<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/NCT01701856</url>
  </required_header>
  <id_info>
    <org_study_id>EOC.NSI.11.01</org_study_id>
    <nct_id>NCT01701856</nct_id>
  </id_info>
  <brief_title>Natalizumab De-escalation to Interferon-beta-1b in Patients With Relapsing-remitting Multiple Sclerosis</brief_title>
  <official_title>Natalizumab De-escalation to Interferon-beta-1b in Patients With Relapsing-remitting Multiple Sclerosis: A Swiss Multicenter Study Prospective, Controlled, Single-arm, Open-label, Multi-centre, Phase IV Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Claudio Gobbi</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bayer</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Ospedale Civico, Lugano</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Multiple Sclerosis (MS) is the most common neurological disorder causing disability in young&#xD;
      adults affecting approximately 1 in 1.000 people in western countries. The clinical&#xD;
      manifestations usually begin at the age of 20 to 40 years with a median age of 28 years at&#xD;
      onset with acute episodes of neurological dysfunction, followed by periods of partial or&#xD;
      complete remission and clinical stability in between relapses. This relapsing-remitting phase&#xD;
      (RR-MS) of the disease is usually followed by progressive clinical disability (secondary&#xD;
      progressive phase, SP-MS).&#xD;
&#xD;
      At present, there is no cure for MS. Based on the pathological concept that neuroinflammation&#xD;
      is the common element leading or contributing to neurodegenerative changes, immune&#xD;
      interventions have been introduced into clinical practice such as Natalizumab (Tysabri), a&#xD;
      humanized monoclonal antibody. Natalizumab (Tysabri) is indicated as a disease-modifying&#xD;
      monotherapy of highly active relapsing MS. The associated risks, especially progressive&#xD;
      multifocal leukoencephalopathy, necessitate active monitoring of patients and a continuous&#xD;
      discussion of optimum use of this drug. In clinical practice, the question how to manage&#xD;
      patients on natalizumab at a higher risk for progressive multifocal leukoencephalopathy&#xD;
      remains unresolved.&#xD;
&#xD;
      This prospective, controlled (comparison to the period prior to natalizumab treatment),&#xD;
      single-arm, open-label, multi-centre, phase IV study aims to evaluating the concept of&#xD;
      natalizumab de-escalation to interferon-beta-1b e.o.d in relapsing-remitting multiple&#xD;
      sclerosis patients, who consider stopping natalizumab due to a benefit-risk assessment. In&#xD;
      particular, to evaluating if interferon beta-1b treatment may be able to overcome the&#xD;
      recurrence of significant clinical and radiological disease activity after natalizumab&#xD;
      cessation and may keep disease activity better under control as compared to the time prior to&#xD;
      natalizumab.&#xD;
&#xD;
      The study population includes patients with relapsing-remitting multiple sclerosis (RR-MS)&#xD;
      being treated at least for 12 months with natalizumab and having decided to stop natalizumab&#xD;
      treatment and to de-escalate their therapy to a first line treatment with interferon beta-1b.&#xD;
      They will be treated during 12 months with interferon-beta 1b 250 mcg given subcutaneously&#xD;
      every other day. A 12-month follow-up period with the same treatment is planned.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Problems to recruit the needed number of patients in the planned time&#xD;
  </why_stopped>
  <start_date>September 2012</start_date>
  <completion_date type="Actual">October 2013</completion_date>
  <primary_completion_date type="Actual">October 2013</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>Annualized relapse rate on study compared to annualized relapse rate in the year prior to natalizumab initiation on first line disease modifying treatment (month -24 to -12)</measure>
    <time_frame>12 months</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Annualized relapse rate on study compared to annualized relapse rate in the year prior to natalizumab initiation on first line disease modifying treatment (month -24 to -12)</measure>
    <time_frame>3 months</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Annualized relapse rate on study compared to annualized relapse rate in the year prior to natalizumab initiation on first line disease modifying treatment (month -24 to -12)</measure>
    <time_frame>6 months</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Annualized relapse rate on study compared to annualized relapse rate in the year prior to natalizumab initiation on first line disease modifying treatment (month -24 to -12)</measure>
