End-stage Renal Disease
Conditions
Keywords
Induction, rATG, Calcineurin-inhibitor withdrawal
Brief summary
This 2 x 2 sequential factorial study evaluates two potential improvements to the standard immunosuppression regimen used at the investigators' institution to prevent rejection of transplanted kidneys. These two potential improvements are each applied in sequence to half of the study patients, creating 4 study arms; the other half receive the standard treatment. The two potential improvements are: 1. Administering the immunosuppression induction agent rATG (rabbit anti-thymocyte globulin) in a single dose at the time of transplantation, instead of in the usual series of 4 smaller doses over 6 days. 2. After 6 months, modifying the maintenance immunosuppression used to prevent rejection by replacing the drug tacrolimus with mycophenolate mofetil (MMF). The two interventions, spaced sequentially six months apart, enable independent analysis of the two treatments so long as it can be shown that there is no synergistic interaction between them.
Detailed description
The two treatment innovations in this study of immunosuppression in kidney transplantation are aimed at making the transplanted kidney function sooner and last longer than is usual with standard immunosuppression regimens, but without increasing the likelihood of rejection. The first innovation, delivering the induction agent rATG in a single large dose rather than as a series of smaller doses over 6-8 days, is expected to produce better graft function right away, possibly by reducing some of the injury to the kidney that accompanies the restoration of blood flow during transplantation (reperfusion injury). Some evidence has been developed by investigators elsewhere to suggest this will happen. The second innovation, replacing tacrolimus with MMF after 6 months, is intended to eliminate a well-established major cause of ongoing toxic damage to the kidney. While tacrolimus does a good job of preventing rejection, the cost in continuing toxic injury to the kidney is high, leading inevitably to eventual graft failure, the inability of the transplanted kidney to continue filtering the blood and making adequate volumes of high-quality urine.
Interventions
DRUGrabbit anti-thymocyte globulin - single dose
A single 6 mg/kg dose of rATG administered intravenously over 24 hours, beginning before kidney transplantation. Administration of the drug is begun as early as practical, usually after general anesthesia has been established but before surgery has started. The rATG is therefore administered for about two hours before blood flow is restored to the kidney undergoing transplantation.
DRUGmycophenolate mofetil
Patients are switched approximately 6 months after kidney transplantation from maintenance immunosuppression with tacrolimus and sirolimus to maintenance with mycophenolate mofetil and sirolimus. The drug is administered orally, taken daily, with dose adjusted in proportion to measured blood levels, and is required indefinitely to prevent rejection of the transplanted kidney.
DRUGrabbit anti-thymocyte globulin - 4 doses
6 mg/kg rabbit anti-thymocyte globulin delivered in 4 doses of 1.5 mg/kg each, the first administered at the time of kidney transplantation. Subsequent doses are administered on days 2, 4, and 6.
DRUGsirolimus
Oral maintenance immunosuppressant administered daily, dose adjusted according to measured serum trough levels, continued indefinitely to prevent kidney rejection
DRUGtacrolimus
Oral maintenance immunosuppressant, taken daily, dose adjusted to maintain target blood trough levels, required indefinitely to prevent kidney rejection.
Sponsors
Genzyme, a Sanofi Company
University of Nebraska
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Primary renal transplant recipient for end-stage renal disease
Exclusion criteria
* Recipient age \< 18 years or \> 65 years * Previous history of CMV disease * Hepatitis B and C recipients * Primary disease states that require steroids for immunosuppression * Re-transplant with immunological cause of renal or pancreas loss * Non heart beating donors * Recipient of pediatric en bloc kidneys * Recipient with a Panel Reactive Antibody (PRA) score \>75% * Patients who have received 3 or more prior transplants, excluding pancreas * Patients who are past recipients of other solid organ transplants * Previous history of BK virus * Previous treatment with Thymoglobulin * Allergy to rabbits * Simultaneous Kidney/Pancreas transplantation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Chronic Allograft Nephropathy (Cumulative Calcineurin-inhibitor Nephrotoxicity/Transplant Nephropathy) Per Protocol Surveillance Kidney Biopsies (Banff Grading Criteria). | Two years | Protocol kidney biopsies collected at approximately 12 and 24 months were scored by a transplant renal pathologist blinded to treatment group assignment for evidence of rejection, BK virus nephropathy, antibody-mediated rejection, recurrent disease, inflammation, and Banff 2005 categories of chronic renal injury. Chronic injury categories were arteriolar hyaline thickening (ah), allograft glomerulopathy (cg), interstitial fibrosis (ci), tubular atrophy (ct), and vascular fibrous intimal thickening (cv). Severity scores within each category could be 0 (\<5%; none or minimal), 1 (\>5% - \<25%; mild), 2 (\>25% - \<50%, moderate), or 3 (\>50%, severe). The proportions of patients in each severity grade (0, 1, 2, and 3) for both the individual categories and a composite were compared using Fisher's exact test. |
