Study in Recipients of Renal Transplant Allograft to Evaluate the Impact of Two Immunosuppressive Regimens

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by Northwestern University
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
Lorenzo Gallon, Northwestern University
ClinicalTrials.gov Identifier:
NCT01653847
First received: April 4, 2012
Last updated: June 10, 2014
Last verified: June 2014
  Purpose

The immune system is the body's defense against infection and other disease. After transplantation, the body sees the new organ as "foreign" and tries to destroy or "reject" it. Immunosuppressive medications help to prevent the immune system from attacking a transplanted organ. The primary purpose of this study is to investigate the impact of two maintenance immunosuppressive regimens. Subjects who enroll in this study will be randomly selected to have tacrolimus and everolimus (group 1) or tacrolimus and mycophenolate mofetil (group 2) as their immunosuppression medication.

This study will enroll adult patients who are scheduled to receive a kidney transplant.

The study is designed to understand the mechanisms of Everolimus in regards to kidney function in transplant recipients. The investigators hypothesis is that decreased exposure to Tacrolimus to the immune system will then translate in better renal allograft function.


Condition Intervention
End Stage Renal Failure With Renal Transplant
Drug: Tacrolimus with MMF
Drug: Group 2: Tacrolimus with Everolimus.

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Impact of Two Prednisone-free Maintenance Immunosuppressive Regimens With Reduced Dose FK506+Everolimus vs. Standard Dose Tacrolimus (FK506)+ Mycophenolate Mofetil (MMF) on Subpopulation of T and B Cells, Renal Allograft Function and Gene Expression Profiles in Renal Allograft Biopsies at 12 Months Post-transplant. Prospective Single Center Study in Recipients of Renal Transplant Allograft.

Resource links provided by NLM:


Further study details as provided by Northwestern University:

Primary Outcome Measures:
  • Change in T cell & B cell generation, function and gene expression [ Time Frame: baseline - 12 months post transplant ] [ Designated as safety issue: No ]
    Evaluate the change in regulatory T cell generation and review the relationship of the newly generated T cells with their function in the two maintenance immunosuppressive regimens at baseline, 3, 6 and 12 months post-transplant.

  • Change in Renal allograft function [ Time Frame: baseline - 12 months post transplant ] [ Designated as safety issue: No ]
    Evaluate the change in graft function at 12 months post-transplant from baseline.

  • Change in T and B cell immune response [ Time Frame: baseline - 12 months post transplant ] [ Designated as safety issue: No ]
    Evaluate change in T and B cell immune response gene expression through RNA analysis at baseline, 3, 6 and 12 months post-transplant.


Secondary Outcome Measures:
  • Change in Renal allograft immunohistopathology & gene expression post-transplant [ Time Frame: baseline - 12 months post transplant ] [ Designated as safety issue: No ]
    1) Evaluate the change in allograft immunohistopathology and gene expression profiles at baseline, 3 and 12 months post-transplant.

  • compare the impact of the two maintenance immunosuppressive regimens on acute rejection, graft loss and death at 12 months post transplant. [ Time Frame: baseline - 12 months post transplant ] [ Designated as safety issue: No ]
    evaluate the impact of the two maintenance immunosuppressive regimens on acute rejection, graft loss and death at 12 months post transplant.

  • Change in Renal Allograft survival [ Time Frame: baseline - 12 months post transplant ] [ Designated as safety issue: No ]
    Evaluate the change in graft survival at 12 months post-transplant from baseline. Specifically acute rejection, graft loss and death.


Estimated Enrollment: 88
Study Start Date: February 2013
Estimated Study Completion Date: April 2016
Estimated Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Group 1: Tacrolimus with MMF.
This group will receive a standard dose Tacrolimus and MMF. This will follow standard of care protocol at Northwestern Memorial Hospital's Comprehensive Transplant Center.
Drug: Tacrolimus with MMF
Standard dose Tacrolimus and MMF. This will follow standard of care procedures at Northwestern Memorial Hospital's Comprehensive Transplant Center. MMF trough or area under the concentration time curve (AUC) shall not be used to adjust dosing. In this group, Tacrolimus will be initiated according to our practice. The Tacrolimus dose will be adjusted from day 3 on to achieve a target whole blood trough concentration of 8 ng/mL to 10 ng/mL. From month 2 until Month 6, the target Tacrolimus trough level will be reduced to 6 ng/mL to 8 ng/mL. After month 6, the target level of Tacrolimus will be reduced to 4 ng/mL to 8 ng/mL.
Other Names:
  • Tacrolimus
  • FK 506
  • mycophenolate mofetil
  • MMF
Active Comparator: Group 2: Tacrolimus with Everolimus
This group will receive a low dose Tacrolimus with concentration controlled Everolimus
Drug: Group 2: Tacrolimus with Everolimus.
From day 5 on, the starting dose of Everolimus (0.75 mg bid) will be increased if the trough level is < 3 ng/mL, or reduced if the trough level is > 8 ng/mL. Tacrolimus will be initiated according to our practice. In this treatment arm, the Tacrolimus dose will be adjusted from day 3 on, to a target whole blood trough concentration of 4 ng/mL to 7 ng/mL. From month 2 until Month 6, the target Tacrolimus trough level will be 3 ng/mL to 6 ng/mL. After month 6, the Tacrolimus dose should be adjusted in order to achieve a target trough level of 2 ng/mL to 5 ng/mL. MMF dose will be initiated as 1 g b.i.d. (2 g/day). Adjustments should be made for adverse events including but not limited to gastrointestinal intolerance and a decrease in white blood cell (WBC).
Other Names:
  • Everolimus
  • Zortress
  • Tacrolimus
  • FK 506
No Intervention: Donors
One time blood samples will be collected from kidney donors to recipients in this study

