<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/NCT01678937</url>
  </required_header>
  <id_info>
    <org_study_id>1783-011</org_study_id>
    <nct_id>NCT01678937</nct_id>
  </id_info>
  <brief_title>Immune Tolerance and Alloreactivity in Liver Transplant Recipients on Different Monotherapy Immunosuppressive Agents</brief_title>
  <official_title>Immune Tolerance and Alloreactivity in Liver Transplant Recipients on Different Monotherapy Immunosuppressive Agents</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Northwestern University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Northwestern Memorial Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Northwestern University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study is being done with the purpose of trying to understand if and why transplant&#xD;
      recipients may develop tolerance to their transplanted organ. Tolerance means being able to&#xD;
      lower or take away immunosuppression (anti-rejection medications) without causing organ&#xD;
      rejection.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Life-long immunosuppressive therapy is typically required in the majority of liver allograft&#xD;
      recipients. In the early years of liver transplantation (LT), the majority of deaths occurred&#xD;
      secondary to graft loss from acute or chronic rejection despite immunosuppression (IS). With&#xD;
      the advent of more powerful and specific IS agents, e.g. calcineurin-inhibitors (CNIs)&#xD;
      cyclosporine (CyA) and tacrolimus (TAC), graft rejection rates significantly declined and&#xD;
      short and long term graft/patient survival dramatically improved. However, along with the&#xD;
      advance in survival rates came the adverse effects of long term immunosuppression (IS), e.g.&#xD;
      morbidity and mortality from cardiovascular events, renal insufficiency, infectious&#xD;
      complications, recurrent viral hepatitis and malignancy. These events are exacerbated by&#xD;
      pre-existing conditions and an aging transplant population. Immunosuppression tapering or&#xD;
      withdrawal could lower the incidence of these complications and improve long term graft and&#xD;
      patient survival.&#xD;
&#xD;
      Therefore, the study proposed is a laboratory investigation (using blood samples collected&#xD;
      from the subjects) comparing immune tolerance and alloreactivity profiles in LT recipients on&#xD;
      monotherapy IS or converted to rapamycin monotherapy, to determine tolerogenic properties of&#xD;
      the different IS agents. Knowledge of these properties would support the need for specific IS&#xD;
      therapy to promote immune tolerance and consider IS withdrawal.&#xD;
&#xD;
      Monotherapy patients will be identified by the organ transplant database and medical charts&#xD;
      at Northwestern. Patients will be invited to participate in the study and asked to undergo&#xD;
      venipunctures for our analysis. Patient demographics, laboratories and other clinical data&#xD;
      will be recorded. Patients on CNI monotherapy are continuously being identified for&#xD;
      conversion to rapamycin monotherapy during clinic visits or chart reviews at Northwestern.&#xD;
      Patients are selected for conversion due to significant CNI side effects, e.g. chronic kidney&#xD;
      disease (creatinine clearance &lt; 50 in the absence of significant proteinuria &gt; 1g, poorly&#xD;
      controlled diabetes mellitus/hypertension/hyperlipidemia, peripheral neuropathy). In general,&#xD;
      patients are converted from CNIs to rapamycin over 2-3 weeks once therapeutic rapamycin&#xD;
      levels are achieved.&#xD;
&#xD;
      Study procedures will be carried out by the investigators and associated personnel. Patients&#xD;
      will be assigned a number in numerical order, to remove patient identifiers from the data&#xD;
      analysis. A separate screening/enrollment log will be kept separate from the data. Baseline&#xD;
      characteristics of the patients will be recorded: age, sex, liver disease, past medical&#xD;
      history, history of acute rejection or other graft dysfunction, other post-LT complications,&#xD;
      previous and current IS regimens. Monotherapy patients (10 from CyA, Tacrolimus, and MMF; 5&#xD;
      rapamycin) will be identified as above and asked to participate. Blood will be drawn at one&#xD;
      time point for the following analysis:&#xD;
&#xD;
        -  Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to&#xD;
           process antigens (CD83; CD205); markers that have been shown to induce regulatory T&#xD;
           cells (ILT3; ILT4).&#xD;
&#xD;
        -  Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low&#xD;
           cells).&#xD;
&#xD;
        -  HLA microchimerism &amp; HLA G&#xD;
&#xD;
      Ten patients who have been pre-selected for rapamycin conversion will have the above assays&#xD;
      performed two weeks prior to conversion and 3-6 months following conversion. They will also&#xD;
      have liver function and drug level tests.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>September 2007</start_date>
