Median Daily Doses of Immunosuppressants in a Clinical Trial

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Supplementary Digital Content (SDC)

Table S1. Median daily dose of tacrolimus, MMF and corticosteroids (FAS)

Arm 1 Tac BD 0.2mg/kg/day

(n=309)

Arm 2 Tac QD 0.2mg/kg/day

(n=302)

(n=304)

Arm 4 Tac QD 0.2mg/kg/day +

Bas*

(n=283) Tacrolimus (mg/kg)

Week 1 0.16 (0.04; 0.38) 0.17 (0.0; 0.32) 0.23 (0.04; 0.44) 0.18 (0.02; 0.28) Week 2 0.15 (0.01; 0.57) 0.16 (0.0; 0.53) 0.18 (0.01; 0.79) 0.17 (0.0; 0.48) Week 3 0.14 (0.01; 0.97) 0.16 (0.0; 0.62) 0.19 (0.0; 0.64) 0.17 (0.0; 0.43) Week 4 0.13 (0.0; 0.97) 0.15 (0.0; 0.74) 0.18 (0.01; 0.73) 0.15 (0.0; 0.39) Month 2 0.12 (0.02; 0.79) 0.13 (0.03; 0.54) 0.15 (0.0; 0.67) 0.13 (0.0; 0.39) Month 3 0.09 (0.01; 0.4) 0.11 (0.02; 0.54) 0.12 (0.01; 0.79) 0.11 (0.01; 0.39) Month 4 0.07 (0.0; 0.37) 0.1 (0.0; 0.47) 0.11 (0.01; 0.54) 0.09 (0.02; 0.39) Month 5 0.07 (0.01; 0.48) 0.09 (0.0; 0.53) 0.1 (0.01; 0.41) 0.09 (0.01; 0.34) Month 6 0.07 (0.01; 0.48) 0.08 (0.01; 0.55) 0.09 (0.01; 0.33) 0.08 (0.01; 0.31) Corticosteroids (mg)

Week 1 125.9 (26; 703) 125.9 (14; 511) 125.9 (14; 662) 89.3 (0; 625) Week 2 20.0 (0; 529) 20.0 (3; 693) 20.0 (0; 544) 0.0 (0; 625) Week 4 15.0 (0; 360) 15.0 (0; 401) 15.0 (0; 353) 0.0 (0; 335) Month 2 9.6 (0; 237) 9.8 (5; 198) 9.6 (1; 1077) 0.0 (0; 375) Month 3 5.0 (0; 486) 5.0 (0; 103) 5.0 (3; 237) 0.0 (0; 200) Month 6 5.0 (0; 667) 5.0 (0; 74) 5.0 (0; 57) 0.0 (0; 47) MMF (g)

Week 1 2.0 (0.0; 2.0) 2.0 (0.0; 2.0) 2.0 (1.0; 3.0) 2.0 (0.0; 2.0) Week 2 2.0 (0.0; 2.0) 2.0 (0.0; 3.0) 2.0 (0.5; 3.0) 2.0 (0.0; 2.0) Week 4 1.0 (0.0; 3.0) 1.0 (0.0; 2.0) 1.0 (0.0; 3.0) 1.0 (0.0; 2.0) Month 3 1.0 (0.0; 2.5) 1.0 (0.0; 2.0) 1.0 (0.0; 3.0) 1.0 (0.0; 2.0) Month 6 1.0 (0.0; 2.5) 1.0 (0.0; 2.0) 1.0 (0.0; 3.0) 1.0 (0.0; 2.0) Data are shown as median (minimum; maximum)

Bas, basiliximab; FAS, full analysis set; MMF, mycophenolate mofetil; Tac, tacrolimus

*patients also received a steroid bolus (≤500mg) at Day 0

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Table S2. Biopsy-confirmed acute rejection by severity (FAS)

Arm 1 Tac BD 0.2mg/kg/day

Arm 4 Tac QD 0.2mg/kg/day +

Bas

n=309 n=302 n=304 n=283

BCAR, n (%) 42 (13.6) 31 (10.3) 49 (16.1) 36 (12.7)

Grade 1 (mild) 24 (7.8) 13 (4.3) 28 (9.2) 16 (5.7)

Grade 2 (moderate) 18 (5.8) 15 (5.0) 19 (6.3) 18 (6.4)

Grade 3 (severe) 0 3 (1.0) 2 (0.7) 2 (0.7)

Corticosteroid-sensitive BCAR

26 (8.4) 18 (6.0) 31 (10.2) 22 (7.8)

Data are shown as number of patients (%)

Bas, basiliximab; BCAR, biopsy-confirmed acute rejection; FAS, full analysis set; Tac, tacrolimus

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Table S3. Summary of important treatment-emergent adverse events, laboratory parameters and concomitant medications of interest

Patients Arm 1

Tac BD 0.2mg/kg/day (n=311)

Arm 2 Tac QD 0.2mg/kg/day

(n=309)

Arm 3 Tac QD 0.3mg/kg/day

(n=307)

Arm 4 Tac QD 0.2mg/kg/day +

Bas (n=287)

n (%) n (%) n (%) n (%) Any TEAE 293 (94.2) 289 (93.5) 295 (96.1) 270 (94.1) Severe adverse events 72 (23.2) 77 (24.9) 82 (26.7) 86 (30.0) Causally related: 197 (63.3) 195 (63.1) 200 (65.1) 185 (64.5)

