<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/NCT02198248</url>
  </required_header>
  <id_info>
    <org_study_id>G25051</org_study_id>
    <secondary_id>UMIN000014222</secondary_id>
    <nct_id>NCT02198248</nct_id>
  </id_info>
  <brief_title>Low-dose Glucocorticoid Vasculitis Induction Study</brief_title>
  <acronym>LoVAS</acronym>
  <official_title>Low-dose Glucocorticoids Plus Rituximab Versus High-dose Glucocorticoids Plus Rituximab for Remission Induction in ANCA-associated Vasculitis; a Multicentre, Open Label, Randomised Control Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Chiba University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Chiba University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Previous reports suggested conventional immunosuppressants such as cyclophosphamide could not&#xD;
      reduce glucocorticoid dose in remission induction in ANCA-associated vasculitis because of&#xD;
      lower remission rate and higher relapse rate. However those reports didn't include rituximab.&#xD;
&#xD;
      B cell depletion therapy by rituximab is a new strategy for remission induction in&#xD;
      ANCA-associated vasculitis. The RAVE and RITUXVAS trial (NEJM 2010, both) showed high-dose&#xD;
      glucocorticoid plus rituximab had roughly the same efficacy and safety as high-dose&#xD;
      glucocorticoid plus IV-cyclophosphamide. In addition, recent retrospective observational&#xD;
      studies reported low-dose glucocorticoid plus rituximab led to re-induction in severe&#xD;
      relapsing ANCA-associated vasculitis.&#xD;
&#xD;
      Thus, the investigators aim to investigate whether rituximab can reduce glucocorticoid dose&#xD;
      in induction remission in ANCA-associated vasculitis (to show non-inferiority for efficacy&#xD;
      between low-dose and high-dose glucocorticoid plus rituximab). Participants will be&#xD;
      randomised to the &quot;low-dose glucocorticoid plus rituximab&quot; or the high-dose glucocorticoid&#xD;
      plus rituximab&quot; groups. Primary endpoint is proportion of remission at 6 months, then data&#xD;
      regarding relapse and long-term safety will be collected until 24 months.&#xD;
&#xD;
      The study has been designed by the principal and coordinating investigators. It will include&#xD;
      140 participants from 18 hospitals in Japan. It is funded by Chiba University Hospital and&#xD;
      Chiba East Hospital.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      ANCA (anti-neutrophil cytoplasmic antibody)-associated vasculitis is characterised by small&#xD;
      vessel vasculitis and presence of autoantibodies, ANCA. It can be a life-threatening disease&#xD;
      with renal/respiratory failure. Current standard therapy in induction remission for&#xD;
      ANCA-associated vasculitis is combination of high-dose glucocorticoid and&#xD;
      IV-cyclophosphamide. This regimen is effective (remission rate; 80-90%), but often cause&#xD;
      various glucocorticoid-related side effects. Especially, infection is related to death. Thus&#xD;
      a new regimen reducing glucocorticoid dose is required.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">October 2014</start_date>
  <completion_date type="Anticipated">June 2021</completion_date>
  <primary_completion_date type="Actual">December 2019</primary_completion_date>
  <phase>Phase 4</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>Proportion of the patients achieving remission</measure>
    <time_frame>6 months</time_frame>
    <description>Remission; BVAS ver.3=0 (or 1 with only one minor and persistent BVAS item) and prednisolone &lt;10mg/day</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to remission</measure>
    <time_frame>assessed at 1, 2, 4 and 6 months</time_frame>
    <description>Remission; BVAS ver.3=0 (or 1 with only one minor and persistent BVAS item) and prednisolone &lt;10mg/day</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival, disease free survival, time to end-stage renal disease, time to the first serious adverse event</measure>
    <time_frame>0-24 months</time_frame>
    <description>Assessed by Kaplan-Meier curves</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportions of death, relapse, end-stage renal disease and the composite of these</measure>
    <time_frame>at 6 and 24 months</time_frame>
    <description>Assessed by Kaplan-Meier curves</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportions of major relapse</measure>
    <time_frame>at 24 months</time_frame>
    <description>major relapse is relapse with one or more BVAS major items</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Birmingham Vasculitis Activity Score (BVAS) version 3</measure>
    <time_frame>assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months</time_frame>
    <description>BVAS is a scoring system for assessing disease activity of vasculitis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Vasculitis Damage Index (VDI)</measure>
    <time_frame>assessed at 0, 6, 12, 18 and 24 months</time_frame>
    <description>VDI is a scoring system for assessing irreversible disease damage due to vasculitis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Short-Form 36 (SF-36)</measure>
    <time_frame>assessed at 0, 6, 12, 18 and 24 months</time_frame>
    <description>SF-36 is a scoring system for assessing patient QOL.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient global assessment (visualised analogue scale)</measure>
    <time_frame>assessed at 0, 6, 12, 18 and 24 months</time_frame>
    <description>global assessments for disease activity and treatment toxicity</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Accumulative dose of glucocorticoids</measure>
    <time_frame>assessed at 6 and 24 months</time_frame>
