<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/NCT01697267</url>
  </required_header>
  <id_info>
    <org_study_id>RITAZAREM</org_study_id>
    <secondary_id>2012-001102-14</secondary_id>
    <nct_id>NCT01697267</nct_id>
  </id_info>
  <brief_title>Rituximab Vasculitis Maintenance Study</brief_title>
  <acronym>RITAZAREM</acronym>
  <official_title>An International, Open Label, Randomised Controlled Trial Comparing Rituximab With Azathioprine as Maintenance Therapy in Relapsing ANCA-associated Vasculitis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Cambridge University Hospitals NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Arthritis Research UK</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Roche Pharma AG</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Genentech, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Pennsylvania</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Cambridge University Hospitals NHS Foundation Trust</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Rituximab is now established as an effective drug for anti-neutrophil cytoplasmic antibody&#xD;
      (ANCA) vasculitis following major European and US trials reported in 2010. After a time, its&#xD;
      effect wears off and the disease can return. This occurs in at least half of patients within&#xD;
      2 years of receiving Rituximab. A preliminary study in Cambridge has suggested that repeating&#xD;
      rituximab every six months stops the disease returning and is safe.&#xD;
&#xD;
      The RITAZAREM trial will find out whether repeating rituximab stops vasculitis returning and&#xD;
      whether it works better than the older treatments, azathioprine or methotrexate. It will also&#xD;
      tell us how long patients remain well after the repeated rituximab treatments are stopped,&#xD;
      and if repeated rituximab is safe. We should also learn useful information about the effects&#xD;
      of rituximab on quality of life and economic measures. The trial results will help decide the&#xD;
      best treatment for future patients who have their vasculitis initially treated with&#xD;
      rituximab.&#xD;
&#xD;
      RITAZAREM aims to recruit patients with established ANCA vasculitis whose disease has come&#xD;
      back 'relapsing vasculitis'. All patients will be treated with rituximab and steroids and we&#xD;
      anticipate that most will respond well. If their disease is under reasonable control after&#xD;
      four months, further treatment with either rituximab (a single dose ever four months for two&#xD;
      years) or azathioprine tablets will be chosen randomly. The patients in the rituximab and&#xD;
      azathioprine groups will then be compared. Patients will be in the trial for four years.&#xD;
&#xD;
      The study has been designed by members of the European Vasculitis Study group (EUVAS) and the&#xD;
      Vasculitis Clinical Research Consortium (VCRC). It will include 190 participants from 30&#xD;
      hospitals in Europe, the USA, Australia and Mexico.&#xD;
&#xD;
      RITAZAREM is being funded by Arthritis Research UK, the U.S. National Institutes of Health&#xD;
      and by Roche/Genentech.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patients will be recruited at the time of relapse. All will receive rituximab 375 mg/m2/week&#xD;
      x 4 and glucocorticoids.&#xD;
&#xD;
      Those patients that achieve disease control (BVAS/WG ≤ 1 and daily prednisone dose ≤ 10 mg)&#xD;
      by month 4 will be randomised to the rituximab or control remission maintenance groups.&#xD;
&#xD;
      Treatment is protocolised for the entire duration of the study, until the common close date,&#xD;
      when the final patient recruited has completed 36 months within the study or until the&#xD;
      patient has completed 48 months on study whichever the sooner. Patients in the rituximab arm&#xD;
      will receive treatment until month 20, and those in the azathioprine arm until month 27.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 2013</start_date>
  <completion_date type="Actual">November 21, 2019</completion_date>
  <primary_completion_date type="Actual">November 22, 2018</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Relapse-free Survival</measure>
    <time_frame>Any patients who have not relapsed at up to a maximum of 4 years will be censored.</time_frame>
    <description>The primary efficacy outcome measure of the trial is relapse-free survival, where a relapse is either major or minor. The primary analysis will be a Cox regression model adjusted for the stratification factors (ANCA type, relapse severity and prednisone induction regimen) for the difference in the distribution of relapse-free survival between the rituximab arm and the azathioprine (control) arm (two-sided at α-level of 5%).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Participants in Remission at 24 and 48 Months</measure>
    <time_frame>24 and 48 months</time_frame>
    <description>Proportion of patients who maintain remission at 24 and 48 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Combined Damage Assessment Score (Disease Related Damage Assessment)</measure>
    <time_frame>data in Rows represent the change from randomization (month 4) to months 12, 24, 36, and 48.</time_frame>
    <description>Cumulative accrual of damage as measured by the combined damage assessment score (CDA). Each persistent or new occurrence of damage is given a score of 1. The cumulative accrual of damage is obtained by summing across the different types of damage to get an overall score (max score = 64).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative GC Exposure</measure>
    <time_frame>Up to 48 months</time_frame>
    <description>Cumulative glucocorticoid (GC) exposure during the trial. The trial had a common close out date when the final patient reached month 36 in the trial. Patients were followed until month 48 or the common close out date, whichever happened sooner. Therefore, follow up varied between 36 and 48 months. Cumulative glucocorticoid exposure is presented as a dose in mg for during the treatment period (up to month 24) and across the whole trial (until month 48 or common close out when the final patient reached month 36).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Severe Adverse Event Rate</measure>
    <time_frame>Up to 48 months</time_frame>
    <description>Severe adverse event (SAE) rate</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Infection Rates</measure>
    <time_frame>Up to 4 years</time_frame>
    <description>Infection (treated with intravenous or oral antibiotics) rates</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health-related Quality of Life Using the SF-36 Physical Composite</measure>
    <time_frame>4 months</time_frame>
    <description>The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health-related Quality of Life Using the SF-36 Mental Composite</measure>
    <time_frame>4 months</time_frame>
    <description>The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health-related Quality of Life Using the SF-36 Physical Composite</measure>
    <time_frame>12 months</time_frame>
    <description>The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health-related Quality of Life Using the SF-36 Mental Composite</measure>
    <time_frame>12 months</time_frame>
    <description>The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health-related Quality of Life Using the SF-36 Physical Composite</measure>
    <time_frame>24 months</time_frame>
    <description>The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health-related Quality of Life Using the SF-36 Mental Composite</measure>
    <time_frame>24 months</time_frame>
    <description>The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health-related Quality of Life Using the SF-36 Physical Composite</measure>
    <time_frame>36 months</time_frame>
    <description>The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health-related Quality of Life Using the SF-36 Mental Composite</measure>
    <time_frame>36 months</time_frame>
    <description>The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health-related Quality of Life Using the SF-36 Physical Composite</measure>
    <time_frame>48 months</time_frame>
    <description>The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health-related Quality of Life Using the SF-36 Mental Composite</measure>
    <time_frame>48 months</time_frame>
    <description>The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">188</enrollment>
  <condition>Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis</condition>
  <condition>Microscopic Polyangiitis</condition>
  <condition>Wegener Granulomatosis</condition>
  <arm_group>
    <arm_group_label>Rituximab Maintenance</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Rituximab maintenance: 1g at 4, 8, 12, 16 &amp; 20 months with standardised steroid taper</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Azathioprine Maintenance</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Azathioprine Maintenance: 2mg/kg/day with standardised steroid taper, from month 4 (randomisation) (200 mg maximum daily dose). Azathioprine withdrawn at month 27.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Rituximab</intervention_name>
    <description>Rituximab IV infusion 1000 mg x 1 dose at months 4, 8, 12, 16 and 20 and glucocorticoids. Four - six hour infusion. Treatment with rituximab will cease at month 20.</description>
    <arm_group_label>Rituximab Maintenance</arm_group_label>
    <other_name>Rituxan</other_name>
    <other_name>MabThera</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Azathioprine</intervention_name>
    <description>Oral dosage form. Target dose is 2mg/kg; maximum daily dose is 200mg. This should be continued until month 24. The dose should then by reduced by 50% and azathioprine completely withdrawn at month 27.&#xD;
The dose should be rounded down to the nearest 25mg. The dose may vary on alternate days e.g. 100mg one day, 150mg the next for patients on an overall dose of 125mg daily.&#xD;
If patients are aged over 60 years, reduce the dose by 25%. If patients are aged over 75 years, reduce the dose by 50%.</description>
    <arm_group_label>Azathioprine Maintenance</arm_group_label>
    <other_name>Imuran</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. A diagnosis of AAV [granulomatosis with polyangiitis or microscopic polyangiitis],&#xD;
             according to the definitions of the Chapel Hill Consensus Conference&#xD;
&#xD;
          2. Current or historical PR3/MPO ANCA positivity by ELISA&#xD;
&#xD;
          3. Disease relapse defined by one major or three minor disease activity items on the&#xD;
             Birmingham Vasculitis Activity Score for Wegeners (BVAS/WG), in patients that have&#xD;
             previously achieved remission following at least 3 months of induction therapy, with a&#xD;
             combination of glucocorticoids and an immunosuppressive agent (cyclophosphamide or&#xD;
             methotrexate or rituximab or mycophenolate mofetil)&#xD;
&#xD;
          4. Written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Age &lt; 15 years (age &lt; 18 years at centres that do not treat paediatric patients)&#xD;
&#xD;
          2. Exclusions related to medication:&#xD;
&#xD;
             Previous therapy with:&#xD;
&#xD;
               1. Any biological B cell depleting agent (such as rituximab or belimumab) within the&#xD;
                  past 6 months&#xD;
&#xD;
               2. Alemtuzumab or anti-thymocyte globulin (ATG) within the last 12 months&#xD;
&#xD;
               3. IVIg, infliximab, etanercept, adalimumab, abatacept or plasma exchange in past 3&#xD;
                  months&#xD;
&#xD;
               4. Any investigational agent within 28 days of screening, or 5 half lives of the&#xD;
                  investigational drug (whichever is longer)&#xD;
&#xD;
          3. Exclusions related to general health:&#xD;
&#xD;
               1. Significant or uncontrolled medical disease not related to AAV, which in the&#xD;
                  investigators opinion would preclude patient participation&#xD;
&#xD;
               2. Presence of another multisystem autoimmune disease, including Churg Strauss&#xD;
                  syndrome, systemic lupus erythematosus, anti-GBM disease, or cryoglobulinaemic&#xD;
                  vasculitis,&#xD;
&#xD;
               3. Any concomitant condition anticipated to likely require greater than 4 weeks per&#xD;
                  year of oral or systemic glucocorticoid use and which would preclude compliance&#xD;
