<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/NCT03002038</url>
  </required_header>
  <id_info>
    <org_study_id>395275</org_study_id>
    <nct_id>NCT03002038</nct_id>
  </id_info>
  <brief_title>Comparison of Clinical Effects of Azathioprine and Rituximab NMO-SD Patients</brief_title>
  <official_title>Comparison of Annual Relapse Rate, Expanded Disability Status Scale, and Side Effects Between Azathioprine and Rituximab in Patients With Neuromyelitis Optica Spectrum Disorders</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Isfahan University of Medical Sciences</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Isfahan University of Medical Sciences</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to compare annual relapse rate, expanded disability status&#xD;
      scale, and side effects of azathioprine and rituximab in patients with neuromyelitis optica&#xD;
      spectrum disorder during a one year follow up through a randomized clinical trial.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Neuromyelitis Optica Spectrum Disorder (NMO-SD) is a recurrent inflammatory demyelinating&#xD;
      disease affecting the central nervous system. The disease is clinically recognized by optic&#xD;
      neuritis and transverse myelitis and is associated with high risk of mortality. Each attack&#xD;
      worsens patients' disability. This means that after 5 years of the disease onset, half of&#xD;
      patients need to use wheelchair and approximately 50% of them become blind.&#xD;
&#xD;
      Considering that the disease can be disabling for patients, the maintenance treatment should&#xD;
      be applied in addition to treatment of acute attacks, in order to prevent future recurrences.&#xD;
      Acute attacks are usually treated with high doses of intravenous corticosteroids.&#xD;
      Plasmapheresis is also used when patients fail to response to corticosteroids. B lymphocyte&#xD;
      inhibitors are used as the maintenance therapy in these patients. First line therapeutic&#xD;
      medications include azathioprine and rituximab which are being recommended for long term&#xD;
      therapy and second line medications include methotrexate and mycophenolate mofetil.&#xD;
&#xD;
      Azathioprine is an immune-modulatory agent which is available in the oral form and don't&#xD;
      require hospitalization to be administered, however, because of side effects such as bone&#xD;
      marrow suppression and hepatotoxicity, periodic check of blood cells and liver enzymes are&#xD;
      needed. Rituximab is a cluster of differentiation antigen 20 inhibitor which leads to&#xD;
      decreased B lymphocytes and antibody in patients. This medication is only available in the&#xD;
      injectable form and needs hospitalization to be administered. Close monitory is needed during&#xD;
      the administration considering severe side effects such as allergic reactions and respiratory&#xD;
      distress. However, laboratory tests are not needed in patients taking rituximab although it&#xD;
      is more expensive than azathioprine. No clinical trial has been performed previously to&#xD;
      compare clinical efficacy of these two drugs in NMO-SD patients. Therefore, we aimed to&#xD;
      compare their efficacy through a randomized clinical trial.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>September 2015</start_date>
  <completion_date type="Actual">December 2016</completion_date>
  <primary_completion_date type="Actual">November 2016</primary_completion_date>
  <phase>Phase 2/Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Annual Relapse Rate</measure>
    <time_frame>one year</time_frame>
    <description>annual relapse rate will be measured in the baseline (according to patients' history in the last year) and after 12 months of intervention.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Expanded Disability Status Scale</measure>
    <time_frame>one year</time_frame>
    <description>expanded disability status scale will be measured in the baseline and after 12 months of intervention.&#xD;
Expanded disability status scale (EDSS) is a measure of disability for patients. The score ranges from 0-10, with 0 showing normal neurological exam and 10 showing death due to the disabling disease. Thus, higher scores represent more profound levels of disability.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Number of Participants With Adverse Drug Reactions</measure>
    <time_frame>one year</time_frame>
    <description>adverse drug reactions will be observed closely and reported during the intervention. We will compare the number of adverse drug reactions in two groups. Also, adverse drug reactions will be described by details in each group.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">86</enrollment>
  <condition>Neuromyelitis Optica Spectrum Disorder</condition>
  <arm_group>
    <arm_group_label>Azathioprine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients in this group will receive 50 mg of azathioprine, two times each day and gradually increased to maximum dose of 3 g daily with the aim of lymphocytes count less than 1500.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Rituximab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients in this group will receive 1g of Rituximab in 500 cc normal saline serum through intravenous infusion with two weeks intervals (as one course) and each course of treatment is repeated every 6 months.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Azathioprine</intervention_name>
