Belatacept Compared to Tacrolimus in Deceased Donor Renal Transplant Recipients

Study Overview
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Brief Summary
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The main purpose of this study is to ﬁnd out whether treatment to prevent kidney rejection with belatacept in presence of Thymoglobulin induction and withdrawal of steroids will result in less delayed graft function or sleepy kidney after transplant than that seen in patients who get tacrolimus as their main drug to prevent rejection instead of belatacept. The investigators will also look at whether patients who get belatacept have the same, lesser or more problems that those who get tacrolimus.

Detailed Description
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New York Presbyterian Hospital-Columbia University Medical Center (NYPH-CUMC) performs nearly 250 renal transplants annually; of these approximately half are recipients of a variety of deceased donor kidneys, usually with cold ischemia time (CIT) >24 hours leading to an approximate incidence of delayed graft function (DGF) of 50%. The main focus of this study will be to determine whether initial immunosuppression with belatacept with Thymoglobulin induction will result in lower incidence and/or more rapid disappearance of DGF than that observed in patients who receive tacrolimus based immunosuppression. NGAL determinations will bne made in the first months after transplantation to correlate with clinical DGF.

Official Title
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A Randomized Clinical Trial of Efficacy and Safety on the Use of Belatacept as Compared to Tacrolimus in the Setting of Rabbit Antithymocyte Globulin Induction and Rapid Steroid Discontinuation in Deceased Donor Renal Transplant Recipients With a Focus on Ameliorating Delayed Graft Function

Conditions
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Implant or Graft; Rejection

Intervention / Treatment
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* Drug: Belatacept
* Drug: Tacrolimus
* Drug: Mycophenolate
* Drug: rATG
* Drug: Methylprednisolone
* Procedure: Renal transplant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have known Epstein-Barr virus (EBV) serostatus, and that status must be positive Adult patients ≥18 years of age, receiving a deceased donor kidney transplant at Columbia University Medical Center (CUMC) Patients with a PRA ≤ of 50 Primary or re-transplant candidates (no more than 5th renal transplant) Deceased donor renal transplant recipients Candidates eligible for rATG induction Patients fully consented prior to transplantation Women of reproductive age who are willing to delay pregnancy for the duration of the study and use appropriate recommended contraception Exclusion Criteria: Seronegative or unknown EBV serologic status (due to the risk of post-transplant lymphoproliferative disorder, PTLD), predominantly involving the central nervous system. Patients with tuberculosis who have not been treated for latent infection. Scheduled to undergo multi-organ transplantation Recipients of previous non-renal organ transplant Patient receiving 5th renal transplant at the time of screening. Patients with a PRA > 50 Recipient is pre-emptive status. Recipient with positive flow crossmatch. History or known HIV Known hypersensitivity or contra-indications to Belatacept, Tacrolimus, Mycophenolate mofetil (cellcept), or mycophenolic acid Use of an investigational drug in the past 30 days before day of surgery Enrolled in a clinical trial other than the current Lactating or pregnant women Donor specific antibodies (DSA) identified at the time of transplantation ABO incompatible renal transplant

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: Belatacept Immunosuppression<br>Renal transplant recipients will receive steroids (Methylprednisolone), rATG, Belatacept and Mycophenolate. Subjects will be followed for primary endpoint to Day 7 and Month 3 after transplantation and secondary endpoints of kidney function and patient and graft survival up to month 36 after transplantation. | Drug: Belatacept<br>* Belatacept 10 mg/kg will be administered in the operating room approximately 1 hour prior to kidney allograft reperfusion (Day 0). It will then be administered at 10 mg/kg on the following post-transplantation days: Day 5, 14, 30, 56, and 84. Belatacept 5 mg/kg will be administered every four weeks thereafter until end of study.<br>* Other names: Nulojix;Drug: Mycophenolate<br>* An immunosuppressive agent used with other medicines to lower the body's natural immunity in patients who receive kidney transplants. 720 mg by mouth every 12 hours (Day 0)(1080 mg AA). (standard of care)<br>* Other names: Myfortic;Drug: rATG<br>* 1.5 mg/kg IV daily on Day 0-3. (standard of care)<br>* Other names: induction with rabbit anti-thymocyte globulin;Drug: Methylprednisolone<br>* 500 mg (Day 0), 250mg (Day 1), 125mg (Day 2), 75 mg (Day 3) IV administered from Day 0-3. (standard of care)<br>* Other names: Medrol;Procedure: Renal transplant<br>* Standard organ transplant of a kidney into a patient with end-stage renal disease.<br>* Other names: Kidney transplant;|
| Active Comparator: Standard Immunosuppression (Tacrolimus)<br>Renal transplant recipients will receive standard immunosuppressive therapy, including steroids (Methylprednisolone), rATG, Tacrolimus and Mycophenolate. Subjects will be followed for primary endpoint to Day 7 and Month 3 after transplantation and secondary endpoints of kidney function and patient and graft survival up to month 36 after transplantation. | Drug: Tacrolimus<br>* Tacrolimus 0.05 mg/kg by mouth every 12 hours will be on Day 0 after transplantation. It will then be administered at 8-12 ng/mL on the following post-transplantation days: Day 3-90; at 8-10 ng/mL Day 91-180. Tacrolimus 6 - 8 ng/mL will be administered daily thereafter until end of study. (standard of care)<br>* Other names: Prograf;Drug: Mycophenolate<br>* An immunosuppressive agent used with other medicines to lower the body's natural immunity in patients who receive kidney transplants. 720 mg by mouth every 12 hours (Day 0)(1080 mg AA). (standard of care)<br>* Other names: Myfortic;Drug: rATG<br>* 1.5 mg/kg IV daily on Day 0-3. (standard of care)<br>* Other names: induction with rabbit anti-thymocyte globulin;Drug: Methylprednisolone<br>* 500 mg (Day 0), 250mg (Day 1), 125mg (Day 2), 75 mg (Day 3) IV administered from Day 0-3. (standard of care)<br>* Other names: Medrol;Procedure: Renal transplant<br>* Standard organ transplant of a kidney into a patient with end-stage renal disease.<br>* Other names: Kidney transplant;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Delayed Graft Function (DGF) | To assess whether treatment with Thymoglobulin induction and belatacept based maintenance immunosuppression would reduce delayed graft function (DGF) rates among recipients of deceased donor renal transplants as measured by clinical findings and NGAL marker, as specified below and defined by others. This will be compared to the incidence of DGF in patients treated with a Tacrolimus based regimen. Patients who require hemodialysis in the first 7 days after transplantation and/or patients whose serum creatinine decreases <10% during 3 consecutive days after the transplant will be considered to have DGF in the absence of other confounding factors such as obstruction or infection. NGAL will be used as a verification marker of DGF. | Up to 3 months post-transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Allograft Survival | Allograft survival is defined as functioning renal transplant. | Up to 1 year post-transplantation | 
| Number of Participants With an Allograft Rejection Episode | All rejection episodes will be confirmed by renal transplant biopsy provoked by change in renal function not explained by other clinical causes. | Up to 1 year post-transplantation | 
| Estimated Glomerular Filtration Rate (eGFR) | Estimated glomerular filtration rate (eGFR) is based on a blood sample (serum creatinine value), age, race, and gender. eGFR estimates best the function of the kidney at any one time. | Up to 1 year post-transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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kidney, renal, transplant, belatacept, delayed graft function, thymoglobulin, tacrolimus, kidney function, immunosuppression, NGAL