xml: <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/NCT06033196</url>
    </required_header>
    <id_info>
      <org_study_id>DAIT CTOT-45</org_study_id>
      <nct_id>NCT06033196</nct_id>
    </id_info>
    <brief_title>Tocilizumab in Lung Transplantation</brief_title>
    <acronym>ALL IN LUNG</acronym>
    <official_title>Targeting Inflammation and Alloimmunity in Lung Transplant Recipients With Tocilizumab (CTOT-45)</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>National Institute of Allergy and Infectious Diseases (NIAID)</agency>
        <agency_class>NIH</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>National Institute of Allergy and Infectious Diseases (NIAID)</source>
    <oversight_info>
      <has_dmc>Yes</has_dmc>
      <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        This is a trial in which 350 primary lung transplant recipients will be randomized (1:1) to&#xD;
        receive either Tocilizumab (six doses over 20 weeks) plus standard triple maintenance&#xD;
        immunosuppression or placebo (sterile normal saline) plus standard triple maintenance&#xD;
        immunosuppression (Tacrolimus, Mycophenolate Mofetil, corticosteroids).&#xD;
  &#xD;
        The primary objective is to test the hypothesis that treatment with triple maintenance&#xD;
        immunosuppression plus Tocilizumab (TCZ) is superior to triple maintenance immunosuppression&#xD;
        plus placebo (saline) as defined by a composite endpoint of a) CLAD, b) listed for&#xD;
        re-transplantation, and c) death&#xD;
      </textblock>
    </brief_summary>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">October 1, 2023</start_date>
    <completion_date type="Anticipated">October 31, 2028</completion_date>
    <primary_completion_date type="Anticipated">October 31, 2028</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>Double (Participant, Investigator)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Proportion of subjects who meet any one of the pre-specified events detailed in the outcome description: from Baseline up to 36 months</measure>
      <time_frame>Over a period of 3 years after transplantation</time_frame>
      <description>The development of Chronic Lung Allograft Dysfunction (CLAD)&#xD;
  The development of any form of CLAD will be defined according to the standard 2019 The International Society for Heart and Lung Transplantation (ISHLT) criteria.&#xD;
  Listed for re-transplantation&#xD;
  Re-transplantation defined as the subject has been formally registered on the United Network for Organ Sharing (UNOS) waiting list to undergo a second lung transplant surgery&#xD;
  Death&#xD;
  Primary analysis will be conducted according to an Intent-to-treat (ITT) principle and therefore will include all randomized subjects who receive Tocilizumab(TCZ) or placebo. The time from randomization to development of CLAD will be compared between the two treatment groups (TCZ vs. placebo) using a Pearson's chi-square test.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Time to the onset of CLAD, being listed for re-transplantation, or death</measure>
      <time_frame>At 3 years after transplantation</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Cumulative incidence of Chronic Lung Allograft Dysfunction (CLAD)</measure>
      <time_frame>At 3 years after transplantation</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Cumulative incidence listed for re-transplantation</measure>
      <time_frame>At 3 years after transplantation</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Cumulative incidence of death</measure>
      <time_frame>At 3 years after transplantation</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Incidence of Primary Graft Dysfunction (PGD) grade 3</measure>
      <time_frame>At any timepoint in the first 72 hours</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Freedom from Acute Cellular Rejection (ACR) grade &gt;=A2</measure>
      <time_frame>At 3 years after transplantation</time_frame>
      <description>Transbronchial lung biopsies will be performed according to the local center standard of care using the 2007 International Society for Heart and Lung Transplantation (ISHLT) criteria.&#xD;
  Acute Cellular Rejection (A grade Rejection) Scale:&#xD;
  None (A0)&#xD;
  Minimal (A1)&#xD;
  Mild (A2)&#xD;
  Moderate (A3)&#xD;
  Severe (A4)&#xD;
  Ungradable (AX)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Proportion of subjects free from Antibody Mediated Rejection (AMR)</measure>
      <time_frame>At 3 years after transplantation</time_frame>
      <description>Antibody mediated rejection studies will be performed using original H&amp;E stained slides, trichrome/elastic trichrome stain, and C4d immunostain (5 slides per case), along with positive controls</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Proportion of subjects free from the development of de novo donor specific antibodies (dnDSA)</measure>
