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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 (SIMCER)

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ClinicalTrials.gov Identifier: NCT01625377
Recruitment Status : Completed
First Posted : June 21, 2012
Results First Posted : April 27, 2016
Last Update Posted : April 27, 2016
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Liver Transplantation
Interventions Drug: tacrolimus
Drug: everolimus
Drug: Basiliximab
Drug: Mycophenolic Acid
Drug: Corticosteroids
Enrollment 188
Recruitment Details  
Pre-assignment Details Total 188 patients were randomized
Arm/Group Title Tacrolimus Everolimus (RAD001)
Hide Arm/Group Description 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

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).

Period Title: Overall Study
Started 95 [1] 93
Safety Set of Population 94 90
Intent to Treat Population 93 90
Completed 88 71
Not Completed 7 22
Reason Not Completed
Death             1             1
Administrative Problem             1             1
Protocol Violation             0             3
Adverse Event             3             16
Graft loss             1             0
Unsatisfactory therapeutic effect             0             1
Abnormal laboratory values             1             0
[1]
"Started" indicates randomized patients.
Arm/Group Title Tacrolimus Everolimus (RAD001) Total
Hide Arm/Group Description 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

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 of all reporting groups
Overall Number of Baseline Participants 95 93 188
Hide Baseline Analysis Population Description
Randomized population
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 95 participants 93 participants 188 participants
55.5  (8.24) 56.5  (8.59) 56.0  (8.41)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 95 participants 93 participants 188 participants
Female
14
  14.7%
14
  15.1%
28
  14.9%
Male
81
  85.3%
79
  84.9%
160
  85.1%
1.Primary Outcome
Title Change From Baseline (Randomization) in Renal Function
Hide Description

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.

Time Frame Baseline, Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Tacrolimus Everolimus (RAD001)
Hide Arm/Group Description:
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

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 Number of Participants Analyzed 93 90
Least Squares Mean (Standard Error)
Unit of Measure: mL/min/1.73m^2
-13.29  (2.75) 1.05  (2.81)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tacrolimus, Everolimus (RAD001)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -14.34
Confidence Interval (2-Sided) 95%
-21.34 to -7.34
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Number of Patients With Treatment Failures
Hide Description

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.

Time Frame At week 12 and week 24
Hide Outcome Measure Data
Hide Analysis Population Description
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 Day 28 and a posterior value were available.
Arm/Group Title Tacrolimus Everolimus (RAD001)
Hide Arm/Group Description:
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

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 Number of Participants Analyzed 93 90
Measure Type: Number
Unit of Measure: Patients
week 12, Treatment failures - NO 91 88
week 12, Treatment failures - YES 2 2
week 24, Treatment failures - NO 89 81
week 24, Treatment failures - YES 4 9
3.Secondary Outcome
Title Number of Patients With Treated or Not Treated Biopsy Proven Acute Rejection (BPAR)
Hide Description Biopsy proven acute rejection was defined as a clinically suspected acute rejection confirmed by biopsy.
Time Frame at 12 week and 24 week
Hide Outcome Measure Data
Hide Analysis Population Description
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 Day 28 and a posterior value were available.
Arm/Group Title Tacrolimus Everolimus (RAD001)
Hide Arm/Group Description:
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

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 Number of Participants Analyzed 93 90
Measure Type: Number
Unit of Measure: Patients
Week 12, Treated BPAR 2 2
Week 12, Not treated BPAR 0 0
Week 24, Treated BPAR 2 8
Week 24, Not Treated BPAR 0 1
4.Secondary Outcome
Title Number of Patients Reported With Different Categories of Severity of BPAR According to Banff Classification
Hide Description

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.

Time Frame at 12 week and 24 week
Hide Outcome Measure Data
Hide Analysis Population Description
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 day 28 and a posterior value were available.
Arm/Group Title Tacrolimus Everolimus (RAD001)
Hide Arm/Group Description:
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

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 Number of Participants Analyzed 93 90
Measure Type: Number
Unit of Measure: Patients
Week 12: Mild 1 1
Week 12: Moderate 1 1
Week 12: Severe 0 0
Week 24: Mild 1 5
Week 24: Moderate 1 3
Week 24: Sever 0 0
5.Secondary Outcome
Title Number of Patients With Treated or Untreated BPAR With RAI Score Greater Than 3
Hide Description

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.