    <description>Accumulative dose of glucocorticoids during the study period</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Numbers of events of adverse events/serious adverse events, proportions of the patients with adverse events/serious adverse events</measure>
    <time_frame>at 6 and 24 months</time_frame>
    <description>Event numbers and proportion of the patients with one or more events are assessed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportions of the patients with new onset diabetes mellitus</measure>
    <time_frame>at 6 and 24 months</time_frame>
    <description>diabetes mellitus requiring drug treatments</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of the patients with new onset insomnia</measure>
    <time_frame>at 6 and 24 months</time_frame>
    <description>insomnia requiring drug treatments</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of the patients with new onset bone fracture, bone density</measure>
    <time_frame>at 6 and 24 months</time_frame>
    <description>bone density is assessed at lumber spines</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of infections, proportions of the patients with infection</measure>
    <time_frame>at 6 and 24 months</time_frame>
    <description>infections requiring drug treatments</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportions of the patients with new onset hypertension</measure>
    <time_frame>at 6 and 24 months</time_frame>
    <description>hypertension requiring drug treatments</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportions of the patients with new onset hyperlipidemia</measure>
    <time_frame>at 6 and 24 months</time_frame>
    <description>hyperlipidemia requiring drug treatments</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportions of patients achieving remission and discontinuance of glucocorticoids</measure>
    <time_frame>at 6 and 24 months</time_frame>
    <description>Remission is BVAS ver3=0 and prednisolone &lt;10mg/day.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Serum immunoglobulin levels</measure>
    <time_frame>assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months</time_frame>
    <description>Serum immunoglobulin levels</description>
  </other_outcome>
  <other_outcome>
    <measure>Peripheral blood B cell counts</measure>
    <time_frame>assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months</time_frame>
    <description>CD19 positive B cells assessed by FACS</description>
  </other_outcome>
  <other_outcome>
    <measure>serum MPO-/PR3-ANCA levels measured by ELISA</measure>
    <time_frame>assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months</time_frame>
    <description>MPO-ANCA and PR3-ANCA are disease specific autoantibodies binding neutrophil cytoplasmic antigen.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">140</enrollment>
  <condition>Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis</condition>
  <condition>Microscopic Polyangiitis</condition>
  <condition>Wegener Granulomatosis</condition>
  <arm_group>
    <arm_group_label>Low-dose glucocorticoid</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Prednisolone will be commenced with dose of 0.5mg/kg/day and will be tapered and off within 6 months. If a patient fails to achieve BVAS=0, an investigator can postpone the procedure of stopping prednisolone (prednisolone 5mg/day x 2 weeks, 4mg/day x 2 weeks, 3mg/day x 4 weeks, 2mg/day x 4 weeks, 1mg/day x 4 weeks, then off prednisolone). Once starting the procedure, prednisolone must be off after 16 weeks. Patients will also receive rituximab (375mg/m2/w x4).&#xD;
After achieving remission, patients will be receive rituximab (1g/body or 0.5g/bodyx2) every 6 months as remission maintenance therapy.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>High-dose glucocorticoid</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Prednisolone will be commenced with dose of 1.0mg/kg/day and will be tapered to 10mg/day within 6 months. Patients will also receive rituximab (375mg/m2/w x4).&#xD;
After achieving remission, patients will be receive rituximab (1g/body or 0.5g/bodyx2) every 6 months as remission maintenance therapy. There's no limitation by the protocol regarding further prednisolone tapering.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rituximab</intervention_name>
    <description>Patients will be administered rituximab (375mg/m2/w x4 infusions) for reducing glucocorticoid dose in remission induction phase.</description>
    <arm_group_label>High-dose glucocorticoid</arm_group_label>
    <arm_group_label>Low-dose glucocorticoid</arm_group_label>
    <other_name>Rituxan</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Glucocorticoids</intervention_name>
    <description>&quot;Low-dose&quot; group commenced 0.5mg/kg/day, then taper and stop within 6 months following pre-defined schedule.&#xD;
&quot;High-dose&quot; group commenced 1.0mg/kg/day, then taper to 10mg/day within 6 months following pre-defined schedule.</description>
    <arm_group_label>High-dose glucocorticoid</arm_group_label>
    <arm_group_label>Low-dose glucocorticoid</arm_group_label>
    <other_name>Predonine</other_name>
    <other_name>Prednisolone</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Provision of written informed consent by a patient or a surrogate decision maker&#xD;
&#xD;
          2. Age=&gt;20 years&#xD;
&#xD;
          3. New clinical diagnosis of ANCA-associated vasculitis (granulomatosis with&#xD;
             polyangiitis, microscopic polyangiitis or renal limited ANCA-associated vasculitis)&#xD;
             consistent with the 2012 Chapel Hill consensus definitions&#xD;
&#xD;
          4. Positive test by ELISA for proteinase 3-ANCA or myeloperoxidase-ANCA&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Prior treatment for ANCA-associated vasculitis before trial entry&#xD;
