Trial Outcomes & Findings for A Multicentre, Randomised, Open-label, Controlled, 12-month Follow-up Study to Assess Impact on Renal Function of an Immunosuppression Regimen Based on Tacrolimus Minimisation in Association With Everolimus in de Novo Liver Transplant Recipients. (NCT NCT02040584)

NCT ID: NCT02040584

Last Updated: 2019-06-13

Results Overview

Clinical benefit is defined as: • an improvement in 1 or 2 ranges of the eGFR, according to MDRD-4 at Week 52 post-transplant in patients with values of 30-\<45 or 45-\<60 mL/min/1.73 m2 in Week 4. or • stabilisation of eGFR in patients with values ≥60 mL/min/1.73 m2 at Week 4 and maintained at Week 52 post-transplant.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

217 participants

Primary outcome timeframe

week 4, week 52.

Results posted on

2019-06-13

Participant Flow

Patients enrolled were 217, patients in the safety population were 215, and patients in the ITT population were 211.

The intention-to-treat population (ITT) that was used for all efficacy analyses included all randomised patients who had received at least one dose of the study medication (safety population) and had at least one assessment subsequent to the randomisation visit for determining the primary efficacy endpoint.

Participant milestones

Participant milestones
Measure	Experimental Group Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids	Control Group Treatment with TAC + MMF + corticosteroids
Overall Study STARTED	105	106
Overall Study COMPLETED	70	74
Overall Study NOT COMPLETED	35	32

Reasons for withdrawal

Reasons for withdrawal
Measure	Experimental Group Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids	Control Group Treatment with TAC + MMF + corticosteroids
Overall Study Adverse Event	13	6
Overall Study Protocol Violation	9	11
Overall Study Unsatisfactory therapeutic effect	0	1
Overall Study Death	6	3
Overall Study Transplant rejection/retransplant	0	1
Overall Study Immunosuppressant/prohibited med use	7	10

Baseline Characteristics

A Multicentre, Randomised, Open-label, Controlled, 12-month Follow-up Study to Assess Impact on Renal Function of an Immunosuppression Regimen Based on Tacrolimus Minimisation in Association With Everolimus in de Novo Liver Transplant Recipients.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Experimental Group n=105 Participants Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids	Control Group n=106 Participants Treatment with TAC + MMF + corticosteroids	Total n=211 Participants Total of all reporting groups
Age, Continuous	58.43 years STANDARD_DEVIATION 6.37 • n=5 Participants	55.84 years STANDARD_DEVIATION 7.45 • n=7 Participants	57.13 years STANDARD_DEVIATION 7.04 • n=5 Participants
Sex: Female, Male Female	14 Participants n=5 Participants	16 Participants n=7 Participants	30 Participants n=5 Participants
Sex: Female, Male Male	91 Participants n=5 Participants	90 Participants n=7 Participants	181 Participants n=5 Participants

PRIMARY outcome

Timeframe: week 4, week 52.

Population: ITT

Outcome measures

Outcome measures
Measure	Experimental Group n=105 Participants Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids	Control Group n=106 Participants Treatment with TAC + MMF + corticosteroids	20 to 24 Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score 20 to 24	25 to 29 Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score 25 to 29	> = 30 Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score \> = 30	<= 14 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score \<= 14	15 to 19 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 15 to 19	20 to 24 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 20 to 24	25 to 29 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 25 to 29	> = 30 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score \> = 30
Percentages of Participants Showing Clinical Benefit by Renal Function Stratification > = 30 - 45 ml/min/1.73m^2 at Week 52	4.76 Percentages of partcipants	3.77 Percentages of partcipants	—	—	—	—	—	—	—	—
Percentages of Participants Showing Clinical Benefit by Renal Function Stratification > = 45 - <60 ml/min/1.73m^2 at Week 52	14.29 Percentages of partcipants	16.04 Percentages of partcipants	—	—	—	—	—	—	—	—
Percentages of Participants Showing Clinical Benefit by Renal Function Stratification > = 60 ml/min/1.73m^2 at Week 52	79.05 Percentages of partcipants	79.25 Percentages of partcipants	—	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Screening visit (transplant), weeks 1,4,12,24,36 and 52 post-transplant

