<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/NCT04507477</url>
  </required_header>
  <id_info>
    <org_study_id>19-6260</org_study_id>
    <nct_id>NCT04507477</nct_id>
  </id_info>
  <brief_title>Ex-vivo Delivery of Rituximab to Prevent PTLD in EBV Mismatch Lung Transplant Recipients: A Pilot Trial</brief_title>
  <official_title>Ex-vivo Delivery of Rituximab to Prevent Post-transplant Lymphoproliferative Disease in Epstein-Barr Virus Mismatch Lung Transplant Recipients: A Pilot Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Health Network, Toronto</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Health Network, Toronto</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Post-transplant lymphoproliferative disorders (PTLD) can present as a type of malignancy that&#xD;
      limits patient and graft survival after solid organ transplantation. Many early PTLDs are&#xD;
      driven by the Epstein-Barr Virus (EBV).&#xD;
&#xD;
      Once acquired, EBV virus establishes latency in B-cells and can reactivate under&#xD;
      immunosuppression. The highest risk transplant type to develop PTLD are lung transplants who&#xD;
      have newly acquired EBV from their donors (D+/R-). There are no good modalities to prevent&#xD;
      PTLD from developing after transplant. Rituximab is a monoclonal antibody that depletes&#xD;
      B-cells thereby also reducing the burden of EBV. However, rituximab can have toxicities when&#xD;
      given intravenously including infusion reactions and increased risk of reactions.&#xD;
&#xD;
      Furthermore, more than one dose is usually required. The Toronto Transplant program has&#xD;
      developed a technology called ex vivo lung perfusion that repairs lungs outside of the body.&#xD;
      Preliminary work has shown that rituximab given through the EVLP circuit can coat B-cells. We&#xD;
      have also shown that there is no toxicity to the lung by giving rituximab. The current highly&#xD;
      novel study proposes to treat donor lungs ex-vivo with rituximab in order to decrease the&#xD;
      amount of B-cells and EBV in the graft. These lungs will then be transplanted into EBV&#xD;
      negative patients with the hope that transmission of EBV would be reduced or prevented. Ten&#xD;
      patients will be included in the current trial. Outcomes include safety, EBV viral load, and&#xD;
      B-cell measurements in biopsies.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Previous studies have shown that EBV D+/R- lung transplant patients have a high rate of&#xD;
      post-transplant lymphoproliferative disease up to 22%. Various methods have been proposed to&#xD;
      decrease the risk of PTLD in EBV D+/R- organ transplants. These include a) antiviral&#xD;
      prophylaxis with valganciclovir; b) EBV viral load monitoring and reduction of&#xD;
      immunosuppression; c) avoidance of polyclonal antibody induction; d) treatment of EBV viremia&#xD;
      with ganciclovir +/- intravenous immunoglobulin; e) pre-emptive systemic rituximab for EBV&#xD;
      viremia. Antiviral strategies which include (val)ganciclovir in particular do not have proven&#xD;
      efficacy in this setting. In addition, current antivirals do NOT target latent virus which&#xD;
      would be the predominant form of virus in the allograft, and is also the predominant viral&#xD;
      state that drives B-cell proliferation. Rituximab is a chimeric monoclonal antibody that&#xD;
      targets CD20+ B-cells. It has been used clinically for many years to treat a variety of&#xD;
      diseases and is used in transplantation for induction. Rituximab has been used successfully&#xD;
      as a prophylactic and therapeutic drug for the reduction of EBV viremia and PTLD in&#xD;
      hematopoietic stem cell transplant recipients. Ex-Vivo Lung Perfusion (EVLP) is a novel&#xD;
      method of donor lung preservation and treatment developed in Toronto which allows donor lungs&#xD;
      to be treated for up to 12h or more under protective physiological conditions. This&#xD;
      essentially creates a critical time window in which donor lungs can be optimally repaired&#xD;