      <time_frame>At 3 years after transplantation</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Incidence of Gastrointestinal (GI) tract perforation</measure>
      <time_frame>At 3 years after transplantation</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Incidence of serious infections requiring intravenous antimicrobial therapy and need for hospitalization</measure>
      <time_frame>At 3 years after transplantation</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Incidence of confirmed bacterial infection requiring antimicrobial therapy</measure>
      <time_frame>At 3 years after transplantation</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Incidence of confirmed Cytomegalovirus (CMV) infection requiring antimicrobial therapy</measure>
      <time_frame>At 3 years after transplantation</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Incidence of confirmed mold infection requiring antimicrobial therapy</measure>
      <time_frame>At 3 years after transplantation</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Incidence of confirmed mycobacterial infection requiring antimicrobial therapy</measure>
      <time_frame>At 3 years after transplantation</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Incidence of confirmed community-acquired respiratory viral infection, including coronavirus disease 2019 (COVID-19) infection</measure>
      <time_frame>At 3 years after transplantation</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Incidence of discontinuation of Tocilizumab (TCZ) due to an adverse event</measure>
      <time_frame>At 3 years after transplantation</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Incidence of discontinuation of Tocilizumab (TCZ) due to serious adverse event</measure>
      <time_frame>At 3 years after transplantation</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Incidence of discontinuation of Tocilizumab (TCZ) placebo due to an adverse event</measure>
      <time_frame>At 3 years after transplantation</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Incidence of discontinuation of Tocilizumab (TCZ) placebo due to serious adverse event</measure>
      <time_frame>At 3 years after transplantation</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Incidence of malignancy excluding squamous or basal cell skin cancer</measure>
      <time_frame>At 3 years after transplantation</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Incidence of Tuberculosis (TB)</measure>
      <time_frame>At 3 years after transplantation</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Incidence of Post-transplant lymphoproliferative disease (PTLD)</measure>
      <time_frame>At 3 years after transplantation</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Time to the onset of Chronic Lung Allograft Dysfunction (CLAD)</measure>
      <time_frame>At 3 years after transplantation</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Time to the onset of being listed for re-transplantation</measure>
      <time_frame>At 3 years after transplantation</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Time to the onset of death</measure>
      <time_frame>At 3 years after transplantation</time_frame>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">350</enrollment>
    <condition>Lung Transplant</condition>
    <arm_group>
      <arm_group_label>Tocilizumab Group</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Subject in this group will receive ACTEMRA(R) (Tocilizumab) ,(six injections over 20 weeks) plus standard triple maintenance immunosuppression of Tacrolimus, Mycophenolate Mofetil, corticosteroids</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Placebo Group</arm_group_label>
      <arm_group_type>Placebo Comparator</arm_group_type>
      <description>Subject in this group will receive placebo for Tocilizumab (sterile normal saline) plus standard triple maintenance immunosuppression of Tacrolimus, Mycophenolate Mofetil, corticosteroids</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Tocilizumab</intervention_name>
      <description>The initial dose of tocilizumab will be administered in the operating room before reperfusion of the first lung during the lung transplant surgery.&#xD;
  6 doses will be given once every four weeks over a 20-week period. The dose is approved for pediatric patients who weigh 30 kg or more</description>
      <arm_group_label>Tocilizumab Group</arm_group_label>
      <other_name>ACTEMRA</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Placebo for Tocilizumab</intervention_name>
      <description>Placebo 0.9% Sodium Chloride Injection USP (Normal Saline)&#xD;