Time Frame At 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
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 day 28 and a posterior value were available.
Arm/Group Title Tacrolimus Everolimus (RAD001)
Hide Arm/Group Description:
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

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 Number of Participants Analyzed 93 90
Measure Type: Number
Unit of Measure: Patients
Not Treated BPAR: RAI score >3 0 0
Not Treated BPAR: Missing RAI score 0 1
Treated BPAR: RAI score >3 2 8
6.Secondary Outcome
Title Number of Patients With Death or Graft Loss
Hide Description 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.
Time Frame at week 24
Hide Outcome Measure Data
Hide Analysis Population Description
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 day 28 and a posterior value were available.
Arm/Group Title Tacrolimus Everolimus (RAD001)
Hide Arm/Group Description:
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

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 Number of Participants Analyzed 93 90
Measure Type: Number
Unit of Measure: Patients
Graft Loss 1 0
Death 1 1
7.Secondary Outcome
Title Change From Baseline (Randomization) in Serum Creatinine
Hide Description

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.

Time Frame Baseline, Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Tacrolimus Everolimus (RAD001)
Hide Arm/Group Description:
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

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 Number of Participants Analyzed 93 90
Mean (Standard Deviation)
Unit of Measure: µmol/L
7.2  (36.0) -1.3  (38.53)
8.Secondary Outcome
Title Change From Baseline (Randomization) in Urine Protein/Creatinine Ratio
Hide Description 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.
Time Frame Baseline, week 24
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Tacrolimus Everolimus (RAD001)
Hide Arm/Group Description:
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

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 Number of Participants Analyzed 64 61
Mean (Standard Deviation)
Unit of Measure: mg/mmol
-2.3  (27.89) 21.9  (92.00)
9.Secondary Outcome
Title Change From Baseline (Randomization) in Creatinine Clearance Estimated Using the Adjusted Cockcroft-Gault Formula
Hide Description 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.
Time Frame Baseline, Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Tacrolimus Everolimus (RAD001)
Hide Arm/Group Description:
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

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 Number of Participants Analyzed 93 90
Mean (Standard Deviation)
Unit of Measure: mL/min/1.73m^2
-9.0  (30.63) 0.7  (25.65)
10.Secondary Outcome
Title Change From Baseline (Randomization) in Glomerular Filtration Rate Estimated by Abbreviated Modification of Diet in Renal Disease (MDRD) Formula
Hide Description

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.

Time Frame Baseline, Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Tacrolimus Everolimus (RAD001)
Hide Arm/Group Description:
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

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 Number of Participants Analyzed 93 90
Mean (Standard Deviation)
Unit of Measure: mL/min/1.73m^2
-11.8  (34.01) 0.1  (32.59)
11.Secondary Outcome
Title Change From Baseline (Randomization) in Glomerular Filtration Rate Estimated by CKD-EPI Formula
Hide Description

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.

Time Frame Baseline, Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Tacrolimus Everolimus (RAD001)
Hide Arm/Group Description:
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

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 Number of Participants Analyzed 93 90
Mean (Standard Deviation)
Unit of Measure: mL/min/1.73m^2
-6.9  (20.11) 2.4  (22.18)
12.Secondary Outcome
Title Number of Patients in Different Stages of Chronic Kidney Diseases According to the K/DOQI Classification System
Hide Description

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)

Time Frame At Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Tacrolimus Everolimus (RAD001)
Hide Arm/Group Description:
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

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 Number of Participants Analyzed 86 74
Measure Type: Number
Unit of Measure: Patients
Stage 1 24 41
Stage 2 34 29
Stage 3 28 4
Stage 4 0 0
Stage 5 0 0
13.Secondary Outcome
Title Number of Patients With Any Adverse Events, Serious Adverse Events, Death and Premature Discontinuation
Hide Description Baseline was Day 28 visit. This endpoint reports patients with total adverse events (any), serious adverse events, death and premature discontinuation.
Time Frame Baseline to 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Tacrolimus Everolimus (RAD001)
Hide Arm/Group Description:
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