      prior to transplant. An advantage of ex-vivo delivery of rituximab includes the ability to&#xD;
      deliver high-doses locally to the graft while potentially avoiding serious adverse effects in&#xD;
      the recipient. Pre-clinical studies have shown that adding rituximab to the perfusate allows&#xD;
      for safe delivery of the drug directly to the lungs and adjacent lymph nodes and is&#xD;
      non-toxic. EBV D+/R- lung transplant patients have a high rate of PTLD. There are no proven&#xD;
      prevention measures. Rituximab is a commonly used medication in transplant patients as well&#xD;
      as for other indications. Rituximab depletes B cells in lung tissues and may reduce the&#xD;
      transmission of EBV, thereby preventing PTLD. Giving Rituximab directly to the lungs will&#xD;
      avoid systemic toxicity in the patient. The investigators hypothesize that donor lungs&#xD;
      treated with Rituximab during ex vivo lung perfusion will result in B-cell depletion and&#xD;
      therefore be less likely to transmit EBV, thereby reducing the risk of PTLD in the lung&#xD;
      recipient. As noted above the advantages of delivering rituximab ex vivo include prevention&#xD;
      of adverse effects of rituximab including systemic depletion of B-cells, reduced systemic&#xD;
      immunosuppression, and infusion-related toxicities, and ability to deliver a high-dose&#xD;
      locally to the allograft.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">July 7, 2020</start_date>
  <completion_date type="Anticipated">February 7, 2023</completion_date>
  <primary_completion_date type="Anticipated">December 7, 2022</primary_completion_date>
  <phase>Phase 1/Phase 2</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>
    <intervention_model_description>At our institution, approximately 50% of donor lungs are put on ex-vivo lung perfusion (EVLP) for clinical purposes. If a patient consents to participate in this study and their donor is EBV positive, the donor lungs will first be put on EVLP. Rituximab will be administered to the donor lungs while they are on EVLP for 3 to 4 hours before the transplant is done in order to reduce the amount of EBV virus. The amount of time the donor lungs are on EVLP will not be changed as a result of participating in this study.</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of patients with Primary Graft Dysfunction</measure>
    <time_frame>1 week post-transplant</time_frame>
    <description>Primary graft dysfunction (PGD) will be measured using previously defined criteria: PGD2 will be a PaO2:FiO2 of 200-300 mmHg with pulmonary edema on chest radiograph whereas PGD3 will be a PaO2:FiO2 of &lt;200 mmHg with pulmonary edema on chest radiograph or use of ECMO.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of patients with plasma EBV viral load of &gt;=10,000 copies/mL</measure>
    <time_frame>12 months post-transplant</time_frame>
    <description>Plasma EBV viral load of &gt;=10,000 copies/mL. This will be compared to historic controls.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">10</enrollment>
  <condition>Epstein-Barr Virus Infections</condition>
  <condition>Post-transplant Lymphoproliferative Disorder</condition>
  <arm_group>
    <arm_group_label>Rituximab + Ex-vivo lung perfusion</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Donor lungs deemed suitable for such patients will undergo ex vivo lung perfusion (EVLP) as per standard practice. In clinical practice almost all adult donor lungs are EBV seropositive. If in the rare case the donor lung is EBV seronegative, then the lung transplant candidate/recipient will no longer need to be part of the study. Therefore, for EBV seropositive lungs meant for an EBV seronegative recipient, one dose of rituximab (500mg) will be added to the EVLP perfusate and be allowed to circulate for 3-4 hours. Lungs will then be transplanted as per standard procedure.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Rituximab</intervention_name>