  Placebo will be given as a single intravenous dose, volume matched to tocilizumab. Placebo will be administered over a period of approximately 60 minutes; once every four weeks over a 20-week period. The first placebo dose will be during the transplant surgery before reperfusion of the first lung allograft, with 5 subsequent monthly doses</description>
      <arm_group_label>Placebo Group</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
          Study Entry:&#xD;
  &#xD;
            1. Subject and/or parent guardian must be able to understand the purpose of the study and&#xD;
               willing to participate and sign informed consent/assent&#xD;
  &#xD;
            2. Greater than or equal to 30 kg body weight&#xD;
  &#xD;
            3. Listed for a primary lung transplant&#xD;
  &#xD;
            4. No previous or planned desensitization therapy prior to transplant&#xD;
  &#xD;
            5. Serum Immunoglobulin G (IgG) level greater than 400 mg/dL. Patients treated with&#xD;
               intravenous immune globulin (IVIG) for hypogammaglobulinemia are eligible for&#xD;
               enrollment if their serum IgG level is greater than 400 mg/dL 14 or more days after&#xD;
               the most recent IVIG treatment&#xD;
  &#xD;
            6. For women of child-bearing potential, willingness to use highly-effective&#xD;
               contraception; according to the Food and Drug Administration (FDA) Office of Women's&#xD;
               Health (http://www.fda.gov/birthcontrol).&#xD;
  &#xD;
               Female participants of child-bearing potential must consult with their physician and&#xD;
               determine the most suitable method(s) from this list to be used for the duration of&#xD;
               the study. Those who choose oral contraception must agree to use a second form of&#xD;
               contraception after administration of study drug for a period of 1 year after the last&#xD;
               dose of study drug&#xD;
  &#xD;
            7. Tested negative for latent TB infection (LTBI) using a PPD or interferon-gamma release&#xD;
               assay (i.e., QuantiFERON-TB, T-SPOT.TB) within 1 year prior to transplant or has&#xD;
               completed appropriate LTBI therapy within the 1 year prior to transplant&#xD;
  &#xD;
            8. In the absence of contraindication, vaccinations must be up to date per the Division&#xD;
               of Allergy, Immunology, and Transplantation (DAIT) Guidance for Patients in Transplant&#xD;
               Trials&#xD;
  &#xD;
          Randomization:&#xD;
  &#xD;
            1. Provide written informed consent for the study participation, and agree to continue in&#xD;
               the study&#xD;
  &#xD;
            2. Undergoing single or bilateral lung transplant&#xD;
  &#xD;
            3. Agreement to use contraception; according to the FDA Office of Women's Health&#xD;
               (http://www.fda.gov/birthcontrol), there are a number of birth control methods that&#xD;
               are more than 80% effective. Female participants of child-bearing potential must&#xD;
               consult with their physician and determine the most suitable method(s) from this list&#xD;
               to be used for the duration of the study. Those who choose oral contraception must&#xD;
               agree to use a second form of contraception after administration of study drug for a&#xD;
               period of 1 year after the last dose of study drug&#xD;
  &#xD;
            4. Negative physical crossmatch, if the results are available at the time of&#xD;
               randomization&#xD;
  &#xD;
            5. No desensitization therapy prior to transplant&#xD;
  &#xD;
            6. Negative pregnancy test (serum or urine) for women of child-bearing potential within&#xD;
               48 hours prior to transplant&#xD;
  &#xD;
            7. Negative severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) Polymerase Chain&#xD;
               Reaction (PCR) testing for the recipient prior to transplant as per institutional&#xD;
               policy&#xD;
  &#xD;
            8. Negative SARS-CoV2 PCR testing for the donor prior to transplant as per institutional&#xD;
               policy&#xD;
  &#xD;
            9. Recipient of lungs that have been supported with ex vivo lung perfusion (EVLP) devices&#xD;
               are permitted&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
          Study Entry:&#xD;
  &#xD;
            1. Listed for multi-organ transplant (e.g., heart-lung, liver-lung, kidney-lung)&#xD;
  &#xD;
            2. Prior history of organ or cellular transplantation&#xD;
  &#xD;
            3. Received treatment to deplete Human Leukocyte Antigens (HLA) antibodies before&#xD;
               transplantation&#xD;
  &#xD;
            4. Currently breast-feeding a child or plans to become pregnant during the timeframe of&#xD;
               the study follow up period&#xD;
  &#xD;
