<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/NCT02188719</url>
  </required_header>
  <id_info>
    <org_study_id>DAIT RTB-002</org_study_id>
    <secondary_id>R34AI095135</secondary_id>
    <secondary_id>U01AI110658</secondary_id>
    <secondary_id>NIAID CRMS ID#: 20182</secondary_id>
    <nct_id>NCT02188719</nct_id>
  </id_info>
  <brief_title>Donor-Alloantigen-Reactive Regulatory T Cell (darTregs) in Liver Transplantation</brief_title>
  <acronym>deLTa</acronym>
  <official_title>Donor-Alloantigen-Reactive Regulatory T Cell (darTreg) Therapy in Liver Transplantation (RTB-002)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Institute of Allergy and Infectious Diseases (NIAID)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Rho Federal Systems Division, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>National Institute of Allergy and Infectious Diseases (NIAID)</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is look at the safety of:&#xD;
&#xD;
        -  Taking a specific combination of immunosuppressant drugs after liver transplantation&#xD;
&#xD;
        -  Receiving one of three different doses of donor-alloantigen-reactive regulatory T cells&#xD;
           (darTregs) while taking this specific combination of drugs&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      After liver transplantation, immunosuppressants must be taken every day to prevent the body&#xD;
      from injuring the transplanted liver by a process called rejection. People who take these&#xD;
      drugs may experience side effects.&#xD;
&#xD;
      Studies show that some of body's cells, called T regulatory cells (Tregs), may play a part in&#xD;
      accepting the transplanted liver. The investigators are learning about whether scientists can&#xD;
      take Tregs from the blood of a liver transplant recipient and teach them to protect the&#xD;
      transplanted liver from rejection. In the laboratory, the recipient Tregs are exposed to&#xD;
      cells from the liver donor. Research data suggests that giving these &quot;donor reactive&quot; Tregs&#xD;
      back to the transplant recipient might allow a liver transplant recipient to take lower doses&#xD;
      of immunosuppressants, or perhaps to stop them altogether, without rejecting the liver.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    The trial could not be completed within the grant timeline.&#xD;
  </why_stopped>
  <start_date type="Actual">December 17, 2014</start_date>
  <completion_date type="Actual">June 18, 2019</completion_date>
  <primary_completion_date type="Actual">June 18, 2019</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Percent of Participants With Biopsy-Proven Acute and/or Chronic Rejection</measure>
    <time_frame>Transplantation to 40 Weeks Post Transplantation</time_frame>
    <description>Biopsy-proven acute rejection graded as Mild, Moderate or Severe, per 1997 Banff classification. Chronic Rejection graded using Banff 2000 classification.&#xD;
References: 1.) Banff Schema for Grading Liver Allograft Rejection: An International Consensus Document developed by an international panel of experts in liver transplantation pathology, hepatology, and surgery (Hepatology 1997; 25(3): 658-663). 2.) Update of the International Banff Schema for Liver Allograft Rejection: Working Recommendations for the Histopathologic Staging and Reporting of Chronic Rejection (Hepatology 2000; 31(3): 792-799).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Percent of Participants With Grade 3 or Higher Infectious Adverse Event(s)</measure>
    <time_frame>Transplantation to 40 Weeks Post Transplantation</time_frame>
    <description>The severity of infectious adverse events (AEs) was classified into grades as follows:&#xD;
Grade 1 = asymptomatic; clinical or diagnostic observation only; intervention with oral antibiotic, antifungal, or antiviral agent only; no invasive intervention required&#xD;
Grade 2 = symptomatic; intervention with intravenous antibiotic, antifungal, or antiviral agent; invasive intervention may be required&#xD;
Grade 3 = any infection associated with hemodynamic compromise requiring pressors; any infection necessitating intensive care unit level of care; any infection necessitating operative intervention; any infection involving the central nervous system; any infection with a positive fungal blood culture; any proven or probable aspergillus infection; any tissue invasive fungal infection; any pneumocystis jiroveci infection&#xD;
Grade 4 = life-threatening infection&#xD;
Grade 5 = death resulting from infection</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Percent of Participants With Grade 3 or Higher Wound Complication(s) Adverse Event(s)</measure>
    <time_frame>Transplantation to 40 Weeks Post Transplantation</time_frame>
    <description>The severity of adverse events (AEs) was classified into grades using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 (4/28/2009):&#xD;
Grade 3 wound complications are defined as &quot;Hernia without evidence of strangulation; fascial disruption/dehiscence; primary wound closure or revision by operative intervention indicated&quot;&#xD;
Grade 4 complications are defined as &quot;Hernia with evidence of strangulation; major reconstruction flap, grafting, resection, or amputation indicated&quot;</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Percent of Participants With Grade 2 or Higher Hematologic Adverse Events (AEs) of Anemia, Neutropenia, and/or Thrombocytopenia</measure>
    <time_frame>Transplantation to 40 Weeks Post Transplantation</time_frame>
    <description>The severity of adverse events (AEs) was classified into grades using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 (4/28/2009):&#xD;
Grade 1 = mild AE&#xD;
Grade 2 = moderate AE&#xD;
Grade 3 = severe and undesirable AE&#xD;
Grade 4 = life-threatening or disabling AE&#xD;
Grade 5 = death</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Percent of Participants With Adverse Events (AEs) Attributable to the Donor Alloantigen Reactive Tregs (darTregs) Infusion</measure>
    <time_frame>Transplantation to 40 Weeks Post Transplantation</time_frame>
    <description>AEs classified by the site investigator/clinician as possibly or definitely related to the study treatment, the Donor Alloantigen Reactive Tregs (darTregs) infusion. These AEs include:&#xD;
infusion reaction&#xD;
Grade 3 or higher cytokine release syndrome (Reference: National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 (4/28/2009) grading criteria&#xD;
malignant cellular transformation.</description>
  </primary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">15</enrollment>
  <condition>Liver Transplantation</condition>
  <arm_group>
    <arm_group_label>Cohort 1 - Treg-supportive IS only</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>3 subjects (Cohort 1a) at site 1 (UCSF) and 3 subjects (Cohort 1b) from site 2 (Mayo Rochester) will receive Treg-Supportive immunosuppression (IS) regimen and will not receive Donor-Alloantigen-Reactive T Regulatory Cells (darTregs). Progression from one cohort to the next will depend on the cumulative incidence of sentinel adverse events.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 2 - darTreg infusion,50 million(range 25 to 60 million)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>At least 3 subjects will receive a single infusion of 50 million darTregs. Progression from one cohort to the next will depend on the cumulative incidence of sentinel adverse events.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 3 - darTreg infusion,200 million(range100-240 million)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>At least 3 subjects will receive a single infusion dose of 200 million darTregs. Progression from one cohort to the next will depend on the cumulative incidence of sentinel adverse events.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 4 - darTreg infusion,800 million(range 400-960 million)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Six subjects will receive a single infusion of 800 million darTregs.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Anti-Thymocyte Globulin - Rabbit</intervention_name>
    <description>Liver transplantation/Treg-supportive immunosuppression (IS) treatment. Subjects will be given a dose range of 3.0-4.5 mg/kg total, in divided doses of 1.5 mg/kg/day. Subjects who meet eligibility criteria for Thymoglobulin® administration will be given 1.5 mg/kg intravenously (IV) on post-operative day 3, within 72 hours of transplantation. Additional doses of 1.5 mg/kg IV will be administered until CD3 count is &lt;50/mm^3 or when the maximal dose of 4.5/mg/kg has been given.</description>
    <arm_group_label>Cohort 1 - Treg-supportive IS only</arm_group_label>
    <arm_group_label>Cohort 2 - darTreg infusion,50 million(range 25 to 60 million)</arm_group_label>
    <arm_group_label>Cohort 3 - darTreg infusion,200 million(range100-240 million)</arm_group_label>
    <arm_group_label>Cohort 4 - darTreg infusion,800 million(range 400-960 million)</arm_group_label>
    <other_name>ATG (Anti-Thymocyte Globulin)</other_name>
    <other_name>Thymoglobulin®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>darTreg Infusion</intervention_name>
    <description>A single dose darTreg infusion (Cohorts 2 - 4) will be received as per protocol.</description>
    <arm_group_label>Cohort 2 - darTreg infusion,50 million(range 25 to 60 million)</arm_group_label>
    <arm_group_label>Cohort 3 - darTreg infusion,200 million(range100-240 million)</arm_group_label>
    <arm_group_label>Cohort 4 - darTreg infusion,800 million(range 400-960 million)</arm_group_label>
