<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/NCT03292445</url>
  </required_header>
  <id_info>
    <org_study_id>40442</org_study_id>
    <nct_id>NCT03292445</nct_id>
  </id_info>
  <brief_title>Inducing Graft Tolerance in HLA Haplotype Matched Related and 3 Ag Matched Unrelated Living Donor Kidney Transplantation</brief_title>
  <acronym>CIRM</acronym>
  <official_title>Induction of Immune Tolerance by Total Lymphoid Irradiation, Anti-Thymocyte Globulin and Purified Donor CD34+ and T Cell Transfusion in HLA Haplotype Matched Related and 3 Antigen HLA Matched Unrelated Living Donor Kidney Transplantation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Samuel Strober</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>California Institute for Regenerative Medicine (CIRM)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Stanford University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This research study is to determine if donor blood stem cells given after living, related,&#xD;
      HLA antigen (Ag) haplotype match or living, unrelated donor kidney transplantation. Minimal&#xD;
      HLA antigen matching will include matching of 2 HLA antigens that can be either HLA A, B, and&#xD;
      /or DR. This research will change the immune system such that immunosuppressive drugs can be&#xD;
      completely withdrawn or reduced to minimal dose without kidney rejection.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The objectives of this study are to determine whether patients undergoing kidney transplants&#xD;
      for end stage renal disease (ESRD) can be taken off immune suppression drugs given to prevent&#xD;
      kidney rejection or can be maintained on low dose immune suppression while maintaining normal&#xD;
      kidney function. Patients will receive blood stem cell transfusions from their donors 11 days&#xD;
      after transplant to reduce the risk of graft rejection while tapering the post-transplant&#xD;
      immune suppression drug regimen. Patients will be treated with total lymphoid irradiation&#xD;
      (TLI) and rabbit anti-thymocyte globulin (rATG) followed by transfusion of enriched CD34+&#xD;
      hematopoietic cells containing blood stem cells and CD3+ T cells from their donors in order&#xD;
      to induce blood cell mixed chimerism. These chimeric patients produce blood cells from both&#xD;
      their own and their donors' blood stem cells. Donors will have blood collected by apheresis&#xD;
      after treatment with drugs to &quot;mobilize&quot; blood stem cells from their bone marrow. Collection&#xD;
      of the donor's cells will occur 6-8 weeks before kidney donation surgery. After transplant,&#xD;
      patients will receive a 14 week course of corticosteroid therapy (e.g., Prednisolone) with&#xD;
      gradual dose reduction. They will also receive a 12 month course of mycophenolate mofetil&#xD;
      (MMF) with dose tapering beginning 9 months post-transplant and an 18 month course of&#xD;
      Tacrolimus with tapering also beginning at 9 months post-transplant. Patients will be&#xD;
      monitored for renal function, mixed blood cell chimerism, the appearance of donor specific&#xD;
      antibodies (DSA) from their own immune cells reacting to the transplanted kidney, and&#xD;
      evidence of rejection in any biopsies of the donor kidney after transplant. Immune&#xD;
      suppression drug withdrawal will begin and continue as long as mixed chimerism is maintained,&#xD;
      the patient shows no evidence of graft versus host disease (GVHD), the transplanted kidney&#xD;
      functions well, and there is no indication of kidney rejection in biopsies. Patients not&#xD;
      meeting these criteria will be maintained on low dose immunosuppressive drug therapy unless&#xD;
      more extensive treatments are needed to prevent rejection. Potential candidates need to be&#xD;
      approved for kidney transplant under this protocol and available for close follow-up&#xD;
      post-transplant. This study, sponsored by the California Institute for Regenerative Medicine&#xD;
      (CIRM), is being conducted in parallel with NCT01165762 sponsored by the National Institutes&#xD;
      of Health with distinct reporting and separation of funding support for the patients enrolled&#xD;
      under each sponsor.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">February 14, 2017</start_date>
  <completion_date type="Anticipated">February 14, 2024</completion_date>
  <primary_completion_date type="Anticipated">February 14, 2022</primary_completion_date>
  <phase>Early Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>Total Lymphoid Irradiation, Anti-Thymocyte Globulin and Purified Donor CD34+ and T Cell Transfusion in HLA Haplotype Matched Related and 3 Ag HLA Matched Unrelated Living Donor Kidney Transplantation</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Reduction of dependence on immunosuppressive drugs to prevent graft rejection.</measure>