            5. History of severe allergic and/or anaphylactic reactions to humanized or murine&#xD;
               monoclonal antibodies&#xD;
  &#xD;
            6. Known hypersensitivity or previous treatment with ACTEMRA(R) (tocilizumab)&#xD;
  &#xD;
            7. Infection with human immunodeficiency virus (HIV)&#xD;
  &#xD;
            8. Hepatitis B virus surface antigen or core antibody positive&#xD;
  &#xD;
            9. Hepatitis C virus PCR positive (HCV+) patients who have failed to demonstrate&#xD;
               sustained viral remission (2 consecutive PCR or Nucleic Acid Tests (NAT) negative&#xD;
               tests at least 24 weeks apart), with or without anti-viral treatment;&#xD;
  &#xD;
           10. Chronic infection with Burkholderia cenocepacia or Burkholderia gladioli&#xD;
  &#xD;
           11. Non-tuberculous mycobacterial (NTM) pulmonary disease; if there is a history of NTM&#xD;
               pulmonary disease, culture conversion is necessary for eligibility&#xD;
  &#xD;
           12. Presence of active malignancy or history of malignancy less than 5 years in remission,&#xD;
               excluding adequately treated in-situ cervical carcinoma, low grade prostate carcinoma,&#xD;
               or adequately treated basal or squamous cell carcinoma of the skin&#xD;
  &#xD;
           13. History of hemolytic-uremic syndrome/ thrombotic thrombocytopenia purpura&#xD;
  &#xD;
           14. History of demyelinating disorders (e.g., multiple sclerosis, chronic inflammation&#xD;
               demyelinating polyneuropathy)&#xD;
  &#xD;
           15. Current treatment with alkylating agents such as cyclophosphamide&#xD;
  &#xD;
           16. History of gastrointestinal (GI) tract perforation&#xD;
  &#xD;
           17. History of inflammatory bowel disease except fully excised ulcerative colitis&#xD;
  &#xD;
           18. History of diverticulitis (diverticulosis is not an exclusion) or diverticular&#xD;
               bleeding;&#xD;
  &#xD;
           19. Patients with a platelet count &lt; 100,000/mm^3 (last measurement within 7 days prior to&#xD;
               enrollment)&#xD;
  &#xD;
           20. Patients with an absolute neutrophil count (ANC) &lt; 2,000/mm^3 (last measurement within&#xD;
               7 days prior to enrollment)&#xD;
  &#xD;
           21. Patients with Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT)&#xD;
               levels &gt;3 times upper limit of normal&#xD;
  &#xD;
           22. Patients who use illegal drugs&#xD;
  &#xD;
           23. Use of investigational drugs within 4 weeks prior to enrollment&#xD;
  &#xD;
           24. Any condition that in the opinion of the site Principal Investigator (PI) introduces&#xD;
               undue risk by participating in this study&#xD;
  &#xD;
          Randomization:&#xD;
  &#xD;
            1. Recipient of multi-organ or tissue transplants&#xD;
  &#xD;
            2. Received a live virus vaccine within 30 days prior to randomization&#xD;
  &#xD;
            3. Received treatment to deplete HLA antibodies before transplantation to improve the&#xD;
               possibility of transplantation&#xD;
  &#xD;
            4. Patients with known donor-specific antibody that will require intervention based on&#xD;
               local clinical protocols&#xD;
  &#xD;
            5. History of GI tract perforation&#xD;
  &#xD;
            6. History of inflammatory bowel disease except fully excised ulcerative colitis&#xD;
  &#xD;
            7. History of diverticulitis (diverticulosis is not an exclusion) or diverticular&#xD;
               bleeding&#xD;
  &#xD;
            8. History of severe allergic anaphylactic reactions to humanized or murine monoclonal&#xD;
               antibodies&#xD;
  &#xD;
            9. Known hypersensitivity or previous treatment with ACTEMRA(R) (tocilizumab)&#xD;
  &#xD;
           10. Recipient or donor with infection with human immunodeficiency virus (HIV)&#xD;
  &#xD;
           11. Recipient with hepatitis B virus surface antigen or hepatitis B core antibody positive&#xD;
  &#xD;
           12. Hepatitis B negative transplant recipient that received a transplant from a Hepatitis&#xD;
               B core antibody positive donor unless the recipient has a Hepatitis B Surface Antigen&#xD;
               (HBsAb) titer &gt;10U/L&#xD;
  &#xD;
           13. Recipient of a hepatitis C virus nucleic acid test (NAT) positive donor organ&#xD;
  &#xD;
           14. Latent TB infection (LTBI) and has not completed appropriate therapy&#xD;
  &#xD;
           15. Chronic infection with Burkholderia cenocepacia or Burkholderia gladioli&#xD;
  &#xD;
           16. Non-tuberculous mycobacterial (NTM) pulmonary disease; if there is a history of NTM&#xD;
               pulmonary disease, culture conversion is necessary for eligibility&#xD;
  &#xD;
           17. Presence of active malignancy (except for non-melanoma skin cancer)&#xD;