| Average of Renal Function | Two years | Calculated Glomerular Filtration Rate (GFR) by using the abbreviated MDRD (aMDRD) formula and patient serum creatinine and demographic data; averaged values from months four through 24. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Acute Rejection Per Kidney Biopsy (Banff Grading Criteria) | Two years | — |
| Acute Tubular Necrosis (ATN) Rate, Defined as the Requirement for Dialysis Within 7 Days Post-transplantation. | Seven days | — |
| Graft Survival | Two years | Graft failure = permanent return of patient to dialysis. |
| Patient Survival | Two years | — |
| Safety Profile | Two years | Number of events: cytomegalovirus (CMV) disease, opportunistic infections (bacteremia, abscess, pneumonia, fungal), Post-transplantation Lymphoproliferative Disorder (PTLD), wound healing problems within 30 days, and lymphoceles. |
| New-onset Polyomavirus (BK Virus) Disease Per Kidney Biopsy | Two years | — |
| New-onset Diabetes and Hyperglycemia After Transplantation (NODAT) | Six months | — |
| Ratio of CD4/CD8 Lymphoid Cells | One year | — |
| Lymphoid Cell Sub-type CD3 Absolute Numbers | One year | — |
| Requirement for Additional Immunosuppression (Such as Corticosteroids, Antimetabolites or Other Immunosuppressive Agents) | Two years | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Single Dose rATG (6 mg/kg x 1) and Tacrolimus/Sirolimus Kidney transplant patients receive 6 mg/kg of rATG as a single dose administered intravenously over \<24 hours, beginning before kidney transplantation. Administration of the drug is begun as early as practical, usually after general anesthesia has been established but before surgery has started. The rATG is therefore administered for about two hours before blood flow is restored to the kidney undergoing transplantation. Chronic maintenance immunosuppression is with tacrolimus and sirolimus.
Sirolimus, oral maintenance immunosuppressant administered daily, dose adjusted according to measured serum trough levels, continued indefinitely to prevent kidney rejection
Tacrolimus: Oral maintenance immunosuppressant, taken daily, dose adjusted to maintain target blood trough levels, required indefinitely to prevent kidney rejection. | 44 |
| Divided-dose rATG (1.5mg/kg x 4) and Tacrolimus/Sirolimus Kidney transplant patients receive 6 mg/kg rabbit anti-thymocyte globulin delivered in 4 doses of 1.5 mg/kg each, the first administered at the time of kidney transplantation. Subsequent doses are administered on days 2, 4, and 6. Chronic maintenance immunosuppression is with tacrolimus and sirolimus.
Sirolimus, oral maintenance immunosuppressant administered daily, dose adjusted according to measured serum trough levels, continued indefinitely to prevent kidney rejection
Tacrolimus: Oral maintenance immunosuppressant, taken daily, dose adjusted to maintain target blood trough levels, required indefinitely to prevent kidney rejection. | 44 |
| Single-dose rATG (6mg/kg ) and Sirolimus/Mycophenolate Mofetil Kidney transplant receive the same treatment as in Group 1, until tacrolimus is replaced with mycophenolate mofetil after about 6 months.
Patients are switched approximately 6 months after kidney transplantation from maintenance immunosuppression with tacrolimus and sirolimus to maintenance with mycophenolate mofetil and sirolimus. The drug is administered orally, taken daily, with dose adjusted in proportion to measured blood levels, and is required indefinitely to prevent rejection of the transplanted kidney.
Sirolimus, oral maintenance immunosuppressant administered daily, dose adjusted according to measured serum trough levels, continued indefinitely to prevent kidney rejection
Tacrolimus: Oral maintenance immunosuppressant, taken daily, dose adjusted to maintain target blood trough levels, required indefinitely to prevent kidney rejection. | 45 |
| Divided-dose rATG (6mg/kg ) and Sirolimus/Mycophenolate Mofeti Kidney transplant receive the same treatment as in Group 2, until tacrolimus is replaced with mycophenolate mofetil after about 6 months.
Patients are switched approximately 6 months after kidney transplantation from maintenance immunosuppression with tacrolimus and sirolimus to maintenance with mycophenolate mofetil and sirolimus. The drug is administered orally, taken daily, with dose adjusted in proportion to measured blood levels, and is required indefinitely to prevent rejection of the transplanted kidney.
