<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/NCT01731561</url>
  </required_header>
  <id_info>
    <org_study_id>P110146</org_study_id>
    <secondary_id>2012-001963-66</secondary_id>
    <nct_id>NCT01731561</nct_id>
  </id_info>
  <brief_title>Comparison Study of Two Rituximab Regimens in the Remission of ANCA Associated Vasculitis</brief_title>
  <acronym>MAINRITSAN 2</acronym>
  <official_title>MAINtenance of Remission Using RITuximab in Systemic ANCA-associated Vasculitis II</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assistance Publique - Hôpitaux de Paris</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Assistance Publique - Hôpitaux de Paris</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The aim of this study is to assess the efficacy of a rituximab regimen based on rate of ANCA&#xD;
      and CD19 lymphocytes for maintenance treatment in systemic ANCA-associated vasculitis:&#xD;
      prospective, multicenter, controlled, randomized comparative study of two rituximab regimens:&#xD;
      one based on ANCA and CD19 lymphocytes versus systematic infusions.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Randomized, controlled, national, multicenter, prospective study to compare systematic&#xD;
      rituximab infusions (conventional therapy) to rituximab infusion based on rate of ANCA and&#xD;
      CD19 lymphocytes in patients with systemic ANCA-associated vasculitis, in remission (achieved&#xD;
      with an induction treatment combining corticosteroids and an immunosuppressant after the&#xD;
      first flare of the disease (new diagnosis) or after a relapse. Patients will be stratified by&#xD;
      first flare (66% of the patients) or relapse (33% of the patients). Patients complying with&#xD;
      the inclusion criteria may be included when they are in remission from their vasculitis.&#xD;
      Patients will be included at the time of remission and then randomized. They will receive&#xD;
      maintenance treatment by 1)2 rituximab infusions mg at D1, D15 then every 6 months until&#xD;
      month 18 (i.e. a total of 5 infusions), at the dose of 500 mg. 2) 1 rituximab infusion at the&#xD;
      dose of 500 mg at D0 then ANCA status and CD19+ lymphocyte count will be monitored every 3&#xD;
      months, and patients will receive new 500 mg rituximab infusions either if CD19 are &gt; to&#xD;
      0/mm3, or if ANCA are positive again or if ANCA titer significantly raises. After the 18&#xD;
      month length of maintenance phase, i.e. after stopping immunosuppressive maintenance therapy,&#xD;
      patients will be followed for an additional 10 month period. Patients with granulomatosis&#xD;
      with polyangiitis will be prescribed cotrimoxazole 160/800 tid (for 2 additional years).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 16, 2012</start_date>
  <completion_date type="Actual">April 5, 2016</completion_date>
  <primary_completion_date type="Actual">April 5, 2016</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>Number of relapses</measure>
    <time_frame>at 28 months</time_frame>
    <description>Number of relapses (BVAS&gt;0) majors and minors in each group at the end of the maintenance treatment (18 months treatment + 10 months follow-up)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of patients with ANCA (Anti-Neutrophil Cytoplasmatic Antibodies)</measure>
    <time_frame>at 28 months</time_frame>
    <description>Number of patients with ANCA in each group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of adverse events</measure>
    <time_frame>at 28 months</time_frame>
    <description>To assess the number of adverse events and their severity in each group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality rate</measure>
    <time_frame>at 28 months</time_frame>
    <description>To assess mortality rate in each group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of minor relapse</measure>
    <time_frame>at 28 months</time_frame>
    <description>number of minor relapse in each group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulated dose of corticosteroid treatment</measure>
    <time_frame>at 28 months</time_frame>
    <description>Cumulated dose of corticosteroid treatment in each group at 28 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number and severity of damages</measure>
    <time_frame>at 28 months</time_frame>
    <description>Number and severity of damages in each group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evolution of ANCA and the link of the clinical events</measure>
    <time_frame>at 28 months</time_frame>
    <description>Evolution of ANCA in each group and the link of the clinical events</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Distribution of events by severity</measure>
    <time_frame>at 28 months</time_frame>