&#xD;
          2. ANCA-associated vasculitis related glomerulonephritis (eGFR&lt;15ml/min) or alveolar&#xD;
             hemorrhage (oxygen inhalation &gt;2L/min)&#xD;
&#xD;
          3. Presence of another multisystem autoimmune disease&#xD;
&#xD;
          4. Known infection with HIV; a past or current history of hepatitis B virus or hepatitis&#xD;
             C virus infection&#xD;
&#xD;
          5. Desire to bear children, pregnancy or lactating&#xD;
&#xD;
          6. History of malignancy within the past 5 years or any evidence of persistent malignancy&#xD;
&#xD;
          7. Ongoing or recent (last 1 year) evidence of active tuberculosis&#xD;
&#xD;
          8. Severe allergy or anaphylaxis to monoclonal antibody therapy&#xD;
&#xD;
          9. Any concomitant condition anticipated to likely require oral systemic glucocorticoids,&#xD;
             immunosuppressants, biologics, plasma exchange or IVIg&#xD;
&#xD;
         10. Any biological B cell depleting agent (such as rituximab or belimumab) within the past&#xD;
             6 months&#xD;
&#xD;
         11. Other conditions, in the investigator's opinion, inappropriate for the trial entry&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Hiroshi Nakajima, M.D., Ph.D</last_name>
    <role>Principal Investigator</role>
    <affiliation>Chiba University Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Asahi General Hospital</name>
      <address>
        <city>Asahi</city>
        <state>Chiba</state>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kameda Medical Centre</name>
      <address>
        <city>Kamogawa</city>
        <state>Chiba</state>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Matsudo City Hospital</name>
      <address>
        <city>Matsudo</city>
        <state>Chiba</state>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Japanese Red Cross Narita Hospital</name>
      <address>
        <city>Narita</city>
        <state>Chiba</state>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Shimoshizu Hospital</name>
      <address>
        <city>Yotsukaido</city>
        <state>Chiba</state>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hokkaido University</name>
      <address>
        <city>Sapporo</city>
        <state>Hokkaido</state>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Yokohama Rosai Hospital</name>
      <address>
        <city>Yokohama</city>
        <state>Kanagawa</state>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saitama Medical Center</name>
      <address>
        <city>Kawagoe</city>
        <state>Saitama</state>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dokkyo Medical University</name>
      <address>
        <city>Mibu</city>
        <state>Tochigi</state>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Teikyo University</name>
      <address>
        <city>Itabashi</city>
        <state>Tokyo</state>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Keio University Hospital</name>
      <address>
        <city>Shinanomachi</city>
        <state>Tokyo</state>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Akita University</name>
      <address>
        <city>Akita</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chiba University Hospital</name>
      <address>
        <city>Chiba</city>
        <zip>260-8677</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chiba Aoba Municipal Hospital</name>
      <address>
        <city>Chiba</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chiba East Hospital</name>
      <address>
        <city>Chiba</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fukushima Medical University</name>
      <address>
        <city>Fukushima</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Niigata University</name>
      <address>
        <city>Niigata</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Japan</country>
  </location_countries>
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  </reference>
  <reference>
    <citation>Exley AR, Bacon PA, Luqmani RA, Kitas GD, Gordon C, Savage CO, Adu D. Development and initial validation of the Vasculitis Damage Index for the standardized clinical assessment of damage in the systemic vasculitides. Arthritis Rheum. 1997 Feb;40(2):371-80. doi: 10.1002/art.1780400222.</citation>
    <PMID>9041949</PMID>
  </reference>
  <verification_date>January 2021</verification_date>
  <study_first_submitted>July 18, 2014</study_first_submitted>
  <study_first_submitted_qc>July 21, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 23, 2014</study_first_posted>
  <last_update_submitted>January 25, 2021</last_update_submitted>
  <last_update_submitted_qc>January 25, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">January 27, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Chiba University</investigator_affiliation>
    <investigator_full_name>Shunsuke Furuta</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <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>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>Prednisolone</mesh_term>
    <mesh_term>Rituximab</mesh_term>
    <mesh_term>Glucocorticoids</mesh_term>
  </intervention_browse>
  <pending_results>
    <submitted>July 19, 2022</submitted>
    <returned>June 6, 2023</returned>
    <submitted>June 7, 2023</submitted>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02198248
org study id: G25051
secondary id: UMIN000014222
nct id: NCT02198248
lead sponsor: 
has dmc: Yes
Previous reports suggested conventional immunosuppressants such as cyclophosphamide could not
      reduce glucocorticoid dose in remission induction in ANCA-associated vasculitis because of
      lower remission rate and higher relapse rate. However those reports didn't include rituximab.