    <time_frame>9 months</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Annualized relapse rate on study compared to annualized relapse rate in the year prior to natalizumab initiation on first line disease modifying treatment (month -24 to -12)</measure>
    <time_frame>15 months</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Annualized relapse rate on study compared to annualized relapse rate in the year prior to natalizumab initiation on first line disease modifying treatment (month -24 to -12)</measure>
    <time_frame>18 months</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Annualized relapse rate on study compared to annualized relapse rate in the year prior to natalizumab initiation on first line disease modifying treatment (month -24 to -12)</measure>
    <time_frame>21 months</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Annualized relapse rate on study compared to annualized relapse rate in the year prior to natalizumab initiation on first line disease modifying treatment (month -24 to -12)</measure>
    <time_frame>24 months</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Severity of relapses</measure>
    <time_frame>3 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Severity of relapses</measure>
    <time_frame>6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Severity of relapses</measure>
    <time_frame>9 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Severity of relapses</measure>
    <time_frame>12 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Severity of relapses</measure>
    <time_frame>15 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Severity of relapses</measure>
    <time_frame>18 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Severity of relapses</measure>
    <time_frame>21 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Severity of relapses</measure>
    <time_frame>24 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of relapse free patients</measure>
    <time_frame>3 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of relapse free patients</measure>
    <time_frame>6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of relapse free patients</measure>
    <time_frame>9 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of relapse free patients</measure>
    <time_frame>12 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of relapse free patients</measure>
    <time_frame>15 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of relapse free patients</measure>
    <time_frame>18 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of relapse free patients</measure>
    <time_frame>21 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of relapse free patients</measure>
    <time_frame>24 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>3-month confirmed EDSS progression</measure>
    <time_frame>3 months</time_frame>
    <description>of at least 1.0 points if score &lt; 5.5, at least 0.5 points if score ≥ 5.5</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>3-month confirmed EDSS progression</measure>
    <time_frame>6 months</time_frame>
    <description>of at least 1.0 points if score &lt; 5.5, at least 0.5 points if score ≥ 5.5</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>3-month confirmed EDSS progression</measure>
    <time_frame>9 months</time_frame>
    <description>of at least 1.0 points if score &lt; 5.5, at least 0.5 points if score ≥ 5.5</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>3-month confirmed EDSS progression</measure>
    <time_frame>12 months</time_frame>
    <description>of at least 1.0 points if score &lt; 5.5, at least 0.5 points if score ≥ 5.5</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>3-month confirmed EDSS progression</measure>
    <time_frame>15 months</time_frame>
    <description>of at least 1.0 points if score &lt; 5.5, at least 0.5 points if score ≥ 5.5</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>3-month confirmed EDSS progression</measure>
    <time_frame>18 months</time_frame>
    <description>of at least 1.0 points if score &lt; 5.5, at least 0.5 points if score ≥ 5.5</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>3-month confirmed EDSS progression</measure>
    <time_frame>21 months</time_frame>
    <description>of at least 1.0 points if score &lt; 5.5, at least 0.5 points if score ≥ 5.5</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>3-month confirmed EDSS progression</measure>
    <time_frame>24 months</time_frame>
    <description>of at least 1.0 points if score &lt; 5.5, at least 0.5 points if score ≥ 5.5</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MSFC</measure>
    <time_frame>3 months</time_frame>
    <description>Three part instrument composed of Timed-25-foot (7.62 m)-walk, 9 hole-peg-test (9 HPT), 3'' paced auditory serial addition test (PASAT).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MSFC</measure>
    <time_frame>6 months</time_frame>