    <description>Patients are started with Azathioprine 50 mg tablets, taken orally twice a day. The medication dose is increased gradually with the aim of lymphocytes count bellow 1500 and to the maximum dose of 3 g Azathioprine per day. Cell blood count is checked once a week in the first month of treatment, once every two weeks in the second month of treatment, and monthly in the third month of treatment to make decision about medication dose.</description>
    <arm_group_label>Azathioprine</arm_group_label>
    <other_name>Azathioprine Mehrdaru®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rituximab</intervention_name>
    <description>Patients will receive 1 g of Rituximab (two vials of RediTux 500 mg/50 ml) in 500 cc normal saline serum through intravenous infusion and this will be repeated two weeks later. This cycle will be repeated every 6 months.</description>
    <arm_group_label>Rituximab</arm_group_label>
    <other_name>RediTux®</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Diagnosis of neuromyelitis optica spectrum disorder based on the recent guidelines in&#xD;
             2015&#xD;
&#xD;
          -  Expanded disability status scale between 0 and 7&#xD;
&#xD;
          -  Age between 18 and 50 years old&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnancy or lactation during the study&#xD;
&#xD;
          -  Deciding to leave the study by patient&#xD;
&#xD;
          -  Lack of consent to enter the study&#xD;
&#xD;
          -  Lack of cooperation for follow up&#xD;
&#xD;
          -  Severe side effect of the medication&#xD;
&#xD;
          -  Treatment with other immunosuppressant medications (including but not limited to&#xD;
             cyclophosphamide, mycophenolate mofetil, methotrexate, others) within two months&#xD;
             before intervention&#xD;
&#xD;
          -  Taking any other immunosuppressant or other type of medication (including herbal&#xD;
             drugs) without permission of the physician during the study.&#xD;
&#xD;
          -  Presence of other autoimmune disease (including but not limited to Behcet disease,&#xD;
             systemic lupus erythematosus, rheumatoid arthritis, and others)&#xD;
&#xD;
          -  Presence of liver disorders&#xD;
&#xD;
          -  Presence of hematologic disorders&#xD;
&#xD;
          -  Presence of heart failure&#xD;
&#xD;
          -  Receipt of a live vaccine within 4 weeks prior to intervention&#xD;
&#xD;
          -  Previous treatment with Azathioporine or Rituximab&#xD;
&#xD;
          -  History of HIV, hepatitis B, or hepatitis C&#xD;
&#xD;
          -  Ongoing daily steroid use&#xD;
&#xD;
          -  History of severe allergic or anaphylactic reaction to monoclonal antibodies&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Vahid Shaygannejad, M.D.</last_name>
    <role>Study Chair</role>
    <affiliation>Department of Neurology, School of Medicine, Isfahan University of Medical Sciences</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Kashani Hospital</name>
      <address>
        <city>Isfahan</city>
        <zip>8174673461</zip>
        <country>Iran, Islamic Republic of</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Iran, Islamic Republic of</country>
  </location_countries>
  <reference>
    <citation>Sato DK, Lana-Peixoto MA, Fujihara K, de Seze J. Clinical spectrum and treatment of neuromyelitis optica spectrum disorders: evolution and current status. Brain Pathol. 2013 Nov;23(6):647-60. doi: 10.1111/bpa.12087.</citation>
    <PMID>24118482</PMID>
  </reference>
  <reference>
    <citation>Morrow MJ, Wingerchuk D. Neuromyelitis optica. J Neuroophthalmol. 2012 Jun;32(2):154-66. doi: 10.1097/WNO.0b013e31825662f1.</citation>
    <PMID>22617743</PMID>
  </reference>
  <reference>
    <citation>Costanzi C, Matiello M, Lucchinetti CF, Weinshenker BG, Pittock SJ, Mandrekar J, Thapa P, McKeon A. Azathioprine: tolerability, efficacy, and predictors of benefit in neuromyelitis optica. Neurology. 2011 Aug 16;77(7):659-66. doi: 10.1212/WNL.0b013e31822a2780. Epub 2011 Aug 3.</citation>
    <PMID>21813788</PMID>
  </reference>
  <reference>
    <citation>Trebst C, Jarius S, Berthele A, Paul F, Schippling S, Wildemann B, Borisow N, Kleiter I, Aktas O, Kumpfel T; Neuromyelitis Optica Study Group (NEMOS). Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS). J Neurol. 2014 Jan;261(1):1-16. doi: 10.1007/s00415-013-7169-7. Epub 2013 Nov 23.</citation>
    <PMID>24272588</PMID>
  </reference>
  <reference>
    <citation>Kim SH, Huh SY, Lee SJ, Joung A, Kim HJ. A 5-year follow-up of rituximab treatment in patients with neuromyelitis optica spectrum disorder. JAMA Neurol. 2013 Sep 1;70(9):1110-7. doi: 10.1001/jamaneurol.2013.3071.</citation>
    <PMID>23897062</PMID>
  </reference>
  <reference>
    <citation>Katz Sand I. Neuromyelitis Optica Spectrum Disorders. Continuum (Minneap Minn). 2016 Jun;22(3):864-96. doi: 10.1212/CON.0000000000000337.</citation>
    <PMID>27261687</PMID>
  </reference>
  <verification_date>September 2020</verification_date>
  <study_first_submitted>December 21, 2016</study_first_submitted>
  <study_first_submitted_qc>December 22, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 23, 2016</study_first_posted>