Sirolimus, oral maintenance immunosuppressant administered daily, dose adjusted according to measured serum trough levels, continued indefinitely to prevent kidney rejection
Tacrolimus: Oral maintenance immunosuppressant, taken daily, dose adjusted to maintain target blood trough levels, required indefinitely to prevent kidney rejection.. | 45 |
| Total | 178 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| CNI Withdrawal vs. Minimization | Death | 0 | 0 | 0 | 1 |
| CNI Withdrawal vs. Minimization | Graft loss | 0 | 1 | 2 | 0 |
| CNI Withdrawal vs. Minimization | Lost to Follow-up | 0 | 1 | 0 | 1 |
| CNI Withdrawal vs. Minimization | Pancreas transplantation | 1 | 1 | 0 | 0 |
| CNI Withdrawal vs. Minimization | Withdrawal by Subject | 0 | 1 | 1 | 0 |
| Single vs. Divided-dose rATG Induction | Death | 0 | 1 | 0 | 0 |
| Single vs. Divided-dose rATG Induction | Kidney graft primary non-function | 0 | 1 | 0 | 0 |
| Single vs. Divided-dose rATG Induction | Lost to Follow-up | 0 | 1 | 0 | 0 |
| Single vs. Divided-dose rATG Induction | Pancreas transplantation | 0 | 2 | 2 | 2 |
| Single vs. Divided-dose rATG Induction | Protocol Violation | 2 | 3 | 3 | 0 |
| Single vs. Divided-dose rATG Induction | Withdrawal by Subject | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Single Dose rATG (6 mg/kg x 1) and Tacrolimus/Sirolimus | Divided-dose rATG (6mg/kg ) and Sirolimus/Mycophenolate Mofeti | Single-dose rATG (6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Divided-dose rATG (1.5mg/kg x 4) and Tacrolimus/Sirolimus |
|---|---|---|---|---|---|
| Adult Cadaver Donor Nyberg Grade | 13.1 units on a scale STANDARD_DEVIATION 7.4 | 10.5 units on a scale STANDARD_DEVIATION 7.5 | 15.4 units on a scale STANDARD_DEVIATION 7.8 | 11.8 units on a scale STANDARD_DEVIATION 6.9 | 14.6 units on a scale STANDARD_DEVIATION 7 |
| Age, Continuous | 47.2 years STANDARD_DEVIATION 11.8 | 45.8 years STANDARD_DEVIATION 12 | 51.6 years STANDARD_DEVIATION 9.7 | 44.1 years STANDARD_DEVIATION 13.2 | 47.1 years STANDARD_DEVIATION 11.2 |
| Deceased-donor Cold Ischemia Time | 14.5 Hours STANDARD_DEVIATION 7.2 | 14.3 Hours STANDARD_DEVIATION 7 | 15.4 Hours STANDARD_DEVIATION 11 | 14.7 Hours STANDARD_DEVIATION 5.7 | 13.7 Hours STANDARD_DEVIATION 4.1 |
| Donor age | 40.9 years STANDARD_DEVIATION 12.7 | 40.4 years STANDARD_DEVIATION 13.1 | 41.2 years STANDARD_DEVIATION 14 | 37.4 years STANDARD_DEVIATION 12.1 | 44.7 years STANDARD_DEVIATION 10 |
| Donor BMI | 27.6 kg/m^2 STANDARD_DEVIATION 4.8 | 27.7 kg/m^2 STANDARD_DEVIATION 5.7 | 28.3 kg/m^2 STANDARD_DEVIATION 5.1 | 27.1 kg/m^2 STANDARD_DEVIATION 4.2 | 27.3 kg/m^2 STANDARD_DEVIATION 4 |
| Donor final serum creatinine | 1.0 mg/dl STANDARD_DEVIATION 0.5 | 1.0 mg/dl STANDARD_DEVIATION 0.3 | 1.0 mg/dl STANDARD_DEVIATION 0.5 | 1.0 mg/dl STANDARD_DEVIATION 0.5 | 1.1 mg/dl STANDARD_DEVIATION 0.6 |
| Donor gender Female | 100 participants | 26 participants | 25 participants | 28 participants | 21 participants |
| Donor gender Male | 78 participants | 18 participants | 20 participants | 17 participants | 23 participants |
| Donor/recipient height ratio | 0.99 ratio STANDARD_DEVIATION 0.1 | 0.98 ratio STANDARD_DEVIATION 0.07 | 1.00 ratio STANDARD_DEVIATION 0.16 | 0.98 ratio STANDARD_DEVIATION 0.16 | 1.00 ratio STANDARD_DEVIATION 0.17 |
| Donor/Recipient High-Risk CMV Serostatus CMV High-risk | 108 participants | 23 participants | 33 participants | 25 participants | 27 participants |
| Donor/Recipient High-Risk CMV Serostatus CMV Low-risk | 70 participants | 21 participants | 12 participants | 20 participants | 17 participants |
| Donor type Deceased donor | 70 participants | 18 participants | 17 participants | 18 participants | 17 participants |
| Donor type Living donor | 108 participants | 26 participants | 28 participants | 27 participants | 27 participants |
| Patient Body Mass Index (BMI) | 28.5 kg/m^2 STANDARD_DEVIATION 5.7 | 28.5 kg/m^2 STANDARD_DEVIATION 5 | 28.9 kg/m^2 STANDARD_DEVIATION 6.9 | 28.8 kg/m^2 STANDARD_DEVIATION 7 | 27.9 kg/m^2 STANDARD_DEVIATION 6.6 |
