Trial Outcomes & Findings for A National Multi-center Randomized, Open Label Study to Evaluate Efficacy and Safety of Everolimus With EC-MPS Compared to Standard Treatment Combination Tacrolimus and EC-MPS in de Novo Liver Transplant Recipients (NCT NCT01625377)

Last Updated: 2016-04-27

Results Overview

Change in renal function was measured by change in glomerular filtration rate (GFR). GFR calculated using the abbreviated modification of diet in renal disease (aMDRD) formula. GFR in mL/min/1.73m\^2 for men of non-black ethnicity: 186 \* \[C/88\]\^-1.154 \* \[A\]\^-0.023\*G\*R ; C = serum creatinine (in μmol/L); A = Age (in years). G = 0.742 when the patient is a women; Otherwise G=1 R= 1.21 when the patient was of black ethnicity; Otherwise R = 1 Baseline was Day 28 visit.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

188 participants

Primary outcome timeframe

Baseline, Week 24

Results posted on

2016-04-27

Participant Flow

Total 188 patients were randomized

Participant milestones

Participant milestones
Measure	Tacrolimus From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : tacrolimus (C0 6-10 ng/ml) + mycophenolic acid 1440 mg/d ± oral corticosteroids	Everolimus (RAD001) From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : everolimus (recommended starting dose of 2 mg/day, then adjusted to achieve the target 6 ≤ C0 ≤ 10 ng/mL, until W24) + mycophenolic acid 1440 mg/d ± oral corticosteroids. The dose of tacrolimus was reduced by 50% twice: at the introduction of everolimus and at week 8 post-transplantation. Tacrolimus had to be finally discontinued in week 12 post-transplantation (by week 16 at the latest).
Overall Study STARTED	95	93
Overall Study Safety Set of Population	94	90
Overall Study Intent to Treat Population	93	90
Overall Study COMPLETED	88	71
Overall Study NOT COMPLETED	7	22

Reasons for withdrawal

Reasons for withdrawal
Measure	Tacrolimus From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : tacrolimus (C0 6-10 ng/ml) + mycophenolic acid 1440 mg/d ± oral corticosteroids	Everolimus (RAD001) From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : everolimus (recommended starting dose of 2 mg/day, then adjusted to achieve the target 6 ≤ C0 ≤ 10 ng/mL, until W24) + mycophenolic acid 1440 mg/d ± oral corticosteroids. The dose of tacrolimus was reduced by 50% twice: at the introduction of everolimus and at week 8 post-transplantation. Tacrolimus had to be finally discontinued in week 12 post-transplantation (by week 16 at the latest).
Overall Study Death	1	1
Overall Study Administrative Problem	1	1
Overall Study Protocol Violation	0	3
Overall Study Adverse Event	3	16
Overall Study Graft loss	1	0
Overall Study Unsatisfactory therapeutic effect	0	1
Overall Study Abnormal laboratory values	1	0

Baseline Characteristics

A National Multi-center Randomized, Open Label Study to Evaluate Efficacy and Safety of Everolimus With EC-MPS Compared to Standard Treatment Combination Tacrolimus and EC-MPS in de Novo Liver Transplant Recipients

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tacrolimus n=95 Participants From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : tacrolimus (C0 6-10 ng/ml) + mycophenolic acid 1440 mg/d ± oral corticosteroids	Everolimus (RAD001) n=93 Participants From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : everolimus (recommended starting dose of 2 mg/day, then adjusted to achieve the target 6 ≤ C0 ≤ 10 ng/mL, until W24) + mycophenolic acid 1440 mg/d ± oral corticosteroids. The dose of tacrolimus was reduced by 50% twice: at the introduction of everolimus and at week 8 post-transplantation. Tacrolimus had to be finally discontinued in week 12 post-transplantation (by week 16 at the latest).	Total n=188 Participants Total of all reporting groups
Age, Continuous	55.5 Years STANDARD_DEVIATION 8.24 • n=5 Participants	56.5 Years STANDARD_DEVIATION 8.59 • n=7 Participants	56.0 Years STANDARD_DEVIATION 8.41 • n=5 Participants
Sex: Female, Male Female	14 Participants n=5 Participants	14 Participants n=7 Participants	28 Participants n=5 Participants
Sex: Female, Male Male	81 Participants n=5 Participants	79 Participants n=7 Participants	160 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, Week 24

Population: The Intent to treat (ITT) population included all randomized patients who received at least one dose of study treatment post-randomization and for whom a creatinine value a Day 28 and a posterior value were available. The last observation carried forward (LOCF) is used as imputation of missing data.

