de Novo Kidney Transplant Recipients, Renal Transplantation
Conditions
Keywords
Immunosuppression, renal transplantation, once-a-day regimen, steroid withdrawal, drug minimization, immunosuppression for prevention of acute rejections
Brief summary
This study will compare the following immunosuppressive regimens in recipients of kidney transplantation: A) everolimus, cyclosporine and steroids given once-a-day; B) everolimus and cyclosporine given twice a day with steroid withdrawal; C) everolimus, cyclosporine given twice a day and continuous steroids. The purpose of this study is to evaluate regimens A and B in comparison with the control group (group C) for efficacy, using as main endpoint the treatment failure rate, a composite endpoint including death, graft loss, BPAR and lost to follow-up between randomization and Month 12.
Interventions
DRUGeverolimus
Everolimus (Certican®) was provided in blisters containing tablets of 0.25 mg and 0.75 mg. Everolimus was initiated within 48 hours after graft reperfusion and it was administered orally.
DRUGcyclosporine
Cyclosporine for microemulsion (CsA, Sandimmun® Neoral®) was coadministered with everolimus at the same time of the day. CsA was available in alu-alu blisters containing soft gelatine capsules of 100 mg, 50 mg, 25 mg and 10 mg. Oral solution, as bottles containing 50 mL of solution (100 mg/mL) has been provided and used in case the drug had been administered to patients by nasogastric tube immediately after transplant.
DRUGPrednison (continuous steroids)
continuous steroids
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* recipients of 1st or 2nd single kidney transplant * donor age \>14 years * females capable of becoming pregnant must have a negative serum pregnancy test within 7 days prior to or at Baseline (Visit 2), and are required to practice an approved method of birth control for the duration of the study and for a period of 2 months following discontinuation of study medication * patientswho are willing and able to participate in the study and from whom written informed consent has been obtained
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Failure Rate | Between randomization (Month 3) and Month 12 | Occurrence or not of treatment failure in each patient. Treatment failure was defined as a composite endpoint of biopsy-proven acute rejection (a biopsy graded IA, IB, IIA, IIB or III according to Banff '97 grading with 2007 update), graft loss, death or lost to follow-up occurring after randomization (V5) and within M12 (V9). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in the Estimated Glomerular Filtration Rate (eGFR) Between Randomization (Month 3) and Month 12 | Month 3 to Month 12 | eGFR by Nankivell, in terms of descriptive statistics and change vs randomization visit - to compare the changes in the estimated GFR (Nankivell) between randomization and Month 12 in the steroid withdrawal group (Group B) to the change observed in the standard twice-a-day group (Group C), for non-inferiority |
| Biopsy Proven Acute Rejection (BPAR) Rate Between Randomization and Month 12 | Month 3 to Month 12 | Occurrence of BPAR (after randomization) between arm B (steroid withdrawal group) and arm c (standard twice-a-day group). BPAR was defined as a biopsy graded IA, IB, IIA, IIB, or III according to Banff 1997 grading with 2007 update. |
| Number of Participants With Graft and Patient Survival After Randomization | Month 3 to Month 12 | Graft Survival, calculated from the date of transplantation to the date of irreversible graft failure signified by return to long-term retransplantation or the date of the last follow-up during the period when the transplant was still functioning or to the date of death. Patient survival, calculated from the date of transplantation to the date of death or the date of the last follow-up. |
| Change in Estimated Creatine Clearance | M3, M12 | At each visit, estimated creatinine clearance was measured in the local laboratory to analyze the evolution of the renal function. The following indirect measures of renal function were computed: estimated creatinine clearance according to Cockcroft and Gault formula and MDRD formula. |
| Change in Serum Creatinine | M3, M12 | Serum creatinine (a blood measurement) is an important indicator of renal health because it is an easily-measured by-product of muscle metabolism. Measuring serum creatinine is a simple test and it is the most commonly used indicator of renal function. |
Countries
Italy
Participant flow
Recruitment details
A total of 332 patients were screened. 330 were pre-randomized, 2 were not. Additionally, 2 pts were not treated which made the safety/ITT population 328. Of the 328, 184 were randomized and 144 were not. Of the 144, 70 dropped before day 90 & 74 completed the pre-rand period but were not randomized because they were not eligible for randomization.