    <description>Three part instrument composed of Timed-25-foot (7.62 m)-walk, 9 hole-peg-test (9 HPT), 3'' paced auditory serial addition test (PASAT).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MSFC</measure>
    <time_frame>9 months</time_frame>
    <description>Three part instrument composed of Timed-25-foot (7.62 m)-walk, 9 hole-peg-test (9 HPT), 3'' paced auditory serial addition test (PASAT).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MSFC</measure>
    <time_frame>12 months</time_frame>
    <description>Three part instrument composed of Timed-25-foot (7.62 m)-walk, 9 hole-peg-test (9 HPT), 3'' paced auditory serial addition test (PASAT).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MSFC</measure>
    <time_frame>18 months</time_frame>
    <description>Three part instrument composed of Timed-25-foot (7.62 m)-walk, 9 hole-peg-test (9 HPT), 3'' paced auditory serial addition test (PASAT).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MSFC</measure>
    <time_frame>21 months</time_frame>
    <description>Three part instrument composed of Timed-25-foot (7.62 m)-walk, 9 hole-peg-test (9 HPT), 3'' paced auditory serial addition test (PASAT).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MSFC</measure>
    <time_frame>24</time_frame>
    <description>Three part instrument composed of Timed-25-foot (7.62 m)-walk, 9 hole-peg-test (9 HPT), 3'' paced auditory serial addition test (PASAT).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of EDSS score compared to change in the year prior to natalizumab treatment (month -24 to-12</measure>
    <time_frame>3 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of EDSS score compared to change in the year prior to natalizumab treatment (month -24 to-12</measure>
    <time_frame>6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of EDSS score compared to change in the year prior to natalizumab treatment (month -24 to-12</measure>
    <time_frame>9 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of EDSS score compared to change in the year prior to natalizumab treatment (month -24 to-12</measure>
    <time_frame>12 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of MSFC score compared to change in the year prior to natalizumab treatment (month -24 to-12</measure>
    <time_frame>3 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of MSFC score compared to change in the year prior to natalizumab treatment (month -24 to-12</measure>
    <time_frame>6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of MSFC score compared to change in the year prior to natalizumab treatment (month -24 to-12</measure>
    <time_frame>9 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of MSFC score compared to change in the year prior to natalizumab treatment (month -24 to-12</measure>
    <time_frame>12 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of new/enlarging T2-hyperintense lesions</measure>
    <time_frame>6 months</time_frame>
    <description>MRI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of new/enlarging T2-hyperintense lesions</measure>
    <time_frame>12 months</time_frame>
    <description>MRI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of new/enlarging T2-hyperintense lesions</measure>
    <time_frame>24 months</time_frame>
    <description>MRI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Gd-enhancing lesions</measure>
    <time_frame>6 months</time_frame>
    <description>MRI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Gd-enhancing lesions</measure>
    <time_frame>12 months</time_frame>
    <description>MRI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Gd-enhancing lesions</measure>
    <time_frame>24 months</time_frame>
    <description>MRI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>EQ-5D</measure>
    <time_frame>6 months</time_frame>
    <description>Quality of life questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>EQ-5D</measure>
    <time_frame>12 months</time_frame>
    <description>Quality of life questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>EQ-5D</measure>
    <time_frame>24 months</time_frame>
    <description>Quality of life questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>FAMS</measure>
    <time_frame>6 months</time_frame>
    <description>Quality of life questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>FAMS</measure>
    <time_frame>24 months</time_frame>
    <description>Quality of life questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MSFC</measure>
    <time_frame>15 months</time_frame>
    <description>Three part instrument composed of Timed-25-foot (7.62 m)-walk, 9 hole-peg-test (9 HPT), 3'' paced auditory serial addition test (PASAT).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>EQ-5D</measure>
    <time_frame>18 months</time_frame>
    <description>Quality of life questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>FAMS</measure>
    <time_frame>12 months</time_frame>
    <description>Quality of life questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>FAMS</measure>