Population: ITT

Kidney function was assessed over time by creatine clearance based on the Cockcroft-Gault formula. Estimated creatinine clearance (mL/min) = \[(140 - age) x (weight) x (0.85 if female)\] / (72 x serum creatinine). Units: age (years); weight (kg); serum creatinine (mg/dL). The values of the eGFR according to the creatinine clearance (Cockcroft-Gault formula) for the ITT population were ml/min/1.73 m\^2.

Outcome measures

Outcome measures
Measure	Experimental Group n=105 Participants Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids	Control Group n=106 Participants Treatment with TAC + MMF + corticosteroids	20 to 24 Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score 20 to 24	25 to 29 Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score 25 to 29	> = 30 Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score \> = 30	<= 14 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score \<= 14	15 to 19 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 15 to 19	20 to 24 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 20 to 24	25 to 29 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 25 to 29	> = 30 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score \> = 30
Changes in Creatinine Clearance - Cockcroft-Gault Formula Screening	104.67 ml/min/1.73m^2 Standard Deviation 36.40	109.69 ml/min/1.73m^2 Standard Deviation 48.47	—	—	—	—	—	—	—	—
Changes in Creatinine Clearance - Cockcroft-Gault Formula Week 1	116.93 ml/min/1.73m^2 Standard Deviation 44.82	118.09 ml/min/1.73m^2 Standard Deviation 44.82	—	—	—	—	—	—	—	—
Changes in Creatinine Clearance - Cockcroft-Gault Formula Week 4	80.19 ml/min/1.73m^2 Standard Deviation 28.00	91.26 ml/min/1.73m^2 Standard Deviation 37.60	—	—	—	—	—	—	—	—
Changes in Creatinine Clearance - Cockcroft-Gault Formula Week 12	87.76 ml/min/1.73m^2 Standard Deviation 26.51	90.14 ml/min/1.73m^2 Standard Deviation 35.82	—	—	—	—	—	—	—	—
Changes in Creatinine Clearance - Cockcroft-Gault Formula Week 24	89.57 ml/min/1.73m^2 Standard Deviation 32.89	87.93 ml/min/1.73m^2 Standard Deviation 35.92	—	—	—	—	—	—	—	—
Changes in Creatinine Clearance - Cockcroft-Gault Formula Week 36	94.46 ml/min/1.73m^2 Standard Deviation 30.26	90.91 ml/min/1.73m^2 Standard Deviation 35.96	—	—	—	—	—	—	—	—
Changes in Creatinine Clearance - Cockcroft-Gault Formula Week 52	92.21 ml/min/1.73m^2 Standard Deviation 29.96	91.04 ml/min/1.73m^2 Standard Deviation 37.26	—	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Screening visit (transplant), weeks 1,4,12,24,36 and 52 post-transplant

Population: ITT

Kidney function was assessed over time by changes in eGFR according to the MDRD-4 formula. The MDRD-4 formula (Levey et al., 2000) was used based on serum concentration of creatinine (conventional units): eGFR (mL/min/1.73 m2) = 186 x (serum creatinine)-1.154 x (age)-0.203 x (0.742 if female) x (1.210 if of African descent). Units: serum creatinine (mg/dL); age (years).