    <description>For EBV seropositive lungs meant for an EBV seronegative recipient, one dose of rituximab (500mg) will be added to the EVLP perfusate and be allowed to circulate for 3-4 hours.</description>
    <arm_group_label>Rituximab + Ex-vivo lung perfusion</arm_group_label>
    <other_name>Rituxan</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age &gt;=18 years&#xD;
&#xD;
          -  Listed for single or double lung transplantation&#xD;
&#xD;
          -  EBV (EBNA IgG and/or VCA IgG) seronegative (tested within the last 12 months)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  EBV seropositivity at any time prior to transplant&#xD;
&#xD;
          -  History of Cancer (eg, lymphoma)&#xD;
&#xD;
          -  History of receiving rituximab or allergy to rituximab&#xD;
&#xD;
          -  Underlying immunodeficiency (eg, common variable immune deficiency)&#xD;
&#xD;
          -  Unable or unwilling to comply with study procedures&#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>Deepali Kumar</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Health Network, Toronto</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Natalia Pinzon</last_name>
    <phone>416-340-4241</phone>
    <email>natalia.pinzon@uhn.ca</email>
  </overall_contact>
  <location>
    <facility>
      <name>University Health Network, Toronto General Hospital, Multi-Organ Transplant</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G2N2</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Deepali Kumar, MD</last_name>
      <phone>+1 416 340 4800</phone>
      <phone_ext>4241</phone_ext>
      <email>deepali.kumar@uhn.ca</email>
    </contact>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>July 2021</verification_date>
  <study_first_submitted>August 4, 2020</study_first_submitted>
  <study_first_submitted_qc>August 7, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 11, 2020</study_first_posted>
  <last_update_submitted>July 29, 2022</last_update_submitted>
  <last_update_submitted_qc>July 29, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 2, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Rituximab</keyword>
  <keyword>EBV</keyword>
  <keyword>EVLP</keyword>
  <keyword>lung transplant</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Epstein-Barr Virus Infections</mesh_term>
    <mesh_term>Lymphoproliferative Disorders</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rituximab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT04507477
org study id: 19-6260
nct id: NCT04507477
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Post-transplant lymphoproliferative disorders (PTLD) can present as a type of malignancy that
      limits patient and graft survival after solid organ transplantation. Many early PTLDs are
      driven by the Epstein-Barr Virus (EBV).

      Once acquired, EBV virus establishes latency in B-cells and can reactivate under
      immunosuppression. The highest risk transplant type to develop PTLD are lung transplants who
      have newly acquired EBV from their donors (D+/R-). There are no good modalities to prevent
      PTLD from developing after transplant. Rituximab is a monoclonal antibody that depletes
      B-cells thereby also reducing the burden of EBV. However, rituximab can have toxicities when
      given intravenously including infusion reactions and increased risk of reactions.

      Furthermore, more than one dose is usually required. The Toronto Transplant program has
      developed a technology called ex vivo lung perfusion that repairs lungs outside of the body.
      Preliminary work has shown that rituximab given through the EVLP circuit can coat B-cells. We
      have also shown that there is no toxicity to the lung by giving rituximab. The current highly
      novel study proposes to treat donor lungs ex-vivo with rituximab in order to decrease the
      amount of B-cells and EBV in the graft. These lungs will then be transplanted into EBV
      negative patients with the hope that transmission of EBV would be reduced or prevented. Ten
      patients will be included in the current trial. Outcomes include safety, EBV viral load, and
      B-cell measurements in biopsies.