    <time_frame>18 months</time_frame>
    <description>Quality of life questionnaire</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">5</enrollment>
  <condition>Relapsing-remitting Multiple Sclerosis</condition>
  <arm_group>
    <arm_group_label>Interferon beta-1b</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Interferon beta-1b 250 mcg s.c. every other day</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Interferon beta-1b</intervention_name>
    <description>250 mcg, s.c., each other day for 12 months</description>
    <arm_group_label>Interferon beta-1b</arm_group_label>
    <other_name>Betaferon®</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Female or male patients with relapsing-remitting forms of multiple sclerosis&#xD;
             (according to McDonald's criteria);&#xD;
&#xD;
          -  Age between 18 and 70 years;&#xD;
&#xD;
          -  Natalizumab-treatment for at least 12 months following the current Swiss guidelines&#xD;
             for treatment initiation;&#xD;
&#xD;
          -  Treated with a disease-modifying therapy other than interferon beta-1b for at least 12&#xD;
             months before natalizumab was initiated;&#xD;
&#xD;
          -  Never treated with interferon beta-1b;&#xD;
&#xD;
          -  Eligible patients are clinically stable (free from relapses and 6-month confirmed&#xD;
             disability progression for at least 6 months) while on natalizumab-treatment and do&#xD;
             not show any Gd-enhancement on their last MRI performed while on Tysabri;&#xD;
&#xD;
          -  In eligible patients MRI were performed in the past as following&#xD;
&#xD;
               -  6-18 months prior to natalizumab-treatment&#xD;
&#xD;
               -  at natalizumab start&#xD;
&#xD;
               -  12 months after natalizumab initiation;&#xD;
&#xD;
          -  Good records with regard to clinical disease activity (relapse rate, EDSS progression)&#xD;
             in the year prior to natalizumab and during natalizumab;&#xD;
&#xD;
          -  Patients who decide to stop natalizumab treatment after a careful benefit/risk&#xD;
             assessment. Risk for PML increases with duration of natalizumab exposure,&#xD;
             pre-treatment with an immunosuppressant agent or serological status of anti-JC-virus&#xD;
             positivity;&#xD;
&#xD;
          -  Patients, who in context with cessation of natalizumab have decided, after a careful&#xD;
             benefit/risk assessment, to continue treatment of their MS with Interferon beta-1b;&#xD;
&#xD;
          -  Women of potential childbearing with active contraceptive methods;&#xD;
&#xD;
          -  Patients who are willing to undergo study procedures;&#xD;
&#xD;
          -  Patients who are willing to undergo MRI;&#xD;
&#xD;
          -  Patients who are willing and able to sign informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients who have previously entered this study;&#xD;
&#xD;
          -  Natalizumab-treatment for less than 12 months following the current Swiss guidelines&#xD;
             for treatment initiation;&#xD;
&#xD;
          -  Prior treatment with interferon beta-1b (ever interferon beta-1b);&#xD;
&#xD;
          -  Sign of clinical disease activity within the 6 months;&#xD;
&#xD;
          -  One or more relapses and/or 6-month confirmed disability progression during the 6&#xD;
             months prior to the study;&#xD;
&#xD;
          -  Secondary progressive MS;&#xD;
&#xD;
          -  Primary progressive MS;&#xD;
&#xD;
          -  Pregnancy - Serum pregnancy test at screening visit positive- or breast feeding;&#xD;
&#xD;
          -  Uncontrolled, clinically significant heart diseases, such as arrhythmias, angina, or&#xD;
             uncompensated congestive heart failure;&#xD;
&#xD;
          -  History of severe depression or attempted suicide or current suicidal ideation;&#xD;
&#xD;
          -  Medical or psychiatric conditions that compromise the ability to give informed&#xD;
             consent, to comply with the protocol, or to complete the study;&#xD;
&#xD;
          -  Uncontrolled seizure disorder;&#xD;
&#xD;
          -  Myopathy or clinically significant liver disease;&#xD;
&#xD;
          -  Inability, in the opinion of the principal investigator or staff, to comply with&#xD;
             protocol requirements for the duration of the study;&#xD;
&#xD;
          -  Known hypersensitivity to interferon-beta or other human proteins including albumin;&#xD;
&#xD;
          -  Any contraindication for MRI or contrast administration;&#xD;
&#xD;
          -  A history of drug abuse in the 6 months prior to screening;&#xD;
&#xD;
          -  Treatment with any of the following in the 30 days before day 1: systemic&#xD;
             corticosteroids, ACTH, or other investigational drugs;&#xD;
&#xD;
          -  Participation in any other study involving investigational or marketed products,&#xD;