Outcome measures

Outcome measures
Measure	Tacrolimus n=93 Participants From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : tacrolimus (C0 6-10 ng/ml) + mycophenolic acid 1440 mg/d ± oral corticosteroids	Everolimus (RAD001) n=90 Participants From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : everolimus (recommended starting dose of 2 mg/day, then adjusted to achieve the target 6 ≤ C0 ≤ 10 ng/mL, until W24) + mycophenolic acid 1440 mg/d ± oral corticosteroids. The dose of tacrolimus was reduced by 50% twice: at the introduction of everolimus and at week 8 post-transplantation. Tacrolimus had to be finally discontinued in week 12 post-transplantation (by week 16 at the latest).
Change From Baseline (Randomization) in Renal Function	-13.29 mL/min/1.73m^2 Standard Error 2.75	1.05 mL/min/1.73m^2 Standard Error 2.81

SECONDARY outcome

Timeframe: At week 12 and week 24

Incidence of treatment failures, assessed with composite criterion including treated biopsy proven acute rejection (tBPAR) with a rejection activity index (RAI) according to Banff classification \>3, graft loss or death at 6 months. Biopsy proven acute rejection (BPAR) was defined as a clinically suspected acute rejection confirmed by biopsy. The Banff Rejection Activity Index (RAI) comprises 3 components scored from 0 to 3: venous endothelial inflammation; bile duct inflammation damage; and portal inflammation; the scores are combined to an overall score (the RAI) ranging from 0 to 9. An overall score of 0-3 is considered indeterminate, score of 4-5 is mild acute, score of 6-7 is moderate acute , and score of 8-9 is severe acute. Only the episode with the highest total RAI score for each participant was counted. The graft was presumed to be lost on the day the patient was registered again on the waiting list, or the day he/she received a new graft.

Outcome measures

Outcome measures
Measure	Tacrolimus n=93 Participants From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : tacrolimus (C0 6-10 ng/ml) + mycophenolic acid 1440 mg/d ± oral corticosteroids	Everolimus (RAD001) n=90 Participants From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : everolimus (recommended starting dose of 2 mg/day, then adjusted to achieve the target 6 ≤ C0 ≤ 10 ng/mL, until W24) + mycophenolic acid 1440 mg/d ± oral corticosteroids. The dose of tacrolimus was reduced by 50% twice: at the introduction of everolimus and at week 8 post-transplantation. Tacrolimus had to be finally discontinued in week 12 post-transplantation (by week 16 at the latest).
Number of Patients With Treatment Failures week 12, Treatment failures - NO	91 Patients	88 Patients
Number of Patients With Treatment Failures week 12, Treatment failures - YES	2 Patients	2 Patients
Number of Patients With Treatment Failures week 24, Treatment failures - NO	89 Patients	81 Patients
Number of Patients With Treatment Failures week 24, Treatment failures - YES	4 Patients	9 Patients

SECONDARY outcome

Timeframe: at 12 week and 24 week

Biopsy proven acute rejection was defined as a clinically suspected acute rejection confirmed by biopsy.