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 Number of Participants Analyzed 94 90
Measure Type: Number
Unit of Measure: Patients
Any Adverse events 85 81
Serious Adverse events 28 42
Death 1 2
At least one AE led to premature discontinuation 4 18
Time Frame [Not Specified]
Adverse Event Reporting Description 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.
 
Arm/Group Title Tacrolimus Everolimus (RAD001)
Hide Arm/Group Description 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

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).

All-Cause Mortality
Tacrolimus Everolimus (RAD001)
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Tacrolimus Everolimus (RAD001)
Affected / at Risk (%) Affected / at Risk (%)
Total   28/94 (29.79%)   42/90 (46.67%) 
Blood and lymphatic system disorders     
Agranulocytosis  1  1/94 (1.06%)  1/90 (1.11%) 
Anaemia  1  0/94 (0.00%)  1/90 (1.11%) 
Neutropenia  1  0/94 (0.00%)  1/90 (1.11%) 
Pancytopenia  1  0/94 (0.00%)  2/90 (2.22%) 
Thrombotic microangiopathy  1  0/94 (0.00%)  1/90 (1.11%) 
Cardiac disorders     
Cardiac failure  1  1/94 (1.06%)  0/90 (0.00%) 
Cardio-respiratory arrest  1  0/94 (0.00%)  1/90 (1.11%) 
Gastrointestinal disorders     
Abdominal pain  1  1/94 (1.06%)  0/90 (0.00%) 
Ascites  1  2/94 (2.13%)  1/90 (1.11%) 
Colitis  1  0/94 (0.00%)  1/90 (1.11%) 
Constipation  1  0/94 (0.00%)  1/90 (1.11%) 
Diarrhoea  1  4/94 (4.26%)  1/90 (1.11%) 
Pancreatitis  1  0/94 (0.00%)  1/90 (1.11%) 
Pancreatitis acute  1  1/94 (1.06%)  0/90 (0.00%) 
Vomiting  1  1/94 (1.06%)  1/90 (1.11%) 
General disorders     
Device dislocation  1  0/94 (0.00%)  1/90 (1.11%) 
Fatigue  1  0/94 (0.00%)  1/90 (1.11%) 
General physical health deterioration  1  1/94 (1.06%)  2/90 (2.22%) 
Generalised oedema  1  0/94 (0.00%)  1/90 (1.11%) 
Hyperthermia  1  0/94 (0.00%)  1/90 (1.11%) 
Pyrexia  1  1/94 (1.06%)  1/90 (1.11%) 
Sudden death  1  1/94 (1.06%)  0/90 (0.00%) 
Systemic inflammatory response syndrome  1  1/94 (1.06%)  0/90 (0.00%) 
Hepatobiliary disorders     
Bile duct stenosis  1  1/94 (1.06%)  1/90 (1.11%) 
Biloma  1  1/94 (1.06%)  0/90 (0.00%) 
Cholangiolitis  1  0/94 (0.00%)  1/90 (1.11%) 
Cholangitis  1  2/94 (2.13%)  1/90 (1.11%) 
Cholestasis  1  0/94 (0.00%)  1/90 (1.11%) 
Hepatic artery stenosis  1  1/94 (1.06%)  0/90 (0.00%) 
Hepatic function abnormal  1  0/94 (0.00%)  1/90 (1.11%) 
Hepatic vein stenosis  1  1/94 (1.06%)  0/90 (0.00%) 
Hepatic vein thrombosis  1  1/94 (1.06%)  0/90 (0.00%) 
Hepatitis cholestatic  1  1/94 (1.06%)  0/90 (0.00%) 
Hepatocellular injury  1  0/94 (0.00%)  2/90 (2.22%) 
Hepatorenal syndrome  1  1/94 (1.06%)  0/90 (0.00%) 
Jaundice  1  0/94 (0.00%)  1/90 (1.11%) 