             concomitantly or within 30 days prior to entry in the study;&#xD;
&#xD;
          -  Current participation on other clinical trials;&#xD;
&#xD;
          -  Treatment with drugs which might interfere with the evaluation of study drugs during&#xD;
             the study protocol such as immunomodulants, immunosuppressives other than interferon&#xD;
             beta-1b;&#xD;
&#xD;
          -  Likelihood of requiring treatment during the study period with drugs not permitted by&#xD;
             the study protocol such as immunomodulants, immunosuppressives other than interferon&#xD;
             beta-1b.&#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>Claudio Gobbi, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Ospedale Regionale di Lugano - Civico</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Ospedale Regionale di Lugano - Civico</name>
      <address>
        <city>Lugano</city>
        <state>Ticino</state>
        <zip>6903</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Switzerland</country>
  </location_countries>
  <link>
    <url>http://www.eoc.ch</url>
    <description>home page of the main facility</description>
  </link>
  <link>
    <url>http://www.multiplesklerose.ch/</url>
    <description>home page of supporting society for MS patients in Switzerland</description>
  </link>
  <reference>
    <citation>Multiple Sclerosis Therapy Consensus Group (MSTCG); Wiendl H, Toyka KV, Rieckmann P, Gold R, Hartung HP, Hohlfeld R. Basic and escalating immunomodulatory treatments in multiple sclerosis: current therapeutic recommendations. J Neurol. 2008 Oct;255(10):1449-63. doi: 10.1007/s00415-008-0061-1. Epub 2008 Oct 29.</citation>
    <PMID>19005625</PMID>
  </reference>
  <reference>
    <citation>Kappos L, Bates D, Edan G, Eraksoy M, Garcia-Merino A, Grigoriadis N, Hartung HP, Havrdova E, Hillert J, Hohlfeld R, Kremenchutzky M, Lyon-Caen O, Miller A, Pozzilli C, Ravnborg M, Saida T, Sindic C, Vass K, Clifford DB, Hauser S, Major EO, O'Connor PW, Weiner HL, Clanet M, Gold R, Hirsch HH, Radu EW, Sorensen PS, King J. Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring. Lancet Neurol. 2011 Aug;10(8):745-58. doi: 10.1016/S1474-4422(11)70149-1.</citation>
    <PMID>21777829</PMID>
  </reference>
  <reference>
    <citation>Kappos L, Freedman MS, Polman CH, Edan G, Hartung HP, Miller DH, Montalban X, Barkhof F, Radu EW, Metzig C, Bauer L, Lanius V, Sandbrink R, Pohl C; BENEFIT Study Group. Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial. Lancet Neurol. 2009 Nov;8(11):987-97. doi: 10.1016/S1474-4422(09)70237-6. Epub 2009 Sep 10.</citation>
    <PMID>19748319</PMID>
  </reference>
  <reference>
    <citation>Putzki N, Yaldizli O, Buhler R, Schwegler G, Curtius D, Tettenborn B. Natalizumab reduces clinical and MRI activity in multiple sclerosis patients with high disease activity: results from a multicenter study in Switzerland. Eur Neurol. 2010;63(2):101-6. doi: 10.1159/000276400. Epub 2010 Jan 16.</citation>
    <PMID>20090344</PMID>
  </reference>
  <verification_date>January 2014</verification_date>
  <study_first_submitted>September 18, 2012</study_first_submitted>
  <study_first_submitted_qc>October 4, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 5, 2012</study_first_posted>
  <last_update_submitted>January 21, 2014</last_update_submitted>
  <last_update_submitted_qc>January 21, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">January 22, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Ospedale Civico, Lugano</investigator_affiliation>
    <investigator_full_name>Claudio Gobbi</investigator_full_name>
    <investigator_title>Dr. med.</investigator_title>
  </responsible_party>
  <keyword>relapsing-remitting multiple sclerosis</keyword>
  <keyword>natalizumab</keyword>
  <keyword>de-escalation</keyword>
  <keyword>interferon beta-1b</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Multiple Sclerosis</mesh_term>
    <mesh_term>Multiple Sclerosis, Relapsing-Remitting</mesh_term>
    <mesh_term>Sclerosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Interferons</mesh_term>
    <mesh_term>Interferon-beta</mesh_term>
    <mesh_term>Interferon beta-1b</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01701856
org study id: EOC.NSI.11.01
nct id: NCT01701856
lead sponsor: 
collaborator: 
has dmc: Yes
Multiple Sclerosis (MS) is the most common neurological disorder causing disability in young
      adults affecting approximately 1 in 1.000 people in western countries. The clinical
      manifestations usually begin at the age of 20 to 40 years with a median age of 28 years at
      onset with acute episodes of neurological dysfunction, followed by periods of partial or
      complete remission and clinical stability in between relapses. This relapsing-remitting phase
      (RR-MS) of the disease is usually followed by progressive clinical disability (secondary
      progressive phase, SP-MS).