| Patient Panel Reactive Antibody (PRA)(%) | 1.0 % reactive STANDARD_DEVIATION 5.6 | 0.6 % reactive STANDARD_DEVIATION 2.3 | 1.3 % reactive STANDARD_DEVIATION 7.8 | 1.1 % reactive STANDARD_DEVIATION 6.3 | 1.0 % reactive STANDARD_DEVIATION 4.8 |
| Pediatric vs. Adult Donor Adult donor | 168 participants | 41 participants | 42 participants | 42 participants | 43 participants |
| Pediatric vs. Adult Donor Pediatric donor | 10 participants | 3 participants | 3 participants | 3 participants | 1 participants |
| Race/Ethnicity, Customized Caucasian/Asian | 157 participants | 39 participants | 41 participants | 39 participants | 38 participants |
| Race/Ethnicity, Customized Non Caucasian/Asian | 21 participants | 5 participants | 4 participants | 6 participants | 6 participants |
| Sex: Female, Male Female | 57 Participants | 15 Participants | 17 Participants | 11 Participants | 14 Participants |
| Sex: Female, Male Male | 121 Participants | 29 Participants | 28 Participants | 34 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 12 / 44 | 12 / 44 | 11 / 45 | 8 / 45 |
| serious Total, serious adverse events | 9 / 44 | 15 / 44 | 18 / 45 | 21 / 45 |
Outcome results
Primary
Average of Renal Function
Calculated Glomerular Filtration Rate (GFR) by using the abbreviated MDRD (aMDRD) formula and patient serum creatinine and demographic data; averaged values from months four through 24.
Time frame: Two years
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Single Dose rATG (6 mg/kg x 1) and Tacrolimus/Sirolimus | Average of Renal Function | Average GFR, months 16-18 | 57.6 ml/min/1.73m2 | Standard Deviation 20.9 |
| Single Dose rATG (6 mg/kg x 1) and Tacrolimus/Sirolimus | Average of Renal Function | Average GFR, months 19-21 | 56.6 ml/min/1.73m2 | Standard Deviation 20 |
| Single Dose rATG (6 mg/kg x 1) and Tacrolimus/Sirolimus | Average of Renal Function | Average GFR, months 13-15 | 56.8 ml/min/1.73m2 | Standard Deviation 19.2 |
| Single Dose rATG (6 mg/kg x 1) and Tacrolimus/Sirolimus | Average of Renal Function | Average GFR, months 4-6 | 57.3 ml/min/1.73m2 | Standard Deviation 17.6 |
| Single Dose rATG (6 mg/kg x 1) and Tacrolimus/Sirolimus | Average of Renal Function | Average GFR, months 22-24 | 56.9 ml/min/1.73m2 | Standard Deviation 21.9 |
| Single Dose rATG (6 mg/kg x 1) and Tacrolimus/Sirolimus | Average of Renal Function | Average GFR, months 7-9 | 54.8 ml/min/1.73m2 | Standard Deviation 16.5 |
| Single Dose rATG (6 mg/kg x 1) and Tacrolimus/Sirolimus | Average of Renal Function | Average GFR, months 10-12 | 55.8 ml/min/1.73m2 | Standard Deviation 16.6 |
| Single Dose rATG (6 mg/kg x 1) and Tacrolimus/Sirolimus | Average of Renal Function | Average GFR, months 1-3 | 50.4 ml/min/1.73m2 | Standard Deviation 16 |
| Divided-dose rATG (1.5mg/kg x 4) and Tacrolimus/Sirolimus | Average of Renal Function | Average GFR, months 4-6 | 57.3 ml/min/1.73m2 | Standard Deviation 12.5 |
| Divided-dose rATG (1.5mg/kg x 4) and Tacrolimus/Sirolimus | Average of Renal Function | Average GFR, months 22-24 | 57.0 ml/min/1.73m2 | Standard Deviation 16.2 |
| Divided-dose rATG (1.5mg/kg x 4) and Tacrolimus/Sirolimus | Average of Renal Function | Average GFR, months 16-18 | 56.3 ml/min/1.73m2 | Standard Deviation 14.8 |
| Divided-dose rATG (1.5mg/kg x 4) and Tacrolimus/Sirolimus | Average of Renal Function | Average GFR, months 1-3 | 50.1 ml/min/1.73m2 | Standard Deviation 12.5 |
| Divided-dose rATG (1.5mg/kg x 4) and Tacrolimus/Sirolimus | Average of Renal Function | Average GFR, months 19-21 | 54.8 ml/min/1.73m2 | Standard Deviation 17.3 |
| Divided-dose rATG (1.5mg/kg x 4) and Tacrolimus/Sirolimus | Average of Renal Function | Average GFR, months 13-15 | 57.3 ml/min/1.73m2 | Standard Deviation 14.3 |
| Divided-dose rATG (1.5mg/kg x 4) and Tacrolimus/Sirolimus | Average of Renal Function | Average GFR, months 7-9 | 55.0 ml/min/1.73m2 | Standard Deviation 11.8 |