Outcome measures

Outcome measures
Measure	Experimental Group n=105 Participants Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids	Control Group n=106 Participants Treatment with TAC + MMF + corticosteroids	20 to 24 Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score 20 to 24	25 to 29 Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score 25 to 29	> = 30 Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score \> = 30	<= 14 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score \<= 14	15 to 19 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 15 to 19	20 to 24 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 20 to 24	25 to 29 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 25 to 29	> = 30 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score \> = 30
Changes in eGFR Based on the MDRD-4 Formula Screening	100.20 ml/min/1.73m2 Standard Deviation 38.74	99.42 ml/min/1.73m2 Standard Deviation 43.09	—	—	—	—	—	—	—	—
Changes in eGFR Based on the MDRD-4 Formula Week 1	112.86 ml/min/1.73m2 Standard Deviation 50.06	112.15 ml/min/1.73m2 Standard Deviation 48.16	—	—	—	—	—	—	—	—
Changes in eGFR Based on the MDRD-4 Formula Week 4	82.18 ml/min/1.73m2 Standard Deviation 28.47	88.39 ml/min/1.73m2 Standard Deviation 34.32	—	—	—	—	—	—	—	—
Changes in eGFR Based on the MDRD-4 Formula Week 12	85.99 ml/min/1.73m2 Standard Deviation 25.13	83.57 ml/min/1.73m2 Standard Deviation 28.19	—	—	—	—	—	—	—	—
Changes in eGFR Based on the MDRD-4 Formula Week 24	86.02 ml/min/1.73m2 Standard Deviation 31.97	82.00 ml/min/1.73m2 Standard Deviation 26.93	—	—	—	—	—	—	—	—
Changes in eGFR Based on the MDRD-4 Formula Week 36	87.68 ml/min/1.73m2 Standard Deviation 32.49	83.04 ml/min/1.73m2 Standard Deviation 25.56	—	—	—	—	—	—	—	—
Changes in eGFR Based on the MDRD-4 Formula Week 52	86.09 ml/min/1.73m2 Standard Deviation 27.87	83.23 ml/min/1.73m2 Standard Deviation 25.24	—	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Screening visit (transplant), weeks 1,4,12,24,36 and 52 post-transplant

Population: ITT population (patients with MDRD-4 values).

Model for End Stage Liver Disease (MELD) score: ≤14, 15-19, 20-24, 25-29, ≥30. The higher the number indicates the urgency for transplant.

