<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/NCT02201576</url>
  </required_header>
  <id_info>
    <org_study_id>P120119</org_study_id>
    <nct_id>NCT02201576</nct_id>
  </id_info>
  <brief_title>Bortezomib in Rejection of Kidney Transplants</brief_title>
  <acronym>TRIBUTE</acronym>
  <official_title>Treatment of Chronic Active Antibody-mediated Rejection With Bortezomib in Kidney Transplantation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assistance Publique - Hôpitaux de Paris</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Fondation Centaure</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Assistance Publique - Hôpitaux de Paris</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of the study is to assess the efficacy of bortezomib, in association with&#xD;
      steroids, plasma exchange, and polyclonal intravenous immunoglobulins, in the treatment of&#xD;
      chronic antibody mediated rejection due to donor specific anti-HLA antibodies, in kidney&#xD;
      transplant recipients&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Chronic active antibody-mediated rejection (AMR) is considered as a main cause of late&#xD;
      allograft losses in kidney transplant recipients. It is due to the occurrence of de novo&#xD;
      donor-specific anti-HLA antibodies (DSA), i.e. antibodies synthetized by the recipient after&#xD;
      transplantation against its transplant. There is currently to efficient treatment. The&#xD;
      purpose of our study is to determine the efficacy of bortezomib, a proteasome inhibitor, in&#xD;
      the treatment of chronic active antibody-mediated rejection, in association with steroids,&#xD;
      plasma exchanges, and polyclonal intravenous immunoglobulins. Patients are recipients of a&#xD;
      first or a second kidney transplant for more than 3 months. They display de novo DSA i.e. DSA&#xD;
      not detected the day of transplantation and in pre-transplant sera.. They display signs of&#xD;
      chronic active AMR on kidney biopsy i.e. a glomerulitis (g) + peritubular capillaritis (ptc)&#xD;
      Banff score g+ptc ≥ 2, with or without severe chronic glomerulopathy (Banff score cg&lt;3).&#xD;
      Kidney biopsy may have been performed systematically or because of: :&#xD;
&#xD;
        1. detection of de novo DSA ,&#xD;
&#xD;
        2. and /or proteinuria (&gt; 0.5 g/24h)&#xD;
&#xD;
        3. and /or slow graft dysfunction protocol biopsy Primary endpoint is a combined endpoint&#xD;
           one year after inclusion, consisting of the stabilization of histological lesions on a&#xD;
           new kidney biopsy (delta g+ptc ≤1 and delta cg &lt; 1) and a decrease in DSA mean&#xD;
           fluorescence intensity &gt; 50%.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 11, 2015</start_date>
  <completion_date type="Actual">July 16, 2020</completion_date>
  <primary_completion_date type="Actual">July 16, 2020</primary_completion_date>
  <phase>Phase 2</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>histological lesions of humoral rejection and immunodominant donor specific antibody</measure>
    <time_frame>one year</time_frame>
    <description>Between inclusion biopsy and end of study biopsy delta g+ptc ≤1 and delta cg &lt; 1 (Banff score of glomerulitis (g) capillaritis (ptc) and chronic allograft glomerulopathy (cg) Between inclusion and end of study, decrease in mean fluorescence intensity (MFI) of the immunodominant donor specific anti-HLA antibody (DSA with the highest MFI) by Luminex greater than 50%</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>histological lesions of humoral rejection</measure>
    <time_frame>one year</time_frame>
    <description>Between inclusion biopsy and end of study biopsy delta g+ptc ≤1 and delta cg &lt; 1 (Banff score of glomerulitis (g) capillaritis (ptc) and chronic allograft glomerulopathy (cg)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>immunodominant donor specific antibody</measure>
    <time_frame>one year</time_frame>
    <description>Between inclusion and end of study, decrease in mean fluorescence intensity (MFI) of the immunodominant donor specific anti-HLA antibody (DSA with the highest MFI) by Luminex greater than 50%</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>all donor specific antibodies at one year</measure>
    <time_frame>one year</time_frame>
    <description>Between inclusion and end of study, variation of the title of each DSA and the sum of the DSAs</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>all donor specific antibodies</measure>
    <time_frame>6 months</time_frame>
