Kidney Transplantation, Graft Rejection
Conditions
Keywords
Renal transplantation, kidney, and organ transplant, Renal transplant rejection
Brief summary
The purpose of this study was to compare the safety and efficacy of three immunosuppressive treatment regimens following a kidney transplant.
Interventions
DRUGEverolimus
oral, bis in diem/twice a day (bid)
2 oral capsules of mycophenolic acid 360mg administered bid
CsA dose adjustments were based on CsA trough levels (C0).
DRUGBasiliximab
All patients received two 20 mg doses of basiliximab administered intravenously. The first dose was to be given within 2 hours prior to transplant surgery and the second dose was to be administered on day 4, or each dose could have been administered according to local practice.
DRUGCorticosteroids
Oral corticosteroids were administered according to local practice during the trial. At the same center, all patients were to follow the same steroid administration protocol.
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Male and female patients of any race between 18 to 70 years old (inclusive) * Patients who gave written informed consent to participate in the study
Exclusion criteria
* Recipients of multi-organ transplantation * Recipients of a primary cadaveric or primary non-human leucocyte antigen (HLA) identical living donor kidney transplantation. * Graft cold ischemia time greater than 40 hours. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Composite Efficacy Endpoints - 12 Month Analysis | 12 months | The primary efficacy endpoint was the 12 month analysis of primary efficacy failure defined as a composite endpoint including treated biopsy proven acute rejection (BPAR), graft loss, death or loss to follow-up. A treated BPAR episode was defined as a biopsy graded IA, IB, IIA, IIB, or III that was treated with anti-rejection therapy. Graft loss was defined as the allograft was presumed to be lost on the day the patient started dialysis and was not able to subsequently be removed from dialysis as well as re-transplant. |
| Non-inferiority Analysis on Percentage of Participants With Composite Efficacy Endpoints | 12 months | The primary efficacy endpoint was the 12 month analysis of primary efficacy failure defined as a composite endpoint including treated biopsy proven acute rejection (BPAR), graft loss, death or loss to follow-up. In the definition of composite efficacy failure, loss to follow-up includes patients who did not experience treated BPAR, graft loss or death on or after day 1 and whose last day of contact was prior to day 316, the start day of the 12 month visit window. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Non-inferiority Analysis of Renal Function, Calculated by Glomerular Filtration Rate (cGFR) Using Modification of Diet in Renal Disease (MDRD) Formula | at 12 months | Modification of Diet in Renal Disease (MDRD) formula is: GFR \[mL/min/1.73m\^2\] = 186.3\*(C\^-1.154)\*(A\^-0.203)\*G\*R where * C is the serum concentration of creatinine \[mg/dL\], * A is patient age at sample collection date \[years\], * G=0.742 when gender is female, otherwise G=1, * R=1.21 when race is black, otherwise R=1 |
| Percentage of Participants With the Composite Incidence of Graft Loss, Death or Loss to Follow up at 12 Months Post-transplantation | 12 months | Graft loss was defined as graft loss (the allograft was presumed to be lost on the day the patient started dialysis and was not able to subsequently be removed from dialysis) and re-transplant. A loss to follow-up patient in the composite endpoint of graft loss, death or loss to follow-up (the main secondary efficacy endpoint) was a patient who did not experience graft loss or death from day 1 and whose last day of contact was prior to study day 316. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Low-dose Everolimus Group 1.5 mg everolimus (one 0.75-mg tablet bis in diem/twice a day (bid)) + basiliximab + reduced-dose Cyclosporine A (CsA) ± corticosteroids.
The CsA dose was adjusted to attain a trough (C0) value within the pre-specified target ranges: starting at the day 5 visit: 100-200 ng/mL, starting at the month 2 visit: 75-150 ng/mL, starting at the month 4 visit: 50-100 ng/mL and starting at the month 6 visit: 25-50 ng/mL. Patients received their first dose of basiliximab within 2 hours prior to transplant surgery and on day 4 post-transplant or according to local practice. Corticosteroids were administered according to local therapy. | 277 |
| High-dose Everolimus Group 3.0 mg everolimus (two 0.75-mg tablets bid) + basiliximab + reduced-dose CsA ± corticosteroids.
The CsA dose was adjusted to attain a trough (C0) value within the pre-specified target ranges: starting at the day 5 visit: 100-200 ng/mL, starting at the month 2 visit: 75-150 ng/mL, starting at the month 4 visit: 50-100 ng/mL and starting at the month 6 visit: 25-50 ng/mL. Patients received their first dose of basiliximab within 2 hours prior to transplant surgery and on day 4 post-transplant or according to local practice. Corticosteroids were administered according to local therapy. | 279 |
| Control Group 1.44 g Mycophenolic Acid (MPA) (two 360-mg tablets bid) + basiliximab + standard-dose CsA ± corticosteroids.