    <description>Distribution of events by severity and it will be assigned to the drug and its mode of administration and/or the severity of the disease (in each group).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of corticosteroid treatment</measure>
    <time_frame>at 28 months</time_frame>
    <description>The length of corticosteroid treatment in each group at 28 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of B-Lymphocytes CD-19 and the link of the clinical events</measure>
    <time_frame>at 28 months</time_frame>
    <description>The rate of B-Lymphocytes CD-19 and the link of the clinical events</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evolution of gammaglobulins</measure>
    <time_frame>at 28 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life : SF36 (The Short Form (36) Health Survey)</measure>
    <time_frame>at 28 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Functional capacities : HAQ (Health Assessment Questionnaire)</measure>
    <time_frame>at 28 months</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">166</enrollment>
  <condition>Granulomatosis With Polyangiitis</condition>
  <condition>Microscopic Polyangiitis</condition>
  <condition>Renal Limited Forms</condition>
  <arm_group>
    <arm_group_label>Rituximab infusion according biological parameters</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Rituximab infusion based on ANCA and CD19 lymphocytes</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Systematic rituximab infusion</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Semestrial rituximab infusion until 18 months</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rituximab (Arm B)</intervention_name>
    <description>Rituximab infusion will be performed at D1 then ANCA status and CD19+ lymphocyte count will be monitored every 3 months, and patients will receive new 500 mg rituximab infusions either if CD19 are &gt; to 0/mm3, or if ANCA are positive again or if ANCA titer significantly raises. All patients received corticosteroids, starting from induction with prednisone (or equivalent) at a dose of 1 mg/kg/day with gradual tapering according to a regimen adjusted to body weight over a mean of 18 months since diagnosis.</description>
    <arm_group_label>Rituximab infusion according biological parameters</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rituximab (Arm A)</intervention_name>
    <description>Rituximab infusion will be performed at D1, D15, M6, M12 and M18(i.e. a total of 5 infusions), at the dose of 500 mg at a fixed dosage.All patients received corticosteroids, starting from induction with prednisone (or equivalent) at a dose of 1 mg/kg/day with gradual tapering according to a regimen adjusted to body weight over a mean of 18 months since diagnosis.</description>
    <arm_group_label>Systematic rituximab infusion</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Granulomatosis with Polyangiitis Or microscopic polyangiitis complying Or&#xD;
             kidney-limited disease With or without detectable ANCA (anti-neutrophil cytoplasmic&#xD;
             antibodies) at the time of diagnosis or relapse, and at remission.&#xD;
&#xD;
          -  Who have achieved remission using a treatment combining corticosteroids and an&#xD;
             immunosuppressive agent, including corticosteroids, cyclophosphamide IV or oral (the&#xD;
             use of another immunosuppressant is allowed, according to the current French&#xD;
             guidelines, as well as plasma exchanges and/or IV immunoglobulins, or rituximab).&#xD;
&#xD;
          -  Interval of 1 month between the end of the immunosuppressant treatment and the&#xD;
             randomization time if cyclophosphamide or methotrexate were used, interval between 4&#xD;
             and 6 months if rituximab was used&#xD;
&#xD;
          -  Age &gt; 18 years without age limit higher when the diagnosis is confirmed.&#xD;
&#xD;
          -  Informed and having signed the consent form to take part in the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Other systemic vasculitis&#xD;
&#xD;
          -  Secondary vasculitis (following neoplastic disease or an infection in particular)&#xD;
&#xD;
          -  Induction treatment with a regimen not corresponding to that recommended in France.&#xD;
&#xD;
          -  Patient who has not achieved remission.&#xD;
&#xD;
          -  Incapacity or refusal to understand or sign the informed consent form.&#xD;
&#xD;
          -  Incapacity or refusal to adhere to treatment or perform the follow-up examinations&#xD;
             required by the study. Non-compliance&#xD;
&#xD;
          -  Allergy, documented hypersensitivity or contraindication to the study medication&#xD;
             (cyclophosphamide, corticosteroids, azathioprine, rituximab)&#xD;
&#xD;
          -  History of severe allergic or anaphylactic reactions to humanized or murine monoclonal&#xD;
             antibodies.&#xD;
&#xD;