      B cell depletion therapy by rituximab is a new strategy for remission induction in
      ANCA-associated vasculitis. The RAVE and RITUXVAS trial (NEJM 2010, both) showed high-dose
      glucocorticoid plus rituximab had roughly the same efficacy and safety as high-dose
      glucocorticoid plus IV-cyclophosphamide. In addition, recent retrospective observational
      studies reported low-dose glucocorticoid plus rituximab led to re-induction in severe
      relapsing ANCA-associated vasculitis.

      Thus, the investigators aim to investigate whether rituximab can reduce glucocorticoid dose
      in induction remission in ANCA-associated vasculitis (to show non-inferiority for efficacy
      between low-dose and high-dose glucocorticoid plus rituximab). Participants will be
      randomised to the "low-dose glucocorticoid plus rituximab" or the high-dose glucocorticoid
      plus rituximab" groups. Primary endpoint is proportion of remission at 6 months, then data
      regarding relapse and long-term safety will be collected until 24 months.

      The study has been designed by the principal and coordinating investigators. It will include
      140 participants from 18 hospitals in Japan. It is funded by Chiba University Hospital and
      Chiba East Hospital.
ANCA (anti-neutrophil cytoplasmic antibody)-associated vasculitis is characterised by small
      vessel vasculitis and presence of autoantibodies, ANCA. It can be a life-threatening disease
      with renal/respiratory failure. Current standard therapy in induction remission for
      ANCA-associated vasculitis is combination of high-dose glucocorticoid and
      IV-cyclophosphamide. This regimen is effective (remission rate; 80-90%), but often cause
      various glucocorticoid-related side effects. Especially, infection is related to death. Thus
      a new regimen reducing glucocorticoid dose is required.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Proportion of the patients achieving remission
time frame: 6 months
description: Remission; BVAS ver.3=0 (or 1 with only one minor and persistent BVAS item) and prednisolone <10mg/day
measure: Time to remission
time frame: assessed at 1, 2, 4 and 6 months
description: Remission; BVAS ver.3=0 (or 1 with only one minor and persistent BVAS item) and prednisolone <10mg/day
measure: Overall survival, disease free survival, time to end-stage renal disease, time to the first serious adverse event
time frame: 0-24 months
description: Assessed by Kaplan-Meier curves
measure: Proportions of death, relapse, end-stage renal disease and the composite of these
time frame: at 6 and 24 months
description: Assessed by Kaplan-Meier curves
measure: Proportions of major relapse
time frame: at 24 months
description: major relapse is relapse with one or more BVAS major items
measure: Birmingham Vasculitis Activity Score (BVAS) version 3
time frame: assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months
description: BVAS is a scoring system for assessing disease activity of vasculitis
measure: Vasculitis Damage Index (VDI)
time frame: assessed at 0, 6, 12, 18 and 24 months
description: VDI is a scoring system for assessing irreversible disease damage due to vasculitis
measure: Short-Form 36 (SF-36)
time frame: assessed at 0, 6, 12, 18 and 24 months
description: SF-36 is a scoring system for assessing patient QOL.
