<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/NCT02199145</url>
  </required_header>
  <id_info>
    <org_study_id>14-AOI-05</org_study_id>
    <nct_id>NCT02199145</nct_id>
  </id_info>
  <brief_title>Role of Anti-mouse PLA2R1 ELISA in Membranous Nephropathy</brief_title>
  <acronym>SOURIS</acronym>
  <official_title>Indication and Response to Immunosuppressive Treatment in Membranous Nephropathy : Role of Anti-mouse PLA2R1 ELISA</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Centre Hospitalier Universitaire de Nice</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Centre Hospitalier Universitaire de Nice</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Membranous Nephropathy (MN) is an auto-immune kidney disease and a common cause of nephrotic&#xD;
      syndrome. About 30% of MN patients progress to end-stage kidney disease (ESKD) while 30%&#xD;
      undergo spontaneous remission. The phospholipase A2 receptor (PLA2R1) is the major&#xD;
      auto-antigen in idiopathic MN. Anti-PLA2R1 autoantibodies are found during the active phase&#xD;
      of MN. Predictors of disease progression include high titers of anti-PLA2R1 autoantibodies&#xD;
      and serum creatinine levels at presentation, as well as decline in renal function during the&#xD;
      first six months of follow-up. Investigators identified new prognostic factors in a cohort of&#xD;
      41 idiopathic MN patients with nephrotic syndrome and anti-PLA2R1 autoantibodies at the time&#xD;
      of presentation. During a follow-up of at least 36 months, 21 patients had a persistent&#xD;
      nephrotic syndrome (group A) and 20 showed partial or total remission (group R). We first&#xD;
      measured the cross-reactivity of their sera at the time of presentation to human, rabbit and&#xD;
      mouse recombinant PLA2R1 by western blot. All patients exhibited reactivity against human and&#xD;
      rabbit PLA2R1, but only some of them did against mouse PLA2R1. These results suggest the&#xD;
      presence of distinct epitopes that are differentially conserved among PLA2R1&#xD;
      orthologs.Investigators then set-up three parallel ELISAs using human, rabbit and mouse&#xD;
      recombinant PLA2R1. All 41 MN patients showed activity in human and rabbit ELISAs at&#xD;
      presentation but only 32 of them (78%) in mouse ELISA.They finally analyzed the association&#xD;
      between anti-PLA2R1 titers at presentation in the different ELISAs and the subsequent&#xD;
      clinical outcome. The mean anti-PLA2R1 activity was significantly different between group A&#xD;
      and R in mouse ELISA but not in human and rabbit ELISA. Patients with anti-mouse PLA2R1&#xD;
      activity over 605 RU (relative unit)/ml showed a significantly lower survival without&#xD;
      doubling of serum creatinine or ESKD , but patients in the highest tertile of anti-PLA2R1&#xD;
      activity in rabbit and human ELISA did not show a significant increased risk of renal failure&#xD;
      progression. The results suggest that the specific detection of particular anti-PLA2R1&#xD;
      autoantibodies using the novel anti-mouse PLA2R1 ELISA can identify MN patients at risk for&#xD;
      ESKD. The aim is to confirm these result on a prospective cohort.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Membranous Nephropathy (MN) is an auto-immune kidney disease and a common cause of nephrotic&#xD;
      syndrome. About 30% of MN patients progress to end-stage kidney disease (ESKD) while 30%&#xD;
      undergo spontaneous remission. The phospholipase A2 receptor (PLA2R1) is the major&#xD;
      auto-antigen in idiopathic MN. Anti-PLA2R1 autoantibodies are found during the active phase&#xD;
      of MN [2,3]. Predictors of disease progression include high titers of anti-PLA2R1&#xD;
      autoantibodies and serum creatinine levels at presentation, as well as decline in renal&#xD;
      function during the first six months of follow-up. Investigators identified new prognostic&#xD;
      factors in a cohort of 41 idiopathic MN patients with nephrotic syndrome and anti-PLA2R1&#xD;
      autoantibodies at the time of presentation. During a follow-up of at least 36 months, 21&#xD;
      patients had a persistent nephrotic syndrome (group A) and 20 showed partial or total&#xD;
      remission (group R). We first measured the cross-reactivity of their sera at the time of&#xD;
      presentation to human, rabbit and mouse recombinant PLA2R1 by western blot. All patients&#xD;
      exhibited reactivity against human and rabbit PLA2R1, but only some of them did against mouse&#xD;
      PLA2R1. These results suggest the presence of distinct epitopes that are differentially&#xD;
      conserved among PLA2R1 orthologs. We then set-up three parallel ELISAs using human, rabbit&#xD;