    <other_name>Donor-Alloantigen-Reactive Regulatory T Cell Infusion</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Everolimus</intervention_name>
    <description>Liver transplantation/Treg-supportive immunosuppression (IS) treatment. Subjects meeting eligibility criteria for Treg-supportive IS regimen will begin EVR no sooner than 30 days after liver transplantation and no later than 44 days after transplantation; with target trough levels of 6-8 μg/L.EVR target trough levels will be further reduced to 4-6 μg/L 24 - 26 weeks after transplantation.</description>
    <arm_group_label>Cohort 1 - Treg-supportive IS only</arm_group_label>
    <arm_group_label>Cohort 2 - darTreg infusion,50 million(range 25 to 60 million)</arm_group_label>
    <arm_group_label>Cohort 3 - darTreg infusion,200 million(range100-240 million)</arm_group_label>
    <arm_group_label>Cohort 4 - darTreg infusion,800 million(range 400-960 million)</arm_group_label>
    <other_name>EVR</other_name>
    <other_name>Zortress®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tacrolimus</intervention_name>
    <description>Liver transplantation/Treg-supportive immunosuppression (IS) treatment. Between 30 and 44 days following transplant: Subjects who are not eliminated by Exclusion Criteria C1 (Protocol Section 14.3.1) will proceed in the study and receive either TAC-based or EVR- based IS, based on eligibility Criteria C2 (Section 4.3.4 )&#xD;
TAC-based IS: reduce TAC trough level to 3-8 μg/dL; continue MMF&#xD;
EVR-based IS: reduce TAC trough level to 3-8 μg/dL; EVR target trough level of 6-8 μg/dL; decrease then discontinue MMF</description>
    <arm_group_label>Cohort 1 - Treg-supportive IS only</arm_group_label>
    <arm_group_label>Cohort 2 - darTreg infusion,50 million(range 25 to 60 million)</arm_group_label>
    <arm_group_label>Cohort 3 - darTreg infusion,200 million(range100-240 million)</arm_group_label>
    <arm_group_label>Cohort 4 - darTreg infusion,800 million(range 400-960 million)</arm_group_label>
    <other_name>Prograf®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Mycophenolate mofetil</intervention_name>
    <description>Liver transplantation/Treg-supportive immunosuppression (IS) treatment. 1000 mg total daily dose. MMF will be initiated within 24 hours of transplantation. MMF must be discontinued as soon as target EVR trough levels have been achieved.</description>
    <arm_group_label>Cohort 1 - Treg-supportive IS only</arm_group_label>
    <arm_group_label>Cohort 2 - darTreg infusion,50 million(range 25 to 60 million)</arm_group_label>
    <arm_group_label>Cohort 3 - darTreg infusion,200 million(range100-240 million)</arm_group_label>
    <arm_group_label>Cohort 4 - darTreg infusion,800 million(range 400-960 million)</arm_group_label>
    <other_name>MMF</other_name>
    <other_name>Cellcept</other_name>
    <other_name>Myfortic</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Prednisone</intervention_name>
    <description>Liver transplantation/Treg-supportive immunosuppression (IS) treatment. Solumedrol 500 mg will be given IV on the day of transplantation. Additional Solumedrol will be prescribed according to site-specific standard of care. Oral prednisone should be initiated once oral medication is tolerated.</description>
    <arm_group_label>Cohort 1 - Treg-supportive IS only</arm_group_label>
    <arm_group_label>Cohort 2 - darTreg infusion,50 million(range 25 to 60 million)</arm_group_label>
    <arm_group_label>Cohort 3 - darTreg infusion,200 million(range100-240 million)</arm_group_label>
    <arm_group_label>Cohort 4 - darTreg infusion,800 million(range 400-960 million)</arm_group_label>
    <other_name>Solumedrol</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Acetaminophen</intervention_name>
    <description>Pre-medication for single dose darTreg infusion (Cohorts 2 - 4). 650mg of acetaminophen will be administered intravenously or by mouth 30-60 minutes prior to the darTreg infusion.</description>
    <arm_group_label>Cohort 2 - darTreg infusion,50 million(range 25 to 60 million)</arm_group_label>
    <arm_group_label>Cohort 3 - darTreg infusion,200 million(range100-240 million)</arm_group_label>
    <arm_group_label>Cohort 4 - darTreg infusion,800 million(range 400-960 million)</arm_group_label>
    <other_name>Tylenol®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Diphenhydramine</intervention_name>
    <description>Pre-medication for single dose darTreg infusion (Cohorts 2 - 4). 25-50mg of diphenhydramine will be administered intravenously or by mouth 30-60 minutes prior to the darTreg infusion.</description>
    <arm_group_label>Cohort 2 - darTreg infusion,50 million(range 25 to 60 million)</arm_group_label>
    <arm_group_label>Cohort 3 - darTreg infusion,200 million(range100-240 million)</arm_group_label>
    <arm_group_label>Cohort 4 - darTreg infusion,800 million(range 400-960 million)</arm_group_label>
    <other_name>Diphenhydramine Hydrochloride</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Anti-Infective Prophylaxis</intervention_name>
    <description>Intravenous ganciclovir and/or oral Valcyte will be administered for the prophylaxis of cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) for at least six months after liver transplantation.</description>
    <arm_group_label>Cohort 1 - Treg-supportive IS only</arm_group_label>
    <arm_group_label>Cohort 2 - darTreg infusion,50 million(range 25 to 60 million)</arm_group_label>
    <arm_group_label>Cohort 3 - darTreg infusion,200 million(range100-240 million)</arm_group_label>
    <arm_group_label>Cohort 4 - darTreg infusion,800 million(range 400-960 million)</arm_group_label>
    <other_name>Antiviral Prophylaxis</other_name>
    <other_name>ganciclovir</other_name>
    <other_name>Cytovene</other_name>
    <other_name>Valganciclovir</other_name>
    <other_name>Valcyte</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Leukapheresis</intervention_name>
    <description>Leukapheresis is necessary to ensure collection of adequate numbers of autologous Tregs to support ex vivo expansion of darTregs for infusion after liver transplantation.&#xD;
Participants enrolled in Cohorts 3 and 4 will undergo leukapheresis. Participants enrolled in Cohort 2 will have either whole blood collection or leukapheresis for the purpose of isolating autologous Tregs for later manufacture. If a cohort 2 subject has a hemoglobin level &gt;/=10.5 gm/dL, he or she will undergo phlebotomy. If the patient has a hemoglobin level &lt;/=10.5 gm/dL and remains eligible for the study, the patient will undergo leukapheresis.</description>
    <arm_group_label>Cohort 2 - darTreg infusion,50 million(range 25 to 60 million)</arm_group_label>
    <arm_group_label>Cohort 3 - darTreg infusion,200 million(range100-240 million)</arm_group_label>
    <arm_group_label>Cohort 4 - darTreg infusion,800 million(range 400-960 million)</arm_group_label>
    <other_name>Leukocytapheresis</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Blood draws</intervention_name>
    <description>Blood draws are necessary to carefully and frequently evaluate allograft function after liver transplantation and treatment with Treg-supportive IS as well as after darTreg infusion. Peripheral blood samples will be collected and analyzed per protocol throughout subject participation in this study.</description>
    <arm_group_label>Cohort 1 - Treg-supportive IS only</arm_group_label>
    <arm_group_label>Cohort 2 - darTreg infusion,50 million(range 25 to 60 million)</arm_group_label>
    <arm_group_label>Cohort 3 - darTreg infusion,200 million(range100-240 million)</arm_group_label>
    <arm_group_label>Cohort 4 - darTreg infusion,800 million(range 400-960 million)</arm_group_label>
    <other_name>Venipuncture</other_name>
    <other_name>Phlebotomy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Liver biopsies</intervention_name>
    <description>Subjects will have a liver biopsy for this study 12-14 weeks after transplantation. For subjects receiving darTregs, a second biopsy will be performed 7-10 days after darTregs infusion.</description>
    <arm_group_label>Cohort 1 - Treg-supportive IS only</arm_group_label>
    <arm_group_label>Cohort 2 - darTreg infusion,50 million(range 25 to 60 million)</arm_group_label>
    <arm_group_label>Cohort 3 - darTreg infusion,200 million(range100-240 million)</arm_group_label>
    <arm_group_label>Cohort 4 - darTreg infusion,800 million(range 400-960 million)</arm_group_label>
    <other_name>Liver biopsy samples</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Liver transplantation</intervention_name>
    <description>Inclusion in this trial is in the setting of subjects defined as having end-stage liver disease and listed for primary solitary liver transplant.</description>
    <arm_group_label>Cohort 1 - Treg-supportive IS only</arm_group_label>
    <arm_group_label>Cohort 2 - darTreg infusion,50 million(range 25 to 60 million)</arm_group_label>
    <arm_group_label>Cohort 3 - darTreg infusion,200 million(range100-240 million)</arm_group_label>
    <arm_group_label>Cohort 4 - darTreg infusion,800 million(range 400-960 million)</arm_group_label>
    <other_name>Liver transplant</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subjects who meet all of the following criteria are eligible for enrollment as study&#xD;
             participants:&#xD;
&#xD;
               -  Able to understand and provide informed consent&#xD;
&#xD;
               -  End-stage liver disease and listed for primary solitary liver transplant&#xD;
&#xD;