  &#xD;
           18. History of hemolytic-uremic syndrome/ thrombotic thrombocytopenia purpura&#xD;
  &#xD;
           19. History of demyelinating disorders (e.g., multiple sclerosis, chronic inflammation&#xD;
               demyelinating polyneuropathy)&#xD;
  &#xD;
           20. Current treatment with alkylating agents such as cyclophosphamide&#xD;
  &#xD;
           21. Patients with AST or ALT levels &gt; 1.5 times upper limit of normal (last measurement&#xD;
               within 1 day prior to randomization)&#xD;
  &#xD;
           22. Patients with platelet count &lt;100,000/mm^3 (last measurement within 1 day prior to&#xD;
               randomization)&#xD;
  &#xD;
           23. Patients with an absolute neutrophil count (ANC) &lt;2,000/mm^3 (last measurement within&#xD;
               1 day prior to randomization)&#xD;
  &#xD;
           24. Patients who are administered or intended to be administered cytolytic (such as&#xD;
               anti-thymocyte globulin) or anti-CD25 monoclonal antibody agents as induction therapy&#xD;
               in the immediate post- transplant period&#xD;
  &#xD;
           25. Patients who have been treated in the past 3 months, or for whom it is anticipated&#xD;
               that treatment with any immunomodulatory biological agents post-transplant are&#xD;
               excluded&#xD;
  &#xD;
           26. Use of an investigational drug after transplant&#xD;
  &#xD;
           27. Any condition that in the opinion of the site PI introduces undue risk by&#xD;
               participating in this study&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>12 Years</minimum_age>
      <maximum_age>75 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Joren Madsen, MD, D.Phil.</last_name>
      <role>Study Chair</role>
      <affiliation>Massachusetts General Hospital: Transplantation</affiliation>
    </overall_official>
    <overall_official>
      <last_name>Ramsey Hachem, MD</last_name>
      <role>Study Chair</role>
      <affiliation>Washington University School of Medicine in St. Louis: Department of Medicine, Division of Pulmonary and Critical Care, Center for Advanced Medicine</affiliation>
    </overall_official>
    <overall_official>
      <last_name>Daniel Kreisel, M.D.</last_name>
      <role>Study Chair</role>
      <affiliation>Barnes Jewish Hospital at Washington University School of Medicine: Transplantation</affiliation>
    </overall_official>
    <location>
      <facility>
        <name>St. Joseph's Hospital and Medical Center: Transplantation</name>
        <address>
          <city>Phoenix</city>
          <state>Arizona</state>
          <zip>85013</zip>
          <country>United States</country>
        </address>
      </facility>
      <contact>
        <last_name>Brian Mutoff, BSHN, MHA</last_name>
        <phone>602-406-3825</phone>
        <email>Brian.Mutoff@commonspirit.org</email>
      </contact>
    </location>
    <location>
      <facility>
        <name>Cedars Sinai Medical Center: Transplantation</name>
        <address>
          <city>Los Angeles</city>
          <state>California</state>
          <zip>90048</zip>
          <country>United States</country>
        </address>
      </facility>
      <contact>
        <last_name>Emine Gholian, BA</last_name>
        <phone>310-423-8474</phone>
        <email>Emine.Gholian@cshs.org</email>
      </contact>
    </location>
    <location>
      <facility>
        <name>Ronald Reagan UCLA Medical Center: Transplantation</name>
        <address>
          <city>Los Angeles</city>
          <state>California</state>
          <zip>90095</zip>
          <country>United States</country>
        </address>
      </facility>
      <contact>
        <last_name>Paul Lopez, LVN</last_name>
        <phone>310-794-8595</phone>
        <email>plopez@mednet.ucla.edu</email>
      </contact>
    </location>
    <location>
      <facility>
        <name>University of Maryland Medical Center: Transplantation</name>
        <address>
          <city>Baltimore</city>
          <state>Maryland</state>
          <zip>21201</zip>
          <country>United States</country>
        </address>
      </facility>
      <contact>
        <last_name>Toye Jenkins</last_name>
        <email>toye.jenkins@som.umaryland.edu</email>
      </contact>
    </location>
    <location>
      <facility>
        <name>Massachusetts General Hospital: Transplantation</name>
        <address>
          <city>Boston</city>
          <state>Massachusetts</state>
          <zip>02114</zip>
          <country>United States</country>
        </address>
      </facility>
      <contact>
        <last_name>Mamary Kone, MD, MPH</last_name>
        <phone>617-726-1082</phone>
        <email>mkone@mgh.harvard.edu</email>
      </contact>
    </location>
    <location>
      <facility>
        <name>Boston Children's Hospital: Pediatric Transplantation</name>
