Implant or Graft; Rejection
Conditions
Keywords
kidney, renal, transplant, belatacept, delayed graft function, thymoglobulin, tacrolimus, kidney function, immunosuppression, NGAL
Brief summary
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
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.
Interventions
DRUGBelatacept
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.
DRUGTacrolimus
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)
DRUGMycophenolate
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)
DRUGrATG
1.5 mg/kg IV daily on Day 0-3. (standard of care)
DRUGMethylprednisolone
500 mg (Day 0), 250mg (Day 1), 125mg (Day 2), 75 mg (Day 3) IV administered from Day 0-3. (standard of care)
PROCEDURERenal transplant
Standard organ transplant of a kidney into a patient with end-stage renal disease.
Sponsors
Columbia University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Delayed Graft Function (DGF) | Up to 3 months post-transplantation | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Allograft Survival | Up to 1 year post-transplantation | Allograft survival is defined as functioning renal transplant. |
| Number of Participants With an Allograft Rejection Episode | Up to 1 year post-transplantation | All rejection episodes will be confirmed by renal transplant biopsy provoked by change in renal function not explained by other clinical causes. |
| Estimated Glomerular Filtration Rate (eGFR) | Up to 1 year post-transplantation | 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. |
Countries
United States
Participant flow
Pre-assignment details
Patients called into the hospital for potential renal transplants were approached for possible participation in the study if they agreed to discuss research and were eligible per study criteria. Patients were given the option to participate or decline.
Participants by arm
| Arm | Count |
|---|---|
| Belatacept Immunosuppression Renal transplant recipients will receive 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.
Belatacept 10 mg/kg will be administered in the operating room \
1 hr prior to kidney allograft reperfusion (Day 0). It will then be administered at 10 mg/kg on the following post-transplantation days: 5, 14, 30, 56, & 84.
Belatacept 5 mg/kg will be administered every four weeks thereafter until end of study.
Standard of Care:
* Mycophenolate: 720 mg by mouth every 12 hours (Day 0)(1080 mg AA).
* rATG: 1.5 mg/kg IV daily on Day 0-3.
* Methylprednisolone: 500 mg (Day 0), 250mg (Day 1), 125mg (Day 2), 75 mg (Day 3) IV administered Day 0-3. | 28 |
| Standard Immunosuppression (Tacrolimus) 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.
Tacrolimus 0.05 mg/kg PO every 12 hrs will be on Day 0 after transplantation. It will then be administered on the following post-transplantation days: 3-90 at 8-12ng/mL; Day 91-180 at 8-10 ng/mL.
Standard of Care:
* Tacrolimus 6 - 8 ng/mL administered daily thereafter until end of study.
* Mycophenolate: 720 mg by mouth every 12 hours (Day 0)(1080 mg AA).
* rATG: 1.5 mg/kg IV daily on Day 0-3.
* Methylprednisolone: 500 mg (Day 0), 250mg (Day 1), 125mg (Day 2), 75 mg (Day 3) IV administered from Day 0-3. | 29 |
| Total | 57 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Case Cancellations | 2 | 4 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Belatacept Immunosuppression | Standard Immunosuppression (Tacrolimus) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 4 Participants | 11 Participants |
| Age, Categorical Between 18 and 65 years | 21 Participants | 25 Participants | 46 Participants |
| Age, Continuous | 57.4 years | 53.8 years | 55.6 years |
| Sex: Female, Male Female | 14 Participants | 25 Participants | 39 Participants |
| Sex: Female, Male Male | 14 Participants | 4 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 24 | 1 / 24 |
| other Total, other adverse events | 5 / 24 | 3 / 24 |
| serious Total, serious adverse events | 14 / 24 | 15 / 24 |
Outcome results
Primary
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.
Time frame: Up to 3 months post-transplantation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Belatacept Immunosuppression | Number of Participants With Delayed Graft Function (DGF) | 12 Participants |
| Standard Immunosuppression (Tacrolimus) | Number of Participants With Delayed Graft Function (DGF) | 15 Participants |
Secondary
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.
Time frame: Up to 1 year post-transplantation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Belatacept Immunosuppression | Estimated Glomerular Filtration Rate (eGFR) | 46 mL/min/1.73m^2 | Standard Deviation 15.85 |
| Standard Immunosuppression (Tacrolimus) | Estimated Glomerular Filtration Rate (eGFR) | 41 mL/min/1.73m^2 | Standard Deviation 11.45 |
Secondary
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.
Time frame: Up to 1 year post-transplantation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Belatacept Immunosuppression | Number of Participants With an Allograft Rejection Episode | 7 Participants |
| Standard Immunosuppression (Tacrolimus) | Number of Participants With an Allograft Rejection Episode | 11 Participants |
Secondary
Percentage of Participants With Allograft Survival
Allograft survival is defined as functioning renal transplant.
Time frame: Up to 1 year post-transplantation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Belatacept Immunosuppression | Percentage of Participants With Allograft Survival | 24 Participants |
| Standard Immunosuppression (Tacrolimus) | Percentage of Participants With Allograft Survival | 21 Participants |