Trial Outcomes & Findings for Once-a-day Regimen With Everolimus, Low Dose Cyclosporine and Steroids in Comparison With Steroid Withdrawal or Twice a Day Regimen With Everolimus, Low Dose Cyclosporine and Steroids. (NCT NCT01023815)
NCT ID: NCT01023815
Last Updated: 2016-07-19
Results Overview
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).
Recruitment status
COMPLETED
Study phase
PHASE3
Target enrollment
330 participants
Primary outcome timeframe
Between randomization (Month 3) and Month 12
Results posted on
2016-07-19
Participant Flow
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.
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.
Participant milestones
| Measure |
Pre-randomized: Not-randomization Patients (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)
|
Randomized: 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.
|
Randomized: 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.
|
Randomized: 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.
|
|---|---|---|---|---|
|
Pre-randomization Period (Day 1 to 90)
STARTED
|
328
|
0
|
0
|
0
|
|
Pre-randomization Period (Day 1 to 90)
COMPLETED
|
184
|
0
|
0
|
0
|
|
Pre-randomization Period (Day 1 to 90)
NOT COMPLETED
|
144
|
0
|
0
|
0
|
|
Randomized Period (Day 90 to Month 12)
STARTED
|
0
|
45
|
68
|
71
|
|
Randomized Period (Day 90 to Month 12)
COMPLETED
|
0
|
42
|
60
|
68
|
|
Randomized Period (Day 90 to Month 12)
NOT COMPLETED
|
0
|
3
|
8
|
3
|
Reasons for withdrawal
| Measure |
Pre-randomized: Not-randomization Patients (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)
|
Randomized: 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.
|
Randomized: 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.
|
Randomized: 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.
|
|---|---|---|---|---|
|
Pre-randomization Period (Day 1 to 90)
Did not meet inclusion criteria
|
144
|
0
|
0
|
0
|
|
Randomized Period (Day 90 to Month 12)
Withdrawal by Subject
|
0
|
0
|
1
|
1
|
|
Randomized Period (Day 90 to Month 12)
Lost to Follow-up
|
0
|
1
|
1
|
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
|
Baseline Characteristics
Once-a-day Regimen With Everolimus, Low Dose Cyclosporine and Steroids in Comparison With Steroid Withdrawal or Twice a Day Regimen With Everolimus, Low Dose Cyclosporine and Steroids.
Baseline characteristics by cohort
| Measure |
Not Randomized Population (NRP)
n=144 Participants
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)
|
Group A - Once-a-day Regimen
n=45 Participants
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.
|
Group B - Steroid Withdrawal Group
n=68 Participants
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.
|
Group C - Standard Twice-a-day Group
n=71 Participants
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.
|
Total
n=328 Participants
Total of all reporting groups
|
|---|---|---|---|---|---|
|
Age, Continuous
|
52.9 years
STANDARD_DEVIATION 11.5 • n=5 Participants
|
46.6 years
STANDARD_DEVIATION 13.7 • n=7 Participants
|
48.5 years
STANDARD_DEVIATION 11.6 • n=5 Participants
|
49.2 years
STANDARD_DEVIATION 13.0 • n=4 Participants
|
50.3 years
STANDARD_DEVIATION 12.3 • n=21 Participants
|
|
Sex: Female, Male
Female
|
56 Participants
n=5 Participants
|
15 Participants
n=7 Participants
|
22 Participants
n=5 Participants
|
20 Participants
n=4 Participants
|
113 Participants
n=21 Participants
|
|
Sex: Female, Male
Male
|
88 Participants
n=5 Participants
|
30 Participants
n=7 Participants
|
46 Participants
n=5 Participants
|
51 Participants
n=4 Participants
|
215 Participants
n=21 Participants
|
|
Race/Ethnicity, Customized
Caucasian
|
139 Participants
n=5 Participants
|
44 Participants
n=7 Participants
|
68 Participants
n=5 Participants
|
67 Participants
n=4 Participants
|
318 Participants
n=21 Participants
|
|
Race/Ethnicity, Customized
Black
|
3 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
1 Participants
n=4 Participants
|
4 Participants
n=21 Participants
|
|
Race/Ethnicity, Customized
Oriental
|
1 Participants
n=5 Participants
|
1 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
0 Participants
n=4 Participants
|
2 Participants
n=21 Participants
|
|
Race/Ethnicity, Customized
Other
|
1 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
3 Participants
n=4 Participants
|
4 Participants
n=21 Participants
|
|
Smoking Status
No
|
119 Participants
n=5 Participants
|
41 Participants
n=7 Participants
|
58 Participants
n=5 Participants
|
56 Participants
n=4 Participants