        <address>
          <city>Boston</city>
          <state>Massachusetts</state>
          <zip>02215</zip>
          <country>United States</country>
        </address>
      </facility>
      <contact>
        <last_name>Jennifer Arruda, RN</last_name>
        <phone>617-355-6665</phone>
        <email>Jennifer.arruda@childrens.harvard.edu</email>
      </contact>
    </location>
    <location>
      <facility>
        <name>Brigham &amp; Women's Hospital: Transplantation</name>
        <address>
          <city>Boston</city>
          <state>Massachusetts</state>
          <zip>02215</zip>
          <country>United States</country>
        </address>
      </facility>
      <contact>
        <last_name>Nusrath Movval Abdulla</last_name>
        <phone>404-661-3615</phone>
        <email>nmovvalabdulla@bwh.harvard.edu</email>
      </contact>
    </location>
    <location>
      <facility>
        <name>Barnes Jewish Hospital at Washington University School of Medicine: Transplantation</name>
        <address>
          <city>Saint Louis</city>
          <state>Missouri</state>
          <zip>63110</zip>
          <country>United States</country>
        </address>
      </facility>
      <contact>
        <last_name>Brigitte Mittler, CCRC</last_name>
        <phone>314-747-1931</phone>
        <email>b.mittler@wustl.edu</email>
      </contact>
    </location>
    <location>
      <facility>
        <name>St. Louis Children's Hospital: Pediatric Transplantation</name>
        <address>
          <city>Saint Louis</city>
          <state>Missouri</state>
          <zip>63110</zip>
          <country>United States</country>
        </address>
      </facility>
      <contact>
        <last_name>Brigitte Mittler, BA</last_name>
        <phone>314-747-1931</phone>
        <email>b.mittler@wustl.edu</email>
      </contact>
    </location>
    <location>
      <facility>
        <name>Columbia University Medical Center: Transplantation</name>
        <address>
          <city>New York</city>
          <state>New York</state>
          <zip>10032</zip>
          <country>United States</country>
        </address>
      </facility>
      <contact>
        <last_name>Shreena Patel, BA, LPN</last_name>
        <phone>973-722-6835</phone>
        <email>sp3646@cumc.columbia.edu</email>
      </contact>
    </location>
    <location>
      <facility>
        <name>Duke University Medical Center: Transplantation</name>
        <address>
          <city>Durham</city>
          <state>North Carolina</state>
          <zip>27710</zip>
          <country>United States</country>
        </address>
      </facility>
      <contact>
        <last_name>Kathy Lane, BSN, RN</last_name>
        <phone>919-684-2037</phone>
        <email>Kathleen.rohrback@duke.edu</email>
      </contact>
    </location>
    <location>
      <facility>
        <name>Cleveland Clinic Foundation: Transplantation</name>
        <address>
          <city>Cleveland</city>
          <state>Ohio</state>
          <zip>44195</zip>
          <country>United States</country>
        </address>
      </facility>
      <contact>
        <last_name>Stacy Shoemaker, BSN</last_name>
        <phone>216-554-4956</phone>
        <email>Shoemas2@ccf.org</email>
      </contact>
    </location>
    <location>
      <facility>
        <name>University of Pittsburgh Medical Center: Transplantation</name>
        <address>
          <city>Pittsburgh</city>
          <state>Pennsylvania</state>
          <zip>15213</zip>
          <country>United States</country>
        </address>
      </facility>
      <contact>
        <last_name>Vera Iouchmanov, BS, CCRC</last_name>
        <phone>412-864-3052</phone>
        <email>iouchmanovvl@upmc.edu</email>
      </contact>
    </location>
    <location>
      <facility>
        <name>University of Texas Southwestern Medical Center: Transplantation</name>
        <address>
          <city>Dallas</city>
          <state>Texas</state>
          <zip>75390</zip>
          <country>United States</country>
        </address>
      </facility>
      <contact>
        <last_name>Rhoda Annoh-Gordon</last_name>
        <phone>214-645-7108</phone>
        <email>Rhoda.Annoh-Gordon@UTSouthwestern.edu</email>
      </contact>
    </location>
    <location>
      <facility>
        <name>Methodist Hospital: Transplantation</name>
        <address>
          <city>Houston</city>
          <state>Texas</state>
          <zip>77030</zip>
          <country>United States</country>
        </address>
      </facility>
      <contact>
        <last_name>Marcos De Oliveira, BSN, PhD</last_name>
        <phone>346-238-5653</phone>
        <email>mdeoliveira@houstonmethodist.org</email>
      </contact>
    </location>
    <location>
      <facility>
        <name>Toronto General Hospital: Transplantation</name>