  <results_first_submitted>October 2, 2018</results_first_submitted>
  <results_first_submitted_qc>September 29, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">September 30, 2020</results_first_posted>
  <last_update_submitted>September 29, 2020</last_update_submitted>
  <last_update_submitted_qc>September 29, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">September 30, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Isfahan University of Medical Sciences</investigator_affiliation>
    <investigator_full_name>Vahid Shaygannejad</investigator_full_name>
    <investigator_title>Associate Professor of Neurology</investigator_title>
  </responsible_party>
  <keyword>neuromyelitis optica spectrum disorder</keyword>
  <keyword>azathioprine</keyword>
  <keyword>rituximab</keyword>
  <keyword>clinical trial</keyword>
  <keyword>annual relapse rate</keyword>
  <keyword>expanded disability status scale</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neuromyelitis Optica</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rituximab</mesh_term>
    <mesh_term>Azathioprine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>We may share the individual participant data (anonymously) on request of the journal publishing the study report.</ipd_description>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Azathioprine</title>
          <description>Patients in this group will receive 50 mg of azathioprine, two times each day and gradually increased to maximum dose of 3 g daily with the aim of lymphocytes count less than 1500.&#xD;
Azathioprine: Patients are started with Azathioprine 50 mg tablets, taken orally twice a day. The medication dose is increased gradually with the aim of lymphocytes count bellow 1500 and to the maximum dose of 3 g Azathioprine per day. Cell blood count is checked once a week in the first month of treatment, once every two weeks in the second month of treatment, and monthly in the third month of treatment to make decision about medication dose.</description>
        </group>
        <group group_id="P2">
          <title>Rituximab</title>
          <description>Patients in this group will receive 1g of Rituximab in 500 cc normal saline serum through intravenous infusion with two weeks intervals (as one course) and each course of treatment is repeated every 6 months.&#xD;
Rituximab: Patients will receive 1 g of Rituximab (two vials of RediTux 500 mg/50 ml) in 500 cc normal saline serum through intravenous infusion and this will be repeated two weeks later. This cycle will be repeated every 6 months.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="46"/>
                <participants group_id="P2" count="40"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="35"/>
                <participants group_id="P2" count="33"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="11"/>
                <participants group_id="P2" count="7"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Immigration to another region</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Intention to treat analysis</population>
      <group_list>
        <group group_id="B1">
          <title>Azathioprine</title>
          <description>Patients in this group will receive 50 mg of azathioprine, two times each day and gradually increased to maximum dose of 3 g daily with the aim of lymphocytes count less than 1500.&#xD;
Azathioprine: Patients are started with Azathioprine 50 mg tablets, taken orally twice a day. The medication dose is increased gradually with the aim of lymphocytes count bellow 1500 and to the maximum dose of 3 g Azathioprine per day. Cell blood count is checked once a week in the first month of treatment, once every two weeks in the second month of treatment, and monthly in the third month of treatment to make decision about medication dose.</description>
        </group>
        <group group_id="B2">
          <title>Rituximab</title>
          <description>Patients in this group will receive 1g of Rituximab in 500 cc normal saline serum through intravenous infusion with two weeks intervals (as one course) and each course of treatment is repeated every 6 months.&#xD;
Rituximab: Patients will receive 1 g of Rituximab (two vials of RediTux 500 mg/50 ml) in 500 cc normal saline serum through intravenous infusion and this will be repeated two weeks later. This cycle will be repeated every 6 months.</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="46"/>
            <count group_id="B2" value="40"/>
            <count group_id="B3" value="86"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="46"/>
                    <count group_id="B2" value="40"/>
                    <count group_id="B3" value="86"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="32.11" spread="9.36"/>
                    <measurement group_id="B2" value="34.33" spread="5.86"/>
                    <measurement group_id="B3" value="33.14" spread="7.32"/>
                  </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>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="46"/>
                    <count group_id="B2" value="40"/>
                    <count group_id="B3" value="86"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="38"/>
                    <measurement group_id="B2" value="34"/>