| Divided-dose rATG (1.5mg/kg x 4) and Tacrolimus/Sirolimus | Average of Renal Function | Average GFR, months 10-12 | 55.6 ml/min/1.73m2 | Standard Deviation 12.1 |
| Single-dose rATG (6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Average of Renal Function | Average GFR, months 16-18 | 62.3 ml/min/1.73m2 | Standard Deviation 17.6 |
| Single-dose rATG (6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Average of Renal Function | Average GFR, months 7-9 | 61.0 ml/min/1.73m2 | Standard Deviation 15.8 |
| Single-dose rATG (6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Average of Renal Function | Average GFR, months 1-3 | 53.6 ml/min/1.73m2 | Standard Deviation 14.4 |
| Single-dose rATG (6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Average of Renal Function | Average GFR, months 22-24 | 62.9 ml/min/1.73m2 | Standard Deviation 18.6 |
| Single-dose rATG (6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Average of Renal Function | Average GFR, months 13-15 | 61.8 ml/min/1.73m2 | Standard Deviation 15.4 |
| Single-dose rATG (6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Average of Renal Function | Average GFR, months 10-12 | 57.4 ml/min/1.73m2 | Standard Deviation 16.7 |
| Single-dose rATG (6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Average of Renal Function | Average GFR, months 19-21 | 60.2 ml/min/1.73m2 | Standard Deviation 14.7 |
| Single-dose rATG (6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Average of Renal Function | Average GFR, months 4-6 | 60.2 ml/min/1.73m2 | Standard Deviation 15.6 |
| Divided-dose rATG(6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Average of Renal Function | Average GFR, months 22-24 | 57.6 ml/min/1.73m2 | Standard Deviation 17.7 |
| Divided-dose rATG(6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Average of Renal Function | Average GFR, months 19-21 | 56.8 ml/min/1.73m2 | Standard Deviation 18.9 |
| Divided-dose rATG(6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Average of Renal Function | Average GFR, months 1-3 | 50.4 ml/min/1.73m2 | Standard Deviation 17 |
| Divided-dose rATG(6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Average of Renal Function | Average GFR, months 4-6 | 54.8 ml/min/1.73m2 | Standard Deviation 13.2 |
| Divided-dose rATG(6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Average of Renal Function | Average GFR, months 7-9 | 55.8 ml/min/1.73m2 | Standard Deviation 13.2 |
| Divided-dose rATG(6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Average of Renal Function | Average GFR, months 10-12 | 56.6 ml/min/1.73m2 | Standard Deviation 14.4 |
| Divided-dose rATG(6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Average of Renal Function | Average GFR, months 13-15 | 58.5 ml/min/1.73m2 | Standard Deviation 16.6 |
| Divided-dose rATG(6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Average of Renal Function | Average GFR, months 16-18 | 56.6 ml/min/1.73m2 | Standard Deviation 18.4 |
p-value: 0.45General Linear Model
Primary
Chronic Allograft Nephropathy (Cumulative Calcineurin-inhibitor Nephrotoxicity/Transplant Nephropathy) Per Protocol Surveillance Kidney Biopsies (Banff Grading Criteria).
Protocol kidney biopsies collected at approximately 12 and 24 months were scored by a transplant renal pathologist blinded to treatment group assignment for evidence of rejection, BK virus nephropathy, antibody-mediated rejection, recurrent disease, inflammation, and Banff 2005 categories of chronic renal injury. Chronic injury categories were arteriolar hyaline thickening (ah), allograft glomerulopathy (cg), interstitial fibrosis (ci), tubular atrophy (ct), and vascular fibrous intimal thickening (cv). Severity scores within each category could be 0 (\<5%; none or minimal), 1 (\>5% - \<25%; mild), 2 (\>25% - \<50%, moderate), or 3 (\>50%, severe). The proportions of patients in each severity grade (0, 1, 2, and 3) for both the individual categories and a composite were compared using Fisher's exact test.