        <address>
          <city>Toronto</city>
          <state>Ontario</state>
          <zip>M5G 2C4</zip>
          <country>Canada</country>
        </address>
      </facility>
      <contact>
        <last_name>Sharaniyaa Balachandran, BSc, CCRP</last_name>
        <phone>416-340-4800</phone>
        <phone_ext>6549</phone_ext>
        <email>Sharaniyaa.balachandran@uhn.ca</email>
      </contact>
    </location>
    <location>
      <facility>
        <name>Hospital for Sick Children: Pediatric Transplantation</name>
        <address>
          <city>Toronto</city>
          <state>Ontario</state>
          <zip>MG5 2C4</zip>
          <country>Canada</country>
        </address>
      </facility>
      <contact>
        <last_name>Sharaniyaa Balachandran, BSc, CCRP</last_name>
        <phone>416-340-4800</phone>
        <phone_ext>6549</phone_ext>
        <email>Sharaniyaa.balachandran@uhn.ca</email>
      </contact>
    </location>
    <location_countries>
      <country>Canada</country>
      <country>United States</country>
    </location_countries>
    <link>
      <url>https://www.niaid.nih.gov/</url>
      <description>National Institute of Allergy and Infectious Diseases (NIAID)</description>
    </link>
    <link>
      <url>https://www.niaid.nih.gov/about/dait</url>
      <description>Division of Allergy, Immunology, and Transplantation (DAIT)</description>
    </link>
    <verification_date>September 2023</verification_date>
    <study_first_submitted>August 24, 2023</study_first_submitted>
    <study_first_submitted_qc>September 8, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 13, 2023</study_first_posted>
    <last_update_submitted>September 8, 2023</last_update_submitted>
    <last_update_submitted_qc>September 8, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 13, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <keyword>Lung Transplant</keyword>
    <keyword>Tocilizumab</keyword>
    <keyword>Immunosuppression</keyword>
    <keyword>ACTEMRA</keyword>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06033196
  org study id: DAIT CTOT-45
  nct id: NCT06033196
  lead sponsor: 
  has dmc: Yes
  is fda regulated drug: Yes
  is fda regulated device: No
  This is a trial in which 350 primary lung transplant recipients will be randomized (1:1) to
        receive either Tocilizumab (six doses over 20 weeks) plus standard triple maintenance
        immunosuppression or placebo (sterile normal saline) plus standard triple maintenance
        immunosuppression (Tacrolimus, Mycophenolate Mofetil, corticosteroids).
  
        The primary objective is to test the hypothesis that treatment with triple maintenance
        immunosuppression plus Tocilizumab (TCZ) is superior to triple maintenance immunosuppression
        plus placebo (saline) as defined by a composite endpoint of a) CLAD, b) listed for
        re-transplantation, and c) death
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Treatment
  masking: Double (Participant, Investigator)
  measure: Proportion of subjects who meet any one of the pre-specified events detailed in the outcome description: from Baseline up to 36 months
  time frame: Over a period of 3 years after transplantation
  description: The development of Chronic Lung Allograft Dysfunction (CLAD)
  The development of any form of CLAD will be defined according to the standard 2019 The International Society for Heart and Lung Transplantation (ISHLT) criteria.
  Listed for re-transplantation
  Re-transplantation defined as the subject has been formally registered on the United Network for Organ Sharing (UNOS) waiting list to undergo a second lung transplant surgery
  Death
  Primary analysis will be conducted according to an Intent-to-treat (ITT) principle and therefore will include all randomized subjects who receive Tocilizumab(TCZ) or placebo. The time from randomization to development of CLAD will be compared between the two treatment groups (TCZ vs. placebo) using a Pearson's chi-square test.
  measure: Time to the onset of CLAD, being listed for re-transplantation, or death
  time frame: At 3 years after transplantation
  measure: Cumulative incidence of Chronic Lung Allograft Dysfunction (CLAD)
  time frame: At 3 years after transplantation
  measure: Cumulative incidence listed for re-transplantation
  time frame: At 3 years after transplantation
  measure: Cumulative incidence of death
  time frame: At 3 years after transplantation
  measure: Incidence of Primary Graft Dysfunction (PGD) grade 3
  time frame: At any timepoint in the first 72 hours
  measure: Freedom from Acute Cellular Rejection (ACR) grade >=A2
  time frame: At 3 years after transplantation
  description: Transbronchial lung biopsies will be performed according to the local center standard of care using the 2007 International Society for Heart and Lung Transplantation (ISHLT) criteria.