|
274 Participants
n=21 Participants
|
|
Smoking Status
Yes
|
16 Participants
n=5 Participants
|
2 Participants
n=7 Participants
|
2 Participants
n=5 Participants
|
2 Participants
n=4 Participants
|
22 Participants
n=21 Participants
|
|
Smoking Status
Missing
|
9 Participants
n=5 Participants
|
2 Participants
n=7 Participants
|
8 Participants
n=5 Participants
|
13 Participants
n=4 Participants
|
32 Participants
n=21 Participants
|
|
BMI
|
24.6 kg/m^2
STANDARD_DEVIATION 3.4 • n=5 Participants
|
24.9 kg/m^2
STANDARD_DEVIATION 3.6 • n=7 Participants
|
24.1 kg/m^2
STANDARD_DEVIATION 3.3 • n=5 Participants
|
24.2 kg/m^2
STANDARD_DEVIATION 3.6 • n=4 Participants
|
24.4 kg/m^2
STANDARD_DEVIATION 3.4 • n=21 Participants
|
|
Female reproductive status
Childbearing potential with contraceptive protecti
|
11 Participants
n=5 Participants
|
8 Participants
n=7 Participants
|
12 Participants
n=5 Participants
|
4 Participants
n=4 Participants
|
35 Participants
n=21 Participants
|
|
Female reproductive status
Surgically sterilised
|
2 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
2 Participants
n=5 Participants
|
0 Participants
n=4 Participants
|
4 Participants
n=21 Participants
|
|
Female reproductive status
Postmenopausal
|
43 Participants
n=5 Participants
|
7 Participants
n=7 Participants
|
8 Participants
n=5 Participants
|
16 Participants
n=4 Participants
|
74 Participants
n=21 Participants
|
|
Result of HCG pregnancy screen - Negative
Negative
|
10 Participants
n=5 Participants
|
6 Participants
n=7 Participants
|
12 Participants
n=5 Participants
|
4 Participants
n=4 Participants
|
32 Participants
n=21 Participants
|
|
Result of HCG pregnancy screen - Negative
Missing
|
46 Participants
n=5 Participants
|
9 Participants
n=7 Participants
|
10 Participants
n=5 Participants
|
16 Participants
n=4 Participants
|
81 Participants
n=21 Participants
|
PRIMARY outcome
Timeframe: Between randomization (Month 3) and Month 12Population: 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.
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).
Outcome measures
| Measure |
Group A - Once-a-day Regimen
n=45 Participants
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.
|
Group B - Steroid Withdrawal Group
n=68 Participants
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.
|
Group C - Standard Twice-a-day Group
n=71 Participants
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.
|
|---|---|---|---|
|
Treatment Failure Rate
|
3 Participants
|
10 Participants
|
2 Participants
|
SECONDARY outcome
Timeframe: Month 3 to Month 12Population: 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).
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
Outcome measures
| Measure |
Group A - Once-a-day Regimen
n=68 Participants
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.
|
Group B - Steroid Withdrawal Group
n=71 Participants
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.
|
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.
|
|---|---|---|---|
|
Changes in the Estimated Glomerular Filtration Rate (eGFR) Between Randomization (Month 3) and Month 12
|
-1.7 mL/min
Standard Deviation 9.5
|
2.5 mL/min
Standard Deviation 10.6
|
—
|
SECONDARY outcome
Timeframe: Month 3 to Month 12Population: 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).
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.
Outcome measures
| Measure |
Group A - Once-a-day Regimen
n=68 Participants
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.
|
Group B - Steroid Withdrawal Group
n=71 Participants
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.
|
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.
|
|---|---|---|---|
|
Biopsy Proven Acute Rejection (BPAR) Rate Between Randomization and Month 12
|
9 Participants
|
2 Participants
|
—
|
SECONDARY outcome
Timeframe: Month 3 to Month 12Population: 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).
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.
Outcome measures
| Measure |
Group A - Once-a-day Regimen
n=68 Participants
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.
|
Group B - Steroid Withdrawal Group
n=71 Participants
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.
|
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.
|
|---|---|---|---|
|
Number of Participants With Graft and Patient Survival After Randomization
|
68 Participants
|
71 Participants
|
—
|
SECONDARY outcome
Timeframe: M3, M12Population: 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).