                    <measurement group_id="B3" value="72"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race and Ethnicity Not Collected</title>
          <population>Race and Ethnicity were not collected from any participant.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                    <count group_id="B2" value="0"/>
                    <count group_id="B3" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Iran</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="46"/>
                    <count group_id="B2" value="40"/>
                    <count group_id="B3" value="86"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="46"/>
                    <measurement group_id="B2" value="40"/>
                    <measurement group_id="B3" value="86"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Expanded disability status scale</title>
          <description>Expanded disability status scale (EDSS) is a measure of disability for patients. The score ranges from 0-10, with 0 showing normal neurological exam and 10 showing death due to the disabling disease. Thus, higher scores represent more profound levels of disability.</description>
          <population>Per reviewer's comment and to provide consistent results, we changed the baseline info for EDSS to per protocol analysis rather than intended to treat analysis. That's why the numbers decreased in each group.</population>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="35"/>
                    <count group_id="B2" value="33"/>
                    <count group_id="B3" value="68"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2.40" spread="1.24"/>
                    <measurement group_id="B2" value="3.55" spread="1.95"/>
                    <measurement group_id="B3" value="2.96" spread="1.52"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Annualized relapse rate</title>
          <units>numbers of relapses</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="46"/>
                    <count group_id="B2" value="40"/>
                    <count group_id="B3" value="86"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1.02" spread="0.39"/>
                    <measurement group_id="B2" value="1.30" spread="0.65"/>
                    <measurement group_id="B3" value="1.15" spread="0.51"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Positive AQP4-IgG</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="46"/>
                    <count group_id="B2" value="40"/>
                    <count group_id="B3" value="86"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="25"/>
                    <measurement group_id="B2" value="17"/>
                    <measurement group_id="B3" value="42"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Annual Relapse Rate</title>
        <description>annual relapse rate will be measured in the baseline (according to patients' history in the last year) and after 12 months of intervention.</description>
        <time_frame>one year</time_frame>
        <population>Per protocol analysis</population>
        <group_list>
          <group group_id="O1">
            <title>Azathioprine</title>
            <description>Patients in this group will receive 50 mg of azathioprine, two times each day and gradually increased to maximum dose of 3 g daily with the aim of lymphocytes count less than 1500.&#xD;
Azathioprine: Patients are started with Azathioprine 50 mg tablets, taken orally twice a day. The medication dose is increased gradually with the aim of lymphocytes count bellow 1500 and to the maximum dose of 3 g Azathioprine per day. Cell blood count is checked once a week in the first month of treatment, once every two weeks in the second month of treatment, and monthly in the third month of treatment to make decision about medication dose.</description>
          </group>
          <group group_id="O2">
            <title>Rituximab</title>
            <description>Patients in this group will receive 1g of Rituximab in 500 cc normal saline serum through intravenous infusion with two weeks intervals (as one course) and each course of treatment is repeated every 6 months.&#xD;
Rituximab: Patients will receive 1 g of Rituximab (two vials of RediTux 500 mg/50 ml) in 500 cc normal saline serum through intravenous infusion and this will be repeated two weeks later. This cycle will be repeated every 6 months.</description>
          </group>
        </group_list>
        <measure>
          <title>Annual Relapse Rate</title>
          <description>annual relapse rate will be measured in the baseline (according to patients' history in the last year) and after 12 months of intervention.</description>
          <population>Per protocol analysis</population>
          <units>Number of relapses</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="35"/>
                <count group_id="O2" value="33"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1" spread="0.38"/>
                    <measurement group_id="O2" value="1.30" spread="0.68"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Outcome</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.51" spread="0.55"/>
                    <measurement group_id="O2" value="0.21" spread="0.42"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Expanded Disability Status Scale</title>
        <description>expanded disability status scale will be measured in the baseline and after 12 months of intervention.&#xD;