    <description>Between inclusion and month-6, evolution in mean fluorescence intensity (MFI) of all donor specific anti-HLA antibodies by Luminex</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Histological lesions</measure>
    <time_frame>one year</time_frame>
    <description>Description of all histological lesions observed at one-year biopsy according to the Banff classification and comparison with inclusion biopsy: acute cellular rejection, interstitial fibrosis and tubular atrophy, chronic vascular lesions (arteriolar hyalinosis, fibro-intimal thickening), chronic rejection (transplant glomerulopathy, fibroproliferative endarteritis)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>renal function and proteinuria</measure>
    <time_frame>one year</time_frame>
    <description>Evolution between inclusion and end of study at one-year of serum creatinine, estimated GFR (MDRD formula), proteinuria output, proteinuria/creatinuria ratio</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety of bortezomib in renal transplant recipients</measure>
    <time_frame>one year</time_frame>
    <description>Infectious and non-infectious adverse events occurring during study in the two arms of treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient and graft survival</measure>
    <time_frame>one year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>T and B lymphocytes subsets with bortezomib</measure>
    <time_frame>one year</time_frame>
    <description>Flow cytometry study of T and B lymphocytes subsets at inclusion, month-6 and month-12 in patients treated with bortezomib</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">60</enrollment>
  <condition>Chronic Antibody-mediated Transplant Rejection</condition>
  <arm_group>
    <arm_group_label>Bortezomib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Five plasma exchanges, two cycles of bortezomib + dexamethasone, 4 courses of polyclonal intravenous immunoglobulins</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Five plasma exchanges, dexamethasone, 4 courses of polyclonal intravenous immunoglobulins</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bortezomib</intervention_name>
    <description>Five plasma exchanges +0.1 g/kg of intravenous immunoglobulins at the end of each course&#xD;
two cycles of bortezomib (1.3 mg/m2 IV at day-1, day-4, day-8, day-11) + oral dexamethasone (20 mg po at day-1, day-4, day-8, day-11)&#xD;
four courses of polyclonal intravenous immunoglobulins every three weeks (2g/kg, the first two courses are performed simultaneously with the two bortezomib cycles)</description>
    <arm_group_label>Bortezomib</arm_group_label>
    <other_name>Velcade</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Plasma exchanges and intravenous immunoglobulins</intervention_name>
    <description>Five plasma exchanges +0.1 g/kg of intravenous immunoglobulins at the end of each course&#xD;
four courses of polyclonal intravenous immunoglobulins every three weeks (2g/kg)&#xD;
oral dexamethasone (20 mg po at day-1, day-3, day-5, day-7 of the two first intravenous immunoglobulins courses)</description>
    <arm_group_label>Control</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  recipients of a first or a second kidney transplant for more than 3 months&#xD;
&#xD;
          -  age over 18 years&#xD;
&#xD;
          -  with de novo donor specific antibodies (DSA), i.e. antibodies not detected the day of&#xD;
             transplantation and in pre-transplant sera&#xD;
&#xD;
          -  with histological lesions of chronic active antibody-mediated rejection (glomerulitis&#xD;
             + peritubular capillaritis banff score and chronic glomerulopathy (g+ptc ≥ 2) on a&#xD;
             graft biopsy performed because of renal function deterioration, proteinuria, detection&#xD;
             of de novo DSA, or on a systematic biopsy&#xD;
&#xD;
          -  written informed consent&#xD;
&#xD;
          -  Given the teratogenic risks described in the SPCs of Velcade and Cellcept:&#xD;
&#xD;
               -  Women of child bearing age must have a negative pregnancy test the day of the&#xD;
                  inclusion and should use at least one effective contraceptive method before start&#xD;
                  of medication during the treatment and during the study&#xD;
&#xD;
               -  Men old enough to procreate have to use condoms during the treatment and at least&#xD;
                  90 days after the last intake of the treatment during the study. Moreover, given&#xD;
                  SPCs of Cellcept, it is recommended that female partners to use an effective&#xD;
                  method of contraception treatment and for 90 days after the last mycophenolate&#xD;
