled and the early termination of the study resulted in efficacy data not collected, and efficacy outcomes not analyzed, as per the pre-specified plan of analysis.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in T1 Unenhancing Lesion Volume and T2 Lesion Volume From Baseline (Day -1) to Reset Baseline (Week 8)</title>
        <description>As measured by magnetic resonance imaging.</description>
        <time_frame>Baseline (Day -1) to Reset Baseline (Week 8)</time_frame>
        <population>Intent-to-treat population: participants who received at least 1 infusion of study treatment and had an assessment.</population>
        <group_list>
          <group group_id="O1">
            <title>Natalizumab</title>
            <description>natalizumab 300 mg IV every 4 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Change in T1 Unenhancing Lesion Volume and T2 Lesion Volume From Baseline (Day -1) to Reset Baseline (Week 8)</title>
          <description>As measured by magnetic resonance imaging.</description>
          <population>Intent-to-treat population: participants who received at least 1 infusion of study treatment and had an assessment.</population>
          <units>cc</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="43"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Change in T1 Unenhancing Lesion Volume</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.11" spread="0.65"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change in T2 Lesion Volume</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.01" spread="1.76"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Proportion of Participants With NEDA From Week 8 (Reset Baseline) to Week 104</title>
        <description>Proportion of participants with NEDA from Week 8 (Reset Baseline) to Week 104 (with no 12-week confirmed EDSS progression determined at Week 116). NEDA was defined as follows: no EDSS progression (12-week sustained); no relapses; no Gd+ lesions; no new or enlarging T2 hyperintense lesions over 48 weeks after resetting the Baseline at Week 8 to remove contribution of CUA lesions that occurred prior to Week 8, when natalizumab was not yet active. The EDSS quantifies disability in 8 functional systems. The final EDSS score is an ordinal clinical rating scale ranging from 0 (normal neurologic examination) to 10 (death due to MS) in half-point increments.</description>
        <time_frame>from Week 8 (Reset Baseline) to Week 104</time_frame>
        <population>The limited number of participants enrolled and the early termination of the study resulted in efficacy data not collected, and efficacy outcomes not analyzed, as per the pre-specified plan of analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Natalizumab</title>
            <description>natalizumab 300 mg IV every 4 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Proportion of Participants With NEDA From Week 8 (Reset Baseline) to Week 104</title>
          <description>Proportion of participants with NEDA from Week 8 (Reset Baseline) to Week 104 (with no 12-week confirmed EDSS progression determined at Week 116). NEDA was defined as follows: no EDSS progression (12-week sustained); no relapses; no Gd+ lesions; no new or enlarging T2 hyperintense lesions over 48 weeks after resetting the Baseline at Week 8 to remove contribution of CUA lesions that occurred prior to Week 8, when natalizumab was not yet active. The EDSS quantifies disability in 8 functional systems. The final EDSS score is an ordinal clinical rating scale ranging from 0 (normal neurologic examination) to 10 (death due to MS) in half-point increments.</description>
          <population>The limited number of participants enrolled and the early termination of the study resulted in efficacy data not collected, and efficacy outcomes not analyzed, as per the pre-specified plan of analysis.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Pre- and Post-Natalizumab Infusion Annualized Relapse Rate (ARR) Comparison at Month 12</title>
        <description>An MS relapse was defined as the onset of new or recurrent neurological symptoms lasting at least 24 hours, accompanied by new objective abnormalities on a neurological examination, and not explained solely by non-MS processes such as fever, infection, severe stress, or drug toxicity. 95% confidence interval is based on a Poisson regression model.</description>
        <time_frame>From 12 months prior to natalizumab infusion and 12 months post-natalizumab infusion</time_frame>
        <population>Intent-to-treat population: participants who received at least 1 infusion of study treatment and had an assessment.</population>
        <group_list>
          <group group_id="O1">
            <title>Natalizumab</title>
            <description>natalizumab 300 mg IV every 4 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Pre- and Post-Natalizumab Infusion Annualized Relapse Rate (ARR) Comparison at Month 12</title>
          <description>An MS relapse was defined as the onset of new or recurrent neurological symptoms lasting at least 24 hours, accompanied by new objective abnormalities on a neurological examination, and not explained solely by non-MS processes such as fever, infection, severe stress, or drug toxicity. 95% confidence interval is based on a Poisson regression model.</description>
          <population>Intent-to-treat population: participants who received at least 1 infusion of study treatment and had an assessment.</population>
          <units>relapses per subject-year</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="47"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>12 months pre-natalizumab infusion</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.553" lower_limit="1.306" upper_limit="1.847"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>12 months post-natalizumab infusion</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.159" lower_limit="0.076" upper_limit="0.331"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in MSIS-29 Physical Impact Scores From Baseline (Day -1) to Reset Baseline (Week 8)</title>
        <description>The MSIS-29 is a brief self-administered MS-specific instrument measuring physical (20 items) and mental/psychological (9 items) impact of MS. The physical score is generated by summing individual items and then transforming to a scale with a range of 0 to 100, where high scores indicate worse health.</description>
        <time_frame>Baseline (Day -1) to Reset Baseline (Week 8)</time_frame>
