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Immune Tolerance and Alloreactivity in Liver Transplant Recipients on Different Monotherapy Immunosuppressive Agents

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ClinicalTrials.gov Identifier: NCT01678937
Recruitment Status : Completed
First Posted : September 5, 2012
Last Update Posted : April 15, 2015
Sponsor:
Collaborator:
Northwestern Memorial Hospital
Information provided by (Responsible Party):
Josh Levitsky, Northwestern University

July 8, 2011
September 5, 2012
April 15, 2015
September 2007
May 2008   (Final data collection date for 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. [ Time Frame: Two weeks prior to conversion, Months 3 & 6 following conversion ]
    • 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.
  • 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 ]
    • 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).
Same as current
Complete list of historical versions of study NCT01678937 on ClinicalTrials.gov Archive Site
  • 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 ]
    • 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.
  • 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 ]
    • 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)
  • 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 ]
    CNI side effects - hypertension, hyperlipidemia, renal insufficiency, diabetes, neuropathy. Review liver function and drug levels at designated time points.
  • 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 ]
    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.
Same as current
Not Provided
Not Provided
 
Immune Tolerance and Alloreactivity in Liver Transplant Recipients on Different Monotherapy Immunosuppressive Agents
Immune Tolerance and Alloreactivity in Liver Transplant Recipients on Different Monotherapy Immunosuppressive Agents
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
Observational Model: Case Control
Time Perspective: Prospective
Not Provided
Retention:   Samples With DNA
Description:

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)

Non-Probability Sample
Liver transplant patients converting on stable IS monotherapy or undergoing conversion to rapamycin or MMF monotherapy.
  • Liver Transplant Rejection
  • Immunosuppression
  • Procedure: Blood Draw - Rapamycin
    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).
    Other Name: Sirolimus
  • Procedure: Blood Draw from Control Subjects

    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
  • Procedure: Blood Draw - CyA

    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
    Other Name: cyclosporine
  • Procedure: Blood Draw - Tacrolimus

    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
    Other Name: Tacrolimus
  • Procedure: Blood Draw - MMF

    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
    Other Name: mycophenolate mofetil
  • Procedure: Blood Draw - Rapamycin

    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
    Other Name: Rapamycin
  • Control Group

    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:

    1. 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).
    2. Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells), and
    3. HLA microchimerism & HLA G.
    Intervention: Procedure: Blood Draw from Control Subjects
  • Monotherapy Group

    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:

    1. 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).
    2. Regulatory/Suppressor Cells (CD4+CD25+FOXP3+CD127low; and CD8+ CD28- FOXP3+CD127low cells), and
    3. HLA microchimerism & HLA G.
    Interventions:
    • Procedure: Blood Draw - CyA
    • Procedure: Blood Draw - Tacrolimus
    • Procedure: Blood Draw - MMF
    • Procedure: Blood Draw - Rapamycin
  • Conversion Group
    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: Procedure: Blood Draw - Rapamycin

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
31
Same as current
September 2008
May 2008   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  • Age ≥18 years
  • Orthotopic or Living-Related liver transplant (LT) recipient
  • Monotherapy patients: > 6 months with stable graft function on current monotherapy (CNI, MMF, or rapamycin)
  • Converting patients: CNI therapy converting to rapamycin or MMF monotherapy and > 6 months of stable graft function.
  • >1 years post-LT without an acute rejection episode or chronic rejection
  • Normal liver function tests (no recurrent HCV, chronic rejection, autoimmune hepatitis, etc.)
  • No history of induction or lymphocyte depletion therapy

Exclusion Criteria:

  • Multi-visceral organ recipients
  • Graft dysfunction of any etiology
  • Inadequate follow-up or available outcomes
  • Unable to understand, sign or ask questions regarding the informed consent process and protocol
Sexes Eligible for Study: All
18 Years and older   (Adult, Older Adult)
Yes
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT01678937
1783-011
No
Not Provided
Not Provided
Josh Levitsky, Northwestern University
Northwestern University
Northwestern Memorial Hospital
Principal Investigator: Josh Levitsky, MD Northwestern University, Northwestern Memorial Hospital, Northwestern Medical Faculty Foundation
Northwestern University
April 2015