Liver disorder  1  1/94 (1.06%)  0/90 (0.00%) 
Nodular regenerative hyperplasia  1  0/94 (0.00%)  1/90 (1.11%) 
Immune system disorders     
Liver transplant rejection  1  3/94 (3.19%)  5/90 (5.56%) 
Transplant rejection  1  0/94 (0.00%)  2/90 (2.22%) 
Infections and infestations     
Abdominal wall abscess  1  0/94 (0.00%)  1/90 (1.11%) 
Abscess oral  1  0/94 (0.00%)  1/90 (1.11%) 
Campylobacter infection  1  0/94 (0.00%)  1/90 (1.11%) 
Cholangitis suppurative  1  1/94 (1.06%)  0/90 (0.00%) 
Clostridium difficile colitis  1  1/94 (1.06%)  0/90 (0.00%) 
Cytomegalovirus infection  1  1/94 (1.06%)  1/90 (1.11%) 
Erysipelas  1  0/94 (0.00%)  1/90 (1.11%) 
Hepatic infection  1  0/94 (0.00%)  1/90 (1.11%) 
Infectious pleural effusion  1  0/94 (0.00%)  1/90 (1.11%) 
Liver abscess  1  0/94 (0.00%)  1/90 (1.11%) 
Lung infection  1  1/94 (1.06%)  1/90 (1.11%) 
Oral infection  1  0/94 (0.00%)  1/90 (1.11%) 
Pneumococcal infection  1  1/94 (1.06%)  0/90 (0.00%) 
Pyelonephritis  1  0/94 (0.00%)  1/90 (1.11%) 
Sepsis  1  0/94 (0.00%)  5/90 (5.56%) 
Septic arthritis staphylococcal  1  1/94 (1.06%)  0/90 (0.00%) 
Septic shock  1  1/94 (1.06%)  1/90 (1.11%) 
Sinusitis aspergillus  1  1/94 (1.06%)  0/90 (0.00%) 
Soft tissue infection  1  1/94 (1.06%)  0/90 (0.00%) 
Urinary tract infection  1  0/94 (0.00%)  1/90 (1.11%) 
Injury, poisoning and procedural complications     
Anastomotic stenosis  1  1/94 (1.06%)  0/90 (0.00%) 
Biliary anastomosis complication  1  4/94 (4.26%)  5/90 (5.56%) 
Liver graft loss  1  1/94 (1.06%)  0/90 (0.00%) 
Overdose  1  0/94 (0.00%)  1/90 (1.11%) 
Post procedural bile leak  1  1/94 (1.06%)  1/90 (1.11%) 
Rib fracture  1  0/94 (0.00%)  1/90 (1.11%) 
Spinal fracture  1  1/94 (1.06%)  0/90 (0.00%) 
Vascular pseudoaneurysm  1  1/94 (1.06%)  0/90 (0.00%) 
Wound evisceration  1  0/94 (0.00%)  1/90 (1.11%) 
Investigations     
Weight decreased  1  1/94 (1.06%)  0/90 (0.00%) 
Metabolism and nutrition disorders     
Diabetes mellitus  1  0/94 (0.00%)  1/90 (1.11%) 
Diabetes mellitus inadequate control  1  1/94 (1.06%)  0/90 (0.00%) 
Hyperkalaemia  1  1/94 (1.06%)  0/90 (0.00%) 
Hyponatraemia  1  1/94 (1.06%)  0/90 (0.00%) 
Musculoskeletal and connective tissue disorders     
Back pain  1  0/94 (0.00%)  2/90 (2.22%) 
Chondrocalcinosis  1  1/94 (1.06%)  0/90 (0.00%) 
Osteoporotic fracture  1  0/94 (0.00%)  1/90 (1.11%) 
Nervous system disorders     
Convulsion  1  1/94 (1.06%)  0/90 (0.00%) 
Psychiatric disorders     
Depression  1  0/94 (0.00%)  1/90 (1.11%) 
Renal and urinary disorders     
Renal failure  1  4/94 (4.26%)  3/90 (3.33%) 
Renal failure acute  1  2/94 (2.13%)  2/90 (2.22%) 
Respiratory, thoracic and mediastinal disorders     