  <completion_date type="Actual">September 2008</completion_date>
  <primary_completion_date type="Actual">May 2008</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Track interval outcome measures for development of higher percentages of FOXP3+ T1 regulatory cells in stable liver transplant recipients on rapamycin or MMF monotherapy compared to CNI monotherapy.</measure>
    <time_frame>Two weeks prior to conversion, Months 3 &amp; 6 following conversion</time_frame>
    <description>Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).&#xD;
Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells).&#xD;
Liver function and drug levels.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Track interval outcome measures for development of higher percentages of FOXP3+ T regulatory cells in liver transplant recipients after conversion from CNI to rapamycin comparing to MMF monotherapy.</measure>
    <time_frame>Two weeks prior to conversion, Months 3 &amp; 6 following conversion</time_frame>
    <description>Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).&#xD;
Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Track interval outcome measures for development of higher percentages of immunophenotypic markers associated with regulatory T cell production in stable liver transplant recipients on rapamycin or MMF monotherapy compared to CNI monotherapy.</measure>
    <time_frame>Two weeks prior to conversion, Months 3 &amp; 6 following conversion</time_frame>
    <description>Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).&#xD;
Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells).&#xD;
HLA microchimerism &amp; HLA G (dendritic cell ratios, soluble HLA G)&#xD;
Liver function and drug levels.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Track interval outcome measures for development of higher percentages of immunophenotypic markers associated with regulatory T cell production in liver transplant recipients after conversion from CNI to rapamycin or MMF monotherapy.</measure>
    <time_frame>Two weeks prior to conversion, Months 3 &amp; 6 following conversion</time_frame>
    <description>Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).&#xD;
Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells).&#xD;
HLA microchimerism &amp; HLA G (dendritic cell ratios, soluble HLA G)(hypertension, hyperlipidemia, renal insufficiency, diabetes, neuropathy)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Document improvement in adverse CNI side effects after conversion to rapamycin or MMF monotherapy, comparing designated time points.</measure>
    <time_frame>Two weeks prior to conversion, Months 3 &amp; 6 following conversion</time_frame>
    <description>CNI side effects - hypertension, hyperlipidemia, renal insufficiency, diabetes, neuropathy. Review liver function and drug levels at designated time points.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Document the development of any adverse rapamycin or MMF side effects after conversion, comparing designated time points.</measure>
    <time_frame>Two weeks prior to conversion, Months 3 &amp; 6 following conversion</time_frame>
    <description>Document Rapamycin side effects - oral ulcers, edema, pancytopenia, gastrointestinal dysfunction; or MMF side effects - pancytopenia, gastrointestinal dysfunction. Review liver function and drug levels at designated time points.</description>
  </secondary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Actual">31</enrollment>
  <condition>Liver Transplant Rejection</condition>
  <condition>Immunosuppression</condition>
  <arm_group>
    <arm_group_label>Control Group</arm_group_label>
    <description>Ten Healthy individuals will have blood drawn (4 green top tubes(40 ml = 8 tsp.)) at one time point at Northwestern for control purposes. Blood will be drawn to conduct the following tests:&#xD;
Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).&#xD;
Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells), and&#xD;
HLA microchimerism &amp; HLA G.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Monotherapy Group</arm_group_label>
    <description>Monotherapy patients [cyclosporine (CyA) (10 patients), Tacrolimus (5 patients), mycophenolate mofetil (MMF) (10 patients), rapamycin (10 patients)]: Blood will be drawn at one time point (4 green top tubes (40 ml = 8 tsp.)) to conduct the following tests:&#xD;
Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).&#xD;
Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells), and&#xD;
HLA microchimerism &amp; HLA G.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Conversion Group</arm_group_label>
    <description>Ten CNI monotherapy/dual therapy (CNI + MMF) patients pre-selected for conversion to rapamycin or wean to MMF monotherapy. Assays performed 2 weeks prior to conversion, 3-6 months following successful conversion. Liver function/drug levels monitored weekly during conversion until stable levels achieved. Patients converting from CNI monotherapy to rapamycin monotherapy (2-4 wks.): CNI discontinued when 2 therapeutic rapamycin levels (5-10) reached, graft function stable (clinical care protocol). MMF conversion: MMF dose slowly increased to 3 g/day (max.) while CNI therapy reduced by 1-2 mg/day (FK506) or 25-50 mg/day (CyA) monthly until CNI discontinued (1-6 months) (clinical care protocol). Monthly liver function/drug levels performed after successful conversion (standard of care).</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Blood Draw - Rapamycin</intervention_name>