The CsA dose was adjusted to attain a C0 value within the following range for the time of the study: starting at the day 5 visit: 200-300 ng/mL, starting at the month 2 visit and thereafter: 100-250 ng/mL. Patients received their first dose of basiliximab within 2 hours prior to transplant surgery and on day 4 post-transplant or according to local practice. Corticosteroids were administered according to local therapy. | 277 |
| Total | 833 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 9 | 10 | 8 |
| Overall Study | Graft Loss | 12 | 13 | 8 |
| Overall Study | Lost to Follow-up | 1 | 2 | 1 |
| Overall Study | Withdrawal by Subject | 23 | 16 | 14 |
Baseline characteristics
| Characteristic | Low-dose Everolimus Group | High-dose Everolimus Group | Control Group | Total |
|---|---|---|---|---|
| Age Continuous | 45.7 Years STANDARD_DEVIATION 12.72 | 45.3 Years STANDARD_DEVIATION 13.36 | 47.2 Years STANDARD_DEVIATION 12.74 | 46.1 Years STANDARD_DEVIATION 12.95 |
| Sex: Female, Male Female | 100 Participants | 88 Participants | 88 Participants | 276 Participants |
| Sex: Female, Male Male | 177 Participants | 191 Participants | 189 Participants | 557 Participants |
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 | 268 / 274 | 272 / 278 | 264 / 273 |
| serious Total, serious adverse events | 176 / 274 | 193 / 278 | 168 / 273 |
Outcome results
Primary
Non-inferiority Analysis on Percentage of Participants With Composite Efficacy Endpoints
The primary efficacy endpoint was the 12 month analysis of primary efficacy failure defined as a composite endpoint including treated biopsy proven acute rejection (BPAR), graft loss, death or loss to follow-up. In the definition of composite efficacy failure, loss to follow-up includes patients who did not experience treated BPAR, graft loss or death on or after day 1 and whose last day of contact was prior to day 316, the start day of the 12 month visit window.
Time frame: 12 months
Population: Intention-to-treat population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low-dose Everolimus Group | Non-inferiority Analysis on Percentage of Participants With Composite Efficacy Endpoints | 27.1 Percentage of Participants |
| High-dose Everolimus Group | Non-inferiority Analysis on Percentage of Participants With Composite Efficacy Endpoints | 21.5 Percentage of Participants |
| Control Group | Non-inferiority Analysis on Percentage of Participants With Composite Efficacy Endpoints | 25.3 Percentage of Participants |
Comparison: Everolimus is non-inferior to mycophenolic acid (MPA) if the upper limit of the 95% confidence interval for the difference in percentage of participants composite efficacy failure is \<10%.p-value: 0.01495% CI: [-5.5, 9.1]Z - test
Comparison: Everolimus is non-inferior to MPA if the upper limit of the 95% confidence interval for the difference in composite efficacy failure rates is \<10%.p-value: <0.00195% CI: [-10.8, 3.3]Z-test
Primary
Number of Participants With Composite Efficacy Endpoints - 12 Month Analysis
The primary efficacy endpoint was the 12 month analysis of primary efficacy failure defined as a composite endpoint including treated biopsy proven acute rejection (BPAR), graft loss, death or loss to follow-up. A treated BPAR episode was defined as a biopsy graded IA, IB, IIA, IIB, or III that was treated with anti-rejection therapy. Graft loss was defined as the allograft was presumed to be lost on the day the patient started dialysis and was not able to subsequently be removed from dialysis as well as re-transplant.