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.
Outcome measures
| Measure |
Group A - Once-a-day Regimen
n=68 Participants
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.
|
Group B - Steroid Withdrawal Group
n=71 Participants
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.
|
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.
|
|---|---|---|---|
|
Change in Estimated Creatine Clearance
Using Cockcroft and Gault model @ month 3
|
64.8 mL/min
Standard Deviation 21.8
|
63.0 mL/min
Standard Deviation 20.9
|
—
|
|
Change in Estimated Creatine Clearance
Using Cockcroft and Gault model @ month 12
|
62.3 mL/min
Standard Deviation 21.4
|
66.9 mL/min
Standard Deviation 24.7
|
—
|
|
Change in Estimated Creatine Clearance
Using MDRD-4 formular @ month 3
|
57.9 mL/min
Standard Deviation 20.0
|
58.8 mL/min
Standard Deviation 21.8
|
—
|
|
Change in Estimated Creatine Clearance
Using MDRD-4 formular @ month 12
|
53.6 mL/min
Standard Deviation 18.9
|
61.8 mL/min
Standard Deviation 23.1
|
—
|
SECONDARY outcome
Timeframe: M3, M12Population: 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).
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.
Outcome measures
| Measure |
Group A - Once-a-day Regimen
n=68 Participants
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.
|
Group B - Steroid Withdrawal Group
n=71 Participants
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.
|
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.
|
|---|---|---|---|
|
Change in Serum Creatinine
Serum Creatinine @ month 3
|
1.4 mg/dL
Standard Deviation 0.4
|
1.4 mg/dL
Standard Deviation 0.4
|
—
|
|
Change in Serum Creatinine
Serum Creatinine @ month 12
|
1.5 mg/dL
Standard Deviation 0.5
|
1.4 mg/dL
Standard Deviation 0.5
|
—
|
Adverse Events
Not Randomized Population (NRP)
Serious events: 65 serious events
Other events: 108 other events
Deaths: 0 deaths
Group A - Once-a-day Regimen
Serious events: 18 serious events
Other events: 35 other events
Deaths: 0 deaths
Group B - Steroid Withdrawal Group
Serious events: 24 serious events
Other events: 56 other events
Deaths: 0 deaths
Group C - Standard Twice-a-day Group
Serious events: 25 serious events
Other events: 57 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
Not Randomized Population (NRP)
n=144 participants at risk
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).
This population 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) and described with respect to baseline characteristics, treatment and outcome variables.
|
Group A - Once-a-day Regimen
n=45 participants at risk
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.
|
Group B - Steroid Withdrawal Group
n=68 participants at risk
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.
|
Group C - Standard Twice-a-day Group
n=71 participants at risk
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.
|
|---|---|---|---|---|
|
Blood and lymphatic system disorders
Anaemia
|
2.1%
3/144
|
0.00%
0/45
|
1.5%
1/68
|
0.00%
0/71
|
|
Blood and lymphatic system disorders
Leukopenia
|
1.4%
2/144
|
0.00%
0/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Blood and lymphatic system disorders
Pancytopenia
|
1.4%
2/144
|
0.00%
0/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Blood and lymphatic system disorders
Thrombocytopenia
|
0.69%
1/144
|
0.00%
0/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Cardiac disorders
Acute myocardial infarction
|
0.69%
1/144
|
0.00%
0/45
|
1.5%
1/68