Outcome measures

Outcome measures
Measure	Tacrolimus n=93 Participants From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : tacrolimus (C0 6-10 ng/ml) + mycophenolic acid 1440 mg/d ± oral corticosteroids	Everolimus (RAD001) n=90 Participants From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : everolimus (recommended starting dose of 2 mg/day, then adjusted to achieve the target 6 ≤ C0 ≤ 10 ng/mL, until W24) + mycophenolic acid 1440 mg/d ± oral corticosteroids. The dose of tacrolimus was reduced by 50% twice: at the introduction of everolimus and at week 8 post-transplantation. Tacrolimus had to be finally discontinued in week 12 post-transplantation (by week 16 at the latest).
Number of Patients With Treated or Not Treated Biopsy Proven Acute Rejection (BPAR) Week 24, Treated BPAR	2 Patients	8 Patients
Number of Patients With Treated or Not Treated Biopsy Proven Acute Rejection (BPAR) Week 12, Treated BPAR	2 Patients	2 Patients
Number of Patients With Treated or Not Treated Biopsy Proven Acute Rejection (BPAR) Week 12, Not treated BPAR	0 Patients	0 Patients
Number of Patients With Treated or Not Treated Biopsy Proven Acute Rejection (BPAR) Week 24, Not Treated BPAR	0 Patients	1 Patients

SECONDARY outcome

Timeframe: at 12 week and 24 week

Biopsy proven acute rejection was defined as a clinically suspected acute rejection confirmed by biopsy. The severity of BPAR was categorized as : Mild (Banff grade I, RAI = 4 and 5) Moderate (Banff grade II, RAI = 6 and 7) Severe (Banff grade III, RAI = 8 and 9) Banff Rejection Activity Index (RAI) comprises 3 components scored from 0 to 3: venous endothelial inflammation; bile duct inflammation damage; and portal inflammation; the scores are combined to an overall score (the RAI) ranging from 0 to 9. An overall score of 0-3 is considered indeterminate, score of 4-5 is mild acute, score of 6-7 is moderate acute , and score of 8-9 is severe acute. Only the episode with the highest total RAI score for each participant was counted.

Outcome measures

Outcome measures
Measure	Tacrolimus n=93 Participants From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : tacrolimus (C0 6-10 ng/ml) + mycophenolic acid 1440 mg/d ± oral corticosteroids	Everolimus (RAD001) n=90 Participants From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : everolimus (recommended starting dose of 2 mg/day, then adjusted to achieve the target 6 ≤ C0 ≤ 10 ng/mL, until W24) + mycophenolic acid 1440 mg/d ± oral corticosteroids. The dose of tacrolimus was reduced by 50% twice: at the introduction of everolimus and at week 8 post-transplantation. Tacrolimus had to be finally discontinued in week 12 post-transplantation (by week 16 at the latest).
Number of Patients Reported With Different Categories of Severity of BPAR According to Banff Classification Week 12: Mild	1 Patients	1 Patients
Number of Patients Reported With Different Categories of Severity of BPAR According to Banff Classification Week 12: Moderate	1 Patients	1 Patients
Number of Patients Reported With Different Categories of Severity of BPAR According to Banff Classification Week 12: Severe	0 Patients	0 Patients
Number of Patients Reported With Different Categories of Severity of BPAR According to Banff Classification Week 24: Mild	1 Patients	5 Patients
Number of Patients Reported With Different Categories of Severity of BPAR According to Banff Classification Week 24: Moderate	1 Patients	3 Patients
Number of Patients Reported With Different Categories of Severity of BPAR According to Banff Classification Week 24: Sever	0 Patients	0 Patients

SECONDARY outcome

Timeframe: At 24 weeks

Biopsy proven acute rejection (BPAR) was defined as a clinically suspected acute rejection confirmed by biopsy. The Banff Rejection Activity Index (RAI) comprises 3 components scored from 0 to 3: venous endothelial inflammation; bile duct inflammation damage; and portal inflammation; the scores are combined to an overall score (the RAI) ranging from 0 to 9. An overall score of 0-3 is considered indeterminate, score of 4-5 is mild acute, score of 6-7 is moderate acute , and score of 8-9 is severe acute. Only the episode with the highest total RAI score for each participant was counted. The patients with treated or untreated BPAR having RAI score \> 3 were reported in this end point.

