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

Not Applicable

Completed

• Conditions: End Stage Renal Failure With Renal Transplant
• Interventions: Drug: Tacrolimus with MMF

• Registration Number: NCT01653847
• Lead Sponsor: Northwestern University

Brief Summary

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.

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.

Study Timeline

• Study First Submitted: 2012-04-04
• Study First Submitted QC: 2012-07-30
• Study First Posted: 2012-07-31
• Study Start: 2013-02
• Primary Completion: 2020-05
• Study Completion: 2020-05
• Results First Submitted: 2020-11-17
• Status Verified: 2021-02
• Results First Submitted QC: 2021-02-10
• Last Update Submitted: 2021-02-10
• Results First Posted: 2021-03-02
• Last Update Posted: 2021-03-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 88

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%

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group 1: Tacrolimus with MMF.	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.

Primary Outcome Measures

Name	Time	Method
Change in T Cell & B Cell Generation	Baseline, 3 months, and 12 months post-transplant	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 and 12 months post-transplant.
Change in Glomerular Filtration Rate (GFR)	3 months, 6 months, and 12 months post-transplant	Evaluate the change in graft function (as measured by GFR) at 12 months post-transplant from baseline.

Secondary Outcome Measures

Name	Time	Method
Patient Survival	baseline - 24 months post transplant	The number of patients who were alive at 2 years post transplant
Renal Allograft Survival	12 months post-transplant	The number of subjects with renal allograft survival.
Acute Rejection	12 months post transplant	Number of subjects who experience acute rejection of the renal allograft.

Trial Locations

Locations (1)

Northwestern Memorial Hospital; 🇺🇸 Chicago, Illinois, United States