|
0.00%
0/71
|
|
Cardiac disorders
Atrial fibrillation
|
0.00%
0/144
|
0.00%
0/45
|
1.5%
1/68
|
0.00%
0/71
|
|
Cardiac disorders
Mitral valve incompetence
|
0.69%
1/144
|
0.00%
0/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Cardiac disorders
Supraventricular tachycardia
|
0.00%
0/144
|
0.00%
0/45
|
1.5%
1/68
|
0.00%
0/71
|
|
Gastrointestinal disorders
Abdominal hernia
|
0.00%
0/144
|
2.2%
1/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Gastrointestinal disorders
Abdominal pain
|
0.69%
1/144
|
2.2%
1/45
|
0.00%
0/68
|
1.4%
1/71
|
|
Gastrointestinal disorders
Diarrhoea
|
0.00%
0/144
|
0.00%
0/45
|
1.5%
1/68
|
0.00%
0/71
|
|
Gastrointestinal disorders
Enteritis
|
0.00%
0/144
|
0.00%
0/45
|
1.5%
1/68
|
0.00%
0/71
|
|
Gastrointestinal disorders
Haematemesis
|
0.69%
1/144
|
0.00%
0/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Gastrointestinal disorders
Intestinal obstruction
|
0.69%
1/144
|
0.00%
0/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Gastrointestinal disorders
Localised intraabdominal fluid collection
|
0.00%
0/144
|
2.2%
1/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Gastrointestinal disorders
Oesophagitis
|
0.69%
1/144
|
0.00%
0/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Gastrointestinal disorders
Subileus
|
0.00%
0/144
|
2.2%
1/45
|
0.00%
0/68
|
0.00%
0/71
|
|
General disorders
Device occlusion
|
0.00%
0/144
|
0.00%
0/45
|
1.5%
1/68
|
0.00%
0/71
|
|
General disorders
Hyperpyrexia
|
0.00%
0/144
|
0.00%
0/45
|
5.9%
4/68
|
0.00%
0/71
|
|
General disorders
Impaired healing
|
0.69%
1/144
|
0.00%
0/45
|
0.00%
0/68
|
0.00%
0/71
|
|
General disorders
Implant site haematoma
|
0.69%
1/144
|
0.00%
0/45
|
0.00%
0/68
|
0.00%
0/71
|
|
General disorders
Oedema
|
0.00%
0/144
|
0.00%
0/45
|
1.5%
1/68
|
0.00%
0/71
|
|
General disorders
Oedema peripheral
|
0.00%
0/144
|
0.00%
0/45
|
1.5%
1/68
|
1.4%
1/71
|
|
General disorders
Pyrexia
|
1.4%
2/144
|
4.4%
2/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Hepatobiliary disorders
Cholecystitis acute
|
0.00%
0/144
|
2.2%
1/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Immune system disorders
Kidney transplant rejection
|
1.4%
2/144
|
4.4%
2/45
|
1.5%
1/68
|
1.4%
1/71
|
|
Immune system disorders
Transplant rejection
|
7.6%
11/144
|
0.00%
0/45
|
8.8%
6/68
|
2.8%
2/71
|
|
Infections and infestations
Abscess
|
0.00%
0/144
|
0.00%
0/45
|
0.00%
0/68
|
1.4%
1/71
|
|
Infections and infestations
BK virus infection
|
0.00%
0/144
|
0.00%
0/45
|
0.00%
0/68
|
1.4%
1/71
|
|
Infections and infestations
Bacterial pyelonephritis
|
0.00%
0/144
|
0.00%
0/45
|
1.5%
1/68
|
0.00%
0/71
|
|
Infections and infestations
Bronchopneumonia
|
1.4%
2/144
|
0.00%
0/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Infections and infestations
Cytomegalovirus infection
|
0.00%
0/144
|
0.00%
0/45
|
0.00%
0/68
|
1.4%
1/71
|
|
Infections and infestations
Endocarditis
|
0.69%
1/144
|
0.00%
0/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Infections and infestations
Gastroenteritis
|
0.00%
0/144
|
0.00%
0/45
|
2.9%
2/68
|
2.8%
2/71
|
|
Infections and infestations
H1N1 influenza
|
0.00%
0/144
|
0.00%
0/45
|
0.00%
0/68
|
1.4%
1/71
|
|
Infections and infestations
Human polyomavirus infection
|
0.69%
1/144
|
0.00%
0/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Infections and infestations
Lobar pneumonia
|
0.69%
1/144
|
0.00%
0/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Infections and infestations
Pneumonia
|
0.00%
0/144
|
0.00%