measure: Patient global assessment (visualised analogue scale)
time frame: assessed at 0, 6, 12, 18 and 24 months
description: global assessments for disease activity and treatment toxicity
measure: Accumulative dose of glucocorticoids
time frame: assessed at 6 and 24 months
description: Accumulative dose of glucocorticoids during the study period
measure: Numbers of events of adverse events/serious adverse events, proportions of the patients with adverse events/serious adverse events
time frame: at 6 and 24 months
description: Event numbers and proportion of the patients with one or more events are assessed.
measure: Proportions of the patients with new onset diabetes mellitus
time frame: at 6 and 24 months
description: diabetes mellitus requiring drug treatments
measure: Proportion of the patients with new onset insomnia
time frame: at 6 and 24 months
description: insomnia requiring drug treatments
measure: Proportion of the patients with new onset bone fracture, bone density
time frame: at 6 and 24 months
description: bone density is assessed at lumber spines
measure: Number of infections, proportions of the patients with infection
time frame: at 6 and 24 months
description: infections requiring drug treatments
measure: Proportions of the patients with new onset hypertension
time frame: at 6 and 24 months
description: hypertension requiring drug treatments
measure: Proportions of the patients with new onset hyperlipidemia
time frame: at 6 and 24 months
description: hyperlipidemia requiring drug treatments
measure: Proportions of patients achieving remission and discontinuance of glucocorticoids
time frame: at 6 and 24 months
description: Remission is BVAS ver3=0 and prednisolone <10mg/day.
measure: Serum immunoglobulin levels
time frame: assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months
description: Serum immunoglobulin levels
measure: Peripheral blood B cell counts
time frame: assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months
description: CD19 positive B cells assessed by FACS
measure: serum MPO-/PR3-ANCA levels measured by ELISA
time frame: assessed at 0, 1, 2, 4, 6, 9, 12, 18 and 24 months
description: MPO-ANCA and PR3-ANCA are disease specific autoantibodies binding neutrophil cytoplasmic antigen.
arm group label: Low-dose glucocorticoid
arm group type: Experimental
description: Prednisolone will be commenced with dose of 0.5mg/kg/day and will be tapered and off within 6 months. If a patient fails to achieve BVAS=0, an investigator can postpone the procedure of stopping prednisolone (prednisolone 5mg/day x 2 weeks, 4mg/day x 2 weeks, 3mg/day x 4 weeks, 2mg/day x 4 weeks, 1mg/day x 4 weeks, then off prednisolone). Once starting the procedure, prednisolone must be off after 16 weeks. Patients will also receive rituximab (375mg/m2/w x4).
After achieving remission, patients will be receive rituximab (1g/body or 0.5g/bodyx2) every 6 months as remission maintenance therapy.
arm group label: High-dose glucocorticoid
arm group type: Active Comparator
description: Prednisolone will be commenced with dose of 1.0mg/kg/day and will be tapered to 10mg/day within 6 months. Patients will also receive rituximab (375mg/m2/w x4).
After achieving remission, patients will be receive rituximab (1g/body or 0.5g/bodyx2) every 6 months as remission maintenance therapy. There's no limitation by the protocol regarding further prednisolone tapering.
intervention type: Drug
intervention name: Rituximab
description: Patients will be administered rituximab (375mg/m2/w x4 infusions) for reducing glucocorticoid dose in remission induction phase.
arm group label: High-dose glucocorticoid
arm group label: Low-dose glucocorticoid
other name: Rituxan
intervention type: Drug
intervention name: Glucocorticoids
description: "Low-dose" group commenced 0.5mg/kg/day, then taper and stop within 6 months following pre-defined schedule.
"High-dose" group commenced 1.0mg/kg/day, then taper to 10mg/day within 6 months following pre-defined schedule.
arm group label: High-dose glucocorticoid
arm group label: Low-dose glucocorticoid
other name: Predonine
other name: Prednisolone
criteria: 
gender: All
minimum age: 20 Years
maximum age: N/A
healthy volunteers: No
last name: Hiroshi Nakajima, M.D., Ph.D
role: Principal Investigator
affiliation: Chiba University Hospital
facility: 
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country: Japan
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: 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: Jayne DR, Gaskin G, Rasmussen N, Abramowicz D, Ferrario F, Guillevin L, Mirapeix E, Savage CO, Sinico RA, Stegeman CA, Westman KW, van der Woude FJ, de Lind van Wijngaarden RA, Pusey CD; European Vasculitis Study Group. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol. 2007 Jul;18(7):2180-8. doi: 10.1681/ASN.2007010090. Epub 2007 Jun 20.