                  intake by the partner male&#xD;
&#xD;
          -  affiliated with social security health insurance&#xD;
&#xD;
          -  patients with cell rejection lesions associated with chronic humoral rejection lesions&#xD;
             active may be included in the study. This rejection can be treated with 3 boluses of&#xD;
             500 mg of methyl prednisolone prior to inclusion.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  patient with preformed DSA&#xD;
&#xD;
          -  recipient of a 3rd or 4th kidney transplant&#xD;
&#xD;
          -  recipient of a transplant combined with another not renal organ&#xD;
&#xD;
          -  patient with a history of humoral acute rejection during the current transplantation&#xD;
&#xD;
          -  estimated GFR below 20 ml/min/1,73m2&#xD;
&#xD;
          -  severe transplant glomerulopathy (cg score = 3)&#xD;
&#xD;
          -  severe peripheral neuropathy, thrombopenia &lt; 100 000 mm3 , neutropenia &lt; 1000 mm3&#xD;
             and/or an uncontrolled evolutionary infection&#xD;
&#xD;
          -  chronic active hepatitis B (positive HBs antigen or HBV DNA), positive chronic&#xD;
             hepatitis C and/or known HIV infection&#xD;
&#xD;
          -  allergy to bore or bortezomib or to one of the excipient&#xD;
&#xD;
          -  hepatic failure, abnormal liver tests (bilirubin &gt;3N, transaminases &gt;3n), infiltrative&#xD;
             pneumopathy, pericarditis&#xD;
&#xD;
          -  risk of non-adherence to treatment or protocol&#xD;
&#xD;
          -  inclusion in another clinical therapeutic trial&#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>Christophe Legendre, MD, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Assistance Publique - Hôpitaux de Paris</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Renaud Snanoudj, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Assistance Publique - Hôpitaux de Paris</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hopital Necker Enfants-malades</name>
      <address>
        <city>Paris</city>
        <zip>75015</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>October 2019</verification_date>
  <study_first_submitted>July 17, 2014</study_first_submitted>
  <study_first_submitted_qc>July 25, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 28, 2014</study_first_posted>
  <last_update_submitted>September 14, 2020</last_update_submitted>
  <last_update_submitted_qc>September 14, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">September 16, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Chronic antibody-mediated rejection,</keyword>
  <keyword>transplant rejection, kidney transplantation,</keyword>
  <keyword>proteasome inhibitor,</keyword>
  <keyword>anti-HLA antibodies,</keyword>
  <keyword>immunosuppressive agents</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bortezomib</mesh_term>
    <mesh_term>Immunoglobulins</mesh_term>
    <mesh_term>Immunoglobulins, Intravenous</mesh_term>
    <mesh_term>Antibodies</mesh_term>
    <mesh_term>gamma-Globulins</mesh_term>
    <mesh_term>Rho(D) Immune Globulin</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/NCT02201576
org study id: P120119
nct id: NCT02201576
lead sponsor: 
collaborator: 
has dmc: Yes
The purpose of the study is to assess the efficacy of bortezomib, in association with
      steroids, plasma exchange, and polyclonal intravenous immunoglobulins, in the treatment of
      chronic antibody mediated rejection due to donor specific anti-HLA antibodies, in kidney
      transplant recipients
Chronic active antibody-mediated rejection (AMR) is considered as a main cause of late
      allograft losses in kidney transplant recipients. It is due to the occurrence of de novo
      donor-specific anti-HLA antibodies (DSA), i.e. antibodies synthetized by the recipient after
      transplantation against its transplant. There is currently to efficient treatment. The
      purpose of our study is to determine the efficacy of bortezomib, a proteasome inhibitor, in
      the treatment of chronic active antibody-mediated rejection, in association with steroids,
      plasma exchanges, and polyclonal intravenous immunoglobulins. Patients are recipients of a
      first or a second kidney transplant for more than 3 months. They display de novo DSA i.e. DSA
      not detected the day of transplantation and in pre-transplant sera.. They display signs of
      chronic active AMR on kidney biopsy i.e. a glomerulitis (g) + peritubular capillaritis (ptc)
      Banff score g+ptc ≥ 2, with or without severe chronic glomerulopathy (Banff score cg<3).