    <description>Ten calcineurin-inhibitors (CNI) monotherapy or dual therapy (CNI+MMF) patients will have blood taken (40 ml=8 tsp.) 2 wks. prior to conversion, 3-6 months post successful conversion. 1) Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28-FOXP3+CD127low cells). 2) Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers shown to induce regulatory T cells (ILT3; ILT4), 3) Soluble HLA G, and 4) Liver function/drug levels. If problems develop during conversion (e.g. acute rejection, significant drug side effects) requiring discontinuation of rapamycin, MMF and/or reversion to CNI therapy, assays will not be performed. Monthly liver function/drug levels performed after successful conversion (standard of care).</description>
    <arm_group_label>Conversion Group</arm_group_label>
    <other_name>Sirolimus</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Blood Draw from Control Subjects</intervention_name>
    <description>Ten healthy individuals will have blood drawn (40 ml = 8 teaspoons (tsps.)).Blood will be drawn at one time point for the following:&#xD;
Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).&#xD;
Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells).&#xD;
HLA microchimerism &amp; HLA G</description>
    <arm_group_label>Control Group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Blood Draw - CyA</intervention_name>
    <description>Blood drawn from 10 patients on cyclosporine (CyA) (40 ml = 8 tsp.)). Blood will be drawn at one time point for the following:&#xD;
Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).&#xD;
Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells).&#xD;
HLA microchimerism &amp; HLA G</description>
    <arm_group_label>Monotherapy Group</arm_group_label>
    <other_name>cyclosporine</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Blood Draw - Tacrolimus</intervention_name>
    <description>Blood drawn from 5 patients on Tacrolimus (40 ml = 8 tsp.) at one time point for the following:&#xD;
Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).&#xD;
Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells).&#xD;
HLA microchimerism &amp; HLA G</description>
    <arm_group_label>Monotherapy Group</arm_group_label>
    <other_name>Tacrolimus</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Blood Draw - MMF</intervention_name>
    <description>Blood will be drawn from 10 patients on mycophenolate mofetil (MMF) (40 ml or the equivalent of 8 teaspoons). Blood will be drawn at one time point for the following analysis:&#xD;
Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).&#xD;
Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells).&#xD;
HLA microchimerism &amp; HLA G</description>
    <arm_group_label>Monotherapy Group</arm_group_label>
    <other_name>mycophenolate mofetil</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Blood Draw - Rapamycin</intervention_name>
    <description>Blood drawn from 10 patients on rapamycin (40 ml = 8 tsp.)) at one time point for the following:&#xD;
Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).&#xD;
Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells).&#xD;
HLA microchimerism &amp; HLA G</description>
    <arm_group_label>Monotherapy Group</arm_group_label>
    <other_name>Rapamycin</other_name>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Blood tests: Monotherapy patients&#xD;
&#xD;
        1. Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28-FOXP3+CD127low&#xD;
           cells).&#xD;
&#xD;
        2. Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to&#xD;
           process antigens (CD83; CD205); markers that have been shown to induce regulatory T&#xD;
           cells (ILT3; ILT4).&#xD;
&#xD;
        3. Soluble HLA G&#xD;
&#xD;
      Blood tests: Conversion patients&#xD;
&#xD;
        1. Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28-FOXP3+CD127low&#xD;
           cells).&#xD;
&#xD;
        2. Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to&#xD;
           process antigens (CD83; CD205); markers that have been shown to induce regulatory T&#xD;
           cells (ILT3; ILT4),&#xD;
&#xD;
        3. Soluble HLA G, and&#xD;
&#xD;
        4. Liver function and drug levels.&#xD;
&#xD;
      Blood tests: Healthy controls (same tests as Monotherapy Group)&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Liver transplant patients converting on stable IS monotherapy or undergoing conversion to&#xD;
        rapamycin or MMF monotherapy.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥18 years&#xD;
&#xD;
          -  Orthotopic or Living-Related liver transplant (LT) recipient&#xD;
&#xD;
          -  Monotherapy patients: &gt; 6 months with stable graft function on current monotherapy&#xD;
             (CNI, MMF, or rapamycin)&#xD;
&#xD;