0/45
|
1.5%
1/68
|
2.8%
2/71
|
|
Infections and infestations
Pyelonephritis
|
0.00%
0/144
|
0.00%
0/45
|
0.00%
0/68
|
2.8%
2/71
|
|
Infections and infestations
Pyelonephritis acute
|
0.69%
1/144
|
2.2%
1/45
|
1.5%
1/68
|
0.00%
0/71
|
|
Infections and infestations
Sepsis
|
0.69%
1/144
|
0.00%
0/45
|
1.5%
1/68
|
0.00%
0/71
|
|
Infections and infestations
Septic shock
|
0.69%
1/144
|
0.00%
0/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Infections and infestations
Urinary tract infection
|
0.00%
0/144
|
4.4%
2/45
|
8.8%
6/68
|
0.00%
0/71
|
|
Infections and infestations
Wound infection
|
1.4%
2/144
|
0.00%
0/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Injury, poisoning and procedural complications
Complications of transplanted kidney
|
2.8%
4/144
|
2.2%
1/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Injury, poisoning and procedural complications
Graft loss
|
4.9%
7/144
|
0.00%
0/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Injury, poisoning and procedural complications
Graft thrombosis
|
0.69%
1/144
|
0.00%
0/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Injury, poisoning and procedural complications
Perirenal haematoma
|
0.69%
1/144
|
2.2%
1/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Injury, poisoning and procedural complications
Toxicity to various agents
|
2.8%
4/144
|
0.00%
0/45
|
4.4%
3/68
|
1.4%
1/71
|
|
Injury, poisoning and procedural complications
Urinary anastomotic leak
|
0.69%
1/144
|
2.2%
1/45
|
0.00%
0/68
|
1.4%
1/71
|
|
Injury, poisoning and procedural complications
Vascular graft complication
|
0.69%
1/144
|
0.00%
0/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Investigations
Blood creatinine increased
|
3.5%
5/144
|
4.4%
2/45
|
7.4%
5/68
|
4.2%
3/71
|
|
Investigations
Platelet count decreased
|
0.69%
1/144
|
0.00%
0/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Metabolism and nutrition disorders
Dehydration
|
0.00%
0/144
|
0.00%
0/45
|
1.5%
1/68
|
0.00%
0/71
|
|
Metabolism and nutrition disorders
Diabetes mellitus
|
0.00%
0/144
|
0.00%
0/45
|
1.5%
1/68
|
0.00%
0/71
|
|
Musculoskeletal and connective tissue disorders
Arthralgia
|
0.69%
1/144
|
0.00%
0/45
|
0.00%
0/68
|
1.4%
1/71
|
|
Musculoskeletal and connective tissue disorders
Osteonecrosis
|
0.00%
0/144
|
2.2%
1/45
|
0.00%
0/68
|
1.4%
1/71
|
|
Musculoskeletal and connective tissue disorders
Synovial cyst
|
0.00%
0/144
|
2.2%
1/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder neoplasm
|
0.00%
0/144
|
0.00%
0/45
|
0.00%
0/68
|
1.4%
1/71
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Renal cancer
|
0.00%
0/144
|
2.2%
1/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Nervous system disorders
Syncope
|
0.00%
0/144
|
0.00%
0/45
|
0.00%
0/68
|
1.4%
1/71
|
|
Psychiatric disorders
Delirium
|
0.00%
0/144
|
0.00%
0/45
|
1.5%
1/68
|
0.00%
0/71
|
|
Renal and urinary disorders
Hydronephrosis
|
1.4%
2/144
|
0.00%
0/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Renal and urinary disorders
Oliguria
|
0.00%
0/144
|
0.00%
0/45
|
2.9%
2/68
|
0.00%
0/71
|
|
Renal and urinary disorders
Proteinuria
|
0.69%
1/144
|
0.00%
0/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Renal and urinary disorders
Renal artery dissection
|
0.00%
0/144
|
0.00%
0/45
|
0.00%
0/68
|
1.4%
1/71
|
|
Renal and urinary disorders
Renal artery stenosis
|
2.1%
3/144
|
0.00%
0/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Renal and urinary disorders
Renal artery thrombosis
|
0.69%
1/144
|
0.00%