                  with the glucocorticoid protocol (e.g. poorly-controlled asthma, COPD, psoriasis,&#xD;
                  or inflammatory bowel disease).&#xD;
&#xD;
               4. History of severe allergic or anaphylactic reactions to humanised or murine&#xD;
                  chimeric monoclonal antibodies&#xD;
&#xD;
               5. Known infection with HIV (HIV testing will not be a requirement for trial entry);&#xD;
                  a past or current history of hepatitis B virus or hepatitis C virus infection.&#xD;
&#xD;
               6. Ongoing or recent (last 12 months) evidence of active tuberculosis or known&#xD;
                  active infection (screening for tuberculosis is part of &quot;standard of care&quot; in&#xD;
                  patients with established AAV) or evidence of untreated latent tuberculosis.&#xD;
                  Screening for tuberculosis is as per local practice.&#xD;
&#xD;
               7. History of malignancy within the past five years or any evidence of persistent&#xD;
                  malignancy, except fully excised basal cell or squamous cell carcinomas of the&#xD;
                  skin, or cervical carcinoma in situ which has been treated or excised in a&#xD;
                  curative procedure.&#xD;
&#xD;
               8. Pregnancy or inadequate contraception in pre-menopausal women&#xD;
&#xD;
               9. Breast feeding or lactating&#xD;
&#xD;
          4. Exclusion criteria related to laboratory parameters:&#xD;
&#xD;
               1. Bone marrow suppression as evidenced by a total white count &lt; 4 x109/l,&#xD;
                  haemoglobin &lt; 7 gm/dl or platelet count &lt; 100,000/μl&#xD;
&#xD;
               2. Aspartate aminotransferase or alanine aminotransferase or amylase &gt; 2.5 times the&#xD;
                  upper limit of normal, unless attributed to vasculitis&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>15 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>David Jayne</last_name>
    <role>Study Chair</role>
    <affiliation>Cambridge University Hospitals NHS Foundation Trust</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Peter Merkel</last_name>
    <role>Study Chair</role>
    <affiliation>University of Pennsylvania</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cedars-Sinai Medical Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90048</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Michigan</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital for Special Surgery</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10021</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of North Carolina</name>
      <address>
        <city>Chapel Hill</city>
        <state>North Carolina</state>
        <zip>27599</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cleveland Clinic</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44195</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Pennsylvania</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Pittsburgh</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15260</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Utah</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84112</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Canberra Hospital</name>
      <address>
        <city>Garran</city>
        <state>Australian Capital Territory</state>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Brisbane &amp; Women's Hospital</name>
      <address>
        <city>Herston</city>
        <state>Queensland</state>
        <zip>4029</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Adelaide Hospital</name>
      <address>
        <city>Adelaide</city>
        <state>South Australia</state>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Joseph's Healthcare</name>
      <address>
        <city>Hamilton</city>
        <state>Ontario</state>
        <zip>L8N 4A6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mount Sinai Hospital</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5T 3L9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>General Faculty Hospital</name>
      <address>
        <city>Prague</city>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cork University Hospital</name>
      <address>
        <city>Cork</city>
        <country>Ireland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital of Parma</name>
      <address>
        <city>Parma</city>
        <zip>43100</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Okayama University</name>
      <address>
        <city>Kita-ku</city>
        <state>Okayama</state>
        <zip>700-0082</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chiba University</name>
      <address>
        <city>Chiba-shi</city>
        <zip>263-8522</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kitano Hospital</name>
      <address>
        <city>Kyoto</city>
        <zip>606-8501</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Miyazaki</name>
      <address>
        <city>Miyazaki</city>
        <zip>889-2192</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Teikyo University</name>
      <address>
        <city>Tokyo</city>
        <zip>173-0003</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Tokyo Metropolitan Geriatric</name>
      <address>
        <city>Tokyo</city>
        <zip>173-0015</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kyorin University school of medicine</name>
      <address>
        <city>Tokyo</city>
        <zip>192-0005</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Auckland City Hospital</name>
      <address>
        <city>Grafton</city>
        <state>Auckland</state>
        <zip>1023</zip>
        <country>New Zealand</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>North Shore Hospital</name>
      <address>
        <city>Westlake</city>
        <state>Auckland</state>
        <country>New Zealand</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Karolinska University Hospital</name>
      <address>
        <city>Stockholm</city>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Leicester General Hospital</name>
      <address>
        <city>Leicester</city>
        <state>Leicestershire</state>
        <zip>LE5 4PW</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Queen Elizabeth Hospital</name>
      <address>
        <city>Birmingham</city>
        <zip>B15 2WB</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Brighton and Sussex University Hospitals</name>
      <address>
        <city>Brighton</city>
        <zip>BN2 5BE</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Addenbrooke's Hospital</name>
      <address>
        <city>Cambridge</city>
        <zip>CB2 0QQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Russells Hall Hospital</name>
      <address>
        <city>Dudley</city>
        <zip>DY1 2HQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ipswich Hospital</name>
      <address>
        <city>Ipswich</city>
        <zip>IP4 5PD</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chapel Allerton Hospital</name>
      <address>
        <city>Leeds</city>
        <zip>LS7 4SA</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Imperial College</name>
      <address>
        <city>London</city>
        <zip>W12 0NN</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>James Cook University Hospital</name>
      <address>
        <city>Middlesbrough</city>
        <zip>TS4 3BW</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Queen's Medical Centre Campus, Nottingham University Hosp</name>
      <address>
        <city>Nottingham</city>
        <zip>NG7 2UH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Oxford</name>
      <address>
        <city>Oxford</city>
        <zip>OX1 2JD</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
    <country>Canada</country>
    <country>Czechia</country>
    <country>Ireland</country>
    <country>Italy</country>
    <country>Japan</country>
    <country>New Zealand</country>
    <country>Sweden</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>Czech Republic</country>
  </removed_countries>
  <reference>
    <citation>Watts RA, Suppiah R, Merkel PA, Luqmani R. Systemic vasculitis--is it time to reclassify? Rheumatology (Oxford). 2011 Apr;50(4):643-5. doi: 10.1093/rheumatology/keq229. Epub 2010 Jul 20. No abstract available.</citation>
    <PMID>20647295</PMID>
  </reference>
  <reference>
    <citation>Falk RJ, Jennette JC. ANCA disease: where is this field heading? J Am Soc Nephrol. 2010 May;21(5):745-52. doi: 10.1681/ASN.2009121238. Epub 2010 Apr 15.</citation>
    <PMID>20395376</PMID>
  </reference>
  <reference>
    <citation>Watts RA, Scott DG. Epidemiology of the vasculitides. Curr Opin Rheumatol. 2003 Jan;15(1):11-6. doi: 10.1097/00002281-200301000-00003.</citation>
    <PMID>12496504</PMID>
  </reference>
  <reference>
    <citation>Booth AD, Almond MK, Burns A, Ellis P, Gaskin G, Neild GH, Plaisance M, Pusey CD, Jayne DR; Pan-Thames Renal Research Group. Outcome of ANCA-associated renal vasculitis: a 5-year retrospective study. Am J Kidney Dis. 2003 Apr;41(4):776-84. doi: 10.1016/s0272-6386(03)00025-8.</citation>
    <PMID>12666064</PMID>
  </reference>
  <reference>
    <citation>Jayne D, Rasmussen N, Andrassy K, Bacon P, Tervaert JW, Dadoniene J, Ekstrand A, Gaskin G, Gregorini G, de Groot K, Gross W, Hagen EC, Mirapeix E, Pettersson E, Siegert C, Sinico A, Tesar V, Westman K, Pusey C; European Vasculitis Study Group. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003 Jul 3;349(1):36-44. doi: 10.1056/NEJMoa020286.</citation>
    <PMID>12840090</PMID>
  </reference>
  <reference>
    <citation>de Groot K, Harper L, Jayne DR, Flores Suarez LF, Gregorini G, Gross WL, Luqmani R, Pusey CD, Rasmussen N, Sinico RA, Tesar V, Vanhille P, Westman K, Savage CO; EUVAS (European Vasculitis Study Group). Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med. 2009 May 19;150(10):670-80. doi: 10.7326/0003-4819-150-10-200905190-00004.</citation>
    <PMID>19451574</PMID>
  </reference>
  <reference>
    <citation>De Groot K, Rasmussen N, Bacon PA, Tervaert JW, Feighery C, Gregorini G, Gross WL, Luqmani R, Jayne DR. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2005 Aug;52(8):2461-9. doi: 10.1002/art.21142.</citation>
    <PMID>16052573</PMID>
  </reference>
  <reference>
    <citation>Wegener's Granulomatosis Etanercept Trial (WGET) Research Group. Etanercept plus standard therapy for Wegener's granulomatosis. N Engl J Med. 2005 Jan 27;352(4):351-61. doi: 10.1056/NEJMoa041884.</citation>
    <PMID>15673801</PMID>
  </reference>
  <reference>
    <citation>Seo P, Min YI, Holbrook JT, Hoffman GS, Merkel PA, Spiera R, Davis JC, Ytterberg SR, St Clair EW, McCune WJ, Specks U, Allen NB, Luqmani RA, Stone JH; WGET Research Group. Damage caused by Wegener's granulomatosis and its treatment: prospective data from the Wegener's Granulomatosis Etanercept Trial (WGET). Arthritis Rheum. 2005 Jul;52(7):2168-78. doi: 10.1002/art.21117.</citation>
    <PMID>15986348</PMID>
  </reference>
  <reference>
    <citation>Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R, Newman RA, Hanna N, Anderson DR. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood. 1994 Jan 15;83(2):435-45.</citation>
    <PMID>7506951</PMID>
  </reference>
  <reference>
    <citation>Jones RB, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA, Savage CO, Segelmark M, Tesar V, van Paassen P, Walsh D, Walsh M, Westman K, Jayne DR; European Vasculitis Study Group. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med. 2010 Jul 15;363(3):211-20. doi: 10.1056/NEJMoa0909169.</citation>
    <PMID>20647198</PMID>
  </reference>
  <reference>
    <citation>Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, Kallenberg CG, St Clair EW, Turkiewicz A, Tchao NK, Webber L, Ding L, Sejismundo LP, Mieras K, Weitzenkamp D, Ikle D, Seyfert-Margolis V, Mueller M, Brunetta P, Allen NB, Fervenza FC, Geetha D, Keogh KA, Kissin EY, Monach PA, Peikert T, Stegeman C, Ytterberg SR, Specks U; RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010 Jul 15;363(3):221-32. doi: 10.1056/NEJMoa0909905.</citation>
    <PMID>20647199</PMID>
  </reference>
  <reference>
    <citation>Jones RB, Ferraro AJ, Chaudhry AN, Brogan P, Salama AD, Smith KG, Savage CO, Jayne DR. A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2009 Jul;60(7):2156-68. doi: 10.1002/art.24637.</citation>
    <PMID>19565480</PMID>
  </reference>
  <verification_date>February 2022</verification_date>
  <study_first_submitted>August 31, 2012</study_first_submitted>