        <population>Intent-to-treat population: participants who received at least 1 infusion of study treatment and had an assessment.</population>
        <group_list>
          <group group_id="O1">
            <title>Natalizumab</title>
            <description>natalizumab 300 mg IV every 4 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Change in MSIS-29 Physical Impact Scores From Baseline (Day -1) to Reset Baseline (Week 8)</title>
          <description>The MSIS-29 is a brief self-administered MS-specific instrument measuring physical (20 items) and mental/psychological (9 items) impact of MS. The physical score is generated by summing individual items and then transforming to a scale with a range of 0 to 100, where high scores indicate worse health.</description>
          <population>Intent-to-treat population: participants who received at least 1 infusion of study treatment and had an assessment.</population>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="45"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-2.53" spread="12.42"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From Screening through end of study. Duration of study treatment was up to 13 months.</time_frame>
      <desc>SAEs only were collected per protocol. Events were not coded by MedDRA.</desc>
      <group_list>
        <group group_id="E1">
          <title>Natalizumab</title>
          <description>natalizumab 300 mg IV every 4 weeks</description>
        </group>
      </group_list>
      <serious_events>
        <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="2" subjects_at_risk="47"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="47"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="47"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="0"/>
              </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>
    <limitations_and_caveats>As a result of early study termination and limited available data, no meaningful conclusions can be drawn.</limitations_and_caveats>
    <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/NCT02241785
org study id: 101MS409
secondary id: 2013-005586-39
nct id: NCT02241785
lead sponsor: 
The primary objective of the study is to determine the efficacy of natalizumab (Tysabri,
      BG00002) in participants with relapsing forms of multiple sclerosis (MS) who have failed
      Gilenya or BRACET (Betaseron, Rebif, Avonex, Copaxone, Extavia, Tecfidera) as measured by the
      proportion of participants with no evidence of disease activity (NEDA) at Year 1. The
      secondary objectives in this study population are: change in total T1 hypointense and total
      T2 hyperintense lesion volume; proportion of participants with NEDA at Year 2; evaluation of
      the impact of natalizumab on annualized relapse rate (ARR); and change in Multiple Sclerosis
      Impact Scale-29 (MSIS-29) physical impact score.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Proportion of Participants With No Evidence of Disease Activity (NEDA) From Reset Baseline (Week 8) to Week 56
time frame: Reset Baseline (Week 8) to Week 56
description: The proportion of participants with NEDA, defined as follows: no Expanded Disability Status Scale (EDSS) progression (12-week sustained); no relapses; no gadolinium enhancing (Gd+) lesions; no new or enlarging T2 hyperintense lesions over 48 weeks after resetting the Baseline at Week 8 to remove contribution of combined unique active (CUA) lesions that occurred prior to Week 8, when natalizumab was not yet active. The EDSS quantifies disability in 8 functional systems. The final EDSS score is an ordinal clinical rating scale ranging from 0 (normal neurologic examination) to 10 (death due to MS) in half-point increments.
measure: Change in T1 Unenhancing Lesion Volume and T2 Lesion Volume From Baseline (Day -1) to Reset Baseline (Week 8)
time frame: Baseline (Day -1) to Reset Baseline (Week 8)
description: As measured by magnetic resonance imaging.
measure: Proportion of Participants With NEDA From Week 8 (Reset Baseline) to Week 104
time frame: from Week 8 (Reset Baseline) to Week 104
description: Proportion of participants with NEDA from Week 8 (Reset Baseline) to Week 104 (with no 12-week confirmed EDSS progression determined at Week 116). NEDA was defined as follows: no EDSS progression (12-week sustained); no relapses; no Gd+ lesions; no new or enlarging T2 hyperintense lesions over 48 weeks after resetting the Baseline at Week 8 to remove contribution of CUA lesions that occurred prior to Week 8, when natalizumab was not yet active. The EDSS quantifies disability in 8 functional systems. The final EDSS score is an ordinal clinical rating scale ranging from 0 (normal neurologic examination) to 10 (death due to MS) in half-point increments.
measure: Pre- and Post-Natalizumab Infusion Annualized Relapse Rate (ARR) Comparison at Month 12
time frame: From 12 months prior to natalizumab infusion and 12 months post-natalizumab infusion
description: An MS relapse was defined as the onset of new or recurrent neurological symptoms lasting at least 24 hours, accompanied by new objective abnormalities on a neurological examination, and not explained solely by non-MS processes such as fever, infection, severe stress, or drug toxicity. 95% confidence interval is based on a Poisson regression model.
measure: Change in MSIS-29 Physical Impact Scores From Baseline (Day -1) to Reset Baseline (Week 8)
time frame: Baseline (Day -1) to Reset Baseline (Week 8)
description: The MSIS-29 is a brief self-administered MS-specific instrument measuring physical (20 items) and mental/psychological (9 items) impact of MS. The physical score is generated by summing individual items and then transforming to a scale with a range of 0 to 100, where high scores indicate worse health.
arm group label: natalizumab
arm group type: Experimental
description: natalizumab 300 mg intravenously (IV) every 4 weeks
intervention type: Drug
intervention name: natalizumab
description: Administered as specified in the treatment arm
arm group label: natalizumab
other name: BG00002
other name: Tysabri
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: No
last name: Medical Director
role: Study Director
affiliation: Biogen
facility: 
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country: United States
country: Germany
responsible party type: Sponsor
mesh term: Multiple Sclerosis
mesh term: Sclerosis
mesh term: Natalizumab
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: As a result of early study termination and limited available data, no meaningful conclusions can be drawn.
point of contact: 