Pre-assignment details
During the Pre-randomization Period all patients received the same treatments. At V5 eligible patients were randomized 1:1:1 to one of the treatment arms and entered the Randomized Treatment Period. After Amendment 1 approval, randomization to once-a-day regimen group was stopped and patients were randomized 1:1 to Group B or Group C.
Participants by arm
| Arm | Count |
|---|---|
| Not Randomized Population (NRP) At the Baseline visit, performed up to 48 hours after graft reperfusion, eligible patients entered the Pre-Randomization Period and started study drug treatment (D1 = 1st day of everolimus treatment).
Not-randomization Patients (NRP) was defined in whom a renal transplantation was performed, received at least one dose of study drug (everolimus) but who did not qualify for randomization at Visit 5, Day 90. This group was addressed as not randomized patients (NRP) | 144 |
| Group A - Once-a-day Regimen Change in study design (Amendment 1) stopped the randomization into Group A (once-a-day regimen), due to overall slow enrollment rate and shifted all relative objectives from primary/secondary to exploratory, due to small sample size.
Everolimus: in patients randomized to Group A before Amend 1 approval, from the day following randomization, the whole daily dose of everolimus was taken in the morning, at the same time of the CsA and steroid dosing. At the Rand+1W visit, the everolimus dose was adjusted to reach and maintain everolimus blood levels between 5 and 8 ng/mL until end of Month 12.
Cyclosporine: in patients randomized to Group A before Amend 1 approval, from the day following randomization, the whole cyclosporine daily dose was taken in the morning. The dose was then adjusted to maintain C2 levels between 350 and 700 ng/mL.
Prednisone: In patients randomized to Group A before Amend 1 approval, the dose of prednisone was kept stable at 5 mg/day in the morning. | 45 |
| Group B - Steroid Withdrawal Group Everolimus: after randomization the everolimus dose was adjusted, if necessary, to maintain a C0 within 6-10 ng/mL until M12.
Cyclosporine: after randomization the cyclosporine dose was adjusted to maintain CsA C2 levels within 300-500 ng/mL until M12.
Prednisone: starting from Visit 5 (day 90 ± 28 days), oral prednisone was tapered until complete stop. It was recommended to taper prednisone by 1 mg/week until complete stop in 5 to 6 weeks. | 68 |
| Group C - Standard Twice-a-day Group Everolimus: after randomization the everolimus dose was adjusted, if necessary, in order to maintain a C0 within 6-10 ng/mL until M12.
Cyclosporine: after randomization the cyclosporine dose was gradually adjusted to reach and maintain C2 blood levels of 200-450 ng/mL between Month 6 and Month 12.
Prednisone: the dose of prednisone was kept stable at 5 mg/day in the morning. | 71 |
| Total | 328 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Pre-randomization Period (Day 1 to 90) | Did not meet inclusion criteria | 144 | 0 | 0 | 0 |
| Randomized Period (Day 90 to Month 12) | Administrative Problems | 0 | 1 | 6 | 2 |
| Randomized Period (Day 90 to Month 12) | Graft Loss | 0 | 1 | 0 | 0 |
| Randomized Period (Day 90 to Month 12) | Lost to Follow-up | 0 | 1 | 1 | 0 |
| Randomized Period (Day 90 to Month 12) | Withdrawal by Subject | 0 | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Total | Group C - Standard Twice-a-day Group | Group B - Steroid Withdrawal Group | Group A - Once-a-day Regimen | Not Randomized Population (NRP) |
|---|---|---|---|---|---|
| Age, Continuous | 50.3 years STANDARD_DEVIATION 12.3 | 49.2 years STANDARD_DEVIATION 13 | 48.5 years STANDARD_DEVIATION 11.6 | 46.6 years STANDARD_DEVIATION 13.7 | 52.9 years STANDARD_DEVIATION 11.5 |
| BMI | 24.4 kg/m^2 STANDARD_DEVIATION 3.4 | 24.2 kg/m^2 STANDARD_DEVIATION 3.6 | 24.1 kg/m^2 STANDARD_DEVIATION 3.3 | 24.9 kg/m^2 STANDARD_DEVIATION 3.6 | 24.6 kg/m^2 STANDARD_DEVIATION 3.4 |