    <time_frame>24 months post-transplant</time_frame>
    <description>Percentage of patients able to maintain normal renal function after coming off all immunosuppressive drug therapy and percentage of patients maintaining normal renal function with only minimum effective dose immunosuppressive drug monotherapy.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of rejection episodes requiring corticosteroid therapy</measure>
    <time_frame>24 months post-transplant</time_frame>
    <description>Percentage of patients experiencing biopsy proven rejection episodes requiring corticosteroid therapy.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of graft loss.</measure>
    <time_frame>24 months post-transplant</time_frame>
    <description>Percentage of patients experiencing loss of transplanted kidneys.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">24</enrollment>
  <condition>Immune Tolerance</condition>
  <arm_group>
    <arm_group_label>Immune tolerance after kidney transplant</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Immune tolerance after kidney transplant will be induced by transfusion of enriched donor blood stem cells and T cells to initiate blood cell mixed chimerism in patients conditioned with total lymphoid irradiation and rabbit anti-thymocyte globulin after kidney transplant. Patients will receive corticosteroids for 14 weeks with gradual dose reduction. They will also receive 12 months of mycophenolate mofetil and 18 months of tacrolimus with dose tapering beginning 9 months post-transplant and continuing as long as mixed chimerism is maintained and there is no evidence of graft versus host disease and no kidney rejection evident. Patients losing chimerism will continue on low dose immunosuppressive drug doses unless additional kidney rejection therapy is needed.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Immune tolerance after kidney transplant</intervention_name>
    <description>Induction of immune tolerance after kidney and hematopoietic cell transplantation with a conditioning regimen of total lymphoid irradiation and anti-thymocyte globulin followed by immunosuppressive drugs for 18 months. Immunosuppressive drugs are stopped if stable chimerism is achieved and there is no kidney rejection.</description>
    <arm_group_label>Immune tolerance after kidney transplant</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Donor blood stem cells and T cells</intervention_name>
    <description>Immune tolerance after kidney transplantation resulting from mixed blood cells chimerism will be induced by donor blood stem cells and T cells given to the kidney recipient. Donor cells will be collected by apheresis after &quot;mobilization&quot; of blood stem cells from bone marrow 6-8 weeks before kidney transplant. Collected cells will undergo CD34 selection to recover &gt;10 million donor blood stem cells/kg of patient weight to be combined with up to 150 million donor T cells/kg for transfusion soon after kidney transplant. The IND for this study covers the infusion of donor blood stem cells.</description>
    <arm_group_label>Immune tolerance after kidney transplant</arm_group_label>
    <other_name>Immune tolerance after kidney transplant</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. All consenting adults (18 years of age) living donor renal transplant recipients at&#xD;
             Stanford University Medical Center who have a one haplotype match donor.&#xD;
&#xD;
          2. Patients who agree to participate in the study and sign an Informed Consent.&#xD;
&#xD;
          3. Patients who have no known contraindication to administration of rabbit ATG or&#xD;
             radiation.&#xD;
&#xD;
          4. Males and females of reproductive potential who agree to practice a reliable form of&#xD;
             contraception for at least 24 months posttranplant.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Previous treatment with rabbit ATG or known allergy to rabbit proteins.&#xD;
&#xD;
          2. History of malignancy with the exception of non-melanoma skin malignancies.&#xD;
&#xD;
          3. Pregnant women or nursing mothers.&#xD;
&#xD;
          4. Serological evidence of HIV, Hepatitis B or Hepatitis C infection.&#xD;
&#xD;
          5. Seronegative for Epstein-Barr virus , if donor is seropositive.&#xD;
&#xD;
          6. Leukopenia (with a white blood cell count &lt; 3000/mm3) or thrombocytopenia (with a&#xD;
             platelet count &lt; 100,000/mm3)&#xD;
&#xD;
          7. Panel Reactive antibody greater then 20% or demonstration of donor specific antibody&#xD;
             (DSA).&#xD;
&#xD;