Outcome measures

Outcome measures
Measure	Experimental Group n=52 Participants Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids	Control Group n=25 Participants Treatment with TAC + MMF + corticosteroids	20 to 24 n=21 Participants Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score 20 to 24	25 to 29 n=5 Participants Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score 25 to 29	> = 30 n=1 Participants Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score \> = 30	<= 14 Control Group n=56 Participants Control group (Treatment with TAC + MMF + corticosteroids) with MELD score \<= 14	15 to 19 Control Group n=24 Participants Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 15 to 19	20 to 24 Control Group n=18 Participants Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 20 to 24	25 to 29 Control Group n=3 Participants Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 25 to 29	> = 30 Control Group n=4 Participants Control group (Treatment with TAC + MMF + corticosteroids) with MELD score \> = 30
eGFR Values(MDRD-4 Formula) According to the MELD Score Week 12	85.81 ml/min/1.73m^2 Interval 64.65 to 98.87	88.76 ml/min/1.73m^2 Interval 65.92 to 118.2	83.91 ml/min/1.73m^2 Interval 68.46 to 94.96	94.82 ml/min/1.73m^2 Interval 50.94 to 106.28	56.67 ml/min/1.73m^2 Interval 56.67 to 56.67	83.63 ml/min/1.73m^2 Interval 69.33 to 101.35	67.00 ml/min/1.73m^2 Interval 48.31 to 99.84	87.22 ml/min/1.73m^2 Interval 67.63 to 107.01	65.01 ml/min/1.73m^2 Interval 43.15 to 96.53	81.92 ml/min/1.73m^2 Interval 58.33 to 87.43
eGFR Values(MDRD-4 Formula) According to the MELD Score Screening	96.63 ml/min/1.73m^2 Interval 76.31 to 119.5	90.29 ml/min/1.73m^2 Interval 65.64 to 114.92	88.89 ml/min/1.73m^2 Interval 70.03 to 114.67	104.45 ml/min/1.73m^2 Interval 93.21 to 123.9	38.35 ml/min/1.73m^2 Interval 38.35 to 38.35	102.27 ml/min/1.73m^2 Interval 75.09 to 120.19	93.85 ml/min/1.73m^2 Interval 73.93 to 123.19	91.45 ml/min/1.73m^2 Interval 68.74 to 116.49	99.50 ml/min/1.73m^2 Interval 19.76 to 137.89	53.73 ml/min/1.73m^2 Interval 38.82 to 66.97
eGFR Values(MDRD-4 Formula) According to the MELD Score Week 1	114.00 ml/min/1.73m^2 Interval 94.24 to 142.51	93.31 ml/min/1.73m^2 Interval 76.61 to 127.75	83.45 ml/min/1.73m^2 Interval 66.76 to 114.06	137.61 ml/min/1.73m^2 Interval 124.3 to 148.67	82.04 ml/min/1.73m^2 Interval 82.04 to 82.04	108.64 ml/min/1.73m^2 Interval 83.22 to 138.55	92.98 ml/min/1.73m^2 Interval 55.41 to 129.49	119.19 ml/min/1.73m^2 Interval 100.53 to 147.6	156.41 ml/min/1.73m^2 Interval 29.81 to 184.87	86.45 ml/min/1.73m^2 Interval 57.98 to 117.96
eGFR Values(MDRD-4 Formula) According to the MELD Score Week 4	81.37 ml/min/1.73m^2 Interval 63.46 to 92.2	85.19 ml/min/1.73m^2 Interval 66.09 to 99.26	70.57 ml/min/1.73m^2 Interval 51.9 to 99.02	75.94 ml/min/1.73m^2 Interval 50.93 to 121.86	69.43 ml/min/1.73m^2 Interval 69.43 to 69.43	89.44 ml/min/1.73m^2 Interval 62.78 to 107.55	72.76 ml/min/1.73m^2 Interval 51.64 to 113.93	89.67 ml/min/1.73m^2 Interval 63.89 to 133.44	85.23 ml/min/1.73m^2 Interval 42.83 to 109.13	78.57 ml/min/1.73m^2 Interval 51.47 to 108.61
eGFR Values(MDRD-4 Formula) According to the MELD Score Week 24	80.76 ml/min/1.73m^2 Interval 64.37 to 107.89	81.41 ml/min/1.73m^2 Interval 57.22 to 104.86	78.88 ml/min/1.73m^2 Interval 62.22 to 94.68	84.86 ml/min/1.73m^2 Interval 68.54 to 101.19	60.37 ml/min/1.73m^2 Interval 60.37 to 60.37	80.01 ml/min/1.73m^2 Interval 66.16 to 97.47	70.27 ml/min/1.73m^2 Interval 55.26 to 93.99	82.64 ml/min/1.73m^2 Interval 65.25 to 113.8	88.34 ml/min/1.73m^2 Interval 30.17 to 104.72	62.74 ml/min/1.73m^2 Interval 47.46 to 75.65
eGFR Values(MDRD-4 Formula) According to the MELD Score Week 36	81.96 ml/min/1.73m^2 Interval 64.82 to 111.44	92.44 ml/min/1.73m^2 Interval 68.05 to 113.18	75.62 ml/min/1.73m^2 Interval 61.64 to 100.46	83.09 ml/min/1.73m^2 Interval 55.72 to 110.46	58.07 ml/min/1.73m^2 Interval 58.07 to 58.07	86.72 ml/min/1.73m^2 Interval 72.09 to 97.4	67.90 ml/min/1.73m^2 Interval 54.34 to 90.95	86.17 ml/min/1.73m^2 Interval 68.59 to 107.21	68.32 ml/min/1.73m^2 Interval 57.01 to 79.63	65.58 ml/min/1.73m^2 Interval 45.11 to 73.55
eGFR Values(MDRD-4 Formula) According to the MELD Score Week 52	86.14 ml/min/1.73m^2 Interval 66.7 to 101.59	88.94 ml/min/1.73m^2 Interval 65.24 to 114.5	71.60 ml/min/1.73m^2 Interval 62.48 to 89.66	83.94 ml/min/1.73m^2 Interval 60.69 to 107.2	53.93 ml/min/1.73m^2 Interval 53.93 to 53.93	80.92 ml/min/1.73m^2 Interval 68.98 to 104.03	70.32 ml/min/1.73m^2 Interval 54.12 to 82.38	90.66 ml/min/1.73m^2 Interval 74.52 to 113.18	74.82 ml/min/1.73m^2 Interval 69.0 to 80.63	63.26 ml/min/1.73m^2 Interval 45.52 to 79.77

SECONDARY outcome

Timeframe: Screening visit, week 1,4,18,24, and 52

Population: ITT

The urine protein/creatinine ratio was assessed throughout follow-up in both treatment groups.