          -  Pregnancy, breastfeeding. Women of childbearing age must use a reliable method of&#xD;
             contraception throughout the duration of immunosuppressive treatment up to 1 year&#xD;
             after the last infusion of rituximab&#xD;
&#xD;
          -  Infection by HIV, HCV or HBV&#xD;
&#xD;
          -  Progressive, uncontrolled infection requiring a prolonged treatment (tuberculosis, HIV&#xD;
             infection, etc.).&#xD;
&#xD;
          -  Severe infection declared during the 3 months before randomization (CMV, HBV, HHV8,&#xD;
             HCV, HIV, tuberculosis).&#xD;
&#xD;
          -  Progressive cancer or malignant blood disease diagnosed during the 5 years before the&#xD;
             diagnosis of vasculitis. Patients suffering from non-metastatic prostate cancer or&#xD;
             those cured of a cancer or a malignant blood disorder for more than 5 years and not&#xD;
             taking any antineoplastic agents for more than 5 years may be included.&#xD;
&#xD;
          -  Participation in another clinical research protocol during the 4 weeks before&#xD;
             inclusion.&#xD;
&#xD;
          -  Any medical or psychiatric disorder which, in the investigator's opinion, may prevent&#xD;
             the administration of treatment and patient follow-up according to the protocol,&#xD;
             and/or which may expose the patient to a too greater risk of an adverse effect.&#xD;
&#xD;
          -  No social security&#xD;
&#xD;
          -  Churg and Strauss syndrome&#xD;
&#xD;
          -  Viral, bacterial or fungic or mycobacterial infection uncontrolled in the 4 weeks&#xD;
             before the inclusion&#xD;
&#xD;
          -  History of deep tissue infection (fasciitis, osteomyelitis, septic arthritis)in the&#xD;
             first year before the inclusion&#xD;
&#xD;
          -  History of chronic and severe or recurrent infection or history of preexisting disease&#xD;
             predisposing to severe infection&#xD;
&#xD;
          -  Severe immunodepression&#xD;
&#xD;
          -  Administration of live vaccine in the four weeks before inclusion&#xD;
&#xD;
          -  Severe chronic obstructive pulmonary diseases (VEMS &lt; 50 % or dyspnea grade III)&#xD;
&#xD;
          -  Chronic heart failure stade III and IV (NYHA)&#xD;
&#xD;
          -  History of recent acute coronary syndrome, unrelated to vasculitis&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Loic Guillevin, MD, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Cochin Hospital, Paris, France</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Pierre Charles, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Institut mutualiste, Paris, France</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cochin Hospital</name>
      <address>
        <city>Paris</city>
        <zip>75014</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <link>
    <url>http://www.vascularites.org</url>
    <description>Website of the French Vasculitis Study Group</description>
  </link>
  <verification_date>February 2018</verification_date>
  <study_first_submitted>October 12, 2012</study_first_submitted>
  <study_first_submitted_qc>November 16, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 22, 2012</study_first_posted>
  <last_update_submitted>March 1, 2018</last_update_submitted>
  <last_update_submitted_qc>March 1, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">March 2, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Granulomatosis with Polyangiitis</keyword>
  <keyword>Microscopic polyangiitis</keyword>
  <keyword>Renal limited forms</keyword>
  <keyword>ANCA-associated vasculitis</keyword>
  <keyword>Rituximab</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>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01731561
org study id: P110146
secondary id: 2012-001963-66
nct id: NCT01731561
lead sponsor: 
has dmc: No
The aim of this study is to assess the efficacy of a rituximab regimen based on rate of ANCA
      and CD19 lymphocytes for maintenance treatment in systemic ANCA-associated vasculitis:
      prospective, multicenter, controlled, randomized comparative study of two rituximab regimens:
      one based on ANCA and CD19 lymphocytes versus systematic infusions.
Randomized, controlled, national, multicenter, prospective study to compare systematic
      rituximab infusions (conventional therapy) to rituximab infusion based on rate of ANCA and
      CD19 lymphocytes in patients with systemic ANCA-associated vasculitis, in remission (achieved
      with an induction treatment combining corticosteroids and an immunosuppressant after the
      first flare of the disease (new diagnosis) or after a relapse. Patients will be stratified by
      first flare (66% of the patients) or relapse (33% of the patients). Patients complying with
      the inclusion criteria may be included when they are in remission from their vasculitis.