      At present, there is no cure for MS. Based on the pathological concept that neuroinflammation
      is the common element leading or contributing to neurodegenerative changes, immune
      interventions have been introduced into clinical practice such as Natalizumab (Tysabri), a
      humanized monoclonal antibody. Natalizumab (Tysabri) is indicated as a disease-modifying
      monotherapy of highly active relapsing MS. The associated risks, especially progressive
      multifocal leukoencephalopathy, necessitate active monitoring of patients and a continuous
      discussion of optimum use of this drug. In clinical practice, the question how to manage
      patients on natalizumab at a higher risk for progressive multifocal leukoencephalopathy
      remains unresolved.

      This prospective, controlled (comparison to the period prior to natalizumab treatment),
      single-arm, open-label, multi-centre, phase IV study aims to evaluating the concept of
      natalizumab de-escalation to interferon-beta-1b e.o.d in relapsing-remitting multiple
      sclerosis patients, who consider stopping natalizumab due to a benefit-risk assessment. In
      particular, to evaluating if interferon beta-1b treatment may be able to overcome the
      recurrence of significant clinical and radiological disease activity after natalizumab
      cessation and may keep disease activity better under control as compared to the time prior to
      natalizumab.

      The study population includes patients with relapsing-remitting multiple sclerosis (RR-MS)
      being treated at least for 12 months with natalizumab and having decided to stop natalizumab
      treatment and to de-escalate their therapy to a first line treatment with interferon beta-1b.
      They will be treated during 12 months with interferon-beta 1b 250 mcg given subcutaneously
      every other day. A 12-month follow-up period with the same treatment is planned.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Annualized relapse rate on study compared to annualized relapse rate in the year prior to natalizumab initiation on first line disease modifying treatment (month -24 to -12)
time frame: 12 months
measure: Annualized relapse rate on study compared to annualized relapse rate in the year prior to natalizumab initiation on first line disease modifying treatment (month -24 to -12)
time frame: 3 months
measure: Annualized relapse rate on study compared to annualized relapse rate in the year prior to natalizumab initiation on first line disease modifying treatment (month -24 to -12)
time frame: 6 months
measure: Annualized relapse rate on study compared to annualized relapse rate in the year prior to natalizumab initiation on first line disease modifying treatment (month -24 to -12)
time frame: 9 months
measure: Annualized relapse rate on study compared to annualized relapse rate in the year prior to natalizumab initiation on first line disease modifying treatment (month -24 to -12)
time frame: 15 months
measure: Annualized relapse rate on study compared to annualized relapse rate in the year prior to natalizumab initiation on first line disease modifying treatment (month -24 to -12)
time frame: 18 months
measure: Annualized relapse rate on study compared to annualized relapse rate in the year prior to natalizumab initiation on first line disease modifying treatment (month -24 to -12)
time frame: 21 months
measure: Annualized relapse rate on study compared to annualized relapse rate in the year prior to natalizumab initiation on first line disease modifying treatment (month -24 to -12)
time frame: 24 months
measure: Severity of relapses
time frame: 3 months
measure: Severity of relapses
time frame: 6 months
measure: Severity of relapses
time frame: 9 months
measure: Severity of relapses
time frame: 12 months
measure: Severity of relapses
time frame: 15 months
measure: Severity of relapses
time frame: 18 months
measure: Severity of relapses
time frame: 21 months
measure: Severity of relapses
time frame: 24 months
measure: Proportion of relapse free patients
time frame: 3 months
measure: Proportion of relapse free patients
time frame: 6 months
measure: Proportion of relapse free patients
time frame: 9 months
measure: Proportion of relapse free patients
time frame: 12 months
measure: Proportion of relapse free patients
time frame: 15 months
measure: Proportion of relapse free patients
time frame: 18 months
measure: Proportion of relapse free patients
time frame: 21 months
measure: Proportion of relapse free patients
time frame: 24 months
measure: 3-month confirmed EDSS progression