      and mouse recombinant PLA2R1. All 41 MN patients showed activity in human and rabbit ELISAs&#xD;
      at presentation but only 32 of them (78%) in mouse ELISA.&#xD;
&#xD;
      Investigators finally analyzed the association between anti-PLA2R1 titers at presentation in&#xD;
      the different ELISAs and the subsequent clinical outcome. The mean anti-PLA2R1 activity was&#xD;
      significantly different between group A and R in mouse ELISA in both univariate and&#xD;
      multivariate analyses (p =0.006 and p =0.02, respectively) but not in human and rabbit&#xD;
      ELISAs. An analysis of the mouse ELISA titers defines a threshold of 605 RU/ml above which&#xD;
      100% of patients had a poor prognosis, but no such threshold could be defined in rabbit and&#xD;
      human ELISA. Patients with anti-mouse PLA2R1 activity over 605 RU/ml showed a significantly&#xD;
      lower survival without doubling of serum creatinine or ESKD (p=0.002 using the log-rank&#xD;
      test), but patients in the highest tertile of anti-PLA2R1 activity in rabbit and human ELISAs&#xD;
      did not show a significant increased risk of renal failure progression. The results suggest&#xD;
      that the specific detection of particular anti-PLA2R1 autoantibodies using the novel&#xD;
      anti-mouse PLA2R1 ELISA can identify MN patients at risk for ESKD. The aim is to confirm&#xD;
      these result on a prospective cohort.We propose to measure on a prospective cohort at the&#xD;
      time of MN diagnosis if high titer of anti-mPLA2R1 Ab (anti-mouse phospholipase A2 receptor1&#xD;
      antibodies) is associated with nephrotic proteinuria (over 3.5 g/g) or increased of&#xD;
      creatininemia over 30% at month 6, 12 and 18. An ancillary study will try to characterised&#xD;
      the nephrogenic epitope conserved between human, rabbit and mouse.&#xD;
&#xD;
      Each patient with nephrotic syndrome should benefit of a kidney biopsy. For each patient we&#xD;
      will conserved 2 dry tubes frozen at the time of biopsy. If we confirm the diagnosis of MN&#xD;
      with anti-PLA2R1 Ab, we propose to the patient to be included in this study. He will have a&#xD;
      visit every months for the first three months and every three months after, with collection&#xD;
      of the following: blood pressure, weight, creatinine, albumin, blood electrolytes,&#xD;
      proteinuria / creatinine in sample 1 assay Ac anti-PLA2R1 on 3 ELISA (human, rabbit and&#xD;
      mouse) In case of persistent refractory nephrotic syndrome after 6 months, or the appearance&#xD;
      of a 30% increase in serum creatinine, treatment with rituximab (2 × 1 g IV 15 days) will be&#xD;
      proposed. Clinical and biological monitoring will be continued every 3 months for 18 months.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">July 17, 2015</start_date>
  <completion_date type="Anticipated">August 2020</completion_date>
  <primary_completion_date type="Anticipated">February 2019</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change from baseline Creatininemia level</measure>
    <time_frame>at 6, 12 and 18 months</time_frame>
    <description>30% increase in creatininemia after 6 months of symptomatic treatment with RAAS blocker</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Remission rate in MN</measure>
    <time_frame>at 12 months</time_frame>
    <description>Remission rate in MN one year after Rituximab with absence of nephrotic syndrome and renal insufficiency (estimated by MDRD&gt; 60 ml/min/1, 73m2).&#xD;
(MDRD=Modification of the Diet in Renal Disease)</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">50</enrollment>
  <condition>Membranous Nephropathy</condition>
  <arm_group>
    <arm_group_label>Blood and urine analysis</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>creatinine, albumin, blood electrolytes, proteinuria /creatinine in sample 1 assay Ac anti-PLA2R1 on 3 ELISA (human, rabbit and mouse)</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Blood and urine analysis</intervention_name>
    <description>creatinine, albumin, blood electrolytes, proteinuria / creatinine in sample 1 assay Ac anti-PLA2R1 on 3 ELISA (human, rabbit and mouse)</description>
    <arm_group_label>Blood and urine analysis</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adult patients&#xD;
&#xD;
          -  Patients with MN stade I-II confirmed by kidney biopsy&#xD;
&#xD;
          -  Patients with MDRD&gt;30 ml/mn/1.73m2&#xD;
&#xD;
          -  Patients with anti-PLA2R1 antibodies&#xD;
&#xD;
          -  Effective Contraception for women of childbearing age&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients minors&#xD;
&#xD;
          -  Patients refusing to participate in the study&#xD;
&#xD;
          -  Patients with secondary MN (systemic Lupus, hepatitis B virus, hepatitis C virus or&#xD;
