Renal Transplantation
Conditions
Keywords
Renal transplantation, everolimus, calcineurin inhibitors, GFR
Brief summary
The study is designed to evaluate whether the initiation of everolimus together with the reduction or discontinuation of calcineurin inhibitors (CNIs) will improve graft function in the maintenance of renal transplant recipients with renal impairment by reducing the progression of chronic allograft nephropathy. The development of atherosclerosis in the native arteries of the patients will also be explored.
Interventions
DRUGEverolimus (RAD001)
DRUGMycophenolate acid (MPA)/Azathioprine (AZA)
DRUGSteroids
Sponsors
Novartis Pharmaceuticals
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
* Male or female patient at least 18 years of age. * Patient who has undergone a primary or secondary renal transplant 12-96 months ago from a living related or unrelated donor or a cadaveric donor. * Patient receiving cyclosporine microemulsion with a C2-h level ≥ 400 ng/mL or tacrolimus with a C0-h level ≥ 4 ng/mL with or without mycophenolic acid or azathioprine plus or minus steroids. * The immunosuppressive regimen must remain unchanged within the last 3 months. * Patient with renal impairment defined as GFR between 30 and 70 mL/min/1.73 m\^2 by Cockcroft-Gault formula.
Exclusion criteria
* Patient who is recipient of multiple organ transplants. * Patient with protein/creatinine ratio ≥ 150 (mg/mmol). * Patient with a treated acute rejection episode within the last 3 months. * Patient with any past or present BK-polyomavirus nephropathy. * Patient with de novo or recurrent glomerular nephritis. Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Renal Function Assessed by Measured GFR (mGFR) | 24 months | The acceptable methods for GFR measurement were Chromium 51-Ethylenediaminetetra acetic acid (Cr-EDTA), Technetium 99-Diethylenetriaminepentacetic acid (Tc-DTPA), Iohexol clearance Inuline clearance and Iothalamate clearance. The method should have been consistent for a given patient at every time point. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Safety Parameters | 24 months | The selected safety parameters (such as hypertension, hyperlipidemia, diabetes mellitus, anemia, malignancies ) were derived based on adverse events preferred terms defined in the analysis plan. |
Countries
Switzerland
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group A: No RAD Calcineurin Inhibitors (CNI) ± Mycophenolate Acid (MPA)/Azathioprine (AZA) ± Steroids | 123 |
| Group B : CNI Withdrawal Initiation of everolimus (8-12 ng/mL) with discontinuation of CNI. Everolimus (RAD001) 4 mg initial daily dose. | 127 |
| Group C: CNI Reduction Initiation of everolimus (3-8 ng/mL) with reduction by 70-90% in CNI blood levels. Everolimus (RAD001) 3 mg initial daily dose. | 144 |
| Total | 394 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 0 | 3 | 3 |
| Overall Study | Lost to Follow-up | 6 | 3 | 2 |
| Overall Study | Reason Missing | 0 | 1 | 0 |
| Overall Study | Subject withdrew Informed Consent | 5 | 12 | 8 |
Baseline characteristics
| Characteristic | Group C: CNI Reduction | Group A: No RAD | Group B : CNI Withdrawal | Total |
|---|---|---|---|---|
| Age, Continuous | 49.7 years STANDARD_DEVIATION 12.95 | 48.2 years STANDARD_DEVIATION 12.18 | 49.4 years STANDARD_DEVIATION 11.81 | 49.1 years STANDARD_DEVIATION 12.34 |
| Sex: Female, Male Female | 53 Participants | 41 Participants | 41 Participants | 135 Participants |
| Sex: Female, Male Male | 91 Participants | 82 Participants | 86 Participants | 259 Participants |
| Time since transplantation | 5.4 years STANDARD_DEVIATION 3.99 | 5.8 years STANDARD_DEVIATION 4.14 | 5.4 years STANDARD_DEVIATION 4.28 | 5.6 years STANDARD_DEVIATION 4.13 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 97 / 123 | 116 / 127 | 126 / 144 |
| serious Total, serious adverse events | 52 / 123 | 72 / 127 | 78 / 144 |
Outcome results
Primary
Renal Function Assessed by Measured GFR (mGFR)
The acceptable methods for GFR measurement were Chromium 51-Ethylenediaminetetra acetic acid (Cr-EDTA), Technetium 99-Diethylenetriaminepentacetic acid (Tc-DTPA), Iohexol clearance Inuline clearance and Iothalamate clearance. The method should have been consistent for a given patient at every time point.
Time frame: 24 months
Population: The modified ITT population included all ITT patients who had mGFR or calculated GFR (cGFR) at Month 24 based on all values including those collected after discontinuation of study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: No RAD | Renal Function Assessed by Measured GFR (mGFR) | 46.02 mL/min/1.73m^2 | Standard Deviation 20.358 |
| Group B : CNI Withdrawal | Renal Function Assessed by Measured GFR (mGFR) | 48.00 mL/min/1.73m^2 | Standard Deviation 22.033 |
| Group C: CNI Reduction | Renal Function Assessed by Measured GFR (mGFR) | 46.60 mL/min/1.73m^2 | Standard Deviation 21.079 |
p-value: 0.633295% CI: [-3.5077, 5.7559]ANCOVA
p-value: 0.794395% CI: [-3.8815, 5.0682]ANCOVA
Secondary
Number of Participants With Safety Parameters
The selected safety parameters (such as hypertension, hyperlipidemia, diabetes mellitus, anemia, malignancies ) were derived based on adverse events preferred terms defined in the analysis plan.