  <study_first_submitted_qc>October 1, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 2, 2012</study_first_posted>
  <results_first_submitted>March 17, 2021</results_first_submitted>
  <results_first_submitted_qc>February 18, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">March 18, 2022</results_first_posted>
  <last_update_submitted>February 18, 2022</last_update_submitted>
  <last_update_submitted_qc>February 18, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">March 18, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Cambridge University Hospitals NHS Foundation Trust</investigator_affiliation>
    <investigator_full_name>David Jayne</investigator_full_name>
    <investigator_title>Director, Vasculitis and Lupus Clinic</investigator_title>
  </responsible_party>
  <keyword>vasculitis</keyword>
  <keyword>ANCA vasculitis</keyword>
  <keyword>microscopic polyangiitis</keyword>
  <keyword>granulomatosis</keyword>
  <keyword>Wegener's</keyword>
  <keyword>AAV</keyword>
  <keyword>vasculitides</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Granulomatosis with Polyangiitis</mesh_term>
    <mesh_term>Microscopic Polyangiitis</mesh_term>
    <mesh_term>Vasculitis</mesh_term>
    <mesh_term>Systemic Vasculitis</mesh_term>
    <mesh_term>Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis</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>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>July 12, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/67/NCT01697267/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>January 25, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/67/NCT01697267/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>Of 188 enrolled participants, 170 met the criteria for randomisation and were randomised for treatment.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Rituximab Maintenance</title>
          <description>Rituximab maintenance: 1g at 4, 8, 12, 16 &amp; 20 months with standardised steroid taper&#xD;
Rituximab: Rituximab IV infusion 1000 mg x 1 dose at months 4, 8, 12, 16 and 20 and glucocorticoids. Four - six hour infusion. Treatment with rituximab will cease at month 20.</description>
        </group>
        <group group_id="P2">
          <title>Azathioprine Maintenance</title>
          <description>Azathioprine Maintenance: 2mg/kg/day with standardised steroid taper, from month 4 (randomisation) (200 mg maximum daily dose). Azathioprine withdrawn at month 27.&#xD;
Azathioprine: Oral dosage form. Target dose is 2mg/kg; maximum daily dose is 200mg. This should be continued until month 24. The dose should then by reduced by 50% and azathioprine completely withdrawn at month 27.&#xD;
The dose should be rounded down to the nearest 25mg. The dose may vary on alternate days e.g. 100mg one day, 150mg the next for patients on an overall dose of 125mg daily.&#xD;
If patients are aged over 60 years, reduce the dose by 25%. If patients are aged over 75 years, reduce the dose by 50%.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="85"/>
                <participants group_id="P2" count="85"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Month 24</title>
              <participants_list>
                <participants group_id="P1" count="78"/>
                <participants group_id="P2" count="78"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="71"/>
                <participants group_id="P2" count="70"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="14"/>
                <participants group_id="P2" count="15"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Death</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="5"/>
                <participants group_id="P2" count="5"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Rituximab Maintenance</title>
          <description>Rituximab maintenance: 1g at 4, 8, 12, 16 &amp; 20 months with standardised steroid taper&#xD;
Rituximab: Rituximab IV infusion 1000 mg x 1 dose at months 4, 8, 12, 16 and 20 and glucocorticoids. Four - six hour infusion. Treatment with rituximab will cease at month 20.</description>
        </group>
        <group group_id="B2">
          <title>Azathioprine Maintenance</title>
          <description>Azathioprine Maintenance: 2mg/kg/day with standardised steroid taper, from month 4 (randomisation) (200 mg maximum daily dose). Azathioprine withdrawn at month 27.&#xD;
Azathioprine: Oral dosage form. Target dose is 2mg/kg; maximum daily dose is 200mg. This should be continued until month 24. The dose should then by reduced by 50% and azathioprine completely withdrawn at month 27.&#xD;
The dose should be rounded down to the nearest 25mg. The dose may vary on alternate days e.g. 100mg one day, 150mg the next for patients on an overall dose of 125mg daily.&#xD;
If patients are aged over 60 years, reduce the dose by 25%. If patients are aged over 75 years, reduce the dose by 50%.</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="85"/>
            <count group_id="B2" value="85"/>
            <count group_id="B3" value="170"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="54"/>
                    <measurement group_id="B2" value="51"/>
                    <measurement group_id="B3" value="105"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="31"/>
                    <measurement group_id="B2" value="34"/>
                    <measurement group_id="B3" value="65"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="57.1" spread="15.1"/>
                    <measurement group_id="B2" value="58.6" spread="13.9"/>
                    <measurement group_id="B3" value="57.8" spread="14.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="42"/>
                    <measurement group_id="B2" value="44"/>
                    <measurement group_id="B3" value="86"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="43"/>
                    <measurement group_id="B2" value="41"/>
                    <measurement group_id="B3" value="84"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>White</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="78"/>
                    <measurement group_id="B2" value="77"/>
                    <measurement group_id="B3" value="155"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Black</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Asian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hispanic</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Other</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Canada</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Sweden</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="26"/>
                    <measurement group_id="B2" value="22"/>
                    <measurement group_id="B3" value="48"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Czechia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Japan</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>United Kingdom</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="36"/>
                    <measurement group_id="B2" value="42"/>
                    <measurement group_id="B3" value="78"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Australia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>ANCA type</title>
          <description>Anti-neutrophil cytoplasm antibodies (ANCA) are autoantibodies that target a type of human white blood cell called neutrophils, which are important in health for fighting infection partly through the release of toxic substances that destroy bacteria. In ANCA-associated vasculitis, ANCA specifically bind to two proteins that are normally found in the fluid within the neutrophil (cytoplasm). The two proteins are called proteinase 3 (PR3) and myeloperoxidase (MPO) which can be measured by ELISA (Enzyme-Linked Immunosorbant Assay).</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>anti-PR3</title>
                  <measurement_list>
                    <measurement group_id="B1" value="61"/>
                    <measurement group_id="B2" value="62"/>
                    <measurement group_id="B3" value="123"/>
                  </measurement_list>
                </category>
                <category>
                  <title>anti-MPO</title>
                  <measurement_list>
                    <measurement group_id="B1" value="24"/>
                    <measurement group_id="B2" value="23"/>
                    <measurement group_id="B3" value="47"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Prednisone Induction Regimen</title>
          <description>Patients will be stratified at the time of randomisation according to selected prednisone induction regimen: 1A higher dose induction regimen or&#xD;
1B lower dose induction regimen to take into consideration variability in disease severity and local GC prescribing.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>1A (starting dose 1mg/kg/day)</title>
                  <measurement_list>
                    <measurement group_id="B1" value="24"/>
                    <measurement group_id="B2" value="24"/>
                    <measurement group_id="B3" value="48"/>
                  </measurement_list>
                </category>
                <category>
                  <title>1B (starting dose 0.5mg/kg/day)</title>
                  <measurement_list>
                    <measurement group_id="B1" value="61"/>
                    <measurement group_id="B2" value="61"/>
                    <measurement group_id="B3" value="122"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Relapse type</title>
          <description>Major relapse (severe): The development of a new or recurrent major disease activity item using the BVAS/WG assessment tool Minor relapse (non-severe): Any increase in disease activity that does not meet the definition of Major Relapse</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Severe</title>
                  <measurement_list>
                    <measurement group_id="B1" value="52"/>
                    <measurement group_id="B2" value="54"/>
                    <measurement group_id="B3" value="106"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Non-severe</title>
                  <measurement_list>
                    <measurement group_id="B1" value="33"/>
                    <measurement group_id="B2" value="31"/>
                    <measurement group_id="B3" value="64"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Relapse-free Survival</title>
        <description>The primary efficacy outcome measure of the trial is relapse-free survival, where a relapse is either major or minor. The primary analysis will be a Cox regression model adjusted for the stratification factors (ANCA type, relapse severity and prednisone induction regimen) for the difference in the distribution of relapse-free survival between the rituximab arm and the azathioprine (control) arm (two-sided at α-level of 5%).</description>
        <time_frame>Any patients who have not relapsed at up to a maximum of 4 years will be censored.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Rituximab Maintenance</title>
            <description>Rituximab maintenance: 1g at 4, 8, 12, 16 &amp; 20 months with standardised steroid taper&#xD;
Rituximab: Rituximab IV infusion 1000 mg x 1 dose at months 4, 8, 12, 16 and 20 and glucocorticoids. Four - six hour infusion. Treatment with rituximab will cease at month 20.</description>
          </group>
          <group group_id="O2">
            <title>Azathioprine Maintenance</title>
            <description>Azathioprine Maintenance: 2mg/kg/day with standardised steroid taper, from month 4 (randomisation) (200 mg maximum daily dose). Azathioprine withdrawn at month 27.&#xD;
Azathioprine: Oral dosage form. Target dose is 2mg/kg; maximum daily dose is 200mg. This should be continued until month 24. The dose should then by reduced by 50% and azathioprine completely withdrawn at month 27.&#xD;
The dose should be rounded down to the nearest 25mg. The dose may vary on alternate days e.g. 100mg one day, 150mg the next for patients on an overall dose of 125mg daily.&#xD;
If patients are aged over 60 years, reduce the dose by 25%. If patients are aged over 75 years, reduce the dose by 50%.</description>
          </group>
        </group_list>
        <measure>
          <title>Relapse-free Survival</title>
          <description>The primary efficacy outcome measure of the trial is relapse-free survival, where a relapse is either major or minor. The primary analysis will be a Cox regression model adjusted for the stratification factors (ANCA type, relapse severity and prednisone induction regimen) for the difference in the distribution of relapse-free survival between the rituximab arm and the azathioprine (control) arm (two-sided at α-level of 5%).</description>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="85"/>