          8. Prior organ transplantation.&#xD;
&#xD;
          9. High risk of primary kidney disease recurrence (i.e. primary FSGS).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Samuel Md Strober, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Stanford University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Asha Shori, CCRP</last_name>
    <phone>6507360245</phone>
    <email>ashas@stanford.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Stephan Busque, MD,MS</last_name>
    <phone>650-498-6189</phone>
    <email>sbusque@stanford.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Stanford University Medical Center</name>
      <address>
        <city>Palo Alto</city>
        <state>California</state>
        <zip>94304</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Asha Shori, CCRP</last_name>
      <phone>650-736-0245</phone>
      <email>ashas@stanford.edu</email>
    </contact>
    <contact_backup>
      <last_name>Stephan Busque, MD, MS</last_name>
      <phone>650-498-6189</phone>
      <email>sbusque@stanford.edu</email>
    </contact_backup>
    <investigator>
      <last_name>John D Sandling, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Judith A Shizuru, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Marc L Melcher, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Richard T Hoppe, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Robert Lowsky, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Samuel Strober, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Stephan Busque, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Wisconsin</name>
      <address>
        <city>Madison</city>
        <state>Wisconsin</state>
        <zip>53792-1690</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Dixon Kaufman, MD</last_name>
      <phone>608-265-6471</phone>
      <email>kaufman@surgery.wisc.edu</email>
    </contact>
    <contact_backup>
      <last_name>Tommy Boland</last_name>
      <phone>608-263-9459</phone>
      <email>bolandt@suregery.wisc.edu</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Scandling JD, Busque S, Shizuru JA, Engleman EG, Strober S. Induced immune tolerance for kidney transplantation. N Engl J Med. 2011 Oct 6;365(14):1359-60. doi: 10.1056/NEJMc1107841. No abstract available.</citation>
    <PMID>21991976</PMID>
  </reference>
  <reference>
    <citation>Scandling JD, Busque S, Dejbakhsh-Jones S, Benike C, Sarwal M, Millan MT, Shizuru JA, Lowsky R, Engleman EG, Strober S. Tolerance and withdrawal of immunosuppressive drugs in patients given kidney and hematopoietic cell transplants. Am J Transplant. 2012 May;12(5):1133-45. doi: 10.1111/j.1600-6143.2012.03992.x. Epub 2012 Mar 8.</citation>
    <PMID>22405058</PMID>
  </reference>
  <reference>
    <citation>Scandling JD, Busque S, Shizuru JA, Lowsky R, Hoppe R, Dejbakhsh-Jones S, Jensen K, Shori A, Strober JA, Lavori P, Turnbull BB, Engleman EG, Strober S. Chimerism, graft survival, and withdrawal of immunosuppressive drugs in HLA matched and mismatched patients after living donor kidney and hematopoietic cell transplantation. Am J Transplant. 2015 Mar;15(3):695-704. doi: 10.1111/ajt.13091.</citation>
    <PMID>25693475</PMID>
  </reference>
  <results_reference>
    <citation>Scandling JD, Busque S, Dejbakhsh-Jones S, Benike C, Millan MT, Shizuru JA, Hoppe RT, Lowsky R, Engleman EG, Strober S. Tolerance and chimerism after renal and hematopoietic-cell transplantation. N Engl J Med. 2008 Jan 24;358(4):362-8. doi: 10.1056/NEJMoa074191.</citation>
    <PMID>18216356</PMID>
  </results_reference>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>September 5, 2017</study_first_submitted>
  <study_first_submitted_qc>September 20, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 25, 2017</study_first_posted>
  <last_update_submitted>July 15, 2020</last_update_submitted>
  <last_update_submitted_qc>July 15, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 17, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Stanford University</investigator_affiliation>
    <investigator_full_name>Samuel Strober</investigator_full_name>
    <investigator_title>Professor of Medicine</investigator_title>
  </responsible_party>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03292445
org study id: 40442
nct id: NCT03292445
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This research study is to determine if donor blood stem cells given after living, related,
      HLA antigen (Ag) haplotype match or living, unrelated donor kidney transplantation. Minimal
      HLA antigen matching will include matching of 2 HLA antigens that can be either HLA A, B, and
      /or DR. This research will change the immune system such that immunosuppressive drugs can be
      completely withdrawn or reduced to minimal dose without kidney rejection.