Time frame: 24 months
Population: Safety Population. The Safety Population consisted of all randomized patients who received at least one dose of study drug and had at least one post-baseline safety assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group A: No RAD | Number of Participants With Safety Parameters | Hypertension, No | 117 Participants |
| Group A: No RAD | Number of Participants With Safety Parameters | Hypertension, Yes | 6 Participants |
| Group A: No RAD | Number of Participants With Safety Parameters | Hyperlipidemia, Yes | 6 Participants |
| Group A: No RAD | Number of Participants With Safety Parameters | Hyperlipidemia, No | 117 Participants |
| Group A: No RAD | Number of Participants With Safety Parameters | Diabetes mellitus, Yes | 4 Participants |
| Group A: No RAD | Number of Participants With Safety Parameters | Diabetes mellitus, No | 119 Participants |
| Group A: No RAD | Number of Participants With Safety Parameters | Anemia, Yes | 25 Participants |
| Group A: No RAD | Number of Participants With Safety Parameters | Anemia, No | 98 Participants |
| Group A: No RAD | Number of Participants With Safety Parameters | Malignancies, Yes | 7 Participants |
| Group A: No RAD | Number of Participants With Safety Parameters | Malignancies, No | 116 Participants |
| Group B : CNI Withdrawal | Number of Participants With Safety Parameters | Malignancies, Yes | 9 Participants |
| Group B : CNI Withdrawal | Number of Participants With Safety Parameters | Diabetes mellitus, No | 121 Participants |
| Group B : CNI Withdrawal | Number of Participants With Safety Parameters | Hypertension, Yes | 13 Participants |
| Group B : CNI Withdrawal | Number of Participants With Safety Parameters | Diabetes mellitus, Yes | 6 Participants |
| Group B : CNI Withdrawal | Number of Participants With Safety Parameters | Hypertension, No | 114 Participants |
| Group B : CNI Withdrawal | Number of Participants With Safety Parameters | Malignancies, No | 118 Participants |
| Group B : CNI Withdrawal | Number of Participants With Safety Parameters | Anemia, No | 82 Participants |
| Group B : CNI Withdrawal | Number of Participants With Safety Parameters | Hyperlipidemia, Yes | 18 Participants |
| Group B : CNI Withdrawal | Number of Participants With Safety Parameters | Anemia, Yes | 45 Participants |
| Group B : CNI Withdrawal | Number of Participants With Safety Parameters | Hyperlipidemia, No | 109 Participants |
| Group C: CNI Reduction | Number of Participants With Safety Parameters | Anemia, No | 98 Participants |
| Group C: CNI Reduction | Number of Participants With Safety Parameters | Hyperlipidemia, No | 133 Participants |
| Group C: CNI Reduction | Number of Participants With Safety Parameters | Diabetes mellitus, Yes | 7 Participants |
| Group C: CNI Reduction | Number of Participants With Safety Parameters | Diabetes mellitus, No | 137 Participants |
| Group C: CNI Reduction | Number of Participants With Safety Parameters | Malignancies, Yes | 11 Participants |
| Group C: CNI Reduction | Number of Participants With Safety Parameters | Anemia, Yes | 46 Participants |
| Group C: CNI Reduction | Number of Participants With Safety Parameters | Malignancies, No | 133 Participants |
| Group C: CNI Reduction | Number of Participants With Safety Parameters | Hypertension, Yes | 9 Participants |
| Group C: CNI Reduction | Number of Participants With Safety Parameters | Hypertension, No | 135 Participants |
| Group C: CNI Reduction | Number of Participants With Safety Parameters | Hyperlipidemia, Yes | 11 Participants |
Post Hoc
Change in mGFR by Baseline Calculated Creatinine Clearance (Cockcroft-Gault Formula)
Cockcroft-Gault formula (CrCl): Creatinine Clearance \[mL/min\] = CrCl (males) = (140 - A) \* W / (72 \* C) (males), CrCl (females) = CrCl (males) \* 0.85, Where: * A is age \[years\] * W is body weight \[kg\] * C is the serum concentration of creatinine \[mg/dL\]
Time frame: Baseline and 24 months
Population: Per Protocol Population. The per-protocol (PP) population consisted of the ITT patients excluding those patients with major protocol deviations and those patients who were not able to initiate their randomized regimens as scheduled.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A: No RAD | Change in mGFR by Baseline Calculated Creatinine Clearance (Cockcroft-Gault Formula) | Baseline CrCl(CG) ≤ 50 :(n= 32, 28, 32):- Change | 1.55 mL/min | Standard Deviation 12.833 |
| Group A: No RAD | Change in mGFR by Baseline Calculated Creatinine Clearance (Cockcroft-Gault Formula) | Baseline CrCl(CG) > 50 : (n=31, 29, 39):-Change | -2.55 mL/min | Standard Deviation 19.562 |
| Group B : CNI Withdrawal | Change in mGFR by Baseline Calculated Creatinine Clearance (Cockcroft-Gault Formula) | Baseline CrCl(CG) ≤ 50 :(n= 32, 28, 32):- Change | -5.75 mL/min | Standard Deviation 14.712 |
| Group B : CNI Withdrawal | Change in mGFR by Baseline Calculated Creatinine Clearance (Cockcroft-Gault Formula) | Baseline CrCl(CG) > 50 : (n=31, 29, 39):-Change | 7.32 mL/min | Standard Deviation 21.051 |
| Group C: CNI Reduction | Change in mGFR by Baseline Calculated Creatinine Clearance (Cockcroft-Gault Formula) | Baseline CrCl(CG) ≤ 50 :(n= 32, 28, 32):- Change | 0.82 mL/min | Standard Deviation 19.445 |
| Group C: CNI Reduction | Change in mGFR by Baseline Calculated Creatinine Clearance (Cockcroft-Gault Formula) | Baseline CrCl(CG) > 50 : (n=31, 29, 39):-Change | -0.24 mL/min | Standard Deviation 17.551 |