             cancer)&#xD;
&#xD;
          -  Pregnant women: a urine pregnancy test will be performed for women of childbearing&#xD;
             age. The results will be communicated to the patient by a doctor of his choice.&#xD;
&#xD;
          -  Persons deprived of liberty (administrative or judicial)&#xD;
&#xD;
          -  Persons under guardianship&#xD;
&#xD;
          -  People may not understand the research&#xD;
&#xD;
          -  Persons under guardianship, under judicial protection&#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>Barbara SEITZ-POLSKI, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Nice University Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>CHU de Besançon</name>
      <address>
        <city>Besançon</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Cecile COURIVAUD, MD</last_name>
      <email>ccourivaud@chu-besancon.fr</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>AP-HM</name>
      <address>
        <city>Marseille</city>
        <zip>13354</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Stéphane BURTEY, PU-PH</last_name>
      <email>stephane.burtey@ap-hm.fr</email>
    </contact>
    <investigator>
      <last_name>Stéphane BURTEY, PU-PH</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Nephrology Department, Nice University Hospital</name>
      <address>
        <city>Nice</city>
        <zip>06003</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Barbara SEITZ-POLSKI, PhD</last_name>
      <email>seitz-polski.b@chu-nice.fr</email>
    </contact>
    <investigator>
      <last_name>Barbara SEITZ-POLSKI, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>February 2018</verification_date>
  <study_first_submitted>July 22, 2014</study_first_submitted>
  <study_first_submitted_qc>July 23, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 24, 2014</study_first_posted>
  <last_update_submitted>February 15, 2018</last_update_submitted>
  <last_update_submitted_qc>February 15, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">February 19, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Kidney Diseases</mesh_term>
    <mesh_term>Glomerulonephritis, Membranous</mesh_term>
  </condition_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/NCT02199145
org study id: 14-AOI-05
nct id: NCT02199145
lead sponsor: 
has dmc: No
Membranous Nephropathy (MN) is an auto-immune kidney disease and a common cause of nephrotic
      syndrome. About 30% of MN patients progress to end-stage kidney disease (ESKD) while 30%
      undergo spontaneous remission. The phospholipase A2 receptor (PLA2R1) is the major
      auto-antigen in idiopathic MN. Anti-PLA2R1 autoantibodies are found during the active phase
      of MN. Predictors of disease progression include high titers of anti-PLA2R1 autoantibodies
      and serum creatinine levels at presentation, as well as decline in renal function during the
      first six months of follow-up. Investigators identified new prognostic factors in a cohort of
      41 idiopathic MN patients with nephrotic syndrome and anti-PLA2R1 autoantibodies at the time
      of presentation. During a follow-up of at least 36 months, 21 patients had a persistent
      nephrotic syndrome (group A) and 20 showed partial or total remission (group R). We first
      measured the cross-reactivity of their sera at the time of presentation to human, rabbit and
      mouse recombinant PLA2R1 by western blot. All patients exhibited reactivity against human and
      rabbit PLA2R1, but only some of them did against mouse PLA2R1. These results suggest the
      presence of distinct epitopes that are differentially conserved among PLA2R1
      orthologs.Investigators then set-up three parallel ELISAs using human, rabbit and mouse
      recombinant PLA2R1. All 41 MN patients showed activity in human and rabbit ELISAs at
      presentation but only 32 of them (78%) in mouse ELISA.They finally analyzed the association
      between anti-PLA2R1 titers at presentation in the different ELISAs and the subsequent
      clinical outcome. The mean anti-PLA2R1 activity was significantly different between group A
      and R in mouse ELISA but not in human and rabbit ELISA. Patients with anti-mouse PLA2R1
      activity over 605 RU (relative unit)/ml showed a significantly lower survival without
      doubling of serum creatinine or ESKD , but patients in the highest tertile of anti-PLA2R1
      activity in rabbit and human ELISA did not show a significant increased risk of renal failure
      progression. The results suggest that the specific detection of particular anti-PLA2R1
      autoantibodies using the novel anti-mouse PLA2R1 ELISA can identify MN patients at risk for
      ESKD. The aim is to confirm these result on a prospective cohort.