PMID: 17582159
citation: Fauci AS, Wolff SM, Johnson JS. Effect of cyclophosphamide upon the immune response in Wegener's granulomatosis. N Engl J Med. 1971 Dec 30;285(27):1493-6. doi: 10.1056/NEJM197112302852701. No abstract available.
PMID: 5127139
citation: Popa ER, Stegeman CA, Bos NA, Kallenberg CG, Tervaert JW. Differential B- and T-cell activation in Wegener's granulomatosis. J Allergy Clin Immunol. 1999 May;103(5 Pt 1):885-94. doi: 10.1016/s0091-6749(99)70434-3.
PMID: 10329824
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, 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: Buch MH, Smolen JS, Betteridge N, Breedveld FC, Burmester G, Dorner T, Ferraccioli G, Gottenberg JE, Isaacs J, Kvien TK, Mariette X, Martin-Mola E, Pavelka K, Tak PP, van der Heijde D, van Vollenhoven RF, Emery P; Rituximab Consensus Expert Committee. Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis. 2011 Jun;70(6):909-20. doi: 10.1136/ard.2010.144998. Epub 2011 Mar 6.
PMID: 21378402
citation: Rafailidis PI, Kakisi OK, Vardakas K, Falagas ME. Infectious complications of monoclonal antibodies used in cancer therapy: a systematic review of the evidence from randomized controlled trials. Cancer. 2007 Jun 1;109(11):2182-9. doi: 10.1002/cncr.22666.
PMID: 17429839
citation: Walsh M, Merkel PA, Mahr A, Jayne D. Effects of duration of glucocorticoid therapy on relapse rate in antineutrophil cytoplasmic antibody-associated vasculitis: A meta-analysis. Arthritis Care Res (Hoboken). 2010 Aug;62(8):1166-73. doi: 10.1002/acr.20176.
PMID: 20235186
citation: Wada T, Hara A, Arimura Y, Sada KE, Makino H; Research Group of Intractable Vasculitis, Ministry of Health, Labor, and Welfare of Japan. Risk factors associated with relapse in Japanese patients with microscopic polyangiitis. J Rheumatol. 2012 Mar;39(3):545-51. doi: 10.3899/jrheum.110705. Epub 2011 Dec 15.
PMID: 22174198
citation: Furuta S, Chaudhry AN, Hamano Y, Fujimoto S, Nagafuchi H, Makino H, Matsuo S, Ozaki S, Endo T, Muso E, Ito C, Kusano E, Yamagata M, Ikeda K, Kashiwakuma D, Iwamoto I, Westman K, Jayne D. Comparison of phenotype and outcome in microscopic polyangiitis between Europe and Japan. J Rheumatol. 2014 Feb;41(2):325-33. doi: 10.3899/jrheum.130602. Epub 2014 Jan 15.
PMID: 24429174
citation: Smith RM, Jones RB, Guerry MJ, Laurino S, Catapano F, Chaudhry A, Smith KG, Jayne DR. Rituximab for remission maintenance in relapsing antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2012 Nov;64(11):3760-9. doi: 10.1002/art.34583.
PMID: 22729997
citation: Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, Flores-Suarez LF, Gross WL, Guillevin L, Hagen EC, Hoffman GS, Jayne DR, Kallenberg CG, Lamprecht P, Langford CA, Luqmani RA, Mahr AD, Matteson EL, Merkel PA, Ozen S, Pusey CD, Rasmussen N, Rees AJ, Scott DG, Specks U, Stone JH, Takahashi K, Watts RA. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013 Jan;65(1):1-11. doi: 10.1002/art.37715. No abstract available.
PMID: 23045170
citation: Exley AR, Bacon PA, Luqmani RA, Kitas GD, Gordon C, Savage CO, Adu D. Development and initial validation of the Vasculitis Damage Index for the standardized clinical assessment of damage in the systemic vasculitides. Arthritis Rheum. 1997 Feb;40(2):371-80. doi: 10.1002/art.1780400222.
PMID: 9041949
responsible party type: Principal Investigator
investigator affiliation: Chiba University
investigator full name: Shunsuke Furuta
investigator title: Associate Professor
mesh term: Granulomatosis with Polyangiitis
mesh term: Microscopic Polyangiitis
mesh term: Vasculitis
mesh term: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
mesh term: Prednisolone
mesh term: Rituximab
mesh term: Glucocorticoids
submitted: July 19, 2022
returned: June 6, 2023
submitted: June 7, 2023