  Acute Cellular Rejection (A grade Rejection) Scale:
  None (A0)
  Minimal (A1)
  Mild (A2)
  Moderate (A3)
  Severe (A4)
  Ungradable (AX)
  measure: Proportion of subjects free from Antibody Mediated Rejection (AMR)
  time frame: At 3 years after transplantation
  description: Antibody mediated rejection studies will be performed using original H&E stained slides, trichrome/elastic trichrome stain, and C4d immunostain (5 slides per case), along with positive controls
  measure: Proportion of subjects free from the development of de novo donor specific antibodies (dnDSA)
  time frame: At 3 years after transplantation
  measure: Incidence of Gastrointestinal (GI) tract perforation
  time frame: At 3 years after transplantation
  measure: Incidence of serious infections requiring intravenous antimicrobial therapy and need for hospitalization
  time frame: At 3 years after transplantation
  measure: Incidence of confirmed bacterial infection requiring antimicrobial therapy
  time frame: At 3 years after transplantation
  measure: Incidence of confirmed Cytomegalovirus (CMV) infection requiring antimicrobial therapy
  time frame: At 3 years after transplantation
  measure: Incidence of confirmed mold infection requiring antimicrobial therapy
  time frame: At 3 years after transplantation
  measure: Incidence of confirmed mycobacterial infection requiring antimicrobial therapy
  time frame: At 3 years after transplantation
  measure: Incidence of confirmed community-acquired respiratory viral infection, including coronavirus disease 2019 (COVID-19) infection
  time frame: At 3 years after transplantation
  measure: Incidence of discontinuation of Tocilizumab (TCZ) due to an adverse event
  time frame: At 3 years after transplantation
  measure: Incidence of discontinuation of Tocilizumab (TCZ) due to serious adverse event
  time frame: At 3 years after transplantation
  measure: Incidence of discontinuation of Tocilizumab (TCZ) placebo due to an adverse event
  time frame: At 3 years after transplantation
  measure: Incidence of discontinuation of Tocilizumab (TCZ) placebo due to serious adverse event
  time frame: At 3 years after transplantation
  measure: Incidence of malignancy excluding squamous or basal cell skin cancer
  time frame: At 3 years after transplantation
  measure: Incidence of Tuberculosis (TB)
  time frame: At 3 years after transplantation
  measure: Incidence of Post-transplant lymphoproliferative disease (PTLD)
  time frame: At 3 years after transplantation
  measure: Time to the onset of Chronic Lung Allograft Dysfunction (CLAD)
  time frame: At 3 years after transplantation
  measure: Time to the onset of being listed for re-transplantation
  time frame: At 3 years after transplantation
  measure: Time to the onset of death
  time frame: At 3 years after transplantation
  arm group label: Tocilizumab Group
  arm group type: Experimental
  description: Subject in this group will receive ACTEMRA(R) (Tocilizumab) ,(six injections over 20 weeks) plus standard triple maintenance immunosuppression of Tacrolimus, Mycophenolate Mofetil, corticosteroids
  arm group label: Placebo Group
  arm group type: Placebo Comparator
  description: Subject in this group will receive placebo for Tocilizumab (sterile normal saline) plus standard triple maintenance immunosuppression of Tacrolimus, Mycophenolate Mofetil, corticosteroids
  intervention type: Drug
  intervention name: Tocilizumab
  description: The initial dose of tocilizumab will be administered in the operating room before reperfusion of the first lung during the lung transplant surgery.
  6 doses will be given once every four weeks over a 20-week period. The dose is approved for pediatric patients who weigh 30 kg or more
  arm group label: Tocilizumab Group
  other name: ACTEMRA
  intervention type: Drug
  intervention name: Placebo for Tocilizumab
  description: Placebo 0.9% Sodium Chloride Injection USP (Normal Saline)
  Placebo will be given as a single intravenous dose, volume matched to tocilizumab. Placebo will be administered over a period of approximately 60 minutes; once every four weeks over a 20-week period. The first placebo dose will be during the transplant surgery before reperfusion of the first lung allograft, with 5 subsequent monthly doses
  arm group label: Placebo Group
  criteria: 
  gender: All
  minimum age: 12 Years
  maximum age: 75 Years
  healthy volunteers: No
  last name: Joren Madsen, MD, D.Phil.
  role: Study Chair
  affiliation: Massachusetts General Hospital: Transplantation
  last name: Ramsey Hachem, MD
  role: Study Chair
  affiliation: Washington University School of Medicine in St. Louis: Department of Medicine, Division of Pulmonary and Critical Care, Center for Advanced Medicine
  last name: Daniel Kreisel, M.D.
  role: Study Chair
  affiliation: Barnes Jewish Hospital at Washington University School of Medicine: Transplantation
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  country: Canada
  country: United States
  url: https://www.niaid.nih.gov/
  description: National Institute of Allergy and Infectious Diseases (NIAID)
  url: https://www.niaid.nih.gov/about/dait
  description: Division of Allergy, Immunology, and Transplantation (DAIT)
  responsible party type: Sponsor