Detailed Description:

Immunosuppressive therapy with the calcineurin inhibitors (CNI) Cyclosporine (CsA) and Tacrolimus (Tac), have radically changed the field of organ transplantation. Ironically, although extensively and effectively used for kidney transplantation and other solid organ transplants, CsA and Tac cause important adverse renal side effects: acute and chronic renal dysfunction, hemolytic-uremic syndrome, hypertension, electrolyte disturbances and tubular acidosis. Chronic nephrotoxicity from CNI has been implicated as a principal cause of post-transplant renal dysfunction and it is characterized by an irreversible and progressive tubular atrophy, interstitial fibrosis, and focal hyalinosis of small renal arteries and arterioles. Furthermore, this class of medications is associated also, by blocking Interleukin-2 (IL2) production, with negative impact on regulatory T cells (T-Regs) generation (an important subpopulation of T helper cells that has been associated with positive immunomodulation and donor specific hypo responsiveness).

In renal transplant recipients, complete avoidance of calcineurin inhibitors from the time of renal transplant surgery has been associated with increased incidence of acute cellular rejection, and the combination of mammalian target of rapamycin (mTOR) inhibitors with full dose CNI has been shown to be synergistically nephrotoxic and it has been associated with poor graft outcome. CNI conversion to mTOR inhibitors, at different time point post-transplant, has been tested with promising results, by different investigators and by the investigators group. The investigators have shown that in a Prednisone-free immunosuppression, conversion from Tacrolimus to mTor inhibitors at different time point post transplant is safe, it is not associated with an increased risk of acute rejection and more importantly it is associated with an a persistent increase of regulatory T cells (Data presented at the American Transplant Congress (ATC) 09 and 2010) Recently the A2309 study allowed Everolimus to be FDA approved. The A2309 was a study designed to combined reduced dose Cyclosporine+Everolimus. Interesting the reduced exposure to Cyclosporine was not associated with an increase rate of albumin-creatinine ratio (ACR) and renal allograft function was well maintained compared to the control group. The A2309 opens then an important question regarding the mechanism(s) that can explain the efficacy of a low dose CNI with an mTOR inhibitor in preventing acute allograft rejection.

The present proposal is designed to understand the mechanisms of the synergistic effect(s) of low dose CNI and mTOR inhibitors (Everolimus) in controlling allo-reactive T and B cells while expanding T-Regs.

The investigators hypothesis based in published data and from their laboratory (see preliminary data-Supportive documents), is that mTOR inhibitors allow expansion of T-Regs and low exposure of CNI is sufficient to control allo-reactive T cells. Decrease exposure to CNI and concomitant increase of T-Regs will then translate in better renal allograft function and histology.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Subjects should be adults between 18 and 70 years of age
  2. Subjects can be either gender or of any ethnic background
  3. Subjects should be single organ recipients (kidney only)
  4. Subjects must be able to understand the protocol and provide informed consent.
  5. Recipient of living donor kidney transplants
  6. Panel reactive antibody (PRA) < 20%

Exclusion Criteria:

  1. Subjects with End Stage Renal Disease (ESRD) secondary to primary focal segmental glomerulonephritis (FSGS).
  2. Inability to fully understand the purpose of the study and the inability to sign the informed consent
  3. Subjects with a significant or active infection
  4. Subjects who are pregnant or nursing females
  5. Subjects with a history of severe hyperlipidemia not controlled with statins, patients with Cholesterol > 400mg/dl
  6. Subjects with a platelet count < 100,000mm3, WBC < 2,000mm3 (or clinical practice)
  7. Subjects, who, due to the existence of a surgical, medical or psychiatric condition, other than the current transplant, which in the opinion of the investigator, precludes enrollment into this trial.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01653847

Contacts
Contact: Lorenzo Gallon, MD 312-695-8900 l-gallon@northwestern.edu

Locations
United States, Illinois
Northwestern Memorial Hospital Recruiting
Chicago, Illinois, United States, 60611
Contact: Lorenzo Gallon, MD    312-695-8900    l-gallon@northwestern.edu   
Sponsors and Collaborators
Northwestern University
Novartis
Investigators
Principal Investigator: Lorenzo Gallon, MD Northwestern University
  More Information

No publications provided

Responsible Party: Lorenzo Gallon, Associated Professor of Transplant Nephrology, Northwestern University
ClinicalTrials.gov Identifier: NCT01653847     History of Changes
Other Study ID Numbers: Novartis- Everolimus
Study First Received: April 4, 2012
Last Updated: June 10, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Northwestern University:
transplant
kidney
renal disease

Additional relevant MeSH terms:
Kidney Failure, Chronic
Renal Insufficiency
Renal Insufficiency, Chronic
Kidney Diseases
Urologic Diseases
Immunosuppressive Agents
Mycophenolate mofetil
Everolimus
Sirolimus
Tacrolimus
Mycophenolic Acid
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antifungal Agents
Anti-Infective Agents
Anti-Bacterial Agents

ClinicalTrials.gov processed this record on July 26, 2014