The objectives of this study are to determine whether patients undergoing kidney transplants
      for end stage renal disease (ESRD) can be taken off immune suppression drugs given to prevent
      kidney rejection or can be maintained on low dose immune suppression while maintaining normal
      kidney function. Patients will receive blood stem cell transfusions from their donors 11 days
      after transplant to reduce the risk of graft rejection while tapering the post-transplant
      immune suppression drug regimen. Patients will be treated with total lymphoid irradiation
      (TLI) and rabbit anti-thymocyte globulin (rATG) followed by transfusion of enriched CD34+
      hematopoietic cells containing blood stem cells and CD3+ T cells from their donors in order
      to induce blood cell mixed chimerism. These chimeric patients produce blood cells from both
      their own and their donors' blood stem cells. Donors will have blood collected by apheresis
      after treatment with drugs to "mobilize" blood stem cells from their bone marrow. Collection
      of the donor's cells will occur 6-8 weeks before kidney donation surgery. After transplant,
      patients will receive a 14 week course of corticosteroid therapy (e.g., Prednisolone) with
      gradual dose reduction. They will also receive a 12 month course of mycophenolate mofetil
      (MMF) with dose tapering beginning 9 months post-transplant and an 18 month course of
      Tacrolimus with tapering also beginning at 9 months post-transplant. Patients will be
      monitored for renal function, mixed blood cell chimerism, the appearance of donor specific
      antibodies (DSA) from their own immune cells reacting to the transplanted kidney, and
      evidence of rejection in any biopsies of the donor kidney after transplant. Immune
      suppression drug withdrawal will begin and continue as long as mixed chimerism is maintained,
      the patient shows no evidence of graft versus host disease (GVHD), the transplanted kidney
      functions well, and there is no indication of kidney rejection in biopsies. Patients not
      meeting these criteria will be maintained on low dose immunosuppressive drug therapy unless
      more extensive treatments are needed to prevent rejection. Potential candidates need to be
      approved for kidney transplant under this protocol and available for close follow-up
      post-transplant. This study, sponsored by the California Institute for Regenerative Medicine
      (CIRM), is being conducted in parallel with NCT01165762 sponsored by the National Institutes
      of Health with distinct reporting and separation of funding support for the patients enrolled
      under each sponsor.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Total Lymphoid Irradiation, Anti-Thymocyte Globulin and Purified Donor CD34+ and T Cell Transfusion in HLA Haplotype Matched Related and 3 Ag HLA Matched Unrelated Living Donor Kidney Transplantation
primary purpose: Treatment
masking: None (Open Label)
measure: Reduction of dependence on immunosuppressive drugs to prevent graft rejection.
time frame: 24 months post-transplant
description: Percentage of patients able to maintain normal renal function after coming off all immunosuppressive drug therapy and percentage of patients maintaining normal renal function with only minimum effective dose immunosuppressive drug monotherapy.
measure: Incidence of rejection episodes requiring corticosteroid therapy
time frame: 24 months post-transplant
description: Percentage of patients experiencing biopsy proven rejection episodes requiring corticosteroid therapy.
measure: Incidence of graft loss.
time frame: 24 months post-transplant
description: Percentage of patients experiencing loss of transplanted kidneys.