Expanded disability status scale (EDSS) is a measure of disability for patients. The score ranges from 0-10, with 0 showing normal neurological exam and 10 showing death due to the disabling disease. Thus, higher scores represent more profound levels of disability.</description>
        <time_frame>one year</time_frame>
        <population>Per protocol analysis</population>
        <group_list>
          <group group_id="O1">
            <title>Azathioprine</title>
            <description>Patients in this group will receive 50 mg of azathioprine, two times each day and gradually increased to maximum dose of 3 g daily with the aim of lymphocytes count less than 1500.&#xD;
Azathioprine: Patients are started with Azathioprine 50 mg tablets, taken orally twice a day. The medication dose is increased gradually with the aim of lymphocytes count bellow 1500 and to the maximum dose of 3 g Azathioprine per day. Cell blood count is checked once a week in the first month of treatment, once every two weeks in the second month of treatment, and monthly in the third month of treatment to make decision about medication dose.</description>
          </group>
          <group group_id="O2">
            <title>Rituximab</title>
            <description>Patients in this group will receive 1g of Rituximab in 500 cc normal saline serum through intravenous infusion with two weeks intervals (as one course) and each course of treatment is repeated every 6 months.&#xD;
Rituximab: Patients will receive 1 g of Rituximab (two vials of RediTux 500 mg/50 ml) in 500 cc normal saline serum through intravenous infusion and this will be repeated two weeks later. This cycle will be repeated every 6 months.</description>
          </group>
        </group_list>
        <measure>
          <title>Expanded Disability Status Scale</title>
          <description>expanded disability status scale will be measured in the baseline and after 12 months of intervention.&#xD;
Expanded disability status scale (EDSS) is a measure of disability for patients. The score ranges from 0-10, with 0 showing normal neurological exam and 10 showing death due to the disabling disease. Thus, higher scores represent more profound levels of disability.</description>
          <population>Per protocol analysis</population>
          <units>score 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="35"/>
                <count group_id="O2" value="33"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.40" spread="1.24"/>
                    <measurement group_id="O2" value="3.55" spread="1.95"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Outcome</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.95" spread="1.13"/>
                    <measurement group_id="O2" value="2.56" spread="1.99"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Number of Participants With Adverse Drug Reactions</title>
        <description>adverse drug reactions will be observed closely and reported during the intervention. We will compare the number of adverse drug reactions in two groups. Also, adverse drug reactions will be described by details in each group.</description>
        <time_frame>one year</time_frame>
        <population>intention to treat analysis</population>
        <group_list>
          <group group_id="O1">
            <title>Azathioprine</title>
            <description>Patients in this group will receive 50 mg of azathioprine, two times each day and gradually increased to maximum dose of 3 g daily with the aim of lymphocytes count less than 1500.&#xD;
Azathioprine: Patients are started with Azathioprine 50 mg tablets, taken orally twice a day. The medication dose is increased gradually with the aim of lymphocytes count bellow 1500 and to the maximum dose of 3 g Azathioprine per day. Cell blood count is checked once a week in the first month of treatment, once every two weeks in the second month of treatment, and monthly in the third month of treatment to make decision about medication dose.</description>
          </group>
          <group group_id="O2">
            <title>Rituximab</title>
            <description>Patients in this group will receive 1g of Rituximab in 500 cc normal saline serum through intravenous infusion with two weeks intervals (as one course) and each course of treatment is repeated every 6 months.&#xD;
Rituximab: Patients will receive 1 g of Rituximab (two vials of RediTux 500 mg/50 ml) in 500 cc normal saline serum through intravenous infusion and this will be repeated two weeks later. This cycle will be repeated every 6 months.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Adverse Drug Reactions</title>
          <description>adverse drug reactions will be observed closely and reported during the intervention. We will compare the number of adverse drug reactions in two groups. Also, adverse drug reactions will be described by details in each group.</description>
          <population>intention to treat analysis</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="46"/>
                <count group_id="O2" value="40"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>1 year</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Azathioprine</title>
          <description>Patients in this group will receive 50 mg of azathioprine, two times each day and gradually increased to maximum dose of 3 g daily with the aim of lymphocytes count less than 1500.&#xD;