Outcome measures

Outcome measures
Measure	Experimental Group n=105 Participants Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids	Control Group n=106 Participants Treatment with TAC + MMF + corticosteroids	20 to 24 Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score 20 to 24	25 to 29 Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score 25 to 29	> = 30 Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score \> = 30	<= 14 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score \<= 14	15 to 19 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 15 to 19	20 to 24 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 20 to 24	25 to 29 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 25 to 29	> = 30 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score \> = 30
Urine Protein/Creatinine Ratio Screening	199.89 mg/g Standard Deviation 582.03	131.56 mg/g Standard Deviation 178.95	—	—	—	—	—	—	—	—
Urine Protein/Creatinine Ratio Week 1	252.48 mg/g Standard Deviation 308.22	349.46 mg/g Standard Deviation 396.44	—	—	—	—	—	—	—	—
Urine Protein/Creatinine Ratio Week 4	134.77 mg/g Standard Deviation 175.05	141.71 mg/g Standard Deviation 187.11	—	—	—	—	—	—	—	—
Urine Protein/Creatinine Ratio Week 18	204.26 mg/g Standard Deviation 688.05	105.02 mg/g Standard Deviation 79.61	—	—	—	—	—	—	—	—
Urine Protein/Creatinine Ratio Week 24	200.17 mg/g Standard Deviation 466.55	120.52 mg/g Standard Deviation 108.04	—	—	—	—	—	—	—	—
Urine Protein/Creatinine Ratio Week 52	219.41 mg/g Standard Deviation 406.52	143.05 mg/g Standard Deviation 220.72	—	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Screening visit, week 1,4,18,24, and 52

Population: ITT

The incidence of proteinuria (≥0.5-0.9 g/day, ≥1.0-2.9 g/day and ≥3.0 g/day) was assessed throughout follow-up in both treatment groups. Proteinuria was defined as protein/creatinine ratio ≥ 0.5.

