AzTrials
AzTrials

Liver Transplant RejectionNCT01678937

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

An observational study of Liver Transplant Rejection and Immunosuppression, run by Northwestern University at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and olderHealthy volunteers can take part
Conditions the study is for
Liver Transplant Rejection, Immunosuppression
What is being tested?
Blood Draw - Rapamycin, Blood Draw - CyA and Blood Draw - Tacrolimus
Type of treatment
Surgery or procedure
How many people
31 participants
Where
1 siteUnited States
Study dates
Sep 2007to Sep 2008
Phase
Observational
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • Healthy volunteers accepted
  • Adult, Older adult

Study population: Liver transplant patients converting on stable IS monotherapy or undergoing conversion to rapamycin or MMF monotherapy.

Who may be able to join

  • 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

Who cannot join

  • 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

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Northwestern Memorial Hospital

    Chicago, Illinois, 60611

Other trials in United States

About this study

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.

Read the detailed description

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.

Being tested
Blood Draw - Rapamycin, Blood Draw from Control Subjects, Blood Draw - CyA, Blood Draw - Tacrolimus, Blood Draw - MMF
Keywords
Immunosuppression

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Blood Draw - RapamycinProcedure or surgery

    Also called Sirolimus

    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).

  • Blood Draw from Control SubjectsProcedure or surgery

    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

  • Blood Draw - CyAProcedure or surgery

    Also called cyclosporine

    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

  • Blood Draw - TacrolimusProcedure or surgery

    Also called 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

  • Blood Draw - MMFProcedure or surgery

    Also called mycophenolate mofetil

    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

  • Blood Draw - RapamycinProcedure or surgery

    Also called 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
Study groups in NCT01678937
Study groupRoleWhat they receive
Control GroupTen 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.
Receives: Procedure: Blood Draw from Control Subjects
Monotherapy GroupMonotherapy 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.
Receives: Procedure: Blood Draw - CyA; Procedure: Blood Draw - Tacrolimus; Procedure: Blood Draw - MMF; Procedure: Blood Draw - Rapamycin
Conversion GroupTen 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).
Receives: Procedure: Blood Draw - Rapamycin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    • 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.

    Measured: Two weeks prior to conversion, Months 3 & 6 following conversion

  2. 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.

    • 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).

    Measured: Two weeks prior to conversion, Months 3 & 6 following conversion

Secondary outcomes (4)

  1. 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.

    • 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.

    Measured: Two weeks prior to conversion, Months 3 & 6 following conversion

  2. 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.

    • 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)

    Measured: Two weeks prior to conversion, Months 3 & 6 following conversion

  3. Document improvement in adverse CNI side effects after conversion to rapamycin or MMF monotherapy, comparing designated time points.

    CNI side effects - hypertension, hyperlipidemia, renal insufficiency, diabetes, neuropathy. Review liver function and drug levels at designated time points.

    Measured: Two weeks prior to conversion, Months 3 & 6 following conversion

  4. Document the development of any adverse rapamycin or MMF side effects after conversion, comparing designated time points.

    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.

    Measured: Two weeks prior to conversion, Months 3 & 6 following conversion

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted5 Sep 2012 (estimated)
  2. Study startSep 2007
  3. Primary completionMay 2008
  4. Study completionSep 2008

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Observational
Observational model
Case-control
Time perspective
Prospective
Enrolment
31 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01678937
Sponsor's protocol ID
1783-011
Status last verified
Apr 2015
First submitted
8 Jul 2011
Last updated
15 Apr 2015
Results posted
No
Data monitoring committee
No

Publications

  • 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.

    PubMed 15616214

  • 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.

    PubMed 11502975

  • 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.

    PubMed 16473433

  • 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.

    PubMed 15919439

  • 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.

    PubMed 15176965

  • 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.

    PubMed 12176465

  • 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.

    PubMed 16889539

  • 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.

    PubMed 9123261

  • 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.

    PubMed 9020325

  • 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.

    PubMed 17004249

  • 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.

    PubMed 12780560

  • 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.

    PubMed 9696010

  • 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.

    PubMed 9537430

  • 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.

    PubMed 10940869

  • 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.

    PubMed 16123728

Questions about this trial

What is this clinical trial studying?

An observational study of Liver Transplant Rejection and Immunosuppression, run by Northwestern University at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 15 Apr 2015. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the 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). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01678937, which also lists 21 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Apr 2015.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in