arm group label: Immune tolerance after kidney transplant
arm group type: Experimental
description: Immune tolerance after kidney transplant will be induced by transfusion of enriched donor blood stem cells and T cells to initiate blood cell mixed chimerism in patients conditioned with total lymphoid irradiation and rabbit anti-thymocyte globulin after kidney transplant. Patients will receive corticosteroids for 14 weeks with gradual dose reduction. They will also receive 12 months of mycophenolate mofetil and 18 months of tacrolimus with dose tapering beginning 9 months post-transplant and continuing as long as mixed chimerism is maintained and there is no evidence of graft versus host disease and no kidney rejection evident. Patients losing chimerism will continue on low dose immunosuppressive drug doses unless additional kidney rejection therapy is needed.
intervention type: Procedure
intervention name: Immune tolerance after kidney transplant
description: Induction of immune tolerance after kidney and hematopoietic cell transplantation with a conditioning regimen of total lymphoid irradiation and anti-thymocyte globulin followed by immunosuppressive drugs for 18 months. Immunosuppressive drugs are stopped if stable chimerism is achieved and there is no kidney rejection.
arm group label: Immune tolerance after kidney transplant
intervention type: Drug
intervention name: Donor blood stem cells and T cells
description: Immune tolerance after kidney transplantation resulting from mixed blood cells chimerism will be induced by donor blood stem cells and T cells given to the kidney recipient. Donor cells will be collected by apheresis after "mobilization" of blood stem cells from bone marrow 6-8 weeks before kidney transplant. Collected cells will undergo CD34 selection to recover >10 million donor blood stem cells/kg of patient weight to be combined with up to 150 million donor T cells/kg for transfusion soon after kidney transplant. The IND for this study covers the infusion of donor blood stem cells.
arm group label: Immune tolerance after kidney transplant
other name: Immune tolerance after kidney transplant
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Samuel Md Strober, MD
role: Study Chair
affiliation: Stanford University
last name: Asha Shori, CCRP
phone: 6507360245
email: ashas@stanford.edu
last name: Stephan Busque, MD,MS
phone: 650-498-6189
email: sbusque@stanford.edu
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
investigator: 
facility: 
status: Recruiting
contact: 
contact backup: 
country: United States
citation: Scandling JD, Busque S, Shizuru JA, Engleman EG, Strober S. Induced immune tolerance for kidney transplantation. N Engl J Med. 2011 Oct 6;365(14):1359-60. doi: 10.1056/NEJMc1107841. No abstract available.
PMID: 21991976
citation: Scandling JD, Busque S, Dejbakhsh-Jones S, Benike C, Sarwal M, Millan MT, Shizuru JA, Lowsky R, Engleman EG, Strober S. Tolerance and withdrawal of immunosuppressive drugs in patients given kidney and hematopoietic cell transplants. Am J Transplant. 2012 May;12(5):1133-45. doi: 10.1111/j.1600-6143.2012.03992.x. Epub 2012 Mar 8.
PMID: 22405058
citation: Scandling JD, Busque S, Shizuru JA, Lowsky R, Hoppe R, Dejbakhsh-Jones S, Jensen K, Shori A, Strober JA, Lavori P, Turnbull BB, Engleman EG, Strober S. Chimerism, graft survival, and withdrawal of immunosuppressive drugs in HLA matched and mismatched patients after living donor kidney and hematopoietic cell transplantation. Am J Transplant. 2015 Mar;15(3):695-704. doi: 10.1111/ajt.13091.
PMID: 25693475
citation: Scandling JD, Busque S, Dejbakhsh-Jones S, Benike C, Millan MT, Shizuru JA, Hoppe RT, Lowsky R, Engleman EG, Strober S. Tolerance and chimerism after renal and hematopoietic-cell transplantation. N Engl J Med. 2008 Jan 24;358(4):362-8. doi: 10.1056/NEJMoa074191.
PMID: 18216356
responsible party type: Sponsor-Investigator
investigator affiliation: Stanford University
investigator full name: Samuel Strober
investigator title: Professor of Medicine
sharing ipd: No