               -  Have a calculated Model for End Stage Liver Disease (MELD) score ≤ 25 at the time&#xD;
                  of study entry/consent&#xD;
&#xD;
               -  Female and male subjects with reproductive potential must agree to use effective&#xD;
                  methods of birth control for the duration of the study.&#xD;
&#xD;
               -  If history of Hepatitis C Virus (HCV), have completed or are in current treatment&#xD;
                  for HCV AND have no detectable HCV RNA.&#xD;
&#xD;
               -  Subjects with HCC meeting Milan criteria.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Below are exclusion criteria to be assessed at study enrollment, prior to Stage 1&#xD;
             study procedures. Subjects who meet any of these criteria are not eligible for Stage 1&#xD;
             study procedures. Note that subjects in Cohort 1a or 1b will NOT undergo leukapheresis&#xD;
             regardless of eligibility.&#xD;
&#xD;
               -  End stage liver disease secondary to autoimmune etiology (autoimmune hepatitis,&#xD;
                  primary biliary cirrhosis, or primary sclerosing cholangitis)&#xD;
&#xD;
               -  History of less than 5 years remission of malignancy, except for 1) HCC or 2)&#xD;
                  history of adequately treated in-situ cervical carcinoma, or adequately treated&#xD;
                  basal or squamous cell carcinoma of the skin.&#xD;
&#xD;
               -  History of previous organ, tissue or cell transplant&#xD;
&#xD;
               -  Serologic evidence of human immunodeficiency (HIV) 1 or -2 infection&#xD;
&#xD;
               -  Epstein-Barr Virus (EBV) or cytomegalovirus (CMV) sero-negativity (EBV or CMV&#xD;
                  naïve candidates)&#xD;
&#xD;
               -  Chronic use of systemic glucocorticoids or other Immunosuppression (IS), or&#xD;
                  biologic immunomodulators&#xD;
&#xD;
               -  Chronic condition requiring anti-coagulation after liver transplantation&#xD;
&#xD;
               -  Any chronic illness or prior treatment which, in the opinion of the investigator,&#xD;
                  precludes study participation&#xD;
&#xD;
               -  Participation in any other studies that involved investigational drugs or&#xD;
                  regimens in the preceding year&#xD;
&#xD;
               -  Received any vaccination within 28 days prior to leukapheresis or blood&#xD;
                  collection for Treg manufacture&#xD;
&#xD;
               -  Hemoglobin &lt;9.0 g/dL within 10 days prior to screening&#xD;
&#xD;
               -  Neutrophils &lt;1,500/μL within 10 days prior to screening&#xD;
&#xD;
               -  Platelets &lt;40,000/μL within 10 days prior to screening&#xD;
&#xD;
          -  Thymoglobulin Exclusion Criteria B (Stage 2):&#xD;
&#xD;
               -  Below are exclusion criteria to be assessed prior to administration of&#xD;
                  Thymoglobulin®. Subjects who meet any of these criteria should not receive&#xD;
                  Thymoglobulin®:&#xD;
&#xD;
                    -  Calculated Model for End Stage Liver Disease (MELD) score &gt;25 at the time of&#xD;
                       deceased donor liver transplant&#xD;
&#xD;
                    -  Last alpha-fetoprotein (AFP) obtained prior to liver transplantation &gt;400&#xD;
                       μg/L for candidates with Hepatocellular Carcinoma (HCC)&#xD;
&#xD;
                    -  Unacceptable Peripheral Blood Mononuclear Cells (PBMC) product for&#xD;
                       participants enrolled in Cohorts 2, 3, or 4 per the UCSF The Human Islet and&#xD;
                       Cellular Transplant Facility (HICTF) manufacturing specifications&#xD;
&#xD;
                    -  Absence of donor spleen for any participants&#xD;
&#xD;
                    -  Human leukocyte antigen (HLA)-DR (DR is one of class II antigens) matched to&#xD;
                       donor at both loci&#xD;
&#xD;
                    -  Subject is &lt; 21 or &gt;70 years of age at the time of transplantation&#xD;
&#xD;
                    -  Located in the intensive care unit 72 hours after transplantation&#xD;
&#xD;
                    -  Hemoglobin &lt;8.0 g/dL&#xD;
&#xD;
                    -  Absolute neutrophil count &lt;1,200/μL&#xD;
&#xD;
                    -  Platelets &lt;40,000/μL&#xD;
&#xD;
                    -  Positive pregnancy test for females of child bearing potential&#xD;
&#xD;
                    -  Unexpected histopathology on back table liver biopsy that contraindicates&#xD;
                       the initiation of Treg supportive IS regimen.&#xD;
&#xD;
                    -  Development of a condition requiring chronic anti-coagulation.&#xD;
&#xD;
                    -  Hypersensitivity to rabbit proteins or any excipient in Thymoglobulin®.&#xD;
&#xD;
                    -  Detectable HCV RNA or less than six months after end of treatment for HCV at&#xD;
                       the time of transplantation (i.e., does not meet criteria for SVR).&#xD;
&#xD;
               -  Below are exclusion criteria to be assessed prior to conversion to Everolimus&#xD;
                  (EVR)-based IS regimen. (Assessed at day 30-44 after transplantation for&#xD;
                  continuation in the trial) All subjects regardless of eligibility for EVR&#xD;
                  conversion, with any of the following will not receive darTregs and will move&#xD;
                  into safety follow up:&#xD;
&#xD;
                    -  Explanted liver with evidence of increased risk of recurrent cancer risk&#xD;
                       (hepatocellular (HCC) tumor burden exceeding the Milan criteria; presence of&#xD;
                       vascular invasion; cholangiocarcinoma morphology)&#xD;
&#xD;
                    -  Insufficient depletion of recipient T cells, defined as a nadir CD3 count&#xD;
                       ≥50 cells μ/L (50 cells /mcL) or total lymphocyte count ≥ 0.1x 109/L if CD3&#xD;
                       count is unavailable&#xD;
&#xD;
                    -  Development of a condition requiring chronic anti-coagulation.&#xD;
&#xD;
                    -  Clinical evidence of biliary obstruction&#xD;
&#xD;
                    -  Alanine Aminotransferase (ALT) &gt;2.0 x upper limit of normal (ULN)&#xD;
&#xD;
                    -  Inability to taper off corticosteroids by 44 days (+/- 2 days) after&#xD;
                       transplant&#xD;
&#xD;
                    -  Detectable circulating HCV RNA.&#xD;
&#xD;
        Everolimus Conversion Criteria C2 (assessed prior to conversion to EVR based IS regimen;&#xD;
        EVR cannot be initiated prior to 30 days after liver transplantation). Subjects with any of&#xD;
        the following will remain on TAC-based IS regimen.&#xD;
&#xD;
          -  Evidence of hepatic artery stenosis or thrombosis by Doppler examination or&#xD;
             angiography within 7 days prior to conversion&#xD;
&#xD;
          -  Urine protein/creatinine ratio &gt;1.0 within 7 days prior to conversion&#xD;
&#xD;
          -  Calculated GFR less than 30 ml/min per MDRD4 (Modification of Diet in Renal Disease&#xD;
             Study) equation within 7 days prior to conversion&#xD;
&#xD;
          -  Physical examination documentation of abnormal wound healing or uncontrolled wound&#xD;
             infection&#xD;
&#xD;
          -  Hemoglobin &lt;8.0 g/dL within 7 days prior to conversion&#xD;
&#xD;
          -  Absolute neutrophil count &lt;1,200/μL within 7 days prior to conversion&#xD;
&#xD;
          -  Platelets &lt;50,000/μL within 7 days prior to conversion&#xD;
&#xD;
             *Below are exclusion criteria to be assessed prior to darTreg infusion for subjects in&#xD;
             Cohorts 2, 3, and 4 only. Subjects in Cohort 2, 3, or 4 who meet any of these criteria&#xD;
             should not receive a darTreg-infusion:&#xD;
&#xD;
          -  Inability or unwillingness of participant to give additional written informed consent&#xD;
&#xD;
          -  Unacceptable darTreg product&#xD;
&#xD;
          -  Detectible circulating Epstein-Barr Virus (EBV) or cytomegalovirus (CMV) DNA within 10&#xD;
             days prior to darTreg infusion&#xD;
&#xD;
          -  Detectible Hepatitis B Virus (HBV) DNA within 10 days prior to darTreg infusion&#xD;
&#xD;
          -  Detectable circulating HCV RNA within 10 days prior to darTreg infusion.&#xD;
&#xD;
          -  Alanine Aminotransferase (ALT) &gt;1.5x upper limit of normal within 10 days of darTreg&#xD;
             infusion&#xD;
&#xD;
          -  Most recent, but not greater than 10 days prior to darTreg infusion,12 hour TAC trough&#xD;
             levels of &gt; 8 μg/L for all subjects&#xD;
&#xD;
          -  Most recent, but not greater than 10 days prior to darTreg infusion,12 hour EVR trough&#xD;
             levels of &lt; 5 μg/L for subjects on EVR&#xD;
&#xD;
          -  For subjects on EVR-based IS, received Mycophenolate Mofetil (MMF) within 10 days&#xD;
             prior to darTreg infusion&#xD;
&#xD;
          -  Evidence of acute rejection or chronic rejection according to Banff criteria on&#xD;
             protocol allograft biopsy based on local assessment&#xD;
&#xD;
          -  Received any vaccination within 14 days prior to darTreg infusion&#xD;
&#xD;
          -  Positive pregnancy test for females of child bearing potential&#xD;
&#xD;
          -  Inability or unwillingness of participant to comply with study protocol or procedures.&#xD;
&#xD;
          -  Calculated glomerular filtration rate (eGFR) less than 40 ml/min per MDRD4 equation&#xD;