Outcome measures

Outcome measures
Measure	Tacrolimus n=93 Participants From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : tacrolimus (C0 6-10 ng/ml) + mycophenolic acid 1440 mg/d ± oral corticosteroids	Everolimus (RAD001) n=90 Participants From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : everolimus (recommended starting dose of 2 mg/day, then adjusted to achieve the target 6 ≤ C0 ≤ 10 ng/mL, until W24) + mycophenolic acid 1440 mg/d ± oral corticosteroids. The dose of tacrolimus was reduced by 50% twice: at the introduction of everolimus and at week 8 post-transplantation. Tacrolimus had to be finally discontinued in week 12 post-transplantation (by week 16 at the latest).
Number of Patients With Treated or Untreated BPAR With RAI Score Greater Than 3 Not Treated BPAR: RAI score >3	0 Patients	0 Patients
Number of Patients With Treated or Untreated BPAR With RAI Score Greater Than 3 Not Treated BPAR: Missing RAI score	0 Patients	1 Patients
Number of Patients With Treated or Untreated BPAR With RAI Score Greater Than 3 Treated BPAR: RAI score >3	2 Patients	8 Patients

SECONDARY outcome

Timeframe: at week 24

The graft was presumed to be lost on the day the patient was registered again on the waiting list, or the day he/she received a new graft.

Outcome measures

Outcome measures
Measure	Tacrolimus n=93 Participants From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : tacrolimus (C0 6-10 ng/ml) + mycophenolic acid 1440 mg/d ± oral corticosteroids	Everolimus (RAD001) n=90 Participants From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : everolimus (recommended starting dose of 2 mg/day, then adjusted to achieve the target 6 ≤ C0 ≤ 10 ng/mL, until W24) + mycophenolic acid 1440 mg/d ± oral corticosteroids. The dose of tacrolimus was reduced by 50% twice: at the introduction of everolimus and at week 8 post-transplantation. Tacrolimus had to be finally discontinued in week 12 post-transplantation (by week 16 at the latest).
Number of Patients With Death or Graft Loss Graft Loss	1 Patients	0 Patients
Number of Patients With Death or Graft Loss Death	1 Patients	1 Patients

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: The Intent to treat (ITT) population included all randomized patients who received at least one dose of study treatment post-randomization and for whom a creatinine value at D28 and a posterior value were available. The last observation carried forward (LOCF) is used as imputation of missing data.

Change in serum creatinine concentrations from baseline (randomization) to week 24 post-randomization was one of the efficacy assessments of renal function. Baseline was Day 28 visit.

Outcome measures

Outcome measures
Measure	Tacrolimus n=93 Participants From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : tacrolimus (C0 6-10 ng/ml) + mycophenolic acid 1440 mg/d ± oral corticosteroids	Everolimus (RAD001) n=90 Participants From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : everolimus (recommended starting dose of 2 mg/day, then adjusted to achieve the target 6 ≤ C0 ≤ 10 ng/mL, until W24) + mycophenolic acid 1440 mg/d ± oral corticosteroids. The dose of tacrolimus was reduced by 50% twice: at the introduction of everolimus and at week 8 post-transplantation. Tacrolimus had to be finally discontinued in week 12 post-transplantation (by week 16 at the latest).
Change From Baseline (Randomization) in Serum Creatinine	7.2 µmol/L Standard Deviation 36.0	-1.3 µmol/L Standard Deviation 38.53

SECONDARY outcome

Timeframe: Baseline, week 24

Population: The Intent to treat (ITT) population included all randomized patients who received at least one dose of study treatment post-randomization and for whom urine protein and creatinine value at day 28 and a posterior value were available. LOCF applied.

Change in urine protein/creatinine ratio from baseline (randomization) to week 24 post-randomization was one of the efficacy assessments of renal function. Baseline was Day 28 visit.