Acute respiratory distress syndrome  1  0/94 (0.00%)  1/90 (1.11%) 
Asphyxia  1  0/94 (0.00%)  1/90 (1.11%) 
Dyspnoea  1  1/94 (1.06%)  0/90 (0.00%) 
Lung disorder  1  0/94 (0.00%)  2/90 (2.22%) 
Pleural effusion  1  0/94 (0.00%)  1/90 (1.11%) 
Respiratory distress  1  0/94 (0.00%)  2/90 (2.22%) 
Skin and subcutaneous tissue disorders     
Purpura  1  0/94 (0.00%)  1/90 (1.11%) 
Social circumstances     
Physical disability  1  0/94 (0.00%)  1/90 (1.11%) 
Surgical and medical procedures     
Diabetes mellitus management  1  1/94 (1.06%)  1/90 (1.11%) 
Drain removal  1  1/94 (1.06%)  0/90 (0.00%) 
Umbilical hernia repair  1  1/94 (1.06%)  0/90 (0.00%) 
Vascular disorders     
Arterial stenosis  1  0/94 (0.00%)  2/90 (2.22%) 
Deep vein thrombosis  1  0/94 (0.00%)  1/90 (1.11%) 
Lymphoedema  1  0/94 (0.00%)  2/90 (2.22%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, 15.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Tacrolimus Everolimus (RAD001)
Affected / at Risk (%) Affected / at Risk (%)
Total   68/94 (72.34%)   64/90 (71.11%) 
Blood and lymphatic system disorders     
Anaemia  1  7/94 (7.45%)  12/90 (13.33%) 
Leukopenia  1  8/94 (8.51%)  10/90 (11.11%) 
Lymphopenia  1  6/94 (6.38%)  4/90 (4.44%) 
Neutropenia  1  14/94 (14.89%)  9/90 (10.00%) 
Pancytopenia  1  1/94 (1.06%)  5/90 (5.56%) 
Thrombocytopenia  1  10/94 (10.64%)  8/90 (8.89%) 
Gastrointestinal disorders     
Abdominal pain  1  5/94 (5.32%)  3/90 (3.33%) 
Aphthous stomatitis  1  0/94 (0.00%)  8/90 (8.89%) 
Diarrhoea  1  16/94 (17.02%)  6/90 (6.67%) 
General disorders     
Oedema peripheral  1  6/94 (6.38%)  7/90 (7.78%) 
Hepatobiliary disorders     
Cholestasis  1  12/94 (12.77%)  24/90 (26.67%) 
Hepatocellular injury  1  4/94 (4.26%)  16/90 (17.78%) 
Infections and infestations     
Urinary tract infection  1  6/94 (6.38%)  5/90 (5.56%) 
Metabolism and nutrition disorders     
Dyslipidaemia  1  1/94 (1.06%)  7/90 (7.78%) 
Hyperglycaemia  1  5/94 (5.32%)  6/90 (6.67%) 
Hyperkalaemia  1  3/94 (3.19%)  7/90 (7.78%) 
Hypokalaemia  1  2/94 (2.13%)  11/90 (12.22%) 
Renal and urinary disorders     
Renal failure  1  11/94 (11.70%)  3/90 (3.33%) 
Vascular disorders     
Hypertension  1  12/94 (12.77%)  7/90 (7.78%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, 15.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Name/Title: Study Director
Organization: Novartis Pharmaceuticals
Phone: 862-778-8300
Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01625377     History of Changes
Other Study ID Numbers: CRAD001HFR02
2012-000137-39 ( EudraCT Number )
First Submitted: June 19, 2012
First Posted: June 21, 2012
Results First Submitted: March 25, 2016
Results First Posted: April 27, 2016
Last Update Posted: April 27, 2016