Immune Monitoring and CNI Withdrawal in Low Risk Recipients of Kidney Transplantation

Study Overview
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Brief Summary
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The study will compare how well transplanted kidneys work and the response of people's immune systems as tacrolimus, a calcineurin inhibitor (CNI), is withdrawn. In addition, this research study will evaluate whether reducing immunosuppression can decrease some of these side effects while still preventing rejection of the kidney.

Detailed Description
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Kidney transplantation is a treatment option for people with kidney disease. However, there is still much to learn about how to best care for the transplanted kidney and keep it functioning for a long time. Transplant recipients take immunosuppression (anti-rejection) drugs to prevent their body from rejecting the new kidney. These drugs are used to prevent the immune system from attacking the transplanted kidney. All anti-rejection medications have unwanted side effects. The purpose of this study is to evaluate the safety of slowly removing tacrolimus, a CNI.

Official Title
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Immune Monitoring and Calcineurin Inhibitor (CNI) Withdrawal in Low Risk Recipients of Kidney Transplantation

Conditions
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Kidney Transplant Recipients

Intervention / Treatment
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* Drug: Tacrolimus (CNI) Withdrawal
* Drug: Standard Immunosuppressive Therapy


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA - Initial Enrollment/Screening: Patients who meet all of the following criteria are eligible for enrollment as study subjects: Subject must be able to understand and provide written informed consent; Primary living-donor (related or unrelated) kidney transplant recipients; Peak flow-based PRAs for class I and class II <30%(performed by local center); Current (within 8 weeks prior to transplantation) flow-based PRAs for class I and class II <30% (performed by local center); No donor specific antibody by flow solid phase method on the peak PRA serum (if serum available), or on the current PRA serum (within 8 weeks prior to transplantation) performed by central core laboratory. If the sera for the peak PRA is not available, then only the current PRA serum will be tested; Negative T-cell and B-cell crossmatch by flow cytometry (performed by local center); Female subjects of childbearing potential must have a negative pregnancy test (urine or serum) upon study entry; Female and male subjects with reproductive potential must agree to use FDA approved methods of birth control while participating in the study. Inclusion Criteria for Randomization: Participants who meet all of the following criteria are eligible for randomization: No history of acute rejection episodes; The pre-randomization protocol biopsy should confirm no rejection, including borderline rejection (based on the central pathology read); No donor specific antibody as detected by flow solid phase method (performed by the central core laboratory). EXCLUSION CRITERIA - Initial Enrollment/Screening: Participants who meet any of these criteria are not eligible for enrollment as study subjects: Recipient of multiple organ transplants; Prior history of organ transplantation; Deceased-donor source; Any condition that would preclude protocol biopsies; HLA identical recipients; Currently breast-feeding or plans to become pregnant during the timeframe of the study follow up period; Any condition that, in the opinion of the investigator, would interfere with the subject's ability to comply with study requirements; Inability or unwillingness to comply with study protocol; Use of investigational drugs within 4 weeks of study entry and for the duration of the study; Recent recipient of any licensed or investigational live attenuated vaccine(s) within two months of prior to study entry. Exclusion Criteria for Randomization: Participants who meet any of these criteria are not eligible for randomization: Subjects who receive less than 4.5mg/kg of Rabbit ATG (Thymoglobulin®) induction therapy; Subjects who test positive for BKV by PCR in the blood at 6 months post-transplant; Any condition that would preclude protocol biopsies; Currently breast-feeding or plans to become pregnant during the timeframe of the study follow up period; Any condition that, in the opinion of the investigator, would interfere with the subject's ability to comply with study requirements; Inability or unwillingness of a subject to give written informed consent or comply with study protocol; Use of investigational drugs within 4 weeks of study entry and for the duration of the study; Subjects who receive less than 1500 mg daily of Mycophenolate Mofetil (CellCept®) or equivalent.