Azathioprine: Patients are started with Azathioprine 50 mg tablets, taken orally twice a day. The medication dose is increased gradually with the aim of lymphocytes count bellow 1500 and to the maximum dose of 3 g Azathioprine per day. Cell blood count is checked once a week in the first month of treatment, once every two weeks in the second month of treatment, and monthly in the third month of treatment to make decision about medication dose.</description>
        </group>
        <group group_id="E2">
          <title>Rituximab</title>
          <description>Patients in this group will receive 1g of Rituximab in 500 cc normal saline serum through intravenous infusion with two weeks intervals (as one course) and each course of treatment is repeated every 6 months.&#xD;
Rituximab: Patients will receive 1 g of Rituximab (two vials of RediTux 500 mg/50 ml) in 500 cc normal saline serum through intravenous infusion and this will be repeated two weeks later. This cycle will be repeated every 6 months.</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="46"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="46"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Impaired liver function test</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="46"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Severe allergic reaction</sub_title>
                <description>Allergic reaction to rituximab injection</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="46"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <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="2" subjects_at_risk="46"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Gastrointestinal intolerance</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="46"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Mild/moderate allergic reactions</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="46"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>lack of blinding, uneven assignment of patients to treatment groups, lack of compliance measures, and short follow-up duration</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Dr. Vahid Shaygannejad</name_or_title>
      <organization>Isfahan University of Medical Sciences</organization>
      <phone>+98 913 313 3550</phone>
      <email>shaygannejad@med.mui.ac.ir</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/NCT03002038
org study id: 395275
nct id: NCT03002038
lead sponsor: 
has dmc: No
The purpose of this study is to compare annual relapse rate, expanded disability status
      scale, and side effects of azathioprine and rituximab in patients with neuromyelitis optica
      spectrum disorder during a one year follow up through a randomized clinical trial.
Neuromyelitis Optica Spectrum Disorder (NMO-SD) is a recurrent inflammatory demyelinating
      disease affecting the central nervous system. The disease is clinically recognized by optic
      neuritis and transverse myelitis and is associated with high risk of mortality. Each attack
      worsens patients' disability. This means that after 5 years of the disease onset, half of
      patients need to use wheelchair and approximately 50% of them become blind.

      Considering that the disease can be disabling for patients, the maintenance treatment should
      be applied in addition to treatment of acute attacks, in order to prevent future recurrences.
      Acute attacks are usually treated with high doses of intravenous corticosteroids.
      Plasmapheresis is also used when patients fail to response to corticosteroids. B lymphocyte
      inhibitors are used as the maintenance therapy in these patients. First line therapeutic
      medications include azathioprine and rituximab which are being recommended for long term
      therapy and second line medications include methotrexate and mycophenolate mofetil.

      Azathioprine is an immune-modulatory agent which is available in the oral form and don't
      require hospitalization to be administered, however, because of side effects such as bone
      marrow suppression and hepatotoxicity, periodic check of blood cells and liver enzymes are
      needed. Rituximab is a cluster of differentiation antigen 20 inhibitor which leads to
      decreased B lymphocytes and antibody in patients. This medication is only available in the
      injectable form and needs hospitalization to be administered. Close monitory is needed during
      the administration considering severe side effects such as allergic reactions and respiratory
      distress. However, laboratory tests are not needed in patients taking rituximab although it
      is more expensive than azathioprine. No clinical trial has been performed previously to
      compare clinical efficacy of these two drugs in NMO-SD patients. Therefore, we aimed to
      compare their efficacy through a randomized clinical trial.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Annual Relapse Rate
time frame: one year
description: annual relapse rate will be measured in the baseline (according to patients' history in the last year) and after 12 months of intervention.
measure: Expanded Disability Status Scale
time frame: one year
description: expanded disability status scale will be measured in the baseline and after 12 months of intervention.