0/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Renal and urinary disorders
Renal colic
|
0.00%
0/144
|
0.00%
0/45
|
1.5%
1/68
|
0.00%
0/71
|
|
Renal and urinary disorders
Renal cortical necrosis
|
0.69%
1/144
|
0.00%
0/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Renal and urinary disorders
Renal failure acute
|
0.69%
1/144
|
0.00%
0/45
|
2.9%
2/68
|
0.00%
0/71
|
|
Renal and urinary disorders
Renal impairment
|
3.5%
5/144
|
2.2%
1/45
|
5.9%
4/68
|
8.5%
6/71
|
|
Renal and urinary disorders
Renal tubular necrosis
|
2.1%
3/144
|
0.00%
0/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Renal and urinary disorders
Renal vein thrombosis
|
1.4%
2/144
|
0.00%
0/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Renal and urinary disorders
Ureteral necrosis
|
0.00%
0/144
|
0.00%
0/45
|
0.00%
0/68
|
1.4%
1/71
|
|
Renal and urinary disorders
Ureteric dilatation
|
0.00%
0/144
|
2.2%
1/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Renal and urinary disorders
Ureteric fistula
|
0.69%
1/144
|
0.00%
0/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Renal and urinary disorders
Ureteric stenosis
|
0.69%
1/144
|
2.2%
1/45
|
1.5%
1/68
|
0.00%
0/71
|
|
Renal and urinary disorders
Urinary bladder haemorrhage
|
0.69%
1/144
|
2.2%
1/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Renal and urinary disorders
Urinary fistula
|
1.4%
2/144
|
0.00%
0/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Renal and urinary disorders
Urinary retention
|
0.69%
1/144
|
0.00%
0/45
|
0.00%
0/68
|
1.4%
1/71
|
|
Respiratory, thoracic and mediastinal disorders
Interstitial lung disease
|
0.00%
0/144
|
2.2%
1/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Respiratory, thoracic and mediastinal disorders
Pneumonitis
|
0.00%
0/144
|
0.00%
0/45
|
0.00%
0/68
|
1.4%
1/71
|
|
Surgical and medical procedures
Bladder operation
|
0.00%
0/144
|
0.00%
0/45
|
1.5%
1/68
|
0.00%
0/71
|
|
Surgical and medical procedures
Nephrostomy
|
0.69%
1/144
|
0.00%
0/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Surgical and medical procedures
Ureteral stent removal
|
0.69%
1/144
|
2.2%
1/45
|
0.00%
0/68
|
0.00%
0/71
|
|
Surgical and medical procedures
Urinary tract operation
|
0.00%
0/144
|
0.00%
0/45
|
0.00%
0/68
|
1.4%
1/71
|
|
Vascular disorders
Hypertension
|
0.00%
0/144
|
0.00%
0/45
|
1.5%
1/68
|
1.4%
1/71
|
|
Vascular disorders
Intra-abdominal haematoma
|
0.69%
1/144
|
0.00%
0/45
|
0.00%
0/68
|
1.4%
1/71
|
|
Vascular disorders
Lymphocele
|
1.4%
2/144
|
6.7%
3/45
|
2.9%
2/68
|
1.4%
1/71
|
|
Vascular disorders
Lymphorrhoea
|
0.69%
1/144
|
0.00%
0/45
|
0.00%
0/68
|
1.4%
1/71
|
|
Vascular disorders
Pelvic venous thrombosis
|
0.00%
0/144
|
0.00%
0/45
|
0.00%
0/68
|
1.4%
1/71
|
|
Vascular disorders
Thrombophlebitis superficial
|
0.00%
0/144
|
0.00%
0/45
|
0.00%
0/68
|
1.4%
1/71
|
Other adverse events
| Measure |
Not Randomized Population (NRP)
n=144 participants at risk
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).
This population 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) and described with respect to baseline characteristics, treatment and outcome variables.
|
Group A - Once-a-day Regimen
n=45 participants at risk
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.
|
Group B - Steroid Withdrawal Group
n=68 participants at risk
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.
|
Group C - Standard Twice-a-day Group
n=71 participants at risk
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.