Membranous Nephropathy (MN) is an auto-immune kidney disease and a common cause of nephrotic
      syndrome. About 30% of MN patients progress to end-stage kidney disease (ESKD) while 30%
      undergo spontaneous remission. The phospholipase A2 receptor (PLA2R1) is the major
      auto-antigen in idiopathic MN. Anti-PLA2R1 autoantibodies are found during the active phase
      of MN [2,3]. Predictors of disease progression include high titers of anti-PLA2R1
      autoantibodies and serum creatinine levels at presentation, as well as decline in renal
      function during the first six months of follow-up. Investigators identified new prognostic
      factors in a cohort of 41 idiopathic MN patients with nephrotic syndrome and anti-PLA2R1
      autoantibodies at the time of presentation. During a follow-up of at least 36 months, 21
      patients had a persistent nephrotic syndrome (group A) and 20 showed partial or total
      remission (group R). We first measured the cross-reactivity of their sera at the time of
      presentation to human, rabbit and mouse recombinant PLA2R1 by western blot. All patients
      exhibited reactivity against human and rabbit PLA2R1, but only some of them did against mouse
      PLA2R1. These results suggest the presence of distinct epitopes that are differentially
      conserved among PLA2R1 orthologs. We then set-up three parallel ELISAs using human, rabbit
      and mouse recombinant PLA2R1. All 41 MN patients showed activity in human and rabbit ELISAs
      at presentation but only 32 of them (78%) in mouse ELISA.

      Investigators finally analyzed the association between anti-PLA2R1 titers at presentation in
      the different ELISAs and the subsequent clinical outcome. The mean anti-PLA2R1 activity was
      significantly different between group A and R in mouse ELISA in both univariate and
      multivariate analyses (p =0.006 and p =0.02, respectively) but not in human and rabbit
      ELISAs. An analysis of the mouse ELISA titers defines a threshold of 605 RU/ml above which
      100% of patients had a poor prognosis, but no such threshold could be defined in rabbit and
      human ELISA. Patients with anti-mouse PLA2R1 activity over 605 RU/ml showed a significantly
      lower survival without doubling of serum creatinine or ESKD (p=0.002 using the log-rank
      test), but patients in the highest tertile of anti-PLA2R1 activity in rabbit and human ELISAs
      did not show a significant increased risk of renal failure progression. The results suggest
      that the specific detection of particular anti-PLA2R1 autoantibodies using the novel
      anti-mouse PLA2R1 ELISA can identify MN patients at risk for ESKD. The aim is to confirm
      these result on a prospective cohort.We propose to measure on a prospective cohort at the
      time of MN diagnosis if high titer of anti-mPLA2R1 Ab (anti-mouse phospholipase A2 receptor1
      antibodies) is associated with nephrotic proteinuria (over 3.5 g/g) or increased of
      creatininemia over 30% at month 6, 12 and 18. An ancillary study will try to characterised
      the nephrogenic epitope conserved between human, rabbit and mouse.

      Each patient with nephrotic syndrome should benefit of a kidney biopsy. For each patient we
      will conserved 2 dry tubes frozen at the time of biopsy. If we confirm the diagnosis of MN
      with anti-PLA2R1 Ab, we propose to the patient to be included in this study. He will have a
      visit every months for the first three months and every three months after, with collection
      of the following: blood pressure, weight, creatinine, albumin, blood electrolytes,
      proteinuria / creatinine in sample 1 assay Ac anti-PLA2R1 on 3 ELISA (human, rabbit and
      mouse) In case of persistent refractory nephrotic syndrome after 6 months, or the appearance
      of a 30% increase in serum creatinine, treatment with rituximab (2 × 1 g IV 15 days) will be
      proposed. Clinical and biological monitoring will be continued every 3 months for 18 months.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Change from baseline Creatininemia level
time frame: at 6, 12 and 18 months
description: 30% increase in creatininemia after 6 months of symptomatic treatment with RAAS blocker
measure: Remission rate in MN
time frame: at 12 months
description: Remission rate in MN one year after Rituximab with absence of nephrotic syndrome and renal insufficiency (estimated by MDRD> 60 ml/min/1, 73m2).
(MDRD=Modification of the Diet in Renal Disease)
arm group label: Blood and urine analysis
arm group type: Other
description: creatinine, albumin, blood electrolytes, proteinuria /creatinine in sample 1 assay Ac anti-PLA2R1 on 3 ELISA (human, rabbit and mouse)
intervention type: Procedure
intervention name: Blood and urine analysis
description: creatinine, albumin, blood electrolytes, proteinuria / creatinine in sample 1 assay Ac anti-PLA2R1 on 3 ELISA (human, rabbit and mouse)
arm group label: Blood and urine analysis
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Barbara SEITZ-POLSKI, PhD
role: Principal Investigator
affiliation: Nice University Hospital
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
country: France
responsible party type: Sponsor
mesh term: Kidney Diseases
mesh term: Glomerulonephritis, Membranous