      Kidney biopsy may have been performed systematically or because of: :

        1. detection of de novo DSA ,

        2. and /or proteinuria (> 0.5 g/24h)

        3. and /or slow graft dysfunction protocol biopsy Primary endpoint is a combined endpoint
           one year after inclusion, consisting of the stabilization of histological lesions on a
           new kidney biopsy (delta g+ptc ≤1 and delta cg < 1) and a decrease in DSA mean
           fluorescence intensity > 50%.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: histological lesions of humoral rejection and immunodominant donor specific antibody
time frame: one year
description: Between inclusion biopsy and end of study biopsy delta g+ptc ≤1 and delta cg < 1 (Banff score of glomerulitis (g) capillaritis (ptc) and chronic allograft glomerulopathy (cg) Between inclusion and end of study, decrease in mean fluorescence intensity (MFI) of the immunodominant donor specific anti-HLA antibody (DSA with the highest MFI) by Luminex greater than 50%
measure: histological lesions of humoral rejection
time frame: one year
description: Between inclusion biopsy and end of study biopsy delta g+ptc ≤1 and delta cg < 1 (Banff score of glomerulitis (g) capillaritis (ptc) and chronic allograft glomerulopathy (cg)
measure: immunodominant donor specific antibody
time frame: one year
description: Between inclusion and end of study, decrease in mean fluorescence intensity (MFI) of the immunodominant donor specific anti-HLA antibody (DSA with the highest MFI) by Luminex greater than 50%
measure: all donor specific antibodies at one year
time frame: one year
description: Between inclusion and end of study, variation of the title of each DSA and the sum of the DSAs
measure: all donor specific antibodies
time frame: 6 months
description: Between inclusion and month-6, evolution in mean fluorescence intensity (MFI) of all donor specific anti-HLA antibodies by Luminex
measure: Histological lesions
time frame: one year
description: Description of all histological lesions observed at one-year biopsy according to the Banff classification and comparison with inclusion biopsy: acute cellular rejection, interstitial fibrosis and tubular atrophy, chronic vascular lesions (arteriolar hyalinosis, fibro-intimal thickening), chronic rejection (transplant glomerulopathy, fibroproliferative endarteritis)
measure: renal function and proteinuria
time frame: one year
description: Evolution between inclusion and end of study at one-year of serum creatinine, estimated GFR (MDRD formula), proteinuria output, proteinuria/creatinuria ratio
measure: Safety of bortezomib in renal transplant recipients
time frame: one year
description: Infectious and non-infectious adverse events occurring during study in the two arms of treatment
measure: Patient and graft survival
time frame: one year
measure: T and B lymphocytes subsets with bortezomib
time frame: one year
description: Flow cytometry study of T and B lymphocytes subsets at inclusion, month-6 and month-12 in patients treated with bortezomib
arm group label: Bortezomib
arm group type: Experimental
description: Five plasma exchanges, two cycles of bortezomib + dexamethasone, 4 courses of polyclonal intravenous immunoglobulins
arm group label: Control
arm group type: Active Comparator
description: Five plasma exchanges, dexamethasone, 4 courses of polyclonal intravenous immunoglobulins
intervention type: Drug
intervention name: Bortezomib
description: Five plasma exchanges +0.1 g/kg of intravenous immunoglobulins at the end of each course
two cycles of bortezomib (1.3 mg/m2 IV at day-1, day-4, day-8, day-11) + oral dexamethasone (20 mg po at day-1, day-4, day-8, day-11)
four courses of polyclonal intravenous immunoglobulins every three weeks (2g/kg, the first two courses are performed simultaneously with the two bortezomib cycles)
arm group label: Bortezomib
other name: Velcade
intervention type: Drug
intervention name: Plasma exchanges and intravenous immunoglobulins
description: Five plasma exchanges +0.1 g/kg of intravenous immunoglobulins at the end of each course
four courses of polyclonal intravenous immunoglobulins every three weeks (2g/kg)
oral dexamethasone (20 mg po at day-1, day-3, day-5, day-7 of the two first intravenous immunoglobulins courses)
arm group label: Control
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Christophe Legendre, MD, PhD
role: Study Chair
affiliation: Assistance Publique - Hôpitaux de Paris
last name: Renaud Snanoudj, MD, PhD
role: Principal Investigator
affiliation: Assistance Publique - Hôpitaux de Paris
facility: 
country: France
responsible party type: Sponsor
mesh term: Bortezomib
mesh term: Immunoglobulins
mesh term: Immunoglobulins, Intravenous
mesh term: Antibodies
mesh term: gamma-Globulins
mesh term: Rho(D) Immune Globulin