Organ Transplantation, Renal Transplantation
Conditions
Keywords
Renal transplantation,, everolimus,, immunosuppressants,, basiliximab,, cyclosporine microemulsion discontinuation, cyclosporine microemulsion minimization
Brief summary
The purpose of this study is to evaluate the safety and efficacy of everolimus in combination with basiliximab, and steroids with and without cyclosporine microemulsion in de novo kidney transplant recipients.
Detailed description
This is a combined analysis using 81 patients randomized and treated in CRAD001A2419 (NCT00154284) with 33 randomized and treated in CRAD001A2423 (NCT00170807). This approach is reflected in the protocol amendments for each study, and the one clinical study report for both.
Interventions
DRUGSteroid
Each patient was administered i.v. prednisone (or equivalent) pre- or intra-operatively according to center practice.
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Recipients of a first renal transplant from a primary cadaveric or non-HLA identical living related donor. * Renal cold ischemic time \< 36 hours. * Age of donor \< 65 years.
Exclusion criteria
* Patients who have received an investigational drug within 4 weeks of baseline period. * Patients who are recipients of multiple organ transplants, including any organ other than kidney. * Recipients of non-heart beating donor organs. Other protocol-defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Renal Function Measured by Calculated Glomerular Filtration Rate (GFR Calculated According to the Nankivell Formula) | At Month 3 and Month 12 | Nankivell's formula for calculated GFR is shown below: GFR \[mL/min\] = 6.7/C + W/4 - UREA/2 - 100/H2+ 35 (25 for females). Where W is body weight at specific visit \[kg\], H is height at specific visit \[m\], C is the serum concentration of creatinine \[mmol/L\], and UREA is the serum concentration of urea \[mmol/L\]. UREA was calculated from blood urea nitrogen (BUN) lab data by: UREA = 2.1441\*BUN. If a GFR value from Nankivell formula was less than 10 \[mL/min\], then the value was assigned as 10 \[mL/min\]. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Biopsy-proven Acute Rejection (BPAR) Episodes, Graft Loss, Death or Loss to Follow-up | Month 12 | Renal biopsies were collected for all cases of suspected acute rejection. For these cases, regardless of initiation of anti-rejection treatment, a graft core biopsy had been performed within 48 hours. These biopsies were listed on the Kidney Allograft Biopsy eCRF and the results used for patient management for BPAR. 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. BPAR, graft loss, death, or loss to follow-up was analyzed by means of frequency tables. |
| Serum Creatinine at Month 6 and 12 | 6 month and 12 months | serum creatinine summarized by mean and standard deviation |
| Calculated Creatinine Clearance at 6 Month and 12 Month | 6 month and 12 months | Creatinine clearance calculated by Cockcroft-Gault formula and summarized by mean, and standard deviation. Cockcroft-Gault formula to calculate Creatinine Clearance (CrCl\[mL/min\]) is shown below: CrCl\[mL/min\] = (140 - A) \* W / (72 \* C) \* R. Where A is age at sample date \[years\], W is body weight at specific visit \[kg\], C is the serum concentration of creatinine \[mg/dL\], R = 1 if the patient is male and = 0.85 if female. |
Participant flow
Recruitment details
Subjects were recruited from Spain from July 2005 to July 2008. As per protocol amendment, data were analyzed together with data from study CRAD001A2423 (NCT00154284) and CRAD001A2423 (NCT00170807).