time frame: 3 months
description: of at least 1.0 points if score < 5.5, at least 0.5 points if score ≥ 5.5
measure: 3-month confirmed EDSS progression
time frame: 6 months
description: of at least 1.0 points if score < 5.5, at least 0.5 points if score ≥ 5.5
measure: 3-month confirmed EDSS progression
time frame: 9 months
description: of at least 1.0 points if score < 5.5, at least 0.5 points if score ≥ 5.5
measure: 3-month confirmed EDSS progression
time frame: 12 months
description: of at least 1.0 points if score < 5.5, at least 0.5 points if score ≥ 5.5
measure: 3-month confirmed EDSS progression
time frame: 15 months
description: of at least 1.0 points if score < 5.5, at least 0.5 points if score ≥ 5.5
measure: 3-month confirmed EDSS progression
time frame: 18 months
description: of at least 1.0 points if score < 5.5, at least 0.5 points if score ≥ 5.5
measure: 3-month confirmed EDSS progression
time frame: 21 months
description: of at least 1.0 points if score < 5.5, at least 0.5 points if score ≥ 5.5
measure: 3-month confirmed EDSS progression
time frame: 24 months
description: of at least 1.0 points if score < 5.5, at least 0.5 points if score ≥ 5.5
measure: MSFC
time frame: 3 months
description: Three part instrument composed of Timed-25-foot (7.62 m)-walk, 9 hole-peg-test (9 HPT), 3'' paced auditory serial addition test (PASAT).
measure: MSFC
time frame: 6 months
description: Three part instrument composed of Timed-25-foot (7.62 m)-walk, 9 hole-peg-test (9 HPT), 3'' paced auditory serial addition test (PASAT).
measure: MSFC
time frame: 9 months
description: Three part instrument composed of Timed-25-foot (7.62 m)-walk, 9 hole-peg-test (9 HPT), 3'' paced auditory serial addition test (PASAT).
measure: MSFC
time frame: 12 months
description: Three part instrument composed of Timed-25-foot (7.62 m)-walk, 9 hole-peg-test (9 HPT), 3'' paced auditory serial addition test (PASAT).
measure: MSFC
time frame: 18 months
description: Three part instrument composed of Timed-25-foot (7.62 m)-walk, 9 hole-peg-test (9 HPT), 3'' paced auditory serial addition test (PASAT).
measure: MSFC
time frame: 21 months
description: Three part instrument composed of Timed-25-foot (7.62 m)-walk, 9 hole-peg-test (9 HPT), 3'' paced auditory serial addition test (PASAT).
measure: MSFC
time frame: 24
description: Three part instrument composed of Timed-25-foot (7.62 m)-walk, 9 hole-peg-test (9 HPT), 3'' paced auditory serial addition test (PASAT).
measure: Change of EDSS score compared to change in the year prior to natalizumab treatment (month -24 to-12
time frame: 3 months
measure: Change of EDSS score compared to change in the year prior to natalizumab treatment (month -24 to-12
time frame: 6 months
measure: Change of EDSS score compared to change in the year prior to natalizumab treatment (month -24 to-12
time frame: 9 months
measure: Change of EDSS score compared to change in the year prior to natalizumab treatment (month -24 to-12
time frame: 12 months
measure: Change of MSFC score compared to change in the year prior to natalizumab treatment (month -24 to-12
time frame: 3 months
measure: Change of MSFC score compared to change in the year prior to natalizumab treatment (month -24 to-12
time frame: 6 months
measure: Change of MSFC score compared to change in the year prior to natalizumab treatment (month -24 to-12
time frame: 9 months
measure: Change of MSFC score compared to change in the year prior to natalizumab treatment (month -24 to-12
time frame: 12 months
measure: Number of new/enlarging T2-hyperintense lesions
time frame: 6 months
description: MRI
measure: Number of new/enlarging T2-hyperintense lesions
time frame: 12 months
description: MRI
measure: Number of new/enlarging T2-hyperintense lesions
time frame: 24 months
description: MRI
measure: Number of Gd-enhancing lesions
time frame: 6 months
description: MRI
measure: Number of Gd-enhancing lesions
time frame: 12 months
description: MRI
measure: Number of Gd-enhancing lesions
time frame: 24 months
description: MRI
measure: EQ-5D
time frame: 6 months
description: Quality of life questionnaire
measure: EQ-5D
time frame: 12 months
description: Quality of life questionnaire
measure: EQ-5D
time frame: 24 months
description: Quality of life questionnaire
measure: FAMS
time frame: 6 months
description: Quality of life questionnaire
measure: FAMS
time frame: 24 months
description: Quality of life questionnaire
measure: MSFC
time frame: 15 months
description: Three part instrument composed of Timed-25-foot (7.62 m)-walk, 9 hole-peg-test (9 HPT), 3'' paced auditory serial addition test (PASAT).