Previous studies have shown that EBV D+/R- lung transplant patients have a high rate of
      post-transplant lymphoproliferative disease up to 22%. Various methods have been proposed to
      decrease the risk of PTLD in EBV D+/R- organ transplants. These include a) antiviral
      prophylaxis with valganciclovir; b) EBV viral load monitoring and reduction of
      immunosuppression; c) avoidance of polyclonal antibody induction; d) treatment of EBV viremia
      with ganciclovir +/- intravenous immunoglobulin; e) pre-emptive systemic rituximab for EBV
      viremia. Antiviral strategies which include (val)ganciclovir in particular do not have proven
      efficacy in this setting. In addition, current antivirals do NOT target latent virus which
      would be the predominant form of virus in the allograft, and is also the predominant viral
      state that drives B-cell proliferation. Rituximab is a chimeric monoclonal antibody that
      targets CD20+ B-cells. It has been used clinically for many years to treat a variety of
      diseases and is used in transplantation for induction. Rituximab has been used successfully
      as a prophylactic and therapeutic drug for the reduction of EBV viremia and PTLD in
      hematopoietic stem cell transplant recipients. Ex-Vivo Lung Perfusion (EVLP) is a novel
      method of donor lung preservation and treatment developed in Toronto which allows donor lungs
      to be treated for up to 12h or more under protective physiological conditions. This
      essentially creates a critical time window in which donor lungs can be optimally repaired
      prior to transplant. An advantage of ex-vivo delivery of rituximab includes the ability to
      deliver high-doses locally to the graft while potentially avoiding serious adverse effects in
      the recipient. Pre-clinical studies have shown that adding rituximab to the perfusate allows
      for safe delivery of the drug directly to the lungs and adjacent lymph nodes and is
      non-toxic. EBV D+/R- lung transplant patients have a high rate of PTLD. There are no proven
      prevention measures. Rituximab is a commonly used medication in transplant patients as well
      as for other indications. Rituximab depletes B cells in lung tissues and may reduce the
      transmission of EBV, thereby preventing PTLD. Giving Rituximab directly to the lungs will
      avoid systemic toxicity in the patient. The investigators hypothesize that donor lungs
      treated with Rituximab during ex vivo lung perfusion will result in B-cell depletion and
      therefore be less likely to transmit EBV, thereby reducing the risk of PTLD in the lung
      recipient. As noted above the advantages of delivering rituximab ex vivo include prevention
      of adverse effects of rituximab including systemic depletion of B-cells, reduced systemic
      immunosuppression, and infusion-related toxicities, and ability to deliver a high-dose
      locally to the allograft.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: At our institution, approximately 50% of donor lungs are put on ex-vivo lung perfusion (EVLP) for clinical purposes. If a patient consents to participate in this study and their donor is EBV positive, the donor lungs will first be put on EVLP. Rituximab will be administered to the donor lungs while they are on EVLP for 3 to 4 hours before the transplant is done in order to reduce the amount of EBV virus. The amount of time the donor lungs are on EVLP will not be changed as a result of participating in this study.
primary purpose: Prevention
masking: None (Open Label)
measure: Number of patients with Primary Graft Dysfunction
time frame: 1 week post-transplant
description: Primary graft dysfunction (PGD) will be measured using previously defined criteria: PGD2 will be a PaO2:FiO2 of 200-300 mmHg with pulmonary edema on chest radiograph whereas PGD3 will be a PaO2:FiO2 of <200 mmHg with pulmonary edema on chest radiograph or use of ECMO.
measure: Number of patients with plasma EBV viral load of >=10,000 copies/mL
time frame: 12 months post-transplant
description: Plasma EBV viral load of >=10,000 copies/mL. This will be compared to historic controls.
arm group label: Rituximab + Ex-vivo lung perfusion
arm group type: Experimental
description: Donor lungs deemed suitable for such patients will undergo ex vivo lung perfusion (EVLP) as per standard practice. In clinical practice almost all adult donor lungs are EBV seropositive. If in the rare case the donor lung is EBV seronegative, then the lung transplant candidate/recipient will no longer need to be part of the study. Therefore, for EBV seropositive lungs meant for an EBV seronegative recipient, one dose of rituximab (500mg) will be added to the EVLP perfusate and be allowed to circulate for 3-4 hours. Lungs will then be transplanted as per standard procedure.
intervention type: Biological
intervention name: Rituximab
description: For EBV seropositive lungs meant for an EBV seronegative recipient, one dose of rituximab (500mg) will be added to the EVLP perfusate and be allowed to circulate for 3-4 hours.
arm group label: Rituximab + Ex-vivo lung perfusion
other name: Rituxan
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Deepali Kumar
role: Principal Investigator
affiliation: University Health Network, Toronto
last name: Natalia Pinzon
phone: 416-340-4241
email: natalia.pinzon@uhn.ca
facility: 
status: Recruiting
contact: 
country: Canada
responsible party type: Sponsor
mesh term: Epstein-Barr Virus Infections
mesh term: Lymphoproliferative Disorders
mesh term: Rituximab
sharing ipd: No