Outcome measures

Outcome measures
Measure	Tacrolimus n=64 Participants From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : tacrolimus (C0 6-10 ng/ml) + mycophenolic acid 1440 mg/d ± oral corticosteroids	Everolimus (RAD001) n=61 Participants From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : everolimus (recommended starting dose of 2 mg/day, then adjusted to achieve the target 6 ≤ C0 ≤ 10 ng/mL, until W24) + mycophenolic acid 1440 mg/d ± oral corticosteroids. The dose of tacrolimus was reduced by 50% twice: at the introduction of everolimus and at week 8 post-transplantation. Tacrolimus had to be finally discontinued in week 12 post-transplantation (by week 16 at the latest).
Change From Baseline (Randomization) in Urine Protein/Creatinine Ratio	-2.3 mg/mmol Standard Deviation 27.89	21.9 mg/mmol Standard Deviation 92.00

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: The Intent to treat (ITT) population included all randomized patients who received at least one dose of study treatment post-randomization and for whom a creatinine value at D28 and a posterior value were available. The last observation carried forward (LOCF) is used as imputation of missing data.

Creatinine clearance by the Cockcroft-Gault formula is computed in mL/min/1.73m\^2 from the creatinine clearance in mL/min by multiplying it by 1.73 and dividing it by the body surface area Baseline was Day 28 visit.

Outcome measures

Outcome measures
Measure	Tacrolimus n=93 Participants From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : tacrolimus (C0 6-10 ng/ml) + mycophenolic acid 1440 mg/d ± oral corticosteroids	Everolimus (RAD001) n=90 Participants From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : everolimus (recommended starting dose of 2 mg/day, then adjusted to achieve the target 6 ≤ C0 ≤ 10 ng/mL, until W24) + mycophenolic acid 1440 mg/d ± oral corticosteroids. The dose of tacrolimus was reduced by 50% twice: at the introduction of everolimus and at week 8 post-transplantation. Tacrolimus had to be finally discontinued in week 12 post-transplantation (by week 16 at the latest).
Change From Baseline (Randomization) in Creatinine Clearance Estimated Using the Adjusted Cockcroft-Gault Formula	-9.0 mL/min/1.73m^2 Standard Deviation 30.63	0.7 mL/min/1.73m^2 Standard Deviation 25.65

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: The Intent to treat (ITT) population included all randomized patients who received at least one dose of study treatment post-randomization and for whom a creatinine value at D28 and a posterior value were available. The last observation carried forward (LOCF) is used as imputation of missing data.

Change in glomerular filtration rate was calculated using the MDRD abbreviated formula. GFR in mL/min/1.73m\^2 for men of non-black ethnicity: 186 \* \[C/88\]\^-1.154 \* \[A\]\^-0.023\*G\*R ; C = serum creatinine (in μmol/L); A = Age (in years). G = 0.742 when the patient is a women; Otherwise G=1 R= 1.21 when the patient was of black ethnicity; Otherwise R = 1 Baseline was Day 28 visit.

Outcome measures

Outcome measures
Measure	Tacrolimus n=93 Participants From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : tacrolimus (C0 6-10 ng/ml) + mycophenolic acid 1440 mg/d ± oral corticosteroids	Everolimus (RAD001) n=90 Participants From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : everolimus (recommended starting dose of 2 mg/day, then adjusted to achieve the target 6 ≤ C0 ≤ 10 ng/mL, until W24) + mycophenolic acid 1440 mg/d ± oral corticosteroids. The dose of tacrolimus was reduced by 50% twice: at the introduction of everolimus and at week 8 post-transplantation. Tacrolimus had to be finally discontinued in week 12 post-transplantation (by week 16 at the latest).
Change From Baseline (Randomization) in Glomerular Filtration Rate Estimated by Abbreviated Modification of Diet in Renal Disease (MDRD) Formula	-11.8 mL/min/1.73m^2 Standard Deviation 34.01	0.1 mL/min/1.73m^2 Standard Deviation 32.59

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: The Intent to treat (ITT) population included all randomized patients who received at least one dose of study treatment post-randomization and for whom a creatinine value at D28 and a posterior value were available. The last observation carried forward (LOCF) is used as imputation of missing data.