             within 10 days prior to infusion.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sandy Feng, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of California, San Francisco</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Jeffrey Bluestone, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of California, San Francisco</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Sang-Mo Kang, MD, FACS</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of California, San Francisco</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Qizhi Tang, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of California, San Francisco</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of California, San Francisco</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94143</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Northwestern University</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://www.niaid.nih.gov/</url>
    <description>National Institute of Allergy and Infectious Diseases (NIAID) website</description>
  </link>
  <verification_date>September 2020</verification_date>
  <study_first_submitted>July 10, 2014</study_first_submitted>
  <study_first_submitted_qc>July 10, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 14, 2014</study_first_posted>
  <results_first_submitted>June 16, 2020</results_first_submitted>
  <results_first_submitted_qc>July 17, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">July 20, 2020</results_first_posted>
  <last_update_submitted>September 2, 2020</last_update_submitted>
  <last_update_submitted_qc>September 2, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">September 22, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Donor-Alloantigen-Reactive Regulatory T Cell Therapy</keyword>
  <keyword>Tregs</keyword>
  <keyword>Cell- and Tissue-Based Therapy</keyword>
  <keyword>Immunotherapy, Adoptive</keyword>
  <keyword>Liver Transplantation</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acetaminophen</mesh_term>
    <mesh_term>Diphenhydramine</mesh_term>
    <mesh_term>Promethazine</mesh_term>
    <mesh_term>Mycophenolic Acid</mesh_term>
    <mesh_term>Valganciclovir</mesh_term>
    <mesh_term>Ganciclovir</mesh_term>
    <mesh_term>Anti-Infective Agents</mesh_term>
    <mesh_term>Prednisone</mesh_term>
    <mesh_term>Methylprednisolone Hemisuccinate</mesh_term>
    <mesh_term>Everolimus</mesh_term>
    <mesh_term>Liver Extracts</mesh_term>
    <mesh_term>Tacrolimus</mesh_term>
    <mesh_term>Thymoglobulin</mesh_term>
    <mesh_term>Antilymphocyte Serum</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>August 1, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/19/NCT02188719/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>May 6, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/19/NCT02188719/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Cohort 1</title>
          <description>Participants received Thymoglobulin®+EVR IS but will not receive darTregs</description>
        </group>
        <group group_id="P2">
          <title>Cohort 2</title>
          <description>Participants received Thymoglobulin®+EVR IS and will receive a darTreg infusion of 50 million(range 25 to 60 million) cells.</description>
        </group>
        <group group_id="P3">
          <title>Cohort 3</title>
          <description>Participants received Thymoglobulin®+EVR IS and will receive a darTreg infusion of 200 million(range 100 to 240 million) cells. No participants were enrolled in this cohort.</description>
        </group>
        <group group_id="P4">
          <title>Cohort 4</title>
          <description>Participants received Thymoglobulin®+EVR IS and will receive a darTreg infusion of 800 million(range 400 to 960 million) cells. No participants were enrolled in this cohort.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="9"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="8"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Screen B Ineligible (Page 55, Protocol)</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>All participants assigned to Treatment Cohorts after transplantation.</population>
      <group_list>
        <group group_id="B1">
          <title>Cohort 1</title>
          <description>Participants received Thymoglobulin®+EVR IS but will not receive darTregs</description>
        </group>
        <group group_id="B2">
          <title>Cohort 2</title>
          <description>Participants received Thymoglobulin®+EVR IS and will receive a darTreg infusion of 50 million(range 25 to 60 million) cells.</description>
        </group>
        <group group_id="B3">
          <title>Cohort 3</title>
          <description>Participants received Thymoglobulin®+EVR IS and will receive a darTreg infusion of 200 million(range 100 to 240 million) cells. No participants were enrolled in this cohort.</description>
        </group>
        <group group_id="B4">
          <title>Cohort 4</title>
          <description>Participants received Thymoglobulin®+EVR IS and will receive a darTreg infusion of 800 million(range 400 to 960 million) cells. No participants were enrolled in this cohort.</description>
        </group>
        <group group_id="B5">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="6"/>
            <count group_id="B2" value="9"/>
            <count group_id="B3" value="0"/>
            <count group_id="B4" value="0"/>
            <count group_id="B5" value="15"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="11"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="59" spread="5.5"/>
                    <measurement group_id="B2" value="62" spread="4.2"/>
                    <measurement group_id="B5" value="61" spread="4.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B5" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B5" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B5" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B5" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B5" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B5" value="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Count of Participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B5" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Alanine Aminotransferase (ALT)</title>
          <description>Normal Range in Adults: 7-41 U/L.</description>
          <units>U/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="47.0" spread="66.6"/>
                    <measurement group_id="B2" value="216.4" spread="543.4"/>
                    <measurement group_id="B5" value="148.7" spread="421.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Alkaline Phosphatase</title>
          <description>Normal Range in Adults: 33-96 U/L.</description>
          <units>U/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="64.0" spread="17.3"/>
                    <measurement group_id="B2" value="102.8" spread="44.4"/>
                    <measurement group_id="B5" value="87.3" spread="40.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Gamma-Glutamyl Transferase (GGT)</title>
          <description>Normal Range in Adults: 9-58 U/L.</description>
          <units>U/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="40.0" spread="11.3"/>
                    <measurement group_id="B2" value="115.8" spread="97.0"/>
                    <measurement group_id="B5" value="100.6" spread="91.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Percent of Participants With Biopsy-Proven Acute and/or Chronic Rejection</title>
        <description>Biopsy-proven acute rejection graded as Mild, Moderate or Severe, per 1997 Banff classification. Chronic Rejection graded using Banff 2000 classification.&#xD;
References: 1.) Banff Schema for Grading Liver Allograft Rejection: An International Consensus Document developed by an international panel of experts in liver transplantation pathology, hepatology, and surgery (Hepatology 1997; 25(3): 658-663). 2.) Update of the International Banff Schema for Liver Allograft Rejection: Working Recommendations for the Histopathologic Staging and Reporting of Chronic Rejection (Hepatology 2000; 31(3): 792-799).</description>
        <time_frame>Transplantation to 40 Weeks Post Transplantation</time_frame>
        <population>All transplanted participants.</population>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1</title>
            <description>Participants received Thymoglobulin®+EVR IS but will not receive darTregs</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2</title>
            <description>Participants received Thymoglobulin®+EVR IS and will receive a darTreg infusion of 50 million(range 25 to 60 million) cells.</description>
          </group>
          <group group_id="O3">
            <title>Cohort 3</title>
            <description>Participants received Thymoglobulin®+EVR IS and will receive a darTreg infusion of 200 million(range 100 to 240 million) cells. No participants were enrolled in this cohort.</description>
          </group>
          <group group_id="O4">
            <title>Cohort 4</title>
            <description>Participants received Thymoglobulin®+EVR IS and will receive a darTreg infusion of 800 million(range 400 to 960 million) cells. No participants were enrolled in this cohort.</description>
          </group>
        </group_list>
        <measure>
          <title>Percent of Participants With Biopsy-Proven Acute and/or Chronic Rejection</title>
          <description>Biopsy-proven acute rejection graded as Mild, Moderate or Severe, per 1997 Banff classification. Chronic Rejection graded using Banff 2000 classification.&#xD;