Time frame: Two years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Single Dose rATG (6 mg/kg x 1) and Tacrolimus/Sirolimus | Chronic Allograft Nephropathy (Cumulative Calcineurin-inhibitor Nephrotoxicity/Transplant Nephropathy) Per Protocol Surveillance Kidney Biopsies (Banff Grading Criteria). | Banff histopathology cumulative grade = 0 | 43 percentage of participants |
| Single Dose rATG (6 mg/kg x 1) and Tacrolimus/Sirolimus | Chronic Allograft Nephropathy (Cumulative Calcineurin-inhibitor Nephrotoxicity/Transplant Nephropathy) Per Protocol Surveillance Kidney Biopsies (Banff Grading Criteria). | Banff histopathology cumulative grade = 1 | 37 percentage of participants |
| Single Dose rATG (6 mg/kg x 1) and Tacrolimus/Sirolimus | Chronic Allograft Nephropathy (Cumulative Calcineurin-inhibitor Nephrotoxicity/Transplant Nephropathy) Per Protocol Surveillance Kidney Biopsies (Banff Grading Criteria). | Banff histopathology cumulative grade = 2 | 16 percentage of participants |
| Single Dose rATG (6 mg/kg x 1) and Tacrolimus/Sirolimus | Chronic Allograft Nephropathy (Cumulative Calcineurin-inhibitor Nephrotoxicity/Transplant Nephropathy) Per Protocol Surveillance Kidney Biopsies (Banff Grading Criteria). | Banff histopathology cumulative grade = 3 | 4 percentage of participants |
| Divided-dose rATG (1.5mg/kg x 4) and Tacrolimus/Sirolimus | Chronic Allograft Nephropathy (Cumulative Calcineurin-inhibitor Nephrotoxicity/Transplant Nephropathy) Per Protocol Surveillance Kidney Biopsies (Banff Grading Criteria). | Banff histopathology cumulative grade = 1 | 46 percentage of participants |
| Divided-dose rATG (1.5mg/kg x 4) and Tacrolimus/Sirolimus | Chronic Allograft Nephropathy (Cumulative Calcineurin-inhibitor Nephrotoxicity/Transplant Nephropathy) Per Protocol Surveillance Kidney Biopsies (Banff Grading Criteria). | Banff histopathology cumulative grade = 2 | 9 percentage of participants |
| Divided-dose rATG (1.5mg/kg x 4) and Tacrolimus/Sirolimus | Chronic Allograft Nephropathy (Cumulative Calcineurin-inhibitor Nephrotoxicity/Transplant Nephropathy) Per Protocol Surveillance Kidney Biopsies (Banff Grading Criteria). | Banff histopathology cumulative grade = 3 | 6 percentage of participants |
| Divided-dose rATG (1.5mg/kg x 4) and Tacrolimus/Sirolimus | Chronic Allograft Nephropathy (Cumulative Calcineurin-inhibitor Nephrotoxicity/Transplant Nephropathy) Per Protocol Surveillance Kidney Biopsies (Banff Grading Criteria). | Banff histopathology cumulative grade = 0 | 40 percentage of participants |
| Single-dose rATG (6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Chronic Allograft Nephropathy (Cumulative Calcineurin-inhibitor Nephrotoxicity/Transplant Nephropathy) Per Protocol Surveillance Kidney Biopsies (Banff Grading Criteria). | Banff histopathology cumulative grade = 2 | 2 percentage of participants |
| Single-dose rATG (6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Chronic Allograft Nephropathy (Cumulative Calcineurin-inhibitor Nephrotoxicity/Transplant Nephropathy) Per Protocol Surveillance Kidney Biopsies (Banff Grading Criteria). | Banff histopathology cumulative grade = 1 | 45 percentage of participants |
| Single-dose rATG (6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Chronic Allograft Nephropathy (Cumulative Calcineurin-inhibitor Nephrotoxicity/Transplant Nephropathy) Per Protocol Surveillance Kidney Biopsies (Banff Grading Criteria). | Banff histopathology cumulative grade = 3 | 0 percentage of participants |
| Single-dose rATG (6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Chronic Allograft Nephropathy (Cumulative Calcineurin-inhibitor Nephrotoxicity/Transplant Nephropathy) Per Protocol Surveillance Kidney Biopsies (Banff Grading Criteria). | Banff histopathology cumulative grade = 0 | 53 percentage of participants |
| Divided-dose rATG(6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Chronic Allograft Nephropathy (Cumulative Calcineurin-inhibitor Nephrotoxicity/Transplant Nephropathy) Per Protocol Surveillance Kidney Biopsies (Banff Grading Criteria). | Banff histopathology cumulative grade = 3 | 1 percentage of participants |