          -  Converting patients: CNI therapy converting to rapamycin or MMF monotherapy and &gt; 6&#xD;
             months of stable graft function.&#xD;
&#xD;
          -  &gt;1 years post-LT without an acute rejection episode or chronic rejection&#xD;
&#xD;
          -  Normal liver function tests (no recurrent HCV, chronic rejection, autoimmune&#xD;
             hepatitis, etc.)&#xD;
&#xD;
          -  No history of induction or lymphocyte depletion therapy&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Multi-visceral organ recipients&#xD;
&#xD;
          -  Graft dysfunction of any etiology&#xD;
&#xD;
          -  Inadequate follow-up or available outcomes&#xD;
&#xD;
          -  Unable to understand, sign or ask questions regarding the informed consent process and&#xD;
             protocol&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Josh Levitsky, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Northwestern University, Northwestern Memorial Hospital, Northwestern Medical Faculty Foundation</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Northwestern Memorial Hospital</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.ncbi.nlm.nih.gov/pubmed</url>
    <description>PMID: 19141306</description>
  </link>
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  </reference>
  <reference>
    <citation>Battaglia M, Stabilini A, Draghici E, Gregori S, Mocchetti C, Bonifacio E, Roncarolo MG. Rapamycin and interleukin-10 treatment induces T regulatory type 1 cells that mediate antigen-specific transplantation tolerance. Diabetes. 2006 Jan;55(1):40-9.</citation>
    <PMID>16380475</PMID>
  </reference>
  <reference>
    <citation>Mehling A, Grabbe S, Voskort M, Schwarz T, Luger TA, Beissert S. Mycophenolate mofetil impairs the maturation and function of murine dendritic cells. J Immunol. 2000 Sep 1;165(5):2374-81. doi: 10.4049/jimmunol.165.5.2374.</citation>
    <PMID>10946260</PMID>
  </reference>
  <reference>
    <citation>Gregori S, Casorati M, Amuchastegui S, Smiroldo S, Davalli AM, Adorini L. Regulatory T cells induced by 1 alpha,25-dihydroxyvitamin D3 and mycophenolate mofetil treatment mediate transplantation tolerance. J Immunol. 2001 Aug 15;167(4):1945-53. doi: 10.4049/jimmunol.167.4.1945.</citation>
    <PMID>11489974</PMID>
  </reference>
  <reference>
    <citation>Nikolaeva N, Bemelman FJ, Yong SL, van Lier RA, ten Berge IJ. Rapamycin does not induce anergy but inhibits expansion and differentiation of alloreactive human T cells. Transplantation. 2006 Feb 15;81(3):445-54. doi: 10.1097/01.tp.0000194860.21533.b9.</citation>
    <PMID>16477233</PMID>
  </reference>
  <verification_date>April 2015</verification_date>
  <study_first_submitted>July 8, 2011</study_first_submitted>
  <study_first_submitted_qc>August 30, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 5, 2012</study_first_posted>
  <last_update_submitted>April 14, 2015</last_update_submitted>
  <last_update_submitted_qc>April 14, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">April 15, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Northwestern University</investigator_affiliation>
    <investigator_full_name>Josh Levitsky</investigator_full_name>
    <investigator_title>Associate Professor in Medicine-Hepatology</investigator_title>
  </responsible_party>
  <keyword>Immunosuppression</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cyclosporine</mesh_term>
    <mesh_term>Sirolimus</mesh_term>
    <mesh_term>Mycophenolic Acid</mesh_term>
    <mesh_term>Temsirolimus</mesh_term>
    <mesh_term>MTOR Inhibitors</mesh_term>
    <mesh_term>Tacrolimus</mesh_term>
    <mesh_term>Cyclosporins</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01678937
org study id: 1783-011
nct id: NCT01678937
lead sponsor: 
collaborator: 
has dmc: No
This study is being done with the purpose of trying to understand if and why transplant
      recipients may develop tolerance to their transplanted organ. Tolerance means being able to
      lower or take away immunosuppression (anti-rejection medications) without causing organ
      rejection.
Life-long immunosuppressive therapy is typically required in the majority of liver allograft
      recipients. In the early years of liver transplantation (LT), the majority of deaths occurred
      secondary to graft loss from acute or chronic rejection despite immunosuppression (IS). With
      the advent of more powerful and specific IS agents, e.g. calcineurin-inhibitors (CNIs)
      cyclosporine (CyA) and tacrolimus (TAC), graft rejection rates significantly declined and
      short and long term graft/patient survival dramatically improved. However, along with the
      advance in survival rates came the adverse effects of long term immunosuppression (IS), e.g.
      morbidity and mortality from cardiovascular events, renal insufficiency, infectious
      complications, recurrent viral hepatitis and malignancy. These events are exacerbated by
      pre-existing conditions and an aging transplant population. Immunosuppression tapering or
      withdrawal could lower the incidence of these complications and improve long term graft and
      patient survival.