References: 1.) Banff Schema for Grading Liver Allograft Rejection: An International Consensus Document developed by an international panel of experts in liver transplantation pathology, hepatology, and surgery (Hepatology 1997; 25(3): 658-663). 2.) Update of the International Banff Schema for Liver Allograft Rejection: Working Recommendations for the Histopathologic Staging and Reporting of Chronic Rejection (Hepatology 2000; 31(3): 792-799).</description>
          <population>All transplanted participants.</population>
          <units>Percent of Participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="9"/>
                <count group_id="O3" value="0"/>
                <count group_id="O4" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Mild Acute Rejection</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="11.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Moderate Acute Rejection</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Severe Acute Rejection</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Chronic Rejection</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Percent of Participants With Grade 3 or Higher Infectious Adverse Event(s)</title>
        <description>The severity of infectious adverse events (AEs) was classified into grades as follows:&#xD;
Grade 1 = asymptomatic; clinical or diagnostic observation only; intervention with oral antibiotic, antifungal, or antiviral agent only; no invasive intervention required&#xD;
Grade 2 = symptomatic; intervention with intravenous antibiotic, antifungal, or antiviral agent; invasive intervention may be required&#xD;
Grade 3 = any infection associated with hemodynamic compromise requiring pressors; any infection necessitating intensive care unit level of care; any infection necessitating operative intervention; any infection involving the central nervous system; any infection with a positive fungal blood culture; any proven or probable aspergillus infection; any tissue invasive fungal infection; any pneumocystis jiroveci infection&#xD;
Grade 4 = life-threatening infection&#xD;
Grade 5 = death resulting from infection</description>
        <time_frame>Transplantation to 40 Weeks Post Transplantation</time_frame>
        <population>All transplanted participants.</population>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1</title>
            <description>Participants received Thymoglobulin®+EVR IS but will not receive darTregs</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2</title>
            <description>Participants received Thymoglobulin®+EVR IS and will receive a darTreg infusion of 50 million(range 25 to 60 million) cells.</description>
          </group>
          <group group_id="O3">
            <title>Cohort 3</title>
            <description>Participants received Thymoglobulin®+EVR IS and will receive a darTreg infusion of 200 million(range 100 to 240 million) cells. No participants were enrolled in this cohort.</description>
          </group>
          <group group_id="O4">
            <title>Cohort 4</title>
            <description>Participants received Thymoglobulin®+EVR IS and will receive a darTreg infusion of 800 million(range 400 to 960 million) cells. No participants were enrolled in this cohort.</description>
          </group>
        </group_list>
        <measure>
          <title>Percent of Participants With Grade 3 or Higher Infectious Adverse Event(s)</title>
          <description>The severity of infectious adverse events (AEs) was classified into grades as follows:&#xD;
Grade 1 = asymptomatic; clinical or diagnostic observation only; intervention with oral antibiotic, antifungal, or antiviral agent only; no invasive intervention required&#xD;
Grade 2 = symptomatic; intervention with intravenous antibiotic, antifungal, or antiviral agent; invasive intervention may be required&#xD;
Grade 3 = any infection associated with hemodynamic compromise requiring pressors; any infection necessitating intensive care unit level of care; any infection necessitating operative intervention; any infection involving the central nervous system; any infection with a positive fungal blood culture; any proven or probable aspergillus infection; any tissue invasive fungal infection; any pneumocystis jiroveci infection&#xD;
Grade 4 = life-threatening infection&#xD;
Grade 5 = death resulting from infection</description>
          <population>All transplanted participants.</population>
          <units>Percent of Participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="9"/>
                <count group_id="O3" value="0"/>
                <count group_id="O4" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="11.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Percent of Participants With Grade 3 or Higher Wound Complication(s) Adverse Event(s)</title>
        <description>The severity of adverse events (AEs) was classified into grades using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 (4/28/2009):&#xD;
Grade 3 wound complications are defined as &quot;Hernia without evidence of strangulation; fascial disruption/dehiscence; primary wound closure or revision by operative intervention indicated&quot;&#xD;
Grade 4 complications are defined as &quot;Hernia with evidence of strangulation; major reconstruction flap, grafting, resection, or amputation indicated&quot;</description>
        <time_frame>Transplantation to 40 Weeks Post Transplantation</time_frame>
        <population>All transplanted participants.</population>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1</title>
            <description>Participants received Thymoglobulin®+EVR IS but will not receive darTregs</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2</title>
            <description>Participants received Thymoglobulin®+EVR IS and will receive a darTreg infusion of 50 million(range 25 to 60 million) cells.</description>
          </group>
          <group group_id="O3">
            <title>Cohort 3</title>
            <description>Participants received Thymoglobulin®+EVR IS and will receive a darTreg infusion of 200 million(range 100 to 240 million) cells. No participants were enrolled in this cohort.</description>
          </group>
          <group group_id="O4">
            <title>Cohort 4</title>
            <description>Participants received Thymoglobulin®+EVR IS and will receive a darTreg infusion of 800 million(range 400 to 960 million) cells. No participants were enrolled in this cohort.</description>
          </group>
        </group_list>
        <measure>
          <title>Percent of Participants With Grade 3 or Higher Wound Complication(s) Adverse Event(s)</title>
          <description>The severity of adverse events (AEs) was classified into grades using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 (4/28/2009):&#xD;
Grade 3 wound complications are defined as &quot;Hernia without evidence of strangulation; fascial disruption/dehiscence; primary wound closure or revision by operative intervention indicated&quot;&#xD;
Grade 4 complications are defined as &quot;Hernia with evidence of strangulation; major reconstruction flap, grafting, resection, or amputation indicated&quot;</description>
          <population>All transplanted participants.</population>
          <units>Percent of Participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="9"/>
                <count group_id="O3" value="0"/>
                <count group_id="O4" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Percent of Participants With Grade 2 or Higher Hematologic Adverse Events (AEs) of Anemia, Neutropenia, and/or Thrombocytopenia</title>
        <description>The severity of adverse events (AEs) was classified into grades using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 (4/28/2009):&#xD;
Grade 1 = mild AE&#xD;
Grade 2 = moderate AE&#xD;
Grade 3 = severe and undesirable AE&#xD;
Grade 4 = life-threatening or disabling AE&#xD;
Grade 5 = death</description>
        <time_frame>Transplantation to 40 Weeks Post Transplantation</time_frame>
        <population>All transplanted participants.</population>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1</title>
            <description>Participants received Thymoglobulin®+EVR IS but will not receive darTregs</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2</title>
            <description>Participants received Thymoglobulin®+EVR IS and will receive a darTreg infusion of 50 million(range 25 to 60 million) cells.</description>
          </group>
          <group group_id="O3">
            <title>Cohort 3</title>
            <description>Participants received Thymoglobulin®+EVR IS and will receive a darTreg infusion of 200 million(range 100 to 240 million) cells. No participants were enrolled in this cohort.</description>
          </group>
          <group group_id="O4">
            <title>Cohort 4</title>
            <description>Participants received Thymoglobulin®+EVR IS and will receive a darTreg infusion of 800 million(range 400 to 960 million) cells. No participants were enrolled in this cohort.</description>
          </group>
        </group_list>
        <measure>
          <title>Percent of Participants With Grade 2 or Higher Hematologic Adverse Events (AEs) of Anemia, Neutropenia, and/or Thrombocytopenia</title>
          <description>The severity of adverse events (AEs) was classified into grades using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 (4/28/2009):&#xD;
Grade 1 = mild AE&#xD;
Grade 2 = moderate AE&#xD;
Grade 3 = severe and undesirable AE&#xD;
Grade 4 = life-threatening or disabling AE&#xD;
Grade 5 = death</description>
          <population>All transplanted participants.</population>
          <units>Percent of Participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="9"/>