| Divided-dose rATG(6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Chronic Allograft Nephropathy (Cumulative Calcineurin-inhibitor Nephrotoxicity/Transplant Nephropathy) Per Protocol Surveillance Kidney Biopsies (Banff Grading Criteria). | Banff histopathology cumulative grade = 1 | 41 percentage of participants |
| Divided-dose rATG(6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Chronic Allograft Nephropathy (Cumulative Calcineurin-inhibitor Nephrotoxicity/Transplant Nephropathy) Per Protocol Surveillance Kidney Biopsies (Banff Grading Criteria). | Banff histopathology cumulative grade = 0 | 51 percentage of participants |
| Divided-dose rATG(6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Chronic Allograft Nephropathy (Cumulative Calcineurin-inhibitor Nephrotoxicity/Transplant Nephropathy) Per Protocol Surveillance Kidney Biopsies (Banff Grading Criteria). | Banff histopathology cumulative grade = 2 | 7 percentage of participants |
p-value: 0.0004Chi-squared
Secondary
Acute Rejection Per Kidney Biopsy (Banff Grading Criteria)
Time frame: Two years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Dose rATG (6 mg/kg x 1) and Tacrolimus/Sirolimus | Acute Rejection Per Kidney Biopsy (Banff Grading Criteria) | 7 participants |
| Divided-dose rATG (1.5mg/kg x 4) and Tacrolimus/Sirolimus | Acute Rejection Per Kidney Biopsy (Banff Grading Criteria) | 4 participants |
| Single-dose rATG (6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Acute Rejection Per Kidney Biopsy (Banff Grading Criteria) | 8 participants |
| Divided-dose rATG(6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Acute Rejection Per Kidney Biopsy (Banff Grading Criteria) | 9 participants |
p-value: 0.67Kaplan-Meier
Secondary
Acute Tubular Necrosis (ATN) Rate, Defined as the Requirement for Dialysis Within 7 Days Post-transplantation.
Time frame: Seven days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Dose rATG (6 mg/kg x 1) and Tacrolimus/Sirolimus | Acute Tubular Necrosis (ATN) Rate, Defined as the Requirement for Dialysis Within 7 Days Post-transplantation. | 3 participants |
| Divided-dose rATG (1.5mg/kg x 4) and Tacrolimus/Sirolimus | Acute Tubular Necrosis (ATN) Rate, Defined as the Requirement for Dialysis Within 7 Days Post-transplantation. | 1 participants |
| Single-dose rATG (6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Acute Tubular Necrosis (ATN) Rate, Defined as the Requirement for Dialysis Within 7 Days Post-transplantation. | 6 participants |
| Divided-dose rATG(6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Acute Tubular Necrosis (ATN) Rate, Defined as the Requirement for Dialysis Within 7 Days Post-transplantation. | 2 participants |
p-value: 0.193Fisher Exact
Secondary
Graft Survival
Graft failure = permanent return of patient to dialysis.
Time frame: Two years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Dose rATG (6 mg/kg x 1) and Tacrolimus/Sirolimus | Graft Survival | 0 participants |
| Divided-dose rATG (1.5mg/kg x 4) and Tacrolimus/Sirolimus | Graft Survival | 1 participants |
| Single-dose rATG (6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Graft Survival | 2 participants |
| Divided-dose rATG(6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Graft Survival | 0 participants |
p-value: 0.422Fisher Exact
Secondary
Lymphoid Cell Sub-type CD3 Absolute Numbers
Time frame: One year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Single Dose rATG (6 mg/kg x 1) and Tacrolimus/Sirolimus | Lymphoid Cell Sub-type CD3 Absolute Numbers | 446 CD3 Cell Numbers/mm^3 | Standard Deviation 403 |
| Divided-dose rATG (1.5mg/kg x 4) and Tacrolimus/Sirolimus | Lymphoid Cell Sub-type CD3 Absolute Numbers | 375 CD3 Cell Numbers/mm^3 | Standard Deviation 564 |
| Single-dose rATG (6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Lymphoid Cell Sub-type CD3 Absolute Numbers | 392 CD3 Cell Numbers/mm^3 | Standard Deviation 319 |
| Divided-dose rATG(6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Lymphoid Cell Sub-type CD3 Absolute Numbers | 266 CD3 Cell Numbers/mm^3 | Standard Deviation 211 |
p-value: 0.068Kruskal-Wallis
Secondary
New-onset Diabetes and Hyperglycemia After Transplantation (NODAT)
Time frame: Six months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Dose rATG (6 mg/kg x 1) and Tacrolimus/Sirolimus | New-onset Diabetes and Hyperglycemia After Transplantation (NODAT) | 10 participants |