                <count group_id="O2" value="85"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Total number of patients with a relapse</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="38"/>
                    <measurement group_id="O2" value="60"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Total number of patients with a relapse during treatment</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13"/>
                    <measurement group_id="O2" value="32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Total number of patients with a relapse post treatment</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="25"/>
                    <measurement group_id="O2" value="28"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants in Remission at 24 and 48 Months</title>
        <description>Proportion of patients who maintain remission at 24 and 48 months</description>
        <time_frame>24 and 48 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Rituximab Maintenance</title>
            <description>Rituximab maintenance: 1g at 4, 8, 12, 16 &amp; 20 months with standardised steroid taper&#xD;
Rituximab: Rituximab IV infusion 1000 mg x 1 dose at months 4, 8, 12, 16 and 20 and glucocorticoids. Four - six hour infusion. Treatment with rituximab will cease at month 20.</description>
          </group>
          <group group_id="O2">
            <title>Azathioprine Maintenance</title>
            <description>Azathioprine Maintenance: 2mg/kg/day with standardised steroid taper, from month 4 (randomisation) (200 mg maximum daily dose). Azathioprine withdrawn at month 27.&#xD;
Azathioprine: Oral dosage form. Target dose is 2mg/kg; maximum daily dose is 200mg. This should be continued until month 24. The dose should then by reduced by 50% and azathioprine completely withdrawn at month 27.&#xD;
The dose should be rounded down to the nearest 25mg. The dose may vary on alternate days e.g. 100mg one day, 150mg the next for patients on an overall dose of 125mg daily.&#xD;
If patients are aged over 60 years, reduce the dose by 25%. If patients are aged over 75 years, reduce the dose by 50%.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants in Remission at 24 and 48 Months</title>
          <description>Proportion of patients who maintain remission at 24 and 48 months</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="85"/>
                <count group_id="O2" value="85"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Month 24</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="73"/>
                    <measurement group_id="O2" value="70"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Month 48</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="54"/>
                    <measurement group_id="O2" value="44"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Combined Damage Assessment Score (Disease Related Damage Assessment)</title>
        <description>Cumulative accrual of damage as measured by the combined damage assessment score (CDA). Each persistent or new occurrence of damage is given a score of 1. The cumulative accrual of damage is obtained by summing across the different types of damage to get an overall score (max score = 64).</description>
        <time_frame>data in Rows represent the change from randomization (month 4) to months 12, 24, 36, and 48.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Rituximab Maintenance</title>
            <description>Rituximab maintenance: 1g at 4, 8, 12, 16 &amp; 20 months with standardised steroid taper&#xD;
Rituximab: Rituximab IV infusion 1000 mg x 1 dose at months 4, 8, 12, 16 and 20 and glucocorticoids. Four - six hour infusion. Treatment with rituximab will cease at month 20.</description>
          </group>
          <group group_id="O2">
            <title>Azathioprine Maintenance</title>
            <description>Azathioprine Maintenance: 2mg/kg/day with standardised steroid taper, from month 4 (randomisation) (200 mg maximum daily dose). Azathioprine withdrawn at month 27.&#xD;
Azathioprine: Oral dosage form. Target dose is 2mg/kg; maximum daily dose is 200mg. This should be continued until month 24. The dose should then by reduced by 50% and azathioprine completely withdrawn at month 27.&#xD;
The dose should be rounded down to the nearest 25mg. The dose may vary on alternate days e.g. 100mg one day, 150mg the next for patients on an overall dose of 125mg daily.&#xD;
If patients are aged over 60 years, reduce the dose by 25%. If patients are aged over 75 years, reduce the dose by 50%.</description>
          </group>
        </group_list>
        <measure>
          <title>Combined Damage Assessment Score (Disease Related Damage Assessment)</title>
          <description>Cumulative accrual of damage as measured by the combined damage assessment score (CDA). Each persistent or new occurrence of damage is given a score of 1. The cumulative accrual of damage is obtained by summing across the different types of damage to get an overall score (max score = 64).</description>
          <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="85"/>
                <count group_id="O2" value="85"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Randomisation to month 12</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.275" spread="0.656"/>
                    <measurement group_id="O2" value="0.337" spread="0.610"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Randomisation to month 24</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.571" spread="0.909"/>
                    <measurement group_id="O2" value="0.533" spread="0.777"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Randomisation to month 36</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.676" spread="0.995"/>
                    <measurement group_id="O2" value="0.899" spread="1.352"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Randomisation to month 48</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.09" spread="1.18"/>
                    <measurement group_id="O2" value="1.38" spread="1.65"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Cumulative GC Exposure</title>
        <description>Cumulative glucocorticoid (GC) exposure during the trial. The trial had a common close out date when the final patient reached month 36 in the trial. Patients were followed until month 48 or the common close out date, whichever happened sooner. Therefore, follow up varied between 36 and 48 months. Cumulative glucocorticoid exposure is presented as a dose in mg for during the treatment period (up to month 24) and across the whole trial (until month 48 or common close out when the final patient reached month 36).</description>
        <time_frame>Up to 48 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Rituximab Maintenance</title>
            <description>Rituximab maintenance: 1g at 4, 8, 12, 16 &amp; 20 months with standardised steroid taper&#xD;
Rituximab: Rituximab IV infusion 1000 mg x 1 dose at months 4, 8, 12, 16 and 20 and glucocorticoids. Four - six hour infusion. Treatment with rituximab will cease at month 20.</description>
          </group>
          <group group_id="O2">
            <title>Azathioprine Maintenance</title>
            <description>Azathioprine Maintenance: 2mg/kg/day with standardised steroid taper, from month 4 (randomisation) (200 mg maximum daily dose). Azathioprine withdrawn at month 27.&#xD;
Azathioprine: Oral dosage form. Target dose is 2mg/kg; maximum daily dose is 200mg. This should be continued until month 24. The dose should then by reduced by 50% and azathioprine completely withdrawn at month 27.&#xD;
The dose should be rounded down to the nearest 25mg. The dose may vary on alternate days e.g. 100mg one day, 150mg the next for patients on an overall dose of 125mg daily.&#xD;
If patients are aged over 60 years, reduce the dose by 25%. If patients are aged over 75 years, reduce the dose by 50%.</description>
          </group>
        </group_list>
        <measure>
          <title>Cumulative GC Exposure</title>
          <description>Cumulative glucocorticoid (GC) exposure during the trial. The trial had a common close out date when the final patient reached month 36 in the trial. Patients were followed until month 48 or the common close out date, whichever happened sooner. Therefore, follow up varied between 36 and 48 months. Cumulative glucocorticoid exposure is presented as a dose in mg for during the treatment period (up to month 24) and across the whole trial (until month 48 or common close out when the final patient reached month 36).</description>
          <units>mg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="85"/>
                <count group_id="O2" value="85"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Overall (randomisation to end of trial)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3717" spread="3318"/>
                    <measurement group_id="O2" value="4780" spread="3387"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Maintenance treatment period (randomisation to month 24)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2184" spread="1100"/>
                    <measurement group_id="O2" value="2426" spread="1324"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Severe Adverse Event Rate</title>
        <description>Severe adverse event (SAE) rate</description>
        <time_frame>Up to 48 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Rituximab Maintenance</title>
            <description>Rituximab maintenance: 1g at 4, 8, 12, 16 &amp; 20 months with standardised steroid taper&#xD;
Rituximab: Rituximab IV infusion 1000 mg x 1 dose at months 4, 8, 12, 16 and 20 and glucocorticoids. Four - six hour infusion. Treatment with rituximab will cease at month 20.</description>
          </group>
          <group group_id="O2">
            <title>Azathioprine Maintenance</title>
            <description>Azathioprine Maintenance: 2mg/kg/day with standardised steroid taper, from month 4 (randomisation) (200 mg maximum daily dose). Azathioprine withdrawn at month 27.&#xD;
Azathioprine: Oral dosage form. Target dose is 2mg/kg; maximum daily dose is 200mg. This should be continued until month 24. The dose should then by reduced by 50% and azathioprine completely withdrawn at month 27.&#xD;
The dose should be rounded down to the nearest 25mg. The dose may vary on alternate days e.g. 100mg one day, 150mg the next for patients on an overall dose of 125mg daily.&#xD;
If patients are aged over 60 years, reduce the dose by 25%. If patients are aged over 75 years, reduce the dose by 50%.</description>
          </group>
        </group_list>
        <measure>
          <title>Severe Adverse Event Rate</title>
          <description>Severe adverse event (SAE) rate</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="85"/>
                <count group_id="O2" value="85"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="37"/>
                    <measurement group_id="O2" value="48"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Infection Rates</title>
        <description>Infection (treated with intravenous or oral antibiotics) rates</description>
        <time_frame>Up to 4 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Rituximab Maintenance</title>
            <description>Rituximab maintenance: 1g at 4, 8, 12, 16 &amp; 20 months with standardised steroid taper&#xD;
Rituximab: Rituximab IV infusion 1000 mg x 1 dose at months 4, 8, 12, 16 and 20 and glucocorticoids. Four - six hour infusion. Treatment with rituximab will cease at month 20.</description>
          </group>
          <group group_id="O2">
            <title>Azathioprine Maintenance</title>
            <description>Azathioprine Maintenance: 2mg/kg/day with standardised steroid taper, from month 4 (randomisation) (200 mg maximum daily dose). Azathioprine withdrawn at month 27.&#xD;
Azathioprine: Oral dosage form. Target dose is 2mg/kg; maximum daily dose is 200mg. This should be continued until month 24. The dose should then by reduced by 50% and azathioprine completely withdrawn at month 27.&#xD;
The dose should be rounded down to the nearest 25mg. The dose may vary on alternate days e.g. 100mg one day, 150mg the next for patients on an overall dose of 125mg daily.&#xD;
If patients are aged over 60 years, reduce the dose by 25%. If patients are aged over 75 years, reduce the dose by 50%.</description>
          </group>
        </group_list>