Outcome measures

Outcome measures
Measure	Experimental Group n=105 Participants Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids	Control Group n=106 Participants Treatment with TAC + MMF + corticosteroids	20 to 24 Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score 20 to 24	25 to 29 Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score 25 to 29	> = 30 Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score \> = 30	<= 14 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score \<= 14	15 to 19 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 15 to 19	20 to 24 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 20 to 24	25 to 29 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 25 to 29	> = 30 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score \> = 30
Percentage of Participants With Incidence of Proteinuria ≥ 0.5-1.0 g/day at screening	0.00 Percentages of participants	3.77 Percentages of participants	—	—	—	—	—	—	—	—
Percentage of Participants With Incidence of Proteinuria ≥ 1.0-3.0 g/day at screening	2.00 Percentages of participants	1.89 Percentages of participants	—	—	—	—	—	—	—	—
Percentage of Participants With Incidence of Proteinuria ≥ 3.0 g/day at screening	2.00 Percentages of participants	0.00 Percentages of participants	—	—	—	—	—	—	—	—
Percentage of Participants With Incidence of Proteinuria ≥ 0.5-1.0 g/day at Week 1	3.23 Percentages of participants	18.31 Percentages of participants	—	—	—	—	—	—	—	—
Percentage of Participants With Incidence of Proteinuria ≥ 1.0-3.0 g/day at Week 1	6.45 Percentages of participants	5.63 Percentages of participants	—	—	—	—	—	—	—	—
Percentage of Participants With Incidence of Proteinuria ≥ 3.0 g/day at Week 1	0.00 Percentages of participants	0.00 Percentages of participants	—	—	—	—	—	—	—	—
Percentage of Participants With Incidence of Proteinuria ≥ 0.5-1.0 g/day at Week 4	5.21 Percentages of participants	1.05 Percentages of participants	—	—	—	—	—	—	—	—
Percentage of Participants With Incidence of Proteinuria ≥ 1.0-3.0 g/day at Week 4	0.00 Percentages of participants	1.05 Percentages of participants	—	—	—	—	—	—	—	—
Percentage of Participants With Incidence of Proteinuria ≥ 3.0 g/day at Week 4	0.00 Percentages of participants	0.00 Percentages of participants	—	—	—	—	—	—	—	—
Percentage of Participants With Incidence of Proteinuria ≥ 0.5-1.0 g/day at Week 18	0.00 Percentages of participants	0.00 Percentages of participants	—	—	—	—	—	—	—	—
Percentage of Participants With Incidence of Proteinuria ≥ 1.0-3.0 g/day at Week 18	1.39 Percentages of participants	0.00 Percentages of participants	—	—	—	—	—	—	—	—
Percentage of Participants With Incidence of Proteinuria ≥ 3.0 g/day at Week 18	1.39 Percentages of participants	0.00 Percentages of participants	—	—	—	—	—	—	—	—
Percentage of Participants With Incidence of Proteinuria ≥ 0.5-1.0 g/day at Week 24	7.58 Percentages of participants	1.52 Percentages of participants	—	—	—	—	—	—	—	—
Percentage of Participants With Incidence of Proteinuria ≥ 1.0-3.0 g/day at Week 24	0.00 Percentages of participants	0.00 Percentages of participants	—	—	—	—	—	—	—	—
Percentage of Participants With Incidence of Proteinuria ≥ 3.0 g/day at Week 24	1.52 Percentages of participants	0.00 Percentages of participants	—	—	—	—	—	—	—	—
Percentage of Participants With Incidence of Proteinuria ≥ 0.5-1.0 g/day at Week 52	6.67 Percentages of participants	1.89 Percentages of participants	—	—	—	—	—	—	—	—
Percentage of Participants With Incidence of Proteinuria ≥ 1.0-3.0 g/day at Week 52	3.33 Percentages of participants	1.89 Percentages of participants	—	—	—	—	—	—	—	—
Percentage of Participants With Incidence of Proteinuria ≥ 3.0 g/day at Week 52	0.00 Percentages of participants	0.00 Percentages of participants	—	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Throughout the study period, approximately 2 years and 2 months

Population: ITT

Liver biopsy had to be performed in all cases where acute rejection was suspected. Results of the biopsy were interpreted by the local pathologist (who did not known the treatment given to the patient) according to the Banff classification (1997). Biopsy-proven acute rejection (BPAR) defined as clinical suspicion of acute rejection confirmed in biopsy. Treated BPAR was deemed to be an episode of acute rejection in which the interpretation of the local pathologist showed that it reached any grade of acute rejection under the Banff classification, and for which anti-rejection therapy was administered. Loss of the liver allograft was deemed to have occurred the day that the patient was again included on the waiting list for liver transplant, the day he or she received another allograft or upon the death of the patient. All suspected hepatic allograft rejections were considered acute rejection

Outcome measures

Outcome measures
Measure	Experimental Group n=105 Participants Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids	Control Group n=106 Participants Treatment with TAC + MMF + corticosteroids	20 to 24 Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score 20 to 24	25 to 29 Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score 25 to 29	> = 30 Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score \> = 30	<= 14 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score \<= 14	15 to 19 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 15 to 19	20 to 24 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 20 to 24	25 to 29 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 25 to 29	> = 30 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score \> = 30
Percentage of Participants With Acute Rejection, BPAR, and Treated BPAR Patients with suspected acute rejection	17.14 Percentages of participants	15.09 Percentages of participants	—	—	—	—	—	—	—	—
Percentage of Participants With Acute Rejection, BPAR, and Treated BPAR Patients with BPAR	5.71 Percentages of participants	3.77 Percentages of participants	—	—	—	—	—	—	—	—
Percentage of Participants With Acute Rejection, BPAR, and Treated BPAR Patients with treated BPAR	4.76 Percentages of participants	1.89 Percentages of participants	—	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Throughout study period, approximately 2 years and 2 months

Population: ITT

Time to acute rejection was calculated from the date of transplantation. Acute rejection date was taken from biopsy date, as the date of rejection was not collected. Time to treated BPAR was calculated from the date of transplantation.