      Therefore, the study proposed is a laboratory investigation (using blood samples collected
      from the subjects) comparing immune tolerance and alloreactivity profiles in LT recipients on
      monotherapy IS or converted to rapamycin monotherapy, to determine tolerogenic properties of
      the different IS agents. Knowledge of these properties would support the need for specific IS
      therapy to promote immune tolerance and consider IS withdrawal.

      Monotherapy patients will be identified by the organ transplant database and medical charts
      at Northwestern. Patients will be invited to participate in the study and asked to undergo
      venipunctures for our analysis. Patient demographics, laboratories and other clinical data
      will be recorded. Patients on CNI monotherapy are continuously being identified for
      conversion to rapamycin monotherapy during clinic visits or chart reviews at Northwestern.
      Patients are selected for conversion due to significant CNI side effects, e.g. chronic kidney
      disease (creatinine clearance < 50 in the absence of significant proteinuria > 1g, poorly
      controlled diabetes mellitus/hypertension/hyperlipidemia, peripheral neuropathy). In general,
      patients are converted from CNIs to rapamycin over 2-3 weeks once therapeutic rapamycin
      levels are achieved.

      Study procedures will be carried out by the investigators and associated personnel. Patients
      will be assigned a number in numerical order, to remove patient identifiers from the data
      analysis. A separate screening/enrollment log will be kept separate from the data. Baseline
      characteristics of the patients will be recorded: age, sex, liver disease, past medical
      history, history of acute rejection or other graft dysfunction, other post-LT complications,
      previous and current IS regimens. Monotherapy patients (10 from CyA, Tacrolimus, and MMF; 5
      rapamycin) will be identified as above and asked to participate. Blood will be drawn at one
      time point for the following analysis:

        -  Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to
           process antigens (CD83; CD205); markers that have been shown to induce regulatory T
           cells (ILT3; ILT4).

        -  Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low
           cells).

        -  HLA microchimerism & HLA G

      Ten patients who have been pre-selected for rapamycin conversion will have the above assays
      performed two weeks prior to conversion and 3-6 months following conversion. They will also
      have liver function and drug level tests.
observational model: Case-Control
time perspective: Prospective
measure: Track interval outcome measures for development of higher percentages of FOXP3+ T1 regulatory cells in stable liver transplant recipients on rapamycin or MMF monotherapy compared to CNI monotherapy.
time frame: Two weeks prior to conversion, Months 3 & 6 following conversion
description: Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).
Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells).
Liver function and drug levels.
measure: Track interval outcome measures for development of higher percentages of FOXP3+ T regulatory cells in liver transplant recipients after conversion from CNI to rapamycin comparing to MMF monotherapy.
time frame: Two weeks prior to conversion, Months 3 & 6 following conversion
description: Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).
Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells).
measure: Track interval outcome measures for development of higher percentages of immunophenotypic markers associated with regulatory T cell production in stable liver transplant recipients on rapamycin or MMF monotherapy compared to CNI monotherapy.
time frame: Two weeks prior to conversion, Months 3 & 6 following conversion
description: Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).
Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells).
HLA microchimerism & HLA G (dendritic cell ratios, soluble HLA G)
Liver function and drug levels.
measure: Track interval outcome measures for development of higher percentages of immunophenotypic markers associated with regulatory T cell production in liver transplant recipients after conversion from CNI to rapamycin or MMF monotherapy.
time frame: Two weeks prior to conversion, Months 3 & 6 following conversion
description: Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).
Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells).
HLA microchimerism & HLA G (dendritic cell ratios, soluble HLA G)(hypertension, hyperlipidemia, renal insufficiency, diabetes, neuropathy)
measure: Document improvement in adverse CNI side effects after conversion to rapamycin or MMF monotherapy, comparing designated time points.
time frame: Two weeks prior to conversion, Months 3 & 6 following conversion
description: CNI side effects - hypertension, hyperlipidemia, renal insufficiency, diabetes, neuropathy. Review liver function and drug levels at designated time points.
measure: Document the development of any adverse rapamycin or MMF side effects after conversion, comparing designated time points.
time frame: Two weeks prior to conversion, Months 3 & 6 following conversion
description: Document Rapamycin side effects - oral ulcers, edema, pancytopenia, gastrointestinal dysfunction; or MMF side effects - pancytopenia, gastrointestinal dysfunction. Review liver function and drug levels at designated time points.
arm group label: Control Group
description: Ten Healthy individuals will have blood drawn (4 green top tubes(40 ml = 8 tsp.)) at one time point at Northwestern for control purposes. Blood will be drawn to conduct the following tests:
Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).
Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells), and
HLA microchimerism & HLA G.
arm group label: Monotherapy Group
description: Monotherapy patients [cyclosporine (CyA) (10 patients), Tacrolimus (5 patients), mycophenolate mofetil (MMF) (10 patients), rapamycin (10 patients)]: Blood will be drawn at one time point (4 green top tubes (40 ml = 8 tsp.)) to conduct the following tests:
Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).
Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells), and
HLA microchimerism & HLA G.
arm group label: Conversion Group
description: Ten CNI monotherapy/dual therapy (CNI + MMF) patients pre-selected for conversion to rapamycin or wean to MMF monotherapy. Assays performed 2 weeks prior to conversion, 3-6 months following successful conversion. Liver function/drug levels monitored weekly during conversion until stable levels achieved. Patients converting from CNI monotherapy to rapamycin monotherapy (2-4 wks.): CNI discontinued when 2 therapeutic rapamycin levels (5-10) reached, graft function stable (clinical care protocol). MMF conversion: MMF dose slowly increased to 3 g/day (max.) while CNI therapy reduced by 1-2 mg/day (FK506) or 25-50 mg/day (CyA) monthly until CNI discontinued (1-6 months) (clinical care protocol). Monthly liver function/drug levels performed after successful conversion (standard of care).
intervention type: Procedure
intervention name: Blood Draw - Rapamycin
description: Ten calcineurin-inhibitors (CNI) monotherapy or dual therapy (CNI+MMF) patients will have blood taken (40 ml=8 tsp.) 2 wks. prior to conversion, 3-6 months post successful conversion. 1) Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28-FOXP3+CD127low cells). 2) Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers shown to induce regulatory T cells (ILT3; ILT4), 3) Soluble HLA G, and 4) Liver function/drug levels. If problems develop during conversion (e.g. acute rejection, significant drug side effects) requiring discontinuation of rapamycin, MMF and/or reversion to CNI therapy, assays will not be performed. Monthly liver function/drug levels performed after successful conversion (standard of care).
arm group label: Conversion Group
other name: Sirolimus
intervention type: Procedure
intervention name: Blood Draw from Control Subjects
description: Ten healthy individuals will have blood drawn (40 ml = 8 teaspoons (tsps.)).Blood will be drawn at one time point for the following:
Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).
Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells).
HLA microchimerism & HLA G
arm group label: Control Group
intervention type: Procedure
intervention name: Blood Draw - CyA
description: Blood drawn from 10 patients on cyclosporine (CyA) (40 ml = 8 tsp.)). Blood will be drawn at one time point for the following:
Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).
Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells).
HLA microchimerism & HLA G
arm group label: Monotherapy Group
other name: cyclosporine
intervention type: Procedure
intervention name: Blood Draw - Tacrolimus
description: Blood drawn from 5 patients on Tacrolimus (40 ml = 8 tsp.) at one time point for the following:
Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).
Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells).
HLA microchimerism & HLA G
arm group label: Monotherapy Group
other name: Tacrolimus
intervention type: Procedure
intervention name: Blood Draw - MMF
description: Blood will be drawn from 10 patients on mycophenolate mofetil (MMF) (40 ml or the equivalent of 8 teaspoons). Blood will be drawn at one time point for the following analysis:
Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).
Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells).
HLA microchimerism & HLA G
arm group label: Monotherapy Group
other name: mycophenolate mofetil
intervention type: Procedure
intervention name: Blood Draw - Rapamycin
description: Blood drawn from 10 patients on rapamycin (40 ml = 8 tsp.)) at one time point for the following:
Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to process antigens (CD83; CD205); markers that have been shown to induce regulatory T cells (ILT3; ILT4).
Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells).
HLA microchimerism & HLA G
arm group label: Monotherapy Group
other name: Rapamycin
Blood tests: Monotherapy patients

        1. Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28-FOXP3+CD127low
           cells).