Time frame: 12 months
Population: Intention-to-treat (ITT) population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Low-dose Everolimus Group | Number of Participants With Composite Efficacy Endpoints - 12 Month Analysis | --Treated BPAR | 48 Participants |
| Low-dose Everolimus Group | Number of Participants With Composite Efficacy Endpoints - 12 Month Analysis | --Graft Loss | 13 Participants |
| Low-dose Everolimus Group | Number of Participants With Composite Efficacy Endpoints - 12 Month Analysis | Composite Endpoint (n) | 75 Participants |
| Low-dose Everolimus Group | Number of Participants With Composite Efficacy Endpoints - 12 Month Analysis | --Death | 8 Participants |
| Low-dose Everolimus Group | Number of Participants With Composite Efficacy Endpoints - 12 Month Analysis | --Lost to follow up | 12 Participants |
| High-dose Everolimus Group | Number of Participants With Composite Efficacy Endpoints - 12 Month Analysis | --Graft Loss | 13 Participants |
| High-dose Everolimus Group | Number of Participants With Composite Efficacy Endpoints - 12 Month Analysis | Composite Endpoint (n) | 60 Participants |
| High-dose Everolimus Group | Number of Participants With Composite Efficacy Endpoints - 12 Month Analysis | --Death | 9 Participants |
| High-dose Everolimus Group | Number of Participants With Composite Efficacy Endpoints - 12 Month Analysis | --Treated BPAR | 38 Participants |
| High-dose Everolimus Group | Number of Participants With Composite Efficacy Endpoints - 12 Month Analysis | --Lost to follow up | 6 Participants |
| Control Group | Number of Participants With Composite Efficacy Endpoints - 12 Month Analysis | --Lost to follow up | 9 Participants |
| Control Group | Number of Participants With Composite Efficacy Endpoints - 12 Month Analysis | --Treated BPAR | 50 Participants |
| Control Group | Number of Participants With Composite Efficacy Endpoints - 12 Month Analysis | Composite Endpoint (n) | 70 Participants |
| Control Group | Number of Participants With Composite Efficacy Endpoints - 12 Month Analysis | --Graft Loss | 9 Participants |
| Control Group | Number of Participants With Composite Efficacy Endpoints - 12 Month Analysis | --Death | 6 Participants |
Secondary
Non-inferiority Analysis of Renal Function, Calculated by Glomerular Filtration Rate (cGFR) Using Modification of Diet in Renal Disease (MDRD) Formula
Modification of Diet in Renal Disease (MDRD) formula is: GFR \[mL/min/1.73m\^2\] = 186.3\*(C\^-1.154)\*(A\^-0.203)\*G\*R where * C is the serum concentration of creatinine \[mg/dL\], * A is patient age at sample collection date \[years\], * G=0.742 when gender is female, otherwise G=1, * R=1.21 when race is black, otherwise R=1
Time frame: at 12 months
Population: Intention to treat (ITT) population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low-dose Everolimus Group | Non-inferiority Analysis of Renal Function, Calculated by Glomerular Filtration Rate (cGFR) Using Modification of Diet in Renal Disease (MDRD) Formula | 54.66 mL/min/1.73m^2 |
| High-dose Everolimus Group | Non-inferiority Analysis of Renal Function, Calculated by Glomerular Filtration Rate (cGFR) Using Modification of Diet in Renal Disease (MDRD) Formula | 51.41 mL/min/1.73m^2 |
| Control Group | Non-inferiority Analysis of Renal Function, Calculated by Glomerular Filtration Rate (cGFR) Using Modification of Diet in Renal Disease (MDRD) Formula | 52.24 mL/min/1.73m^2 |
Comparison: The null hypothesis: the mean GFR of the everolimus arm is lower (worse) than that of the MPA arm by 8 mL/min/1.73m\^2 or more.p-value: <0.00195% CI: [-1.6, 6.5]t-test, 2 sided
Comparison: The null hypothesis: the mean GFR of the everolimus arm is lower (worse) than that of the MPA arm by 8 mL/min/1.73m\^2 or more.p-value: <0.00195% CI: [-4.9, 3.3]t-test, 2 sided
Secondary
Percentage of Participants With the Composite Incidence of Graft Loss, Death or Loss to Follow up at 12 Months Post-transplantation
Graft loss was defined as graft loss (the allograft was presumed to be lost on the day the patient started dialysis and was not able to subsequently be removed from dialysis) and re-transplant. A loss to follow-up patient in the composite endpoint of graft loss, death or loss to follow-up (the main secondary efficacy endpoint) was a patient who did not experience graft loss or death from day 1 and whose last day of contact was prior to study day 316.
Time frame: 12 months
Population: Intention-to-treat (ITT) population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low-dose Everolimus Group | Percentage of Participants With the Composite Incidence of Graft Loss, Death or Loss to Follow up at 12 Months Post-transplantation | 11.6 Percentage of participants |
| High-dose Everolimus Group | Percentage of Participants With the Composite Incidence of Graft Loss, Death or Loss to Follow up at 12 Months Post-transplantation | 9.7 Percentage of participants |
| Control Group | Percentage of Participants With the Composite Incidence of Graft Loss, Death or Loss to Follow up at 12 Months Post-transplantation | 9.4 Percentage of participants |
Comparison: Everolimus is non-inferior to mycophenolic acid (MPA) if the upper limit of the 95% confidence interval for the difference in combined graft loss, death or loss to follow-up rates is \<10%.p-value: 0.00195% CI: [-2.9, 7.3]Z-test
Comparison: Everolimus is non-inferior to MPA if the upper limit of the 95% confidence interval for the difference in combined graft loss, death or loss to follow-up rates is \<10%.p-value: <0.00195% CI: [-4.6, 5.2]Z-test