GFR estimated by using the Chronic kidney disease- epidemiology (CKD-EPI) formula: eGFR (mL/min/1.73m\^2) = 141 \* min(C/K,1)\^ α \* max(C/K,1)\^-1.209 \* 0.993\^A \* 1.1018 (if male) \* 1.159 (if black) where C = serum creatinine (in mg/dL) ; A = Age (in years); K = 0.7 for women and 0.9 for men; α = -0.329 for women and -0.411 for men. Baseline was Day 28 visit.

Outcome measures

Outcome measures
Measure	Tacrolimus n=93 Participants From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : tacrolimus (C0 6-10 ng/ml) + mycophenolic acid 1440 mg/d ± oral corticosteroids	Everolimus (RAD001) n=90 Participants From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : everolimus (recommended starting dose of 2 mg/day, then adjusted to achieve the target 6 ≤ C0 ≤ 10 ng/mL, until W24) + mycophenolic acid 1440 mg/d ± oral corticosteroids. The dose of tacrolimus was reduced by 50% twice: at the introduction of everolimus and at week 8 post-transplantation. Tacrolimus had to be finally discontinued in week 12 post-transplantation (by week 16 at the latest).
Change From Baseline (Randomization) in Glomerular Filtration Rate Estimated by CKD-EPI Formula	-6.9 mL/min/1.73m^2 Standard Deviation 20.11	2.4 mL/min/1.73m^2 Standard Deviation 22.18

SECONDARY outcome

Timeframe: At Week 24

Population: ITT population included all randomized patients who received at least one dose of study treatment post-randomization and for whom a creatinine value at D28 and a posterior value were available.

Kidney disease outcomes quality initiative (K/DOQI) classification is based on glomerular filtration rate (GFR), abbreviated MDRD formula (mL/min/1.73m\^2) : Stage 1 : GFR \>= 90; Stage 2 = GFR was between 60-89; Stage 3 = GFR was between 30-59 ; Stage 4 = GFR was between 15-29; Stage 5 = GFR was \< 15 (or dialysis)

Outcome measures

Outcome measures
Measure	Tacrolimus n=86 Participants From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : tacrolimus (C0 6-10 ng/ml) + mycophenolic acid 1440 mg/d ± oral corticosteroids	Everolimus (RAD001) n=74 Participants From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : everolimus (recommended starting dose of 2 mg/day, then adjusted to achieve the target 6 ≤ C0 ≤ 10 ng/mL, until W24) + mycophenolic acid 1440 mg/d ± oral corticosteroids. The dose of tacrolimus was reduced by 50% twice: at the introduction of everolimus and at week 8 post-transplantation. Tacrolimus had to be finally discontinued in week 12 post-transplantation (by week 16 at the latest).
Number of Patients in Different Stages of Chronic Kidney Diseases According to the K/DOQI Classification System Stage 1	24 Patients 27.89	41 Patients 92.00
Number of Patients in Different Stages of Chronic Kidney Diseases According to the K/DOQI Classification System Stage 2	34 Patients	29 Patients
Number of Patients in Different Stages of Chronic Kidney Diseases According to the K/DOQI Classification System Stage 3	28 Patients	4 Patients
Number of Patients in Different Stages of Chronic Kidney Diseases According to the K/DOQI Classification System Stage 4	0 Patients	0 Patients
Number of Patients in Different Stages of Chronic Kidney Diseases According to the K/DOQI Classification System Stage 5	0 Patients	0 Patients

SECONDARY outcome

Timeframe: Baseline to 24 weeks

Population: The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.

Baseline was Day 28 visit. This endpoint reports patients with total adverse events (any), serious adverse events, death and premature discontinuation.