        2. Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to
           process antigens (CD83; CD205); markers that have been shown to induce regulatory T
           cells (ILT3; ILT4).

        3. Soluble HLA G

      Blood tests: Conversion patients

        1. Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28-FOXP3+CD127low
           cells).

        2. Dendritic cell assays: myeloid vs. lymphoid (CD11c; CD123); maturation and ability to
           process antigens (CD83; CD205); markers that have been shown to induce regulatory T
           cells (ILT3; ILT4),

        3. Soluble HLA G, and

        4. Liver function and drug levels.

      Blood tests: Healthy controls (same tests as Monotherapy Group)
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Josh Levitsky, MD
role: Principal Investigator
affiliation: Northwestern University, Northwestern Memorial Hospital, Northwestern Medical Faculty Foundation
facility: 
country: United States
url: http://www.ncbi.nlm.nih.gov/pubmed
description: PMID: 19141306
citation: Sayegh MH, Carpenter CB. Transplantation 50 years later--progress, challenges, and promises. N Engl J Med. 2004 Dec 23;351(26):2761-6. doi: 10.1056/NEJMon043418. No abstract available.
PMID: 15616214
citation: Takatsuki M, Uemoto S, Inomata Y, Egawa H, Kiuchi T, Fujita S, Hayashi M, Kanematsu T, Tanaka K. Weaning of immunosuppression in living donor liver transplant recipients. Transplantation. 2001 Aug 15;72(3):449-54. doi: 10.1097/00007890-200108150-00016.
PMID: 11502975
citation: Tisone G, Orlando G, Cardillo A, Palmieri G, Manzia TM, Baiocchi L, Lionetti R, Anselmo A, Toti L, Angelico M. Complete weaning off immunosuppression in HCV liver transplant recipients is feasible and favourably impacts on the progression of disease recurrence. J Hepatol. 2006 Apr;44(4):702-9. doi: 10.1016/j.jhep.2005.11.047. Epub 2006 Jan 4.
PMID: 16473433
citation: Girlanda R, Rela M, Williams R, O'Grady JG, Heaton ND. Long-term outcome of immunosuppression withdrawal after liver transplantation. Transplant Proc. 2005 May;37(4):1708-9. doi: 10.1016/j.transproceed.2005.03.070.
PMID: 15919439
citation: Hurwitz M, Desai DM, Cox KL, Berquist WE, Esquivel CO, Millan MT. Complete immunosuppressive withdrawal as a uniform approach to post-transplant lymphoproliferative disease in pediatric liver transplantation. Pediatr Transplant. 2004 Jun;8(3):267-72. doi: 10.1111/j.1399-3046.2004.00129.x.
PMID: 15176965
citation: Oike F, Yokoi A, Nishimura E, Ogura Y, Fujimoto Y, Kasahara M, Kaihara S, Kiuchi T, Egawa H, Uemoto S, Tanaka K. Complete withdrawal of immunosuppression in living donor liver transplantation. Transplant Proc. 2002 Aug;34(5):1521. doi: 10.1016/s0041-1345(02)02980-9. No abstract available.
PMID: 12176465
citation: Lerut J, Sanchez-Fueyo A. An appraisal of tolerance in liver transplantation. Am J Transplant. 2006 Aug;6(8):1774-80. doi: 10.1111/j.1600-6143.2006.01396.x.
PMID: 16889539
citation: Mazariegos GV, Reyes J, Marino I, Flynn B, Fung JJ, Starzl TE. Risks and benefits of weaning immunosuppression in liver transplant recipients: long-term follow-up. Transplant Proc. 1997 Feb-Mar;29(1-2):1174-7. doi: 10.1016/s0041-1345(96)00535-0. No abstract available.
PMID: 9123261
citation: Mazariegos GV, Reyes J, Marino IR, Demetris AJ, Flynn B, Irish W, McMichael J, Fung JJ, Starzl TE. Weaning of immunosuppression in liver transplant recipients. Transplantation. 1997 Jan 27;63(2):243-9. doi: 10.1097/00007890-199701270-00012.
PMID: 9020325