                <count group_id="O3" value="0"/>
                <count group_id="O4" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Anemia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="66.7"/>
                    <measurement group_id="O2" value="22.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Neutropenia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="16.7"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Thrombocytopenia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="16.7"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Percent of Participants With Adverse Events (AEs) Attributable to the Donor Alloantigen Reactive Tregs (darTregs) Infusion</title>
        <description>AEs classified by the site investigator/clinician as possibly or definitely related to the study treatment, the Donor Alloantigen Reactive Tregs (darTregs) infusion. These AEs include:&#xD;
infusion reaction&#xD;
Grade 3 or higher cytokine release syndrome (Reference: National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 (4/28/2009) grading criteria&#xD;
malignant cellular transformation.</description>
        <time_frame>Transplantation to 40 Weeks Post Transplantation</time_frame>
        <population>Limited to participants that received darTreg infusion (N=1 study participant).</population>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1</title>
            <description>Participants received Thymoglobulin®+EVR IS but will not receive darTregs</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2</title>
            <description>Participants received Thymoglobulin®+EVR IS and will receive a darTreg infusion of 50 million(range 25 to 60 million) cells.</description>
          </group>
          <group group_id="O3">
            <title>Cohort 3</title>
            <description>Participants received Thymoglobulin®+EVR IS and will receive a darTreg infusion of 200 million(range 100 to 240 million) cells. No participants were enrolled in this cohort.</description>
          </group>
          <group group_id="O4">
            <title>Cohort 4</title>
            <description>Participants received Thymoglobulin®+EVR IS and will receive a darTreg infusion of 800 million(range 400 to 960 million) cells. No participants were enrolled in this cohort.</description>
          </group>
        </group_list>
        <measure>
          <title>Percent of Participants With Adverse Events (AEs) Attributable to the Donor Alloantigen Reactive Tregs (darTregs) Infusion</title>
          <description>AEs classified by the site investigator/clinician as possibly or definitely related to the study treatment, the Donor Alloantigen Reactive Tregs (darTregs) infusion. These AEs include:&#xD;
infusion reaction&#xD;
Grade 3 or higher cytokine release syndrome (Reference: National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 (4/28/2009) grading criteria&#xD;
malignant cellular transformation.</description>
          <population>Limited to participants that received darTreg infusion (N=1 study participant).</population>
          <units>Percent of Participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="1"/>
                <count group_id="O3" value="0"/>
                <count group_id="O4" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>40 weeks</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Cohort 1</title>
          <description>Participants received Thymoglobulin® +EVR IS but will not receive darTregs</description>
        </group>
        <group group_id="E2">
          <title>Cohort 2</title>
          <description>Participants received Thymoglobulin®+EVR IS and will receive a darTreg infusion of 50 million(range 25 to 60 million) cells.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA 14.0</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Iron deficiency anaemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Thrombocytopenia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Gastrooesophageal reflux disease</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Ileus</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Intestinal obstruction</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chest pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Influenza like illness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Oedema</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Biliary ischaemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Portal vein thrombosis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Liver transplant rejection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Gastroenteritis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Tooth infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Viral infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Wound infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Infusion related reaction</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Post procedural haemorrhage</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Postoperative ileus</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Blood alkaline phosphatase increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Blood creatinine increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Gamma-glutamyltransferase increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Weight decreased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>White blood cell count decreased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Failure to thrive</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Hyperkalaemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Hypomagnesaemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Calculus urinary</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Proteinuria</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Renal failure acute</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Hypocapnia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Eczema</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>MedDRA 14.0</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Iron deficiency anaemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Thrombocytopenia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Gastrooesophageal reflux disease</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Ileus</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Intestinal obstruction</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Inguinal hernia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chest pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Influenza like illness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Oedema</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Biliary ischaemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Portal vein thrombosis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Liver transplant rejection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Gastroenteritis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Tooth infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Viral infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Wound infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Infusion related reaction</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Post procedural haemorrhage</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Postoperative ileus</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Blood alkaline phosphatase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Blood creatinine increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Gamma-glutamyltransferase increased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Weight decreased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>White blood cell count decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Failure to thrive</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Hyperkalaemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Hypomagnesaemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Calculus urinary</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Proteinuria</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Renal failure acute</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Hypocapnia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Eczema</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>Enrollment was terminated due to several factors:high number of ineligible subjects, slow enrollment, and manufacturing difficulties within the constraints of the funding period.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Director, Clinical Research Operations Program</name_or_title>
      <organization>DAIT/NIAID</organization>
      <phone>301-594-7669</phone>
      <email>DAITClinicalTrialsGov@niaid.nih.gov</email>
    </point_of_contact>
  </clinical_results>
</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/NCT02188719
org study id: DAIT RTB-002
secondary id: R34AI095135
secondary id: U01AI110658
secondary id: NIAID CRMS ID#: 20182
nct id: NCT02188719
lead sponsor: 
collaborator: 
has dmc: Yes
The purpose of this study is look at the safety of:

        -  Taking a specific combination of immunosuppressant drugs after liver transplantation

        -  Receiving one of three different doses of donor-alloantigen-reactive regulatory T cells
           (darTregs) while taking this specific combination of drugs
After liver transplantation, immunosuppressants must be taken every day to prevent the body
      from injuring the transplanted liver by a process called rejection. People who take these
      drugs may experience side effects.