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tacrolimus (CNI) Withdrawal<br>Subjects randomized (2:1) to tacrolimus (CNI) withdrawal. Recipients of living-donor kidney allografts are given induction therapy with rabbit antithymocyte globulin (RATG, Thymoglobulin®) and treated with a standard immunosuppressive regimen of mycophenolate mofetil (MMF), prednisone and tacrolimus.Subjects without any clinical acute rejection (AR) in the first 6 months, without borderline or acute rejection on the 6 month biopsy, and without donor-specific antibody (DSA) at anytime, including the 6 month test are randomized (2:1) to tacrolimus (CNI) withdrawal. | Drug: Tacrolimus (CNI) Withdrawal<br>* Recipients of living-donor kidney allografts are given induction therapy with rabbit antithymocyte globulin (RATG, Thymoglobulin®) and treated with a regimen of mycophenolate mofetil (MMF), prednisone and tacrolimus. Subjects without any clinical acute rejection (AR) in the first 6 months, without borderline or acute rejection on the 6 month biopsy, and without donor-specific antibody (DSA) at anytime, including the 6 month test will be randomized (2:1) to tacrolimus (CNI) withdrawal.<br>* Other names: CellCept®;Drug: Standard Immunosuppressive Therapy<br>* Recipients of living-donor kidney allografts are given induction therapy with rabbit antithymocyte globulin (RATG, Thymoglobulin®) and treated with a regimen of mycophenolate mofetil (MMF), prednisone and tacrolimus.<br>* Other names: CellCept®;|
| Active Comparator: Standard Immunosuppressive Therapy<br>Subjects randomized to standard immunosuppressive therapy, without subsequent tacrolimus (CNI) withdrawal. Recipients of living-donor kidney allografts are given induction therapy with rabbit antithymocyte globulin (RATG, Thymoglobulin®) and treated with a standard immunosuppressive regimen of mycophenolate mofetil (MMF), prednisone and tacrolimus. Tacrolimus (CNI) withdrawal does not occur. | Drug: Standard Immunosuppressive Therapy<br>* Recipients of living-donor kidney allografts are given induction therapy with rabbit antithymocyte globulin (RATG, Thymoglobulin®) and treated with a regimen of mycophenolate mofetil (MMF), prednisone and tacrolimus.<br>* Other names: CellCept®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Incremental IF/A Scores >2 at 24 Months Post-Randomization | The investigators were not able to assess this outcome, the effect of the intervention on interstitial fibrosis/tubular atrophy (IF/TA; on a 2-year graft biopsy) due to the study's premature termination by the Data Safety Monitoring Board (DSMB) because of absence of equipoise on the basis of predetermined stopping rules. | IF/TA scores on protocol biopsies obtained at 24 months post-randomization will be compared to those obtained at the time of implantation for this measurement. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimated GFR Using the Chronic Kidney Disease Epidemiology (CKD-EPI) Equation | Estimated glomerular filtration rate (eGFR) is a test to measure the level of kidney function. In this measure, the effects of tacrolimus withdrawal on long-term kidney function was assessed by comparing absolute 24 month eGFR (18 months post-randomization) and change in eGFR from 6 to 24 months (randomization to 18 months randomization). Lower numbers indicate poorer kidney function | 6 months post-transplantation, 24 months post-transplantation | 
| Incidence of Acute Rejection | Acute renal allograft rejection is defined as histological reading of borderline or greater determined by the local pathology laboratory. Participants suspected of having a rejection episode on the basis of clinical signs, symptoms, or on the basis of laboratory tests, had a renal ultrasound and underwent a renal transplant biopsy. Any detection of acute cellular rejection or acute humoral rejection resulted in participants in the 'Randomized to Tacrolimus Withdrawal' group to be restarted on tacrolimus and followed per the reduced follow-up schedule of events. | 6 to 18 months post-randomization | 
| Allograft Survival Rate | Allograft survival is defined as participants who did not need to be re-transplanted or placed on dialysis due to the failure of their allograft transplantation during the course of this study. | 6 to 18 months post-randomization | 
| Participant Survival Rate | Number of participants who did not die within the course of this study. | 6 to 18 months post-transplantation | 
| Percentage of Participants With New Donor Specific Antibodies (DSAs) | Donor specific antibodies are antibodies that are directed against antigens expressed on donor organs. These antibodies can result in an immune attack on the transplanted organ, increasing risk of graft loss and/or rejection. | 6 to 18 months post-randomization | 
| Percentage of Participants With Donor-Specific Memory Using Elispot | This endpoint was unable to be analyzed because the study was terminated early after stopping rules were met. | 6 to 18 months post-randomization | 
| Percentage of Participants in the Experimental Arm Off Tacrolimus | Participants in the 'Randomized to Tacrolimus Withdrawal' group were considered fully withdrawn once they no longer received any doses of tacrolimus. Participants met this endpoint if they did not resume taking tacrolimus as of 18 months post randomization with stable allograft function and without rejection of donor-specific antibodies. | 18 months post-randomization | 
| Incremental Change in IF/TA Scores | This endpoint was unable to be analyzed because the study was terminated early after stopping rules were met. | 6 to 18 months post-transplant | 
| Measurement of Urinary Parameters Before and After Randomization | This endpoint was unable to be analyzed because the study was terminated early after stopping rules were met. | 6 months post-transplantation to 18 months post-randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CNI withdrawal, recipients of living-donor kidney allografts, antithymocyte globulin (ATG) induction, calcineurin inhibitors (CNIs)