Outcome measures

Outcome measures
Measure	Tacrolimus n=94 Participants From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : tacrolimus (C0 6-10 ng/ml) + mycophenolic acid 1440 mg/d ± oral corticosteroids	Everolimus (RAD001) n=90 Participants From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : everolimus (recommended starting dose of 2 mg/day, then adjusted to achieve the target 6 ≤ C0 ≤ 10 ng/mL, until W24) + mycophenolic acid 1440 mg/d ± oral corticosteroids. The dose of tacrolimus was reduced by 50% twice: at the introduction of everolimus and at week 8 post-transplantation. Tacrolimus had to be finally discontinued in week 12 post-transplantation (by week 16 at the latest).
Number of Patients With Any Adverse Events, Serious Adverse Events, Death and Premature Discontinuation Any Adverse events	85 Patients	81 Patients
Number of Patients With Any Adverse Events, Serious Adverse Events, Death and Premature Discontinuation Serious Adverse events	28 Patients	42 Patients
Number of Patients With Any Adverse Events, Serious Adverse Events, Death and Premature Discontinuation Death	1 Patients	2 Patients
Number of Patients With Any Adverse Events, Serious Adverse Events, Death and Premature Discontinuation At least one AE led to premature discontinuation	4 Patients	18 Patients

Adverse Events

Tacrolimus

Serious events: 28 serious events

Other events: 68 other events

Deaths: 0 deaths

Everolimus (RAD001)

Serious events: 42 serious events

Other events: 64 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: [email protected]

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

Measure	Tacrolimus n=94 participants at risk From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : tacrolimus (C0 6-10 ng/ml) + mycophenolic acid 1440 mg/d ± oral corticosteroids	Everolimus (RAD001) n=90 participants at risk From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : everolimus (recommended starting dose of 2 mg/day, then adjusted to achieve the target 6 ≤ C0 ≤ 10 ng/mL, until W24) + mycophenolic acid 1440 mg/d ± oral corticosteroids. The dose of tacrolimus was reduced by 50% twice: at the introduction of everolimus and at week 8 post-transplantation. Tacrolimus had to be finally discontinued in week 12 post-transplantation (by week 16 at the latest).
Blood and lymphatic system disorders Anaemia	7.4% 7/94 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.	13.3% 12/90 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.
Blood and lymphatic system disorders Leukopenia	8.5% 8/94 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.	11.1% 10/90 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.
Blood and lymphatic system disorders Lymphopenia	6.4% 6/94 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.	4.4% 4/90 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.
Blood and lymphatic system disorders Neutropenia	14.9% 14/94 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.	10.0% 9/90 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.
Blood and lymphatic system disorders Pancytopenia	1.1% 1/94 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.	5.6% 5/90 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.
Blood and lymphatic system disorders Thrombocytopenia	10.6% 10/94 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.	8.9% 8/90 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.
Gastrointestinal disorders Abdominal pain	5.3% 5/94 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.	3.3% 3/90 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.
Gastrointestinal disorders Aphthous stomatitis	0.00% 0/94 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.	8.9% 8/90 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.
Gastrointestinal disorders Diarrhoea	17.0% 16/94 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.	6.7% 6/90 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.
General disorders Oedema peripheral	6.4% 6/94 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.	7.8% 7/90 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.
Hepatobiliary disorders Cholestasis	12.8% 12/94 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.	26.7% 24/90 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.
Hepatobiliary disorders Hepatocellular injury	4.3% 4/94 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.	17.8% 16/90 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.
Infections and infestations Urinary tract infection	6.4% 6/94 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.	5.6% 5/90 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.
Metabolism and nutrition disorders Dyslipidaemia	1.1% 1/94 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.	7.8% 7/90 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.
Metabolism and nutrition disorders Hyperglycaemia	5.3% 5/94 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.	6.7% 6/90 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.
Metabolism and nutrition disorders Hyperkalaemia	3.2% 3/94 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.	7.8% 7/90 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.
Metabolism and nutrition disorders Hypokalaemia	2.1% 2/94 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.	12.2% 11/90 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.
Renal and urinary disorders Renal failure	11.7% 11/94 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.	3.3% 3/90 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.
Vascular disorders Hypertension	12.8% 12/94 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.	7.8% 7/90 The safety population included all randomized patients who received at least one dose of study treatment post-randomization and for whom there was a post-treatment safety assessment.