        <measure>
          <title>Infection Rates</title>
          <description>Infection (treated with intravenous or oral antibiotics) rates</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="85"/>
                <count group_id="O2" value="85"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="54"/>
                    <measurement group_id="O2" value="62"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Health-related Quality of Life Using the SF-36 Physical Composite</title>
        <description>The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.</description>
        <time_frame>4 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Rituximab Maintenance</title>
            <description>Rituximab maintenance: 1g at 4, 8, 12, 16 &amp; 20 months with standardised steroid taper&#xD;
Rituximab: Rituximab IV infusion 1000 mg x 1 dose at months 4, 8, 12, 16 and 20 and glucocorticoids. Four - six hour infusion. Treatment with rituximab will cease at month 20.</description>
          </group>
          <group group_id="O2">
            <title>Azathioprine Maintenance</title>
            <description>Azathioprine Maintenance: 2mg/kg/day with standardised steroid taper, from month 4 (randomisation) (200 mg maximum daily dose). Azathioprine withdrawn at month 27.&#xD;
Azathioprine: Oral dosage form. Target dose is 2mg/kg; maximum daily dose is 200mg. This should be continued until month 24. The dose should then by reduced by 50% and azathioprine completely withdrawn at month 27.&#xD;
The dose should be rounded down to the nearest 25mg. The dose may vary on alternate days e.g. 100mg one day, 150mg the next for patients on an overall dose of 125mg daily.&#xD;
If patients are aged over 60 years, reduce the dose by 25%. If patients are aged over 75 years, reduce the dose by 50%.</description>
          </group>
        </group_list>
        <measure>
          <title>Health-related Quality of Life Using the SF-36 Physical Composite</title>
          <description>The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.</description>
          <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="83"/>
                <count group_id="O2" value="81"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="36.7" spread="15.4"/>
                    <measurement group_id="O2" value="36.1" spread="14.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Health-related Quality of Life Using the SF-36 Mental Composite</title>
        <description>The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.</description>
        <time_frame>4 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Rituximab Maintenance</title>
            <description>Rituximab maintenance: 1g at 4, 8, 12, 16 &amp; 20 months with standardised steroid taper&#xD;
Rituximab: Rituximab IV infusion 1000 mg x 1 dose at months 4, 8, 12, 16 and 20 and glucocorticoids. Four - six hour infusion. Treatment with rituximab will cease at month 20.</description>
          </group>
          <group group_id="O2">
            <title>Azathioprine Maintenance</title>
            <description>Azathioprine Maintenance: 2mg/kg/day with standardised steroid taper, from month 4 (randomisation) (200 mg maximum daily dose). Azathioprine withdrawn at month 27.&#xD;
Azathioprine: Oral dosage form. Target dose is 2mg/kg; maximum daily dose is 200mg. This should be continued until month 24. The dose should then by reduced by 50% and azathioprine completely withdrawn at month 27.&#xD;
The dose should be rounded down to the nearest 25mg. The dose may vary on alternate days e.g. 100mg one day, 150mg the next for patients on an overall dose of 125mg daily.&#xD;
If patients are aged over 60 years, reduce the dose by 25%. If patients are aged over 75 years, reduce the dose by 50%.</description>
          </group>
        </group_list>
        <measure>
          <title>Health-related Quality of Life Using the SF-36 Mental Composite</title>
          <description>The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.</description>
          <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="83"/>
                <count group_id="O2" value="81"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="51.8" spread="11.3"/>
                    <measurement group_id="O2" value="51.0" spread="11.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Health-related Quality of Life Using the SF-36 Physical Composite</title>
        <description>The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.</description>
        <time_frame>12 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Rituximab Maintenance</title>
            <description>Rituximab maintenance: 1g at 4, 8, 12, 16 &amp; 20 months with standardised steroid taper&#xD;
Rituximab: Rituximab IV infusion 1000 mg x 1 dose at months 4, 8, 12, 16 and 20 and glucocorticoids. Four - six hour infusion. Treatment with rituximab will cease at month 20.</description>
          </group>
          <group group_id="O2">
            <title>Azathioprine Maintenance</title>
            <description>Azathioprine Maintenance: 2mg/kg/day with standardised steroid taper, from month 4 (randomisation) (200 mg maximum daily dose). Azathioprine withdrawn at month 27.&#xD;
Azathioprine: Oral dosage form. Target dose is 2mg/kg; maximum daily dose is 200mg. This should be continued until month 24. The dose should then by reduced by 50% and azathioprine completely withdrawn at month 27.&#xD;
The dose should be rounded down to the nearest 25mg. The dose may vary on alternate days e.g. 100mg one day, 150mg the next for patients on an overall dose of 125mg daily.&#xD;
If patients are aged over 60 years, reduce the dose by 25%. If patients are aged over 75 years, reduce the dose by 50%.</description>
          </group>
        </group_list>
        <measure>
          <title>Health-related Quality of Life Using the SF-36 Physical Composite</title>
          <description>The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.</description>
          <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="80"/>
                <count group_id="O2" value="80"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="38.2" spread="15.2"/>
                    <measurement group_id="O2" value="34.6" spread="15.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Health-related Quality of Life Using the SF-36 Mental Composite</title>
        <description>The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.</description>
        <time_frame>12 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Rituximab Maintenance</title>
            <description>Rituximab maintenance: 1g at 4, 8, 12, 16 &amp; 20 months with standardised steroid taper&#xD;
Rituximab: Rituximab IV infusion 1000 mg x 1 dose at months 4, 8, 12, 16 and 20 and glucocorticoids. Four - six hour infusion. Treatment with rituximab will cease at month 20.</description>
          </group>
          <group group_id="O2">
            <title>Azathioprine Maintenance</title>
            <description>Azathioprine Maintenance: 2mg/kg/day with standardised steroid taper, from month 4 (randomisation) (200 mg maximum daily dose). Azathioprine withdrawn at month 27.&#xD;
Azathioprine: Oral dosage form. Target dose is 2mg/kg; maximum daily dose is 200mg. This should be continued until month 24. The dose should then by reduced by 50% and azathioprine completely withdrawn at month 27.&#xD;
The dose should be rounded down to the nearest 25mg. The dose may vary on alternate days e.g. 100mg one day, 150mg the next for patients on an overall dose of 125mg daily.&#xD;
If patients are aged over 60 years, reduce the dose by 25%. If patients are aged over 75 years, reduce the dose by 50%.</description>
          </group>
        </group_list>
        <measure>
          <title>Health-related Quality of Life Using the SF-36 Mental Composite</title>
          <description>The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.</description>
          <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="80"/>
                <count group_id="O2" value="80"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="50.8" spread="12.4"/>
                    <measurement group_id="O2" value="51.9" spread="11.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Health-related Quality of Life Using the SF-36 Physical Composite</title>
        <description>The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.</description>
        <time_frame>24 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Rituximab Maintenance</title>
            <description>Rituximab maintenance: 1g at 4, 8, 12, 16 &amp; 20 months with standardised steroid taper&#xD;
Rituximab: Rituximab IV infusion 1000 mg x 1 dose at months 4, 8, 12, 16 and 20 and glucocorticoids. Four - six hour infusion. Treatment with rituximab will cease at month 20.</description>
          </group>
          <group group_id="O2">
            <title>Azathioprine Maintenance</title>
            <description>Azathioprine Maintenance: 2mg/kg/day with standardised steroid taper, from month 4 (randomisation) (200 mg maximum daily dose). Azathioprine withdrawn at month 27.&#xD;
Azathioprine: Oral dosage form. Target dose is 2mg/kg; maximum daily dose is 200mg. This should be continued until month 24. The dose should then by reduced by 50% and azathioprine completely withdrawn at month 27.&#xD;
The dose should be rounded down to the nearest 25mg. The dose may vary on alternate days e.g. 100mg one day, 150mg the next for patients on an overall dose of 125mg daily.&#xD;
If patients are aged over 60 years, reduce the dose by 25%. If patients are aged over 75 years, reduce the dose by 50%.</description>
          </group>
        </group_list>
        <measure>
          <title>Health-related Quality of Life Using the SF-36 Physical Composite</title>
          <description>The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.</description>
          <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="77"/>
                <count group_id="O2" value="70"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="36.7" spread="15.8"/>
                    <measurement group_id="O2" value="35.6" spread="14.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Health-related Quality of Life Using the SF-36 Mental Composite</title>
        <description>The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.</description>
        <time_frame>24 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Rituximab Maintenance</title>
            <description>Rituximab maintenance: 1g at 4, 8, 12, 16 &amp; 20 months with standardised steroid taper&#xD;
Rituximab: Rituximab IV infusion 1000 mg x 1 dose at months 4, 8, 12, 16 and 20 and glucocorticoids. Four - six hour infusion. Treatment with rituximab will cease at month 20.</description>
          </group>
          <group group_id="O2">
            <title>Azathioprine Maintenance</title>
            <description>Azathioprine Maintenance: 2mg/kg/day with standardised steroid taper, from month 4 (randomisation) (200 mg maximum daily dose). Azathioprine withdrawn at month 27.&#xD;
Azathioprine: Oral dosage form. Target dose is 2mg/kg; maximum daily dose is 200mg. This should be continued until month 24. The dose should then by reduced by 50% and azathioprine completely withdrawn at month 27.&#xD;
The dose should be rounded down to the nearest 25mg. The dose may vary on alternate days e.g. 100mg one day, 150mg the next for patients on an overall dose of 125mg daily.&#xD;
If patients are aged over 60 years, reduce the dose by 25%. If patients are aged over 75 years, reduce the dose by 50%.</description>
          </group>
        </group_list>
        <measure>
          <title>Health-related Quality of Life Using the SF-36 Mental Composite</title>
          <description>The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.</description>
          <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="77"/>
                <count group_id="O2" value="70"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="51.9" spread="11.9"/>
                    <measurement group_id="O2" value="53.5" spread="10.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Health-related Quality of Life Using the SF-36 Physical Composite</title>
        <description>The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.</description>
        <time_frame>36 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Rituximab Maintenance</title>
            <description>Rituximab maintenance: 1g at 4, 8, 12, 16 &amp; 20 months with standardised steroid taper&#xD;