Participants by arm
| Arm | Count |
|---|---|
| Everolimus (Certican) With Cyclosporine (Neoral) Continuation Patients were treated with everolimus and cyclosporine for 3 months post-transplantation. Everolimus (Certican) was administered orally, in two divided doses (b.i.d), and at the same time as Cyclosporine (Neoral). Everolimus (Certican) dose was adjusted in order to maintain a trough level between 3 and 8 ng/mL until randomization. After randomization the target trough range remained at 3 - 8 ng/mL in the cyclosporine (Neoral) continuation groups for a period of 9 months. Each patient was administered i.v. prednisone (or equivalent) pre- or intra-operatively according to center practice. | 59 |
| Everolimus (Certican) With Cyclosporine (Neoral) Withdrawal Patients were treated with everolimus and cyclosporine for 3 months post-transplantation. Everolimus (Certican) was administered orally, in two divided doses (b.i.d), and at the same time as Cyclosporine (Neoral). Everolimus (Certican) dose was adjusted in order to maintain a trough level between 3 and 8 ng/mL until randomization. Therefore, patients were randomized to cyclosporine withdrawal over a period of 1 month (±1 week) in study A2419 (NCT00154284) and over 3 months (±1 week) in study A2423 (NCT00170807). After randomization, final target trough range for everolimus was 8 - 12 ng/mL. Each patient was administered i.v. prednisone (or equivalent) pre- or intra-operatively according to center practice. | 55 |
| Total | 114 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal laboratory value(s) | 0 | 1 |
| Overall Study | Adverse Event | 6 | 9 |
| Overall Study | Lack of Efficacy | 1 | 2 |
| Overall Study | Protocol Violation | 0 | 1 |
Baseline characteristics
| Characteristic | Everolimus (Certican) With Cyclosporine (Neoral) Continuation | Everolimus (Certican) With Cyclosporine (Neoral) Withdrawal | Total |
|---|---|---|---|
| Age, Continuous | 45.7 years STANDARD_DEVIATION 11.62 | 41.5 years STANDARD_DEVIATION 12.27 | 43.6 years STANDARD_DEVIATION 12.07 |
| Sex: Female, Male Female | 18 Participants | 20 Participants | 38 Participants |
| Sex: Female, Male Male | 41 Participants | 35 Participants | 76 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 38 / 55 | 35 / 59 |
| serious Total, serious adverse events | 16 / 55 | 14 / 59 |
Outcome results
Primary
Renal Function Measured by Calculated Glomerular Filtration Rate (GFR Calculated According to the Nankivell Formula)
Nankivell's formula for calculated GFR is shown below: GFR \[mL/min\] = 6.7/C + W/4 - UREA/2 - 100/H2+ 35 (25 for females). Where W is body weight at specific visit \[kg\], H is height at specific visit \[m\], C is the serum concentration of creatinine \[mmol/L\], and UREA is the serum concentration of urea \[mmol/L\]. UREA was calculated from blood urea nitrogen (BUN) lab data by: UREA = 2.1441\*BUN. If a GFR value from Nankivell formula was less than 10 \[mL/min\], then the value was assigned as 10 \[mL/min\].
Time frame: At Month 3 and Month 12
Population: Intention to treat (ITT) population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Everolimus (Certican) With Cyclosporine (Neoral) Continuation | Renal Function Measured by Calculated Glomerular Filtration Rate (GFR Calculated According to the Nankivell Formula) | GFR at 3 months (Pre-randomization) | 68.5 mL/min per 1.73 m^2 | Standard Deviation 19.92 |
| Everolimus (Certican) With Cyclosporine (Neoral) Continuation | Renal Function Measured by Calculated Glomerular Filtration Rate (GFR Calculated According to the Nankivell Formula) | GFR at 12 months | 63.6 mL/min per 1.73 m^2 | Standard Deviation 14.61 |
| Everolimus (Certican) With Cyclosporine (Neoral) Withdrawal | Renal Function Measured by Calculated Glomerular Filtration Rate (GFR Calculated According to the Nankivell Formula) | GFR at 3 months (Pre-randomization) | 69.2 mL/min per 1.73 m^2 | Standard Deviation 18.4 |
| Everolimus (Certican) With Cyclosporine (Neoral) Withdrawal | Renal Function Measured by Calculated Glomerular Filtration Rate (GFR Calculated According to the Nankivell Formula) | GFR at 12 months | 68.3 mL/min per 1.73 m^2 | Standard Deviation 15.13 |
Secondary
Calculated Creatinine Clearance at 6 Month and 12 Month
Creatinine clearance calculated by Cockcroft-Gault formula and summarized by mean, and standard deviation. Cockcroft-Gault formula to calculate Creatinine Clearance (CrCl\[mL/min\]) is shown below: CrCl\[mL/min\] = (140 - A) \* W / (72 \* C) \* R. Where A is age at sample date \[years\], W is body weight at specific visit \[kg\], C is the serum concentration of creatinine \[mg/dL\], R = 1 if the patient is male and = 0.85 if female.