      Studies show that some of body's cells, called T regulatory cells (Tregs), may play a part in
      accepting the transplanted liver. The investigators are learning about whether scientists can
      take Tregs from the blood of a liver transplant recipient and teach them to protect the
      transplanted liver from rejection. In the laboratory, the recipient Tregs are exposed to
      cells from the liver donor. Research data suggests that giving these "donor reactive" Tregs
      back to the transplant recipient might allow a liver transplant recipient to take lower doses
      of immunosuppressants, or perhaps to stop them altogether, without rejecting the liver.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Percent of Participants With Biopsy-Proven Acute and/or Chronic Rejection
time frame: Transplantation to 40 Weeks Post Transplantation
description: Biopsy-proven acute rejection graded as Mild, Moderate or Severe, per 1997 Banff classification. Chronic Rejection graded using Banff 2000 classification.
References: 1.) Banff Schema for Grading Liver Allograft Rejection: An International Consensus Document developed by an international panel of experts in liver transplantation pathology, hepatology, and surgery (Hepatology 1997; 25(3): 658-663). 2.) Update of the International Banff Schema for Liver Allograft Rejection: Working Recommendations for the Histopathologic Staging and Reporting of Chronic Rejection (Hepatology 2000; 31(3): 792-799).
measure: Percent of Participants With Grade 3 or Higher Infectious Adverse Event(s)
time frame: Transplantation to 40 Weeks Post Transplantation
description: The severity of infectious adverse events (AEs) was classified into grades as follows:
Grade 1 = asymptomatic; clinical or diagnostic observation only; intervention with oral antibiotic, antifungal, or antiviral agent only; no invasive intervention required
Grade 2 = symptomatic; intervention with intravenous antibiotic, antifungal, or antiviral agent; invasive intervention may be required
Grade 3 = any infection associated with hemodynamic compromise requiring pressors; any infection necessitating intensive care unit level of care; any infection necessitating operative intervention; any infection involving the central nervous system; any infection with a positive fungal blood culture; any proven or probable aspergillus infection; any tissue invasive fungal infection; any pneumocystis jiroveci infection
Grade 4 = life-threatening infection
Grade 5 = death resulting from infection
measure: Percent of Participants With Grade 3 or Higher Wound Complication(s) Adverse Event(s)
time frame: Transplantation to 40 Weeks Post Transplantation
description: The severity of adverse events (AEs) was classified into grades using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 (4/28/2009):
Grade 3 wound complications are defined as "Hernia without evidence of strangulation; fascial disruption/dehiscence; primary wound closure or revision by operative intervention indicated"
Grade 4 complications are defined as "Hernia with evidence of strangulation; major reconstruction flap, grafting, resection, or amputation indicated"
measure: Percent of Participants With Grade 2 or Higher Hematologic Adverse Events (AEs) of Anemia, Neutropenia, and/or Thrombocytopenia
time frame: Transplantation to 40 Weeks Post Transplantation
description: The severity of adverse events (AEs) was classified into grades using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 (4/28/2009):
Grade 1 = mild AE
Grade 2 = moderate AE
Grade 3 = severe and undesirable AE
Grade 4 = life-threatening or disabling AE
Grade 5 = death
measure: Percent of Participants With Adverse Events (AEs) Attributable to the Donor Alloantigen Reactive Tregs (darTregs) Infusion
time frame: Transplantation to 40 Weeks Post Transplantation
description: AEs classified by the site investigator/clinician as possibly or definitely related to the study treatment, the Donor Alloantigen Reactive Tregs (darTregs) infusion. These AEs include:
infusion reaction
Grade 3 or higher cytokine release syndrome (Reference: National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 (4/28/2009) grading criteria
malignant cellular transformation.
arm group label: Cohort 1 - Treg-supportive IS only
arm group type: Experimental
description: 3 subjects (Cohort 1a) at site 1 (UCSF) and 3 subjects (Cohort 1b) from site 2 (Mayo Rochester) will receive Treg-Supportive immunosuppression (IS) regimen and will not receive Donor-Alloantigen-Reactive T Regulatory Cells (darTregs). Progression from one cohort to the next will depend on the cumulative incidence of sentinel adverse events.
arm group label: Cohort 2 - darTreg infusion,50 million(range 25 to 60 million)
arm group type: Experimental
description: At least 3 subjects will receive a single infusion of 50 million darTregs. Progression from one cohort to the next will depend on the cumulative incidence of sentinel adverse events.
arm group label: Cohort 3 - darTreg infusion,200 million(range100-240 million)
arm group type: Experimental
description: At least 3 subjects will receive a single infusion dose of 200 million darTregs. Progression from one cohort to the next will depend on the cumulative incidence of sentinel adverse events.
arm group label: Cohort 4 - darTreg infusion,800 million(range 400-960 million)
arm group type: Experimental
description: Six subjects will receive a single infusion of 800 million darTregs.
intervention type: Biological
intervention name: Anti-Thymocyte Globulin - Rabbit
description: Liver transplantation/Treg-supportive immunosuppression (IS) treatment. Subjects will be given a dose range of 3.0-4.5 mg/kg total, in divided doses of 1.5 mg/kg/day. Subjects who meet eligibility criteria for Thymoglobulin® administration will be given 1.5 mg/kg intravenously (IV) on post-operative day 3, within 72 hours of transplantation. Additional doses of 1.5 mg/kg IV will be administered until CD3 count is <50/mm^3 or when the maximal dose of 4.5/mg/kg has been given.
arm group label: Cohort 1 - Treg-supportive IS only
arm group label: Cohort 2 - darTreg infusion,50 million(range 25 to 60 million)
arm group label: Cohort 3 - darTreg infusion,200 million(range100-240 million)
arm group label: Cohort 4 - darTreg infusion,800 million(range 400-960 million)
other name: ATG (Anti-Thymocyte Globulin)
other name: Thymoglobulin®
intervention type: Biological
intervention name: darTreg Infusion
description: A single dose darTreg infusion (Cohorts 2 - 4) will be received as per protocol.
arm group label: Cohort 2 - darTreg infusion,50 million(range 25 to 60 million)
arm group label: Cohort 3 - darTreg infusion,200 million(range100-240 million)
arm group label: Cohort 4 - darTreg infusion,800 million(range 400-960 million)
other name: Donor-Alloantigen-Reactive Regulatory T Cell Infusion
intervention type: Drug
intervention name: Everolimus
description: Liver transplantation/Treg-supportive immunosuppression (IS) treatment. Subjects meeting eligibility criteria for Treg-supportive IS regimen will begin EVR no sooner than 30 days after liver transplantation and no later than 44 days after transplantation; with target trough levels of 6-8 μg/L.EVR target trough levels will be further reduced to 4-6 μg/L 24 - 26 weeks after transplantation.