Rituximab: Rituximab IV infusion 1000 mg x 1 dose at months 4, 8, 12, 16 and 20 and glucocorticoids. Four - six hour infusion. Treatment with rituximab will cease at month 20.</description>
          </group>
          <group group_id="O2">
            <title>Azathioprine Maintenance</title>
            <description>Azathioprine Maintenance: 2mg/kg/day with standardised steroid taper, from month 4 (randomisation) (200 mg maximum daily dose). Azathioprine withdrawn at month 27.&#xD;
Azathioprine: Oral dosage form. Target dose is 2mg/kg; maximum daily dose is 200mg. This should be continued until month 24. The dose should then by reduced by 50% and azathioprine completely withdrawn at month 27.&#xD;
The dose should be rounded down to the nearest 25mg. The dose may vary on alternate days e.g. 100mg one day, 150mg the next for patients on an overall dose of 125mg daily.&#xD;
If patients are aged over 60 years, reduce the dose by 25%. If patients are aged over 75 years, reduce the dose by 50%.</description>
          </group>
        </group_list>
        <measure>
          <title>Health-related Quality of Life Using the SF-36 Physical Composite</title>
          <description>The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.</description>
          <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="74"/>
                <count group_id="O2" value="69"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="34.6" spread="15.9"/>
                    <measurement group_id="O2" value="33.8" spread="15.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Health-related Quality of Life Using the SF-36 Mental Composite</title>
        <description>The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.</description>
        <time_frame>36 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Rituximab Maintenance</title>
            <description>Rituximab maintenance: 1g at 4, 8, 12, 16 &amp; 20 months with standardised steroid taper&#xD;
Rituximab: Rituximab IV infusion 1000 mg x 1 dose at months 4, 8, 12, 16 and 20 and glucocorticoids. Four - six hour infusion. Treatment with rituximab will cease at month 20.</description>
          </group>
          <group group_id="O2">
            <title>Azathioprine Maintenance</title>
            <description>Azathioprine Maintenance: 2mg/kg/day with standardised steroid taper, from month 4 (randomisation) (200 mg maximum daily dose). Azathioprine withdrawn at month 27.&#xD;
Azathioprine: Oral dosage form. Target dose is 2mg/kg; maximum daily dose is 200mg. This should be continued until month 24. The dose should then by reduced by 50% and azathioprine completely withdrawn at month 27.&#xD;
The dose should be rounded down to the nearest 25mg. The dose may vary on alternate days e.g. 100mg one day, 150mg the next for patients on an overall dose of 125mg daily.&#xD;
If patients are aged over 60 years, reduce the dose by 25%. If patients are aged over 75 years, reduce the dose by 50%.</description>
          </group>
        </group_list>
        <measure>
          <title>Health-related Quality of Life Using the SF-36 Mental Composite</title>
          <description>The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.</description>
          <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="74"/>
                <count group_id="O2" value="69"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="52.3" spread="12.5"/>
                    <measurement group_id="O2" value="51.8" spread="10.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Health-related Quality of Life Using the SF-36 Physical Composite</title>
        <description>The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.</description>
        <time_frame>48 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Rituximab Maintenance</title>
            <description>Rituximab maintenance: 1g at 4, 8, 12, 16 &amp; 20 months with standardised steroid taper&#xD;
Rituximab: Rituximab IV infusion 1000 mg x 1 dose at months 4, 8, 12, 16 and 20 and glucocorticoids. Four - six hour infusion. Treatment with rituximab will cease at month 20.</description>
          </group>
          <group group_id="O2">
            <title>Azathioprine Maintenance</title>
            <description>Azathioprine Maintenance: 2mg/kg/day with standardised steroid taper, from month 4 (randomisation) (200 mg maximum daily dose). Azathioprine withdrawn at month 27.&#xD;
Azathioprine: Oral dosage form. Target dose is 2mg/kg; maximum daily dose is 200mg. This should be continued until month 24. The dose should then by reduced by 50% and azathioprine completely withdrawn at month 27.&#xD;
The dose should be rounded down to the nearest 25mg. The dose may vary on alternate days e.g. 100mg one day, 150mg the next for patients on an overall dose of 125mg daily.&#xD;
If patients are aged over 60 years, reduce the dose by 25%. If patients are aged over 75 years, reduce the dose by 50%.</description>
          </group>
        </group_list>
        <measure>
          <title>Health-related Quality of Life Using the SF-36 Physical Composite</title>
          <description>The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.</description>
          <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="55"/>
                <count group_id="O2" value="51"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="35.8" spread="14.9"/>
                    <measurement group_id="O2" value="35.0" spread="16.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Health-related Quality of Life Using the SF-36 Mental Composite</title>
        <description>The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.</description>
        <time_frame>48 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Rituximab Maintenance</title>
            <description>Rituximab maintenance: 1g at 4, 8, 12, 16 &amp; 20 months with standardised steroid taper&#xD;
Rituximab: Rituximab IV infusion 1000 mg x 1 dose at months 4, 8, 12, 16 and 20 and glucocorticoids. Four - six hour infusion. Treatment with rituximab will cease at month 20.</description>
          </group>
          <group group_id="O2">
            <title>Azathioprine Maintenance</title>
            <description>Azathioprine Maintenance: 2mg/kg/day with standardised steroid taper, from month 4 (randomisation) (200 mg maximum daily dose). Azathioprine withdrawn at month 27.&#xD;
Azathioprine: Oral dosage form. Target dose is 2mg/kg; maximum daily dose is 200mg. This should be continued until month 24. The dose should then by reduced by 50% and azathioprine completely withdrawn at month 27.&#xD;
The dose should be rounded down to the nearest 25mg. The dose may vary on alternate days e.g. 100mg one day, 150mg the next for patients on an overall dose of 125mg daily.&#xD;
If patients are aged over 60 years, reduce the dose by 25%. If patients are aged over 75 years, reduce the dose by 50%.</description>
          </group>
        </group_list>
        <measure>
          <title>Health-related Quality of Life Using the SF-36 Mental Composite</title>
          <description>The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.</description>
          <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="55"/>
                <count group_id="O2" value="51"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="50.9" spread="13.0"/>
                    <measurement group_id="O2" value="53.9" spread="9.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events were collected for up to 48 months or until the last patient recruited reached Month 36.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Rituximab Maintenance</title>
          <description>Rituximab maintenance: 1g at 4, 8, 12, 16 &amp; 20 months with standardised steroid taper&#xD;
Rituximab: Rituximab IV infusion 1000 mg x 1 dose at months 4, 8, 12, 16 and 20 and glucocorticoids. Four - six hour infusion. Treatment with rituximab will cease at month 20.</description>
        </group>
        <group group_id="E2">
          <title>Azathioprine Maintenance</title>
          <description>Azathioprine Maintenance: 2mg/kg/day with standardised steroid taper, from month 4 (randomisation) (200 mg maximum daily dose). Azathioprine withdrawn at month 27.&#xD;
Azathioprine: Oral dosage form. Target dose is 2mg/kg; maximum daily dose is 200mg. This should be continued until month 24. The dose should then by reduced by 50% and azathioprine completely withdrawn at month 27.&#xD;
The dose should be rounded down to the nearest 25mg. The dose may vary on alternate days e.g. 100mg one day, 150mg the next for patients on an overall dose of 125mg daily.&#xD;
If patients are aged over 60 years, reduce the dose by 25%. If patients are aged over 75 years, reduce the dose by 50%.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (19.0)</default_vocab>
        <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="3" subjects_at_risk="85"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="19" subjects_at_risk="85"/>
                <counts group_id="E2" subjects_affected="31" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Iron deficiency anaemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Atrioventricular block complete</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Cardiac failure congestive</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Cardiomyopathy</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Coronary artery disease</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Myocardial infarction</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Periorbital oedema</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Oesophageal spasm</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Oesophagitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Pancreatitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Small intestinal obstruction</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Enterovesical fistula</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chest pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Perforated ulcer</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Stenosis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Cholecystitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Cholecystitis acute</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Cholelithiasis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Drug hypersensitivity</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Pulmonary vasculitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Vasculitis</sub_title>
                <counts group_id="E1" events="13" subjects_affected="4" subjects_at_risk="85"/>
                <counts group_id="E2" events="13" subjects_affected="9" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Appendicitis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Bronchitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Cellulitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Dacryocystitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Diverticulitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Gastroenteritis viral</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Influenza</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="85"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Lower respiratory tract infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Peritonitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="85"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Pneumonia klebsiella</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Pneumonia viral</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Escherichia urinary tract infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Periorbital abscess</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Infective exacerbation of chronic obstructive airways disease</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Respiratory tract infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Metapneumovirus infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Oral herpes</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Accident</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Subdural haematoma</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Post procedural complication</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Intra-abdominal haemorrhage</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Vascular access complication</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Medical observation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Transaminases increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Hyperglycaemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Hyperkalaemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Metabolic