| Divided-dose rATG (1.5mg/kg x 4) and Tacrolimus/Sirolimus | New-onset Diabetes and Hyperglycemia After Transplantation (NODAT) | 7 participants |
| Single-dose rATG (6mg/kg ) and Sirolimus/Mycophenolate Mofetil | New-onset Diabetes and Hyperglycemia After Transplantation (NODAT) | 5 participants |
| Divided-dose rATG(6mg/kg ) and Sirolimus/Mycophenolate Mofetil | New-onset Diabetes and Hyperglycemia After Transplantation (NODAT) | 12 participants |
p-value: 0.21Fisher Exact
Secondary
New-onset Polyomavirus (BK Virus) Disease Per Kidney Biopsy
Time frame: Two years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Dose rATG (6 mg/kg x 1) and Tacrolimus/Sirolimus | New-onset Polyomavirus (BK Virus) Disease Per Kidney Biopsy | 1 participants |
| Divided-dose rATG (1.5mg/kg x 4) and Tacrolimus/Sirolimus | New-onset Polyomavirus (BK Virus) Disease Per Kidney Biopsy | 2 participants |
| Single-dose rATG (6mg/kg ) and Sirolimus/Mycophenolate Mofetil | New-onset Polyomavirus (BK Virus) Disease Per Kidney Biopsy | 0 participants |
| Divided-dose rATG(6mg/kg ) and Sirolimus/Mycophenolate Mofetil | New-onset Polyomavirus (BK Virus) Disease Per Kidney Biopsy | 2 participants |
p-value: 0.67Fisher Exact
Secondary
Patient Survival
Time frame: Two years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Dose rATG (6 mg/kg x 1) and Tacrolimus/Sirolimus | Patient Survival | 0 participants |
| Divided-dose rATG (1.5mg/kg x 4) and Tacrolimus/Sirolimus | Patient Survival | 1 participants |
| Single-dose rATG (6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Patient Survival | 0 participants |
| Divided-dose rATG(6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Patient Survival | 1 participants |
p-value: 0.871Fisher Exact
Secondary
Ratio of CD4/CD8 Lymphoid Cells
Time frame: One year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Single Dose rATG (6 mg/kg x 1) and Tacrolimus/Sirolimus | Ratio of CD4/CD8 Lymphoid Cells | 0.84 Ratio of cell counts | Standard Deviation 0.55 |
| Divided-dose rATG (1.5mg/kg x 4) and Tacrolimus/Sirolimus | Ratio of CD4/CD8 Lymphoid Cells | 0.84 Ratio of cell counts | Standard Deviation 0.41 |
| Single-dose rATG (6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Ratio of CD4/CD8 Lymphoid Cells | 0.98 Ratio of cell counts | Standard Deviation 0.53 |
| Divided-dose rATG(6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Ratio of CD4/CD8 Lymphoid Cells | 1.01 Ratio of cell counts | Standard Deviation 0.57 |
p-value: 0.4Kruskal-Wallis
Secondary
Requirement for Additional Immunosuppression (Such as Corticosteroids, Antimetabolites or Other Immunosuppressive Agents)
Time frame: Two years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Dose rATG (6 mg/kg x 1) and Tacrolimus/Sirolimus | Requirement for Additional Immunosuppression (Such as Corticosteroids, Antimetabolites or Other Immunosuppressive Agents) | 7 participants |
| Divided-dose rATG (1.5mg/kg x 4) and Tacrolimus/Sirolimus | Requirement for Additional Immunosuppression (Such as Corticosteroids, Antimetabolites or Other Immunosuppressive Agents) | 5 participants |
| Single-dose rATG (6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Requirement for Additional Immunosuppression (Such as Corticosteroids, Antimetabolites or Other Immunosuppressive Agents) | 6 participants |
| Divided-dose rATG(6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Requirement for Additional Immunosuppression (Such as Corticosteroids, Antimetabolites or Other Immunosuppressive Agents) | 11 participants |
p-value: 0.463Fisher Exact
Secondary
Safety Profile
Number of events: cytomegalovirus (CMV) disease, opportunistic infections (bacteremia, abscess, pneumonia, fungal), Post-transplantation Lymphoproliferative Disorder (PTLD), wound healing problems within 30 days, and lymphoceles.
Time frame: Two years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Dose rATG (6 mg/kg x 1) and Tacrolimus/Sirolimus | Safety Profile | 11 Events |
| Divided-dose rATG (1.5mg/kg x 4) and Tacrolimus/Sirolimus | Safety Profile | 14 Events |
| Single-dose rATG (6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Safety Profile | 10 Events |
| Divided-dose rATG(6mg/kg ) and Sirolimus/Mycophenolate Mofetil | Safety Profile | 17 Events |
p-value: 0.53Fisher Exact