arm group label: Cohort 1 - Treg-supportive IS only
arm group label: Cohort 2 - darTreg infusion,50 million(range 25 to 60 million)
arm group label: Cohort 3 - darTreg infusion,200 million(range100-240 million)
arm group label: Cohort 4 - darTreg infusion,800 million(range 400-960 million)
other name: EVR
other name: Zortress®
intervention type: Drug
intervention name: Tacrolimus
description: Liver transplantation/Treg-supportive immunosuppression (IS) treatment. Between 30 and 44 days following transplant: Subjects who are not eliminated by Exclusion Criteria C1 (Protocol Section 14.3.1) will proceed in the study and receive either TAC-based or EVR- based IS, based on eligibility Criteria C2 (Section 4.3.4 )
TAC-based IS: reduce TAC trough level to 3-8 μg/dL; continue MMF
EVR-based IS: reduce TAC trough level to 3-8 μg/dL; EVR target trough level of 6-8 μg/dL; decrease then discontinue MMF
arm group label: Cohort 1 - Treg-supportive IS only
arm group label: Cohort 2 - darTreg infusion,50 million(range 25 to 60 million)
arm group label: Cohort 3 - darTreg infusion,200 million(range100-240 million)
arm group label: Cohort 4 - darTreg infusion,800 million(range 400-960 million)
other name: Prograf®
intervention type: Drug
intervention name: Mycophenolate mofetil
description: Liver transplantation/Treg-supportive immunosuppression (IS) treatment. 1000 mg total daily dose. MMF will be initiated within 24 hours of transplantation. MMF must be discontinued as soon as target EVR trough levels have been achieved.
arm group label: Cohort 1 - Treg-supportive IS only
arm group label: Cohort 2 - darTreg infusion,50 million(range 25 to 60 million)
arm group label: Cohort 3 - darTreg infusion,200 million(range100-240 million)
arm group label: Cohort 4 - darTreg infusion,800 million(range 400-960 million)
other name: MMF
other name: Cellcept
other name: Myfortic
intervention type: Drug
intervention name: Prednisone
description: Liver transplantation/Treg-supportive immunosuppression (IS) treatment. Solumedrol 500 mg will be given IV on the day of transplantation. Additional Solumedrol will be prescribed according to site-specific standard of care. Oral prednisone should be initiated once oral medication is tolerated.
arm group label: Cohort 1 - Treg-supportive IS only
arm group label: Cohort 2 - darTreg infusion,50 million(range 25 to 60 million)
arm group label: Cohort 3 - darTreg infusion,200 million(range100-240 million)
arm group label: Cohort 4 - darTreg infusion,800 million(range 400-960 million)
other name: Solumedrol
intervention type: Drug
intervention name: Acetaminophen
description: Pre-medication for single dose darTreg infusion (Cohorts 2 - 4). 650mg of acetaminophen will be administered intravenously or by mouth 30-60 minutes prior to the darTreg infusion.
arm group label: Cohort 2 - darTreg infusion,50 million(range 25 to 60 million)
arm group label: Cohort 3 - darTreg infusion,200 million(range100-240 million)
arm group label: Cohort 4 - darTreg infusion,800 million(range 400-960 million)
other name: Tylenol®
intervention type: Drug
intervention name: Diphenhydramine
description: Pre-medication for single dose darTreg infusion (Cohorts 2 - 4). 25-50mg of diphenhydramine will be administered intravenously or by mouth 30-60 minutes prior to the darTreg infusion.
arm group label: Cohort 2 - darTreg infusion,50 million(range 25 to 60 million)
arm group label: Cohort 3 - darTreg infusion,200 million(range100-240 million)
arm group label: Cohort 4 - darTreg infusion,800 million(range 400-960 million)
other name: Diphenhydramine Hydrochloride
intervention type: Drug
intervention name: Anti-Infective Prophylaxis
description: Intravenous ganciclovir and/or oral Valcyte will be administered for the prophylaxis of cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) for at least six months after liver transplantation.
arm group label: Cohort 1 - Treg-supportive IS only
arm group label: Cohort 2 - darTreg infusion,50 million(range 25 to 60 million)
arm group label: Cohort 3 - darTreg infusion,200 million(range100-240 million)
arm group label: Cohort 4 - darTreg infusion,800 million(range 400-960 million)
other name: Antiviral Prophylaxis
other name: ganciclovir
other name: Cytovene
other name: Valganciclovir
other name: Valcyte
intervention type: Procedure
intervention name: Leukapheresis
description: Leukapheresis is necessary to ensure collection of adequate numbers of autologous Tregs to support ex vivo expansion of darTregs for infusion after liver transplantation.
Participants enrolled in Cohorts 3 and 4 will undergo leukapheresis. Participants enrolled in Cohort 2 will have either whole blood collection or leukapheresis for the purpose of isolating autologous Tregs for later manufacture. If a cohort 2 subject has a hemoglobin level >/=10.5 gm/dL, he or she will undergo phlebotomy. If the patient has a hemoglobin level </=10.5 gm/dL and remains eligible for the study, the patient will undergo leukapheresis.
arm group label: Cohort 2 - darTreg infusion,50 million(range 25 to 60 million)
arm group label: Cohort 3 - darTreg infusion,200 million(range100-240 million)
arm group label: Cohort 4 - darTreg infusion,800 million(range 400-960 million)
other name: Leukocytapheresis
intervention type: Procedure
intervention name: Blood draws
description: Blood draws are necessary to carefully and frequently evaluate allograft function after liver transplantation and treatment with Treg-supportive IS as well as after darTreg infusion. Peripheral blood samples will be collected and analyzed per protocol throughout subject participation in this study.
arm group label: Cohort 1 - Treg-supportive IS only
arm group label: Cohort 2 - darTreg infusion,50 million(range 25 to 60 million)
arm group label: Cohort 3 - darTreg infusion,200 million(range100-240 million)
arm group label: Cohort 4 - darTreg infusion,800 million(range 400-960 million)
other name: Venipuncture
other name: Phlebotomy
intervention type: Procedure
intervention name: Liver biopsies
description: Subjects will have a liver biopsy for this study 12-14 weeks after transplantation. For subjects receiving darTregs, a second biopsy will be performed 7-10 days after darTregs infusion.
arm group label: Cohort 1 - Treg-supportive IS only
arm group label: Cohort 2 - darTreg infusion,50 million(range 25 to 60 million)
arm group label: Cohort 3 - darTreg infusion,200 million(range100-240 million)
arm group label: Cohort 4 - darTreg infusion,800 million(range 400-960 million)
other name: Liver biopsy samples
intervention type: Procedure
intervention name: Liver transplantation
description: Inclusion in this trial is in the setting of subjects defined as having end-stage liver disease and listed for primary solitary liver transplant.
arm group label: Cohort 1 - Treg-supportive IS only
arm group label: Cohort 2 - darTreg infusion,50 million(range 25 to 60 million)
arm group label: Cohort 3 - darTreg infusion,200 million(range100-240 million)
arm group label: Cohort 4 - darTreg infusion,800 million(range 400-960 million)
other name: Liver transplant
criteria: 
gender: All
minimum age: 21 Years
maximum age: 70 Years
healthy volunteers: No
last name: Sandy Feng, MD, PhD
role: Principal Investigator
affiliation: University of California, San Francisco
last name: Jeffrey Bluestone, PhD
role: Principal Investigator
affiliation: University of California, San Francisco
last name: Sang-Mo Kang, MD, FACS
role: Principal Investigator
affiliation: University of California, San Francisco
last name: Qizhi Tang, PhD
role: Principal Investigator
affiliation: University of California, San Francisco
facility: 
facility: 
facility: 
country: United States
url: https://www.niaid.nih.gov/
description: National Institute of Allergy and Infectious Diseases (NIAID) website
responsible party type: Sponsor
mesh term: Acetaminophen
mesh term: Diphenhydramine
mesh term: Promethazine
mesh term: Mycophenolic Acid
mesh term: Valganciclovir
mesh term: Ganciclovir
mesh term: Anti-Infective Agents
mesh term: Prednisone
mesh term: Methylprednisolone Hemisuccinate
mesh term: Everolimus
mesh term: Liver Extracts
mesh term: Tacrolimus
mesh term: Thymoglobulin
mesh term: Antilymphocyte Serum
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Enrollment was terminated due to several factors:high number of ineligible subjects, slow enrollment, and manufacturing difficulties within the constraints of the funding period.
point of contact: 