|
|---|---|---|---|---|
|
Blood and lymphatic system disorders
Anaemia
|
36.8%
53/144
|
22.2%
10/45
|
33.8%
23/68
|
18.3%
13/71
|
|
Blood and lymphatic system disorders
Leukopenia
|
9.0%
13/144
|
6.7%
3/45
|
7.4%
5/68
|
1.4%
1/71
|
|
Blood and lymphatic system disorders
Polycythaemia
|
0.00%
0/144
|
6.7%
3/45
|
4.4%
3/68
|
1.4%
1/71
|
|
Cardiac disorders
Atrial fibrillation
|
7.6%
11/144
|
2.2%
1/45
|
0.00%
0/68
|
4.2%
3/71
|
|
Gastrointestinal disorders
Abdominal hernia
|
0.00%
0/144
|
6.7%
3/45
|
2.9%
2/68
|
1.4%
1/71
|
|
Gastrointestinal disorders
Abdominal pain
|
3.5%
5/144
|
8.9%
4/45
|
1.5%
1/68
|
4.2%
3/71
|
|
Gastrointestinal disorders
Constipation
|
6.9%
10/144
|
2.2%
1/45
|
1.5%
1/68
|
9.9%
7/71
|
|
Gastrointestinal disorders
Diarrhoea
|
4.9%
7/144
|
6.7%
3/45
|
11.8%
8/68
|
1.4%
1/71
|
|
Gastrointestinal disorders
Nausea
|
1.4%
2/144
|
6.7%
3/45
|
0.00%
0/68
|
0.00%
0/71
|
|
General disorders
Oedema peripheral
|
4.9%
7/144
|
13.3%
6/45
|
23.5%
16/68
|
12.7%
9/71
|
|
General disorders
Pyrexia
|
9.7%
14/144
|
4.4%
2/45
|
8.8%
6/68
|
2.8%
2/71
|
|
Infections and infestations
Urinary tract infection
|
17.4%
25/144
|
15.6%
7/45
|
20.6%
14/68
|
22.5%
16/71
|
|
Injury, poisoning and procedural complications
Complications of transplanted kidney
|
15.3%
22/144
|
15.6%
7/45
|
8.8%
6/68
|
11.3%
8/71
|
|
Investigations
Blood creatinine increased
|
4.2%
6/144
|
13.3%
6/45
|
7.4%
5/68
|
4.2%
3/71
|
|
Metabolism and nutrition disorders
Acidosis
|
5.6%
8/144
|
0.00%
0/45
|
5.9%
4/68
|
1.4%
1/71
|
|
Metabolism and nutrition disorders
Diabetes mellitus
|
3.5%
5/144
|
2.2%
1/45
|
2.9%
2/68
|
8.5%
6/71
|
|
Metabolism and nutrition disorders
Fluid retention
|
4.9%
7/144
|
4.4%
2/45
|
5.9%
4/68
|
4.2%
3/71
|
|
Metabolism and nutrition disorders
Hypercholesterolaemia
|
5.6%
8/144
|
6.7%
3/45
|
8.8%
6/68
|
9.9%
7/71
|
|
Metabolism and nutrition disorders
Hyperkalaemia
|
6.2%
9/144
|
8.9%
4/45
|
5.9%
4/68
|
5.6%
4/71
|
|
Metabolism and nutrition disorders
Hyperlipidaemia
|
11.1%
16/144
|
26.7%
12/45
|
29.4%
20/68
|
25.4%
18/71
|
|
Metabolism and nutrition disorders
Hyperphosphataemia
|
5.6%
8/144
|
0.00%
0/45
|
1.5%
1/68
|
1.4%
1/71
|
|
Metabolism and nutrition disorders
Hypertriglyceridaemia
|
3.5%
5/144
|
4.4%
2/45
|
4.4%
3/68
|
8.5%
6/71
|
|
Metabolism and nutrition disorders
Hyperuricaemia
|
10.4%
15/144
|
6.7%
3/45
|
10.3%
7/68
|
4.2%
3/71
|
|
Metabolism and nutrition disorders
Hypocalcaemia
|
10.4%
15/144
|
11.1%
5/45
|
10.3%
7/68
|
4.2%
3/71
|
|
Metabolism and nutrition disorders
Hypokalaemia
|
12.5%
18/144
|
13.3%
6/45
|
10.3%
7/68
|
8.5%
6/71
|
|
Musculoskeletal and connective tissue disorders
Arthralgia
|
1.4%
2/144
|
6.7%
3/45
|
8.8%
6/68
|
2.8%
2/71
|
|
Musculoskeletal and connective tissue disorders
Myalgia
|
0.69%
1/144
|
0.00%
0/45
|
5.9%
4/68
|
0.00%
0/71
|
|
Renal and urinary disorders
Renal impairment
|
10.4%
15/144
|
6.7%
3/45
|
4.4%
3/68
|
4.2%
3/71
|
|
Renal and urinary disorders
Renal tubular necrosis
|
5.6%
8/144
|
4.4%
2/45
|
4.4%
3/68
|
2.8%
2/71
|
|
Vascular disorders
Hypertension
|
17.4%
25/144
|
17.8%
8/45
|
16.2%
11/68
|
19.7%
14/71
|
|
Vascular disorders
Lymphocele
|
6.2%
9/144
|
11.1%
5/45
|
10.3%
7/68
|
9.9%
7/71
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.
- Publication restrictions are in place
Restriction type: OTHER