measure: EQ-5D
time frame: 18 months
description: Quality of life questionnaire
measure: FAMS
time frame: 12 months
description: Quality of life questionnaire
measure: FAMS
time frame: 18 months
description: Quality of life questionnaire
arm group label: Interferon beta-1b
arm group type: Experimental
description: Interferon beta-1b 250 mcg s.c. every other day
intervention type: Drug
intervention name: Interferon beta-1b
description: 250 mcg, s.c., each other day for 12 months
arm group label: Interferon beta-1b
other name: Betaferon®
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Claudio Gobbi, MD
role: Principal Investigator
affiliation: Ospedale Regionale di Lugano - Civico
facility: 
country: Switzerland
url: http://www.eoc.ch
description: home page of the main facility
url: http://www.multiplesklerose.ch/
description: home page of supporting society for MS patients in Switzerland
citation: Multiple Sclerosis Therapy Consensus Group (MSTCG); Wiendl H, Toyka KV, Rieckmann P, Gold R, Hartung HP, Hohlfeld R. Basic and escalating immunomodulatory treatments in multiple sclerosis: current therapeutic recommendations. J Neurol. 2008 Oct;255(10):1449-63. doi: 10.1007/s00415-008-0061-1. Epub 2008 Oct 29.
PMID: 19005625
citation: Kappos L, Bates D, Edan G, Eraksoy M, Garcia-Merino A, Grigoriadis N, Hartung HP, Havrdova E, Hillert J, Hohlfeld R, Kremenchutzky M, Lyon-Caen O, Miller A, Pozzilli C, Ravnborg M, Saida T, Sindic C, Vass K, Clifford DB, Hauser S, Major EO, O'Connor PW, Weiner HL, Clanet M, Gold R, Hirsch HH, Radu EW, Sorensen PS, King J. Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring. Lancet Neurol. 2011 Aug;10(8):745-58. doi: 10.1016/S1474-4422(11)70149-1.
PMID: 21777829
citation: Kappos L, Freedman MS, Polman CH, Edan G, Hartung HP, Miller DH, Montalban X, Barkhof F, Radu EW, Metzig C, Bauer L, Lanius V, Sandbrink R, Pohl C; BENEFIT Study Group. Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial. Lancet Neurol. 2009 Nov;8(11):987-97. doi: 10.1016/S1474-4422(09)70237-6. Epub 2009 Sep 10.
PMID: 19748319
citation: Putzki N, Yaldizli O, Buhler R, Schwegler G, Curtius D, Tettenborn B. Natalizumab reduces clinical and MRI activity in multiple sclerosis patients with high disease activity: results from a multicenter study in Switzerland. Eur Neurol. 2010;63(2):101-6. doi: 10.1159/000276400. Epub 2010 Jan 16.
PMID: 20090344
responsible party type: Sponsor-Investigator
investigator affiliation: Ospedale Civico, Lugano
investigator full name: Claudio Gobbi
investigator title: Dr. med.
mesh term: Multiple Sclerosis
mesh term: Multiple Sclerosis, Relapsing-Remitting
mesh term: Sclerosis
mesh term: Interferons
mesh term: Interferon-beta
mesh term: Interferon beta-1b