Outcome measures

Outcome measures
Measure	Experimental Group n=105 Participants Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids	Control Group n=106 Participants Treatment with TAC + MMF + corticosteroids	20 to 24 Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score 20 to 24	25 to 29 Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score 25 to 29	> = 30 Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score \> = 30	<= 14 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score \<= 14	15 to 19 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 15 to 19	20 to 24 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 20 to 24	25 to 29 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 25 to 29	> = 30 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score \> = 30
Time to Rejection Time to acute rejection	3.74 months Standard Deviation 3.15	2.91 months Standard Deviation 2.89	—	—	—	—	—	—	—	—
Time to Rejection Time to treated BPAR	2.65 months Standard Deviation 1.50	3.85 months Standard Deviation 5.25	—	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Throughout study period, approximately 2 years and 2 months

Population: ITT

Severity of acute rejection and treated BPAR was graded according to Banff criteria. Grade of acute rejection according to Banff criteria: mild, moderate, severe.

Outcome measures

Outcome measures
Measure	Experimental Group n=105 Participants Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids	Control Group n=106 Participants Treatment with TAC + MMF + corticosteroids	20 to 24 Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score 20 to 24	25 to 29 Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score 25 to 29	> = 30 Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score \> = 30	<= 14 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score \<= 14	15 to 19 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 15 to 19	20 to 24 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 20 to 24	25 to 29 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 25 to 29	> = 30 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score \> = 30
Severity of Rejection Severity of treated BPAR: Mild (Grade I)	33.33 Percentages of participants	0.00 Percentages of participants	—	—	—	—	—	—	—	—
Severity of Rejection Severity of acute rejection: Mild (Grade I)	13.64 Percentages of participants 3.15	11.11 Percentages of participants 2.89	—	—	—	—	—	—	—	—
Severity of Rejection Severity of acute rejection: Moderate(Grade II)	13.64 Percentages of participants 1.50	5.56 Percentages of participants 5.25	—	—	—	—	—	—	—	—
Severity of Rejection Severity of acute rejection: Severe(Grade III)	0.00 Percentages of participants	5.56 Percentages of participants	—	—	—	—	—	—	—	—
Severity of Rejection Severity of treated BPAR: Moderate(Grade II)	50.00 Percentages of participants	50.00 Percentages of participants	—	—	—	—	—	—	—	—
Severity of Rejection Severity of treated BPAR: Severe(Grade III)	0.00 Percentages of participants	50.00 Percentages of participants	—	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: approximately 2 years and 2 months

Population: ITT

The viral load of HCV-RNA and HCV genotype was assessed in HCV-positive patients. The term "genotype" was used to describe strains of HCV that vary but were related to the virus. Worldwide, there were 11 primary groups of HCV genotypes designated by the numbers from 1-11, with the most common in our setting being subtypes 1a, 1b, 2 and 3, which were identified in the local laboratory according to their usual testing methods.