citation: Donckier V, Troisi R, Le Moine A, Toungouz M, Ricciardi S, Colle I, Van Vlierberghe H, Craciun L, Libin M, Praet M, Noens L, Stordeur P, Andrien M, Lambermont M, Gelin M, Bourgeois N, Adler M, de Hemptinne B, Goldman M. Early immunosuppression withdrawal after living donor liver transplantation and donor stem cell infusion. Liver Transpl. 2006 Oct;12(10):1523-8. doi: 10.1002/lt.20872.
PMID: 17004249
citation: Mazariegos GV, Zahorchak AF, Reyes J, Ostrowski L, Flynn B, Zeevi A, Thomson AW. Dendritic cell subset ratio in peripheral blood correlates with successful withdrawal of immunosuppression in liver transplant patients. Am J Transplant. 2003 Jun;3(6):689-96. doi: 10.1034/j.1600-6143.2003.00109.x.
PMID: 12780560
citation: Wong T, Nouri-Aria KT, Devlin J, Portmann B, Williams R. Tolerance and latent cellular rejection in long-term liver transplant recipients. Hepatology. 1998 Aug;28(2):443-9. doi: 10.1002/hep.510280223.
PMID: 9696010
citation: Devlin J, Doherty D, Thomson L, Wong T, Donaldson P, Portmann B, Williams R. Defining the outcome of immunosuppression withdrawal after liver transplantation. Hepatology. 1998 Apr;27(4):926-33. doi: 10.1002/hep.510270406.
PMID: 9537430
citation: Woltman AM, de Fijter JW, Kamerling SW, Paul LC, Daha MR, van Kooten C. The effect of calcineurin inhibitors and corticosteroids on the differentiation of human dendritic cells. Eur J Immunol. 2000 Jul;30(7):1807-12. doi: 10.1002/1521-4141(200007)30:73.0.CO;2-N.
PMID: 10940869
citation: Koenen HJ, Fasse E, Joosten I. Cyclosporine preserves the anergic state of human T cells induced by costimulation blockade in vitro. Transplantation. 2005 Aug 27;80(4):522-9. doi: 10.1097/01.tp.0000172217.97072.54.
PMID: 16123728
citation: Szabo G, Gavala C, Mandrekar P. Tacrolimus and cyclosporine A inhibit allostimulatory capacity and cytokine production of human myeloid dendritic cells. J Investig Med. 2001 Sep;49(5):442-9. doi: 10.2310/6650.2001.33789.
PMID: 11523700
citation: Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood. 2005 Jun 15;105(12):4743-8. doi: 10.1182/blood-2004-10-3932. Epub 2005 Mar 3.
PMID: 15746082
citation: Battaglia M, Stabilini A, Draghici E, Gregori S, Mocchetti C, Bonifacio E, Roncarolo MG. Rapamycin and interleukin-10 treatment induces T regulatory type 1 cells that mediate antigen-specific transplantation tolerance. Diabetes. 2006 Jan;55(1):40-9.
PMID: 16380475
citation: Mehling A, Grabbe S, Voskort M, Schwarz T, Luger TA, Beissert S. Mycophenolate mofetil impairs the maturation and function of murine dendritic cells. J Immunol. 2000 Sep 1;165(5):2374-81. doi: 10.4049/jimmunol.165.5.2374.
PMID: 10946260
citation: Gregori S, Casorati M, Amuchastegui S, Smiroldo S, Davalli AM, Adorini L. Regulatory T cells induced by 1 alpha,25-dihydroxyvitamin D3 and mycophenolate mofetil treatment mediate transplantation tolerance. J Immunol. 2001 Aug 15;167(4):1945-53. doi: 10.4049/jimmunol.167.4.1945.
PMID: 11489974
citation: Nikolaeva N, Bemelman FJ, Yong SL, van Lier RA, ten Berge IJ. Rapamycin does not induce anergy but inhibits expansion and differentiation of alloreactive human T cells. Transplantation. 2006 Feb 15;81(3):445-54. doi: 10.1097/01.tp.0000194860.21533.b9.
PMID: 16477233
responsible party type: Principal Investigator
investigator affiliation: Northwestern University
investigator full name: Josh Levitsky
investigator title: Associate Professor in Medicine-Hepatology
mesh term: Cyclosporine
mesh term: Sirolimus
mesh term: Mycophenolic Acid
mesh term: Temsirolimus
mesh term: MTOR Inhibitors
mesh term: Tacrolimus
mesh term: Cyclosporins