      Patients will be included at the time of remission and then randomized. They will receive
      maintenance treatment by 1)2 rituximab infusions mg at D1, D15 then every 6 months until
      month 18 (i.e. a total of 5 infusions), at the dose of 500 mg. 2) 1 rituximab infusion at the
      dose of 500 mg at D0 then ANCA status and CD19+ lymphocyte count will be monitored every 3
      months, and patients will receive new 500 mg rituximab infusions either if CD19 are > to
      0/mm3, or if ANCA are positive again or if ANCA titer significantly raises. After the 18
      month length of maintenance phase, i.e. after stopping immunosuppressive maintenance therapy,
      patients will be followed for an additional 10 month period. Patients with granulomatosis
      with polyangiitis will be prescribed cotrimoxazole 160/800 tid (for 2 additional years).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of relapses
time frame: at 28 months
description: Number of relapses (BVAS>0) majors and minors in each group at the end of the maintenance treatment (18 months treatment + 10 months follow-up)
measure: Number of patients with ANCA (Anti-Neutrophil Cytoplasmatic Antibodies)
time frame: at 28 months
description: Number of patients with ANCA in each group
measure: Number of adverse events
time frame: at 28 months
description: To assess the number of adverse events and their severity in each group
measure: Mortality rate
time frame: at 28 months
description: To assess mortality rate in each group
measure: Number of minor relapse
time frame: at 28 months
description: number of minor relapse in each group
measure: Cumulated dose of corticosteroid treatment
time frame: at 28 months
description: Cumulated dose of corticosteroid treatment in each group at 28 months
measure: Number and severity of damages
time frame: at 28 months
description: Number and severity of damages in each group
measure: Evolution of ANCA and the link of the clinical events
time frame: at 28 months
description: Evolution of ANCA in each group and the link of the clinical events
measure: Distribution of events by severity
time frame: at 28 months
description: Distribution of events by severity and it will be assigned to the drug and its mode of administration and/or the severity of the disease (in each group).
measure: Length of corticosteroid treatment
time frame: at 28 months
description: The length of corticosteroid treatment in each group at 28 months
measure: Rate of B-Lymphocytes CD-19 and the link of the clinical events
time frame: at 28 months
description: The rate of B-Lymphocytes CD-19 and the link of the clinical events
measure: Evolution of gammaglobulins
time frame: at 28 months
measure: Quality of life : SF36 (The Short Form (36) Health Survey)
time frame: at 28 months
measure: Functional capacities : HAQ (Health Assessment Questionnaire)
time frame: at 28 months
arm group label: Rituximab infusion according biological parameters
arm group type: Experimental
description: Rituximab infusion based on ANCA and CD19 lymphocytes
arm group label: Systematic rituximab infusion
arm group type: Active Comparator
description: Semestrial rituximab infusion until 18 months
intervention type: Drug
intervention name: Rituximab (Arm B)
description: Rituximab infusion will be performed at D1 then ANCA status and CD19+ lymphocyte count will be monitored every 3 months, and patients will receive new 500 mg rituximab infusions either if CD19 are > to 0/mm3, or if ANCA are positive again or if ANCA titer significantly raises. All patients received corticosteroids, starting from induction with prednisone (or equivalent) at a dose of 1 mg/kg/day with gradual tapering according to a regimen adjusted to body weight over a mean of 18 months since diagnosis.
arm group label: Rituximab infusion according biological parameters
intervention type: Drug
intervention name: Rituximab (Arm A)
description: Rituximab infusion will be performed at D1, D15, M6, M12 and M18(i.e. a total of 5 infusions), at the dose of 500 mg at a fixed dosage.All patients received corticosteroids, starting from induction with prednisone (or equivalent) at a dose of 1 mg/kg/day with gradual tapering according to a regimen adjusted to body weight over a mean of 18 months since diagnosis.
arm group label: Systematic rituximab infusion
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Loic Guillevin, MD, PhD
role: Study Chair
affiliation: Cochin Hospital, Paris, France
last name: Pierre Charles, MD
role: Study Chair
affiliation: Institut mutualiste, Paris, France
facility: 
country: France
url: http://www.vascularites.org
description: Website of the French Vasculitis Study Group
responsible party type: Sponsor
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