Time frame: 6 month and 12 months
Population: Intention to treat (ITT) population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Everolimus (Certican) With Cyclosporine (Neoral) Continuation | Calculated Creatinine Clearance at 6 Month and 12 Month | 6 Month | 72.9 mL/min | Standard Deviation 19.34 |
| Everolimus (Certican) With Cyclosporine (Neoral) Continuation | Calculated Creatinine Clearance at 6 Month and 12 Month | 12 Month | 72.3 mL/min | Standard Deviation 20.5 |
| Everolimus (Certican) With Cyclosporine (Neoral) Withdrawal | Calculated Creatinine Clearance at 6 Month and 12 Month | 6 Month | 63.6 mL/min | Standard Deviation 19.65 |
| Everolimus (Certican) With Cyclosporine (Neoral) Withdrawal | Calculated Creatinine Clearance at 6 Month and 12 Month | 12 Month | 65.6 mL/min | Standard Deviation 19.24 |
Secondary
Number of Participants With Biopsy-proven Acute Rejection (BPAR) Episodes, Graft Loss, Death or Loss to Follow-up
Renal biopsies were collected for all cases of suspected acute rejection. For these cases, regardless of initiation of anti-rejection treatment, a graft core biopsy had been performed within 48 hours. These biopsies were listed on the Kidney Allograft Biopsy eCRF and the results used for patient management for BPAR. 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. BPAR, graft loss, death, or loss to follow-up was analyzed by means of frequency tables.
Time frame: Month 12
Population: Intention to treat (ITT) population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Everolimus (Certican) With Cyclosporine (Neoral) Continuation | Number of Participants With Biopsy-proven Acute Rejection (BPAR) Episodes, Graft Loss, Death or Loss to Follow-up | Biopsy-proven Acute Rejection (BPAR) | 10 Participants |
| Everolimus (Certican) With Cyclosporine (Neoral) Continuation | Number of Participants With Biopsy-proven Acute Rejection (BPAR) Episodes, Graft Loss, Death or Loss to Follow-up | Death | 0 Participants |
| Everolimus (Certican) With Cyclosporine (Neoral) Continuation | Number of Participants With Biopsy-proven Acute Rejection (BPAR) Episodes, Graft Loss, Death or Loss to Follow-up | Loss to Follow-up | 0 Participants |
| Everolimus (Certican) With Cyclosporine (Neoral) Continuation | Number of Participants With Biopsy-proven Acute Rejection (BPAR) Episodes, Graft Loss, Death or Loss to Follow-up | Graft Loss | 0 Participants |
| Everolimus (Certican) With Cyclosporine (Neoral) Withdrawal | Number of Participants With Biopsy-proven Acute Rejection (BPAR) Episodes, Graft Loss, Death or Loss to Follow-up | Loss to Follow-up | 0 Participants |
| Everolimus (Certican) With Cyclosporine (Neoral) Withdrawal | Number of Participants With Biopsy-proven Acute Rejection (BPAR) Episodes, Graft Loss, Death or Loss to Follow-up | Biopsy-proven Acute Rejection (BPAR) | 10 Participants |
| Everolimus (Certican) With Cyclosporine (Neoral) Withdrawal | Number of Participants With Biopsy-proven Acute Rejection (BPAR) Episodes, Graft Loss, Death or Loss to Follow-up | Graft Loss | 0 Participants |
| Everolimus (Certican) With Cyclosporine (Neoral) Withdrawal | Number of Participants With Biopsy-proven Acute Rejection (BPAR) Episodes, Graft Loss, Death or Loss to Follow-up | Death | 0 Participants |
Secondary
Serum Creatinine at Month 6 and 12
serum creatinine summarized by mean and standard deviation
Time frame: 6 month and 12 months
Population: Intention to treat (ITT) population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Everolimus (Certican) With Cyclosporine (Neoral) Continuation | Serum Creatinine at Month 6 and 12 | 6 Month | 120.1 µmol/L | Standard Deviation 31.22 |
| Everolimus (Certican) With Cyclosporine (Neoral) Continuation | Serum Creatinine at Month 6 and 12 | 12 Month | 123.0 µmol/L | Standard Deviation 40.28 |
| Everolimus (Certican) With Cyclosporine (Neoral) Withdrawal | Serum Creatinine at Month 6 and 12 | 6 Month | 139.1 µmol/L | Standard Deviation 47.03 |
| Everolimus (Certican) With Cyclosporine (Neoral) Withdrawal | Serum Creatinine at Month 6 and 12 | 12 Month | 135.6 µmol/L | Standard Deviation 40.61 |