Expanded disability status scale (EDSS) is a measure of disability for patients. The score ranges from 0-10, with 0 showing normal neurological exam and 10 showing death due to the disabling disease. Thus, higher scores represent more profound levels of disability.
measure: Number of Participants With Adverse Drug Reactions
time frame: one year
description: adverse drug reactions will be observed closely and reported during the intervention. We will compare the number of adverse drug reactions in two groups. Also, adverse drug reactions will be described by details in each group.
arm group label: Azathioprine
arm group type: Experimental
description: Patients in this group will receive 50 mg of azathioprine, two times each day and gradually increased to maximum dose of 3 g daily with the aim of lymphocytes count less than 1500.
arm group label: Rituximab
arm group type: Experimental
description: Patients in this group will receive 1g of Rituximab in 500 cc normal saline serum through intravenous infusion with two weeks intervals (as one course) and each course of treatment is repeated every 6 months.
intervention type: Drug
intervention name: Azathioprine
description: Patients are started with Azathioprine 50 mg tablets, taken orally twice a day. The medication dose is increased gradually with the aim of lymphocytes count bellow 1500 and to the maximum dose of 3 g Azathioprine per day. Cell blood count is checked once a week in the first month of treatment, once every two weeks in the second month of treatment, and monthly in the third month of treatment to make decision about medication dose.
arm group label: Azathioprine
other name: Azathioprine Mehrdaru®
intervention type: Drug
intervention name: Rituximab
description: Patients will receive 1 g of Rituximab (two vials of RediTux 500 mg/50 ml) in 500 cc normal saline serum through intravenous infusion and this will be repeated two weeks later. This cycle will be repeated every 6 months.
arm group label: Rituximab
other name: RediTux®
criteria: 
gender: All
minimum age: 18 Years
maximum age: 50 Years
healthy volunteers: No
last name: Vahid Shaygannejad, M.D.
role: Study Chair
affiliation: Department of Neurology, School of Medicine, Isfahan University of Medical Sciences
facility: 
country: Iran, Islamic Republic of
citation: Sato DK, Lana-Peixoto MA, Fujihara K, de Seze J. Clinical spectrum and treatment of neuromyelitis optica spectrum disorders: evolution and current status. Brain Pathol. 2013 Nov;23(6):647-60. doi: 10.1111/bpa.12087.
PMID: 24118482
citation: Morrow MJ, Wingerchuk D. Neuromyelitis optica. J Neuroophthalmol. 2012 Jun;32(2):154-66. doi: 10.1097/WNO.0b013e31825662f1.
PMID: 22617743
citation: Costanzi C, Matiello M, Lucchinetti CF, Weinshenker BG, Pittock SJ, Mandrekar J, Thapa P, McKeon A. Azathioprine: tolerability, efficacy, and predictors of benefit in neuromyelitis optica. Neurology. 2011 Aug 16;77(7):659-66. doi: 10.1212/WNL.0b013e31822a2780. Epub 2011 Aug 3.
PMID: 21813788
citation: Trebst C, Jarius S, Berthele A, Paul F, Schippling S, Wildemann B, Borisow N, Kleiter I, Aktas O, Kumpfel T; Neuromyelitis Optica Study Group (NEMOS). Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS). J Neurol. 2014 Jan;261(1):1-16. doi: 10.1007/s00415-013-7169-7. Epub 2013 Nov 23.
PMID: 24272588
citation: Kim SH, Huh SY, Lee SJ, Joung A, Kim HJ. A 5-year follow-up of rituximab treatment in patients with neuromyelitis optica spectrum disorder. JAMA Neurol. 2013 Sep 1;70(9):1110-7. doi: 10.1001/jamaneurol.2013.3071.
PMID: 23897062
citation: Katz Sand I. Neuromyelitis Optica Spectrum Disorders. Continuum (Minneap Minn). 2016 Jun;22(3):864-96. doi: 10.1212/CON.0000000000000337.
PMID: 27261687
responsible party type: Principal Investigator
investigator affiliation: Isfahan University of Medical Sciences
investigator full name: Vahid Shaygannejad
investigator title: Associate Professor of Neurology
mesh term: Neuromyelitis Optica
mesh term: Rituximab
mesh term: Azathioprine
sharing ipd: Undecided
ipd description: We may share the individual participant data (anonymously) on request of the journal publishing the study report.
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: lack of blinding, uneven assignment of patients to treatment groups, lack of compliance measures, and short follow-up duration
point of contact: 