Outcome measures

Outcome measures
Measure	Experimental Group n=105 Participants Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids	Control Group n=106 Participants Treatment with TAC + MMF + corticosteroids	20 to 24 Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score 20 to 24	25 to 29 Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score 25 to 29	> = 30 Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score \> = 30	<= 14 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score \<= 14	15 to 19 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 15 to 19	20 to 24 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 20 to 24	25 to 29 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 25 to 29	> = 30 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score \> = 30
Percentages of Participants With HCV-positive and HCV Genotype Hepatitis C virus (HVC) positive	33.33 Percentages of participants	36.79 Percentages of participants	—	—	—	—	—	—	—	—
Percentages of Participants With HCV-positive and HCV Genotype HCV genotype 01	80.00 Percentages of participants	76.92 Percentages of participants	—	—	—	—	—	—	—	—
Percentages of Participants With HCV-positive and HCV Genotype HCV genotype 03	17.14 Percentages of participants	10.26 Percentages of participants	—	—	—	—	—	—	—	—
Percentages of Participants With HCV-positive and HCV Genotype HCV genotype 04	2.86 Percentages of participants	2.56 Percentages of participants	—	—	—	—	—	—	—	—
Percentages of Participants With HCV-positive and HCV Genotype non-responders	—	10.26 Percentages of participants	—	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: weeks 6,8,12,18,24,36,52 at 0 (Cmin), and 1 (C1h) hrs post-dose.

the biomarker of personal response to everolimus, monitoring of the activity of the target, kinase P70 S6, in its phosphorylated form at Thr389. EVR=everolimus Cmin=minimum concentration

Outcome measures

Outcome measures
Measure	Experimental Group n=74 Participants Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids	Control Group Treatment with TAC + MMF + corticosteroids	20 to 24 Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score 20 to 24	25 to 29 Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score 25 to 29	> = 30 Experimental group (Minimisation of TAC: Treatment with rTAC+EVR+corticosteroids) with MELD score \> = 30	<= 14 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score \<= 14	15 to 19 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 15 to 19	20 to 24 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 20 to 24	25 to 29 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score 25 to 29	> = 30 Control Group Control group (Treatment with TAC + MMF + corticosteroids) with MELD score \> = 30
Concentration of p-P70S6K Cmin EVR week 52	5.35 ng/ml Standard Deviation 0.97	—	—	—	—	—	—	—	—	—
Concentration of p-P70S6K C1h EVR week 52	16.1 ng/ml Standard Deviation 7.6	—	—	—	—	—	—	—	—	—
Concentration of p-P70S6K Cmin EVR week 6	3.8 ng/ml Standard Deviation 1.7	—	—	—	—	—	—	—	—	—
Concentration of p-P70S6K C1h EVR week 6	6.8 ng/ml Standard Deviation 6.3	—	—	—	—	—	—	—	—	—
Concentration of p-P70S6K Cmin EVR week 8	4.7 ng/ml Standard Deviation 1.6	—	—	—	—	—	—	—	—	—
Concentration of p-P70S6K C1h EVR week 8	9.5 ng/ml Standard Deviation 4.9	—	—	—	—	—	—	—	—	—
Concentration of p-P70S6K Cmin EVR week 12	4.4 ng/ml Standard Deviation 1.8	—	—	—	—	—	—	—	—	—
Concentration of p-P70S6K C1h EVR week 12	16 ng/ml Standard Deviation 9.5	—	—	—	—	—	—	—	—	—
Concentration of p-P70S6K Cmin EVR week 18	6.8 ng/ml Standard Deviation 2.7	—	—	—	—	—	—	—	—	—
Concentration of p-P70S6K C1h EVR week 18	14.6 ng/ml Standard Deviation 6.7	—	—	—	—	—	—	—	—	—
Concentration of p-P70S6K Cmin EVR week 24	5.3 ng/ml Standard Deviation 2.13	—	—	—	—	—	—	—	—	—
Concentration of p-P70S6K C1h EVR week 24	18 ng/ml Standard Deviation 7.2	—	—	—	—	—	—	—	—	—
Concentration of p-P70S6K Cmin EVR week 36	5.1 ng/ml Standard Deviation 1.35	—	—	—	—	—	—	—	—	—
Concentration of p-P70S6K C1h EVR week 36	12.7 ng/ml Standard Deviation 4.2	—	—	—	—	—	—	—	—	—

Adverse Events

Experimental Group

Serious events: 55 serious events

Other events: 97 other events

Deaths: 0 deaths

Control Group

Serious events: 48 serious events

Other events: 105 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 (ie, data from all sites) in the clinical trial.
Publication restrictions are in place

Restriction type: OTHER