| Female reproductive status Childbearing potential with contraceptive protecti | 35 Participants | 4 Participants | 12 Participants | 8 Participants | 11 Participants |
| Female reproductive status Postmenopausal | 74 Participants | 16 Participants | 8 Participants | 7 Participants | 43 Participants |
| Female reproductive status Surgically sterilised | 4 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Black | 4 Participants | 1 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Caucasian | 318 Participants | 67 Participants | 68 Participants | 44 Participants | 139 Participants |
| Race/Ethnicity, Customized Oriental | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 3 Participants | 0 Participants | 0 Participants | 1 Participants |
| Result of HCG pregnancy screen - Negative Missing | 81 Participants | 16 Participants | 10 Participants | 9 Participants | 46 Participants |
| Result of HCG pregnancy screen - Negative Negative | 32 Participants | 4 Participants | 12 Participants | 6 Participants | 10 Participants |
| Sex: Female, Male Female | 113 Participants | 20 Participants | 22 Participants | 15 Participants | 56 Participants |
| Sex: Female, Male Male | 215 Participants | 51 Participants | 46 Participants | 30 Participants | 88 Participants |
| Smoking Status Missing | 32 Participants | 13 Participants | 8 Participants | 2 Participants | 9 Participants |
| Smoking Status No | 274 Participants | 56 Participants | 58 Participants | 41 Participants | 119 Participants |
| Smoking Status Yes | 22 Participants | 2 Participants | 2 Participants | 2 Participants | 16 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 | 108 / 144 | 35 / 45 | 56 / 68 | 57 / 71 |
| serious Total, serious adverse events | 65 / 144 | 18 / 45 | 24 / 68 | 25 / 71 |
Outcome results
Primary
Treatment Failure Rate
Occurrence or not of treatment failure in each patient. Treatment failure was defined as a composite endpoint of biopsy-proven acute rejection (a biopsy graded IA, IB, IIA, IIB or III according to Banff '97 grading with 2007 update), graft loss, death or lost to follow-up occurring after randomization (V5) and within M12 (V9).
Time frame: Between randomization (Month 3) and Month 12
Population: ITT population: all randomized pts who received at least one dose of study drug after Visit 5 \& have at least one post-baseline assessment of the primary efficacy variable. Change in study design stopped the randomization into Group A, due to overall slow enrollment rate \& shifted all relative objectives to exploratory, due to small sample size.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A - Once-a-day Regimen | Treatment Failure Rate | 3 Participants |
| Group B - Steroid Withdrawal Group | Treatment Failure Rate | 10 Participants |
| Group C - Standard Twice-a-day Group | Treatment Failure Rate | 2 Participants |
Secondary
Biopsy Proven Acute Rejection (BPAR) Rate Between Randomization and Month 12
Occurrence of BPAR (after randomization) between arm B (steroid withdrawal group) and arm c (standard twice-a-day group). BPAR was defined as a biopsy graded IA, IB, IIA, IIB, or III according to Banff 1997 grading with 2007 update.
Time frame: Month 3 to Month 12
Population: ITT population, defined as all randomized patients who received at least one dose of study drug after Visit 5 (Day 90) and have at least one post-baseline assessment of the primary efficacy variable (i.e. treatment failure).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A - Once-a-day Regimen | Biopsy Proven Acute Rejection (BPAR) Rate Between Randomization and Month 12 | 9 Participants |
| Group B - Steroid Withdrawal Group | Biopsy Proven Acute Rejection (BPAR) Rate Between Randomization and Month 12 | 2 Participants |
Secondary
Change in Estimated Creatine Clearance
At each visit, estimated creatinine clearance was measured in the local laboratory to analyze the evolution of the renal function. The following indirect measures of renal function were computed: estimated creatinine clearance according to Cockcroft and Gault formula and MDRD formula.