acidosis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Myasthenia gravis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Osteoarthritis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Intervertebral disc protrusion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Myasthenia gravis crisis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Pubis fracture</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Bladder papilloma</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Lung adenocarcinoma</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Pancreatic carcinoma metastatic</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Sarcoma of skin</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Squamous cell carcinoma</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Colon neoplasm 1</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Anal squamous cell carcinoma</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Haemorrhagic stroke</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Sleep apnoea syndrome</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Subdural haemorrhage</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Conversion disorder</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Nephrolithiasis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Proteinuria</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Renal impairment</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Acute kidney injury</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Bronchospasm</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Chronic obstructive pulmonary disease</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Laryngeal stenosis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Pneumonitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Pneumothorax</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Stridor</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Pneumomediastinum</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Aortic valve replacement</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Bunion operation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Cholecystectomy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Colostomy closure</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Dacryocystorhinostomy</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Hip arthroplasty</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="85"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Knee arthroplasty</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Lung lobectomy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Renal transplant</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Spinal decompression</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Renal and pancreas transplant</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Sigmoidectomy</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Cardiac ablation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Infusion</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Colporrhaphy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Thyroidectomy</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Joint resurfacing surgery</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Vascular anastomosis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Haemoptysis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Orthostatic hypotension</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Pulmonary embolism</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Vascular injury</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Vascular pseudoaneurysm</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Haemorrhage</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>MedDRA (19.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="42" subjects_at_risk="85"/>
                <counts group_id="E2" subjects_affected="43" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Malaise</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Cholecystitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Bacterial dacryocystitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Bacterial infection</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Beta haemolytic streptococcal infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Bronchitis haemophilus</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Cellulitis</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="85"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Cellulitis orbital</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Citrobacter infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Cystitis escherichia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Cystitis klebsiella</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Enterococcal infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Escherichia urinary tract infection</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="85"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Haemophilus infection</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="85"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Klebsiella infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Pneumonia haemophilus</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Pneumonia klebsiella</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Pneumonia pneumococca</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Pneumonia pseudomonal</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Proteus infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Pseudomonas bronchitis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Pseudomonas infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Staphylococcal impetigo</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Staphylococcal infection</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="85"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Tonsillitis bacterial</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Urinary tract infection enterococcal</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Body tinea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Candida infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Oesophageal candidiasis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Oral candidiasis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Tinea infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Tinea pedis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Vulvovaginal candidiasis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Vulvovaginal mycotic infection</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Bronchitis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Conjunctivitis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="85"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Cystitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Diverticulitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Ear infection</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="85"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Eye infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Gastrointestinal infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Lower respiratory tract infection</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="85"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Mastoiditis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Otitis media</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Paronychia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Pharyngitis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="85"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Prostate infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Respiratory tract infection</sub_title>
                <counts group_id="E1" events="19" subjects_affected="19" subjects_at_risk="85"/>
                <counts group_id="E2" events="31" subjects_affected="31" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Root canal infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" events="15" subjects_affected="15" subjects_at_risk="85"/>
                <counts group_id="E2" events="10" subjects_affected="10" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="85"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Systemic infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Tonsillitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Tooth abscess</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Tooth infection</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" events="17" subjects_affected="17" subjects_at_risk="85"/>
                <counts group_id="E2" events="17" subjects_affected="17" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="9" subjects_affected="9" subjects_at_risk="85"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Herpes simplex</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Herpes zoster</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Oral herpes</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Respiratory tract infection viral</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Varicella zoster virus infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Viral infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Streptococcus test positive</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Eczema</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="85"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="85"/>
              </event>
              <event>
                <sub_title>Rosacea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="85"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="85"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>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>
    <point_of_contact>
      <name_or_title>Prof David Jayne</name_or_title>
      <organization>Cambridge University Hospitals NHS Foundation Trust</organization>
      <phone>01223 748062</phone>
      <email>dj106@cam.ac.uk</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/NCT01697267
org study id: RITAZAREM
secondary id: 2012-001102-14
nct id: NCT01697267
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
Rituximab is now established as an effective drug for anti-neutrophil cytoplasmic antibody
      (ANCA) vasculitis following major European and US trials reported in 2010. After a time, its
      effect wears off and the disease can return. This occurs in at least half of patients within
      2 years of receiving Rituximab. A preliminary study in Cambridge has suggested that repeating
      rituximab every six months stops the disease returning and is safe.

      The RITAZAREM trial will find out whether repeating rituximab stops vasculitis returning and
      whether it works better than the older treatments, azathioprine or methotrexate. It will also
      tell us how long patients remain well after the repeated rituximab treatments are stopped,
      and if repeated rituximab is safe. We should also learn useful information about the effects
      of rituximab on quality of life and economic measures. The trial results will help decide the
      best treatment for future patients who have their vasculitis initially treated with
      rituximab.

      RITAZAREM aims to recruit patients with established ANCA vasculitis whose disease has come
      back 'relapsing vasculitis'. All patients will be treated with rituximab and steroids and we
      anticipate that most will respond well. If their disease is under reasonable control after
      four months, further treatment with either rituximab (a single dose ever four months for two
      years) or azathioprine tablets will be chosen randomly. The patients in the rituximab and
      azathioprine groups will then be compared. Patients will be in the trial for four years.

      The study has been designed by members of the European Vasculitis Study group (EUVAS) and the
      Vasculitis Clinical Research Consortium (VCRC). It will include 190 participants from 30
      hospitals in Europe, the USA, Australia and Mexico.

      RITAZAREM is being funded by Arthritis Research UK, the U.S. National Institutes of Health
      and by Roche/Genentech.
Patients will be recruited at the time of relapse. All will receive rituximab 375 mg/m2/week
      x 4 and glucocorticoids.

      Those patients that achieve disease control (BVAS/WG ≤ 1 and daily prednisone dose ≤ 10 mg)
      by month 4 will be randomised to the rituximab or control remission maintenance groups.

      Treatment is protocolised for the entire duration of the study, until the common close date,
      when the final patient recruited has completed 36 months within the study or until the
      patient has completed 48 months on study whichever the sooner. Patients in the rituximab arm
      will receive treatment until month 20, and those in the azathioprine arm until month 27.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Relapse-free Survival
time frame: Any patients who have not relapsed at up to a maximum of 4 years will be censored.
description: The primary efficacy outcome measure of the trial is relapse-free survival, where a relapse is either major or minor. The primary analysis will be a Cox regression model adjusted for the stratification factors (ANCA type, relapse severity and prednisone induction regimen) for the difference in the distribution of relapse-free survival between the rituximab arm and the azathioprine (control) arm (two-sided at α-level of 5%).
measure: Number of Participants in Remission at 24 and 48 Months
time frame: 24 and 48 months
description: Proportion of patients who maintain remission at 24 and 48 months
measure: Combined Damage Assessment Score (Disease Related Damage Assessment)
time frame: data in Rows represent the change from randomization (month 4) to months 12, 24, 36, and 48.
description: Cumulative accrual of damage as measured by the combined damage assessment score (CDA). Each persistent or new occurrence of damage is given a score of 1. The cumulative accrual of damage is obtained by summing across the different types of damage to get an overall score (max score = 64).
measure: Cumulative GC Exposure
time frame: Up to 48 months
description: Cumulative glucocorticoid (GC) exposure during the trial. The trial had a common close out date when the final patient reached month 36 in the trial. Patients were followed until month 48 or the common close out date, whichever happened sooner. Therefore, follow up varied between 36 and 48 months. Cumulative glucocorticoid exposure is presented as a dose in mg for during the treatment period (up to month 24) and across the whole trial (until month 48 or common close out when the final patient reached month 36).
measure: Severe Adverse Event Rate
time frame: Up to 48 months
description: Severe adverse event (SAE) rate
measure: Infection Rates
time frame: Up to 4 years
description: Infection (treated with intravenous or oral antibiotics) rates
measure: Health-related Quality of Life Using the SF-36 Physical Composite
time frame: 4 months
description: The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.
measure: Health-related Quality of Life Using the SF-36 Mental Composite
time frame: 4 months
description: The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.
measure: Health-related Quality of Life Using the SF-36 Physical Composite
time frame: 12 months
description: The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.
measure: Health-related Quality of Life Using the SF-36 Mental Composite
time frame: 12 months
description: The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.
measure: Health-related Quality of Life Using the SF-36 Physical Composite
time frame: 24 months
description: The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.
measure: Health-related Quality of Life Using the SF-36 Mental Composite
time frame: 24 months
description: The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.
measure: Health-related Quality of Life Using the SF-36 Physical Composite
time frame: 36 months
description: The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.
measure: Health-related Quality of Life Using the SF-36 Mental Composite
time frame: 36 months
description: The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.
measure: Health-related Quality of Life Using the SF-36 Physical Composite
time frame: 48 months
description: The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.
measure: Health-related Quality of Life Using the SF-36 Mental Composite
time frame: 48 months
description: The 36-Item Short Form Health Survey (SF-36) is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 and transformed to have a mean of 50 and SD of 10 in the reference population, with higher scores indicating a better Health-related Quality of Life.
arm group label: Rituximab Maintenance
arm group type: Experimental
description: Rituximab maintenance: 1g at 4, 8, 12, 16 & 20 months with standardised steroid taper
arm group label: Azathioprine Maintenance
arm group type: Active Comparator
description: Azathioprine Maintenance: 2mg/kg/day with standardised steroid taper, from month 4 (randomisation) (200 mg maximum daily dose). Azathioprine withdrawn at month 27.
intervention type: Biological
intervention name: Rituximab
description: Rituximab IV infusion 1000 mg x 1 dose at months 4, 8, 12, 16 and 20 and glucocorticoids. Four - six hour infusion. Treatment with rituximab will cease at month 20.
arm group label: Rituximab Maintenance
other name: Rituxan
other name: MabThera
intervention type: Drug
intervention name: Azathioprine
description: Oral dosage form. Target dose is 2mg/kg; maximum daily dose is 200mg. This should be continued until month 24. The dose should then by reduced by 50% and azathioprine completely withdrawn at month 27.
The dose should be rounded down to the nearest 25mg. The dose may vary on alternate days e.g. 100mg one day, 150mg the next for patients on an overall dose of 125mg daily.
If patients are aged over 60 years, reduce the dose by 25%. If patients are aged over 75 years, reduce the dose by 50%.
arm group label: Azathioprine Maintenance
other name: Imuran
criteria: 
gender: All
minimum age: 15 Years
maximum age: N/A
healthy volunteers: No
last name: David Jayne
role: Study Chair
affiliation: Cambridge University Hospitals NHS Foundation Trust
last name: Peter Merkel
role: Study Chair
affiliation: University of Pennsylvania
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country: Australia
country: Canada
country: Czechia
country: Ireland
country: Italy
country: Japan
country: New Zealand
country: Sweden
country: United Kingdom
country: United States
country: Czech Republic
citation: Watts RA, Suppiah R, Merkel PA, Luqmani R. Systemic vasculitis--is it time to reclassify? Rheumatology (Oxford). 2011 Apr;50(4):643-5. doi: 10.1093/rheumatology/keq229. Epub 2010 Jul 20. No abstract available.
PMID: 20647295
citation: Falk RJ, Jennette JC. ANCA disease: where is this field heading? J Am Soc Nephrol. 2010 May;21(5):745-52. doi: 10.1681/ASN.2009121238. Epub 2010 Apr 15.
PMID: 20395376
citation: Watts RA, Scott DG. Epidemiology of the vasculitides. Curr Opin Rheumatol. 2003 Jan;15(1):11-6. doi: 10.1097/00002281-200301000-00003.
PMID: 12496504
citation: Booth AD, Almond MK, Burns A, Ellis P, Gaskin G, Neild GH, Plaisance M, Pusey CD, Jayne DR; Pan-Thames Renal Research Group. Outcome of ANCA-associated renal vasculitis: a 5-year retrospective study. Am J Kidney Dis. 2003 Apr;41(4):776-84. doi: 10.1016/s0272-6386(03)00025-8.
PMID: 12666064
citation: Jayne D, Rasmussen N, Andrassy K, Bacon P, Tervaert JW, Dadoniene J, Ekstrand A, Gaskin G, Gregorini G, de Groot K, Gross W, Hagen EC, Mirapeix E, Pettersson E, Siegert C, Sinico A, Tesar V, Westman K, Pusey C; European Vasculitis Study Group. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003 Jul 3;349(1):36-44. doi: 10.1056/NEJMoa020286.
PMID: 12840090
citation: de Groot K, Harper L, Jayne DR, Flores Suarez LF, Gregorini G, Gross WL, Luqmani R, Pusey CD, Rasmussen N, Sinico RA, Tesar V, Vanhille P, Westman K, Savage CO; EUVAS (European Vasculitis Study Group). Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med. 2009 May 19;150(10):670-80. doi: 10.7326/0003-4819-150-10-200905190-00004.
PMID: 19451574
citation: De Groot K, Rasmussen N, Bacon PA, Tervaert JW, Feighery C, Gregorini G, Gross WL, Luqmani R, Jayne DR. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2005 Aug;52(8):2461-9. doi: 10.1002/art.21142.
PMID: 16052573
citation: Wegener's Granulomatosis Etanercept Trial (WGET) Research Group. Etanercept plus standard therapy for Wegener's granulomatosis. N Engl J Med. 2005 Jan 27;352(4):351-61. doi: 10.1056/NEJMoa041884.
PMID: 15673801
citation: Seo P, Min YI, Holbrook JT, Hoffman GS, Merkel PA, Spiera R, Davis JC, Ytterberg SR, St Clair EW, McCune WJ, Specks U, Allen NB, Luqmani RA, Stone JH; WGET Research Group. Damage caused by Wegener's granulomatosis and its treatment: prospective data from the Wegener's Granulomatosis Etanercept Trial (WGET). Arthritis Rheum. 2005 Jul;52(7):2168-78. doi: 10.1002/art.21117.
PMID: 15986348
citation: Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R, Newman RA, Hanna N, Anderson DR. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood. 1994 Jan 15;83(2):435-45.
PMID: 7506951
citation: Jones RB, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA, Savage CO, Segelmark M, Tesar V, van Paassen P, Walsh D, Walsh M, Westman K, Jayne DR; European Vasculitis Study Group. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med. 2010 Jul 15;363(3):211-20. doi: 10.1056/NEJMoa0909169.
PMID: 20647198
citation: Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, Kallenberg CG, St Clair EW, Turkiewicz A, Tchao NK, Webber L, Ding L, Sejismundo LP, Mieras K, Weitzenkamp D, Ikle D, Seyfert-Margolis V, Mueller M, Brunetta P, Allen NB, Fervenza FC, Geetha D, Keogh KA, Kissin EY, Monach PA, Peikert T, Stegeman C, Ytterberg SR, Specks U; RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010 Jul 15;363(3):221-32. doi: 10.1056/NEJMoa0909905.
PMID: 20647199
citation: Jones RB, Ferraro AJ, Chaudhry AN, Brogan P, Salama AD, Smith KG, Savage CO, Jayne DR. A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2009 Jul;60(7):2156-68. doi: 10.1002/art.24637.
PMID: 19565480
responsible party type: Principal Investigator
investigator affiliation: Cambridge University Hospitals NHS Foundation Trust
investigator full name: David Jayne
investigator title: Director, Vasculitis and Lupus Clinic
mesh term: Granulomatosis with Polyangiitis
mesh term: Microscopic Polyangiitis
mesh term: Vasculitis
mesh term: Systemic Vasculitis
mesh term: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
mesh term: Rituximab
mesh term: Azathioprine
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 