Time frame: M3, M12
Population: ITT population, defined as all randomized patients who received at least one dose of study drug after Visit 5 (Day 90) and have at least one post-baseline assessment of the primary efficacy variable (i.e. treatment failure).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A - Once-a-day Regimen | Change in Estimated Creatine Clearance | Using Cockcroft and Gault model @ month 3 | 64.8 mL/min | Standard Deviation 21.8 |
| Group A - Once-a-day Regimen | Change in Estimated Creatine Clearance | Using Cockcroft and Gault model @ month 12 | 62.3 mL/min | Standard Deviation 21.4 |
| Group A - Once-a-day Regimen | Change in Estimated Creatine Clearance | Using MDRD-4 formular @ month 3 | 57.9 mL/min | Standard Deviation 20 |
| Group A - Once-a-day Regimen | Change in Estimated Creatine Clearance | Using MDRD-4 formular @ month 12 | 53.6 mL/min | Standard Deviation 18.9 |
| Group B - Steroid Withdrawal Group | Change in Estimated Creatine Clearance | Using MDRD-4 formular @ month 12 | 61.8 mL/min | Standard Deviation 23.1 |
| Group B - Steroid Withdrawal Group | Change in Estimated Creatine Clearance | Using Cockcroft and Gault model @ month 3 | 63.0 mL/min | Standard Deviation 20.9 |
| Group B - Steroid Withdrawal Group | Change in Estimated Creatine Clearance | Using MDRD-4 formular @ month 3 | 58.8 mL/min | Standard Deviation 21.8 |
| Group B - Steroid Withdrawal Group | Change in Estimated Creatine Clearance | Using Cockcroft and Gault model @ month 12 | 66.9 mL/min | Standard Deviation 24.7 |
Secondary
Change in Serum Creatinine
Serum creatinine (a blood measurement) is an important indicator of renal health because it is an easily-measured by-product of muscle metabolism. Measuring serum creatinine is a simple test and it is the most commonly used indicator of renal function.
Time frame: M3, M12
Population: ITT population, defined as all randomized patients who received at least one dose of study drug after Visit 5 (Day 90) and have at least one post-baseline assessment of the primary efficacy variable (i.e. treatment failure).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A - Once-a-day Regimen | Change in Serum Creatinine | Serum Creatinine @ month 3 | 1.4 mg/dL | Standard Deviation 0.4 |
| Group A - Once-a-day Regimen | Change in Serum Creatinine | Serum Creatinine @ month 12 | 1.5 mg/dL | Standard Deviation 0.5 |
| Group B - Steroid Withdrawal Group | Change in Serum Creatinine | Serum Creatinine @ month 3 | 1.4 mg/dL | Standard Deviation 0.4 |
| Group B - Steroid Withdrawal Group | Change in Serum Creatinine | Serum Creatinine @ month 12 | 1.4 mg/dL | Standard Deviation 0.5 |
Secondary
Changes in the Estimated Glomerular Filtration Rate (eGFR) Between Randomization (Month 3) and Month 12
eGFR by Nankivell, in terms of descriptive statistics and change vs randomization visit - to compare the changes in the estimated GFR (Nankivell) between randomization and Month 12 in the steroid withdrawal group (Group B) to the change observed in the standard twice-a-day group (Group C), for non-inferiority
Time frame: Month 3 to Month 12
Population: ITT population, defined as all randomized patients who received at least one dose of study drug after Visit 5 (Day 90) and have at least one post-baseline assessment of the primary efficacy variable (i.e. treatment failure).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A - Once-a-day Regimen | Changes in the Estimated Glomerular Filtration Rate (eGFR) Between Randomization (Month 3) and Month 12 | -1.7 mL/min | Standard Deviation 9.5 |
| Group B - Steroid Withdrawal Group | Changes in the Estimated Glomerular Filtration Rate (eGFR) Between Randomization (Month 3) and Month 12 | 2.5 mL/min | Standard Deviation 10.6 |
Secondary
Number of Participants With Graft and Patient Survival After Randomization
Graft Survival, calculated from the date of transplantation to the date of irreversible graft failure signified by return to long-term retransplantation or the date of the last follow-up during the period when the transplant was still functioning or to the date of death. Patient survival, calculated from the date of transplantation to the date of death or the date of the last follow-up.
Time frame: Month 3 to Month 12
Population: ITT population, defined as all randomized patients who received at least one dose of study drug after Visit 5 (Day 90) and have at least one post-baseline assessment of the primary efficacy variable (i.e. treatment failure).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A - Once-a-day Regimen | Number of Participants With Graft and Patient Survival After Randomization | 68 Participants |
| Group B - Steroid Withdrawal Group | Number of Participants With Graft and Patient Survival After Randomization | 71 Participants |