Metabolism/nutrition disorders

92 (29.6) 91 (29.4) 92 (30.0) 69 (24.0)

Hyperglycaemia 22 (7.1) 26 (8.4) 28 (9.1) 25 (8.7) Hyperlipidaemia 18 (5.8) 9 (2.9) 10 (3.3) 6 (2.1) Infections/infestations 79 (25.4) 76 (24.6) 72 (23.5) 74 (25.8)

Urinary tract, bacterial

27 (8.7) 24 (7.8) 26 (8.5) 33 (11.5)

Cytomegalovirus 21 (6.8) 12 (3.9) 17 (5.5) 9 (3.1) Kidney/urinary

disorders

40 (12.9) 35 (11.3) 55 (17.9) 44 (15.3)

Nephropathy, toxic 11 (3.5) 10 (3.2) 16 (5.2) 23 (8.0) Kidney impairment 12 (3.9) 12 (3.9) 19 (6.2) 9 (3.1) Nervous system

disorders

35 (11.3) 37 (12.0) 35 (11.4) 35 (12.2)

Tremor 32 (10.3) 33 (10.7) 26 (8.5) 26 (9.1) Investigations 36 (11.6) 40 (12.9) 32 (10.4) 34 (11.8)

Blood creatinine, 23 (7.4) 26 (8.4) 16 (5.2) 14 (4.9)

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increased Immune system disorders

27 (8.7) 29 (9.4) 31 (10.1) 31 (10.8)

Kidney transplant rejection

25 (8.0) 24 (7.8) 30 (9.8) 26 (9.1)

Gastrointestinal disorders

35 (11.3) 27 (8.7) 30 (9.8) 22 (7.7)

Diarrhoea 17 (5.5) 11 (3.6) 16 (5.2) 10 (3.5) Vascular disorders 18 (5.8) 24 (7.8) 13 (4.2) 17 (5.9)

Hypertension 15 (4.8) 21 (6.8) 10 (3.3) 12 (4.2) Blood/lymphatic

system disorders

9 (2.9) 14 (4.5) 15 (4.9) 15 (5.2)

n=274* n=265* n=268* n=247*

n (%) n (%) n (%) n (%)

Diabetes mellitus:

New-onset diabetes

44 (16.1) 35 (13.2) 49 (18.3) 31 (12.6)

Ongoing diabetes^†

41 (15.0) 36 (13.6) 43 (16.0) 20 (8.1)

Ongoing oral antidiabetic or insulin therapy^‡

41 (15.0) 39 (14.7) 43 (16.0) 19 (7.7)

Ongoing insulin therapy^‡

24 (8.8) 21 (7.9) 27 (10.1) 11 (4.5)

n=311 n=309 n=307 n=287 Laboratory parameters Mean

change SD Mean

change SD

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Total cholesterol, mmol/L

0.19 0.08 0.21 0.08 0.18 0.08 –0.12 0.08

HDL, mmol/L 0.11 0.02 0.05 0.02 0.06 0.02 0.00 0.03 LDL, mmol/L 0.18 0.07 0.19 0.07 0.11 0.06 0.04 0.07 HDL:LDL ratio 0.05 1.11 0.06 1.23 0.01 1.02 –0.06 0.93 Triglycerides, mmol/L –0.32 0.07 –0.15 0.07 –0.19 0.07 –0.52 0.07

n=309 n=302 n=304 N=283 Comedications of

interest

n % n % n % N %

Antidiabetic medications

125 40.5 126 41.7 136 44.7 92 32.5

Antihyperlipidaemic medications

141 45.6 141 46.7 138 45.4 130 45.9

Antihypertensive medications

281 90.9 278 92.1 280 92.1 253 89.4

Data are adverse events as reported by the investigators, unless otherwise stated

*Patients without baseline diabetes mellitus or a history of diabetes mellitus

†Diabetes reported as an adverse effect (MedRA) ongoing at end of study or at withdrawal. Within this evaluation, diabetes is defined by a cluster of adverse event Preferred Terms. There were two known occasions where the adverse event was considered to have ended but therapy was continued

‡Ongoing at end of study or at withdrawal

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Bas, basiliximab; MedRA, Medical Dictionary for Regulatory Activities; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SD, standard deviation;

Tac, tacrolimus; TEAE, treatment-emergent adverse event

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Figure S1. Treatment regimens

Bas, basiliximab; MMF, mycophenolate mofetil

Arm 1

Adjusted to achieve the following whole blood trough concentrations:

Tacrolimus BD 0.2mg/kg/day

Day 0–14 10–15ng/mL Day 15–42 5–12ng/mL Day 43–168 5–10ng/mL Tacrolimus QD

0.2mg/kg/day

Tacrolimus QD 0.3mg/kg/day

Tacrolimus QD 0.2mg/kg/day + Bas + steroid

withdrawal

Arm 2 Arm 3 Arm 4

Day 1: methylprednisolone or equivalent 125mg IV bolus

Day 2: prednisolone or equivalent 20mg/day or equivalent tapering to ≤5mg/day from Months 4–6

Day 0: methylprednisolone ≤500mg Basiliximab 20mg 2 hours before surgery and 20mg on Day 4 MMF: 1g preoperatively then 1g BD for 14 days and 0.5g BD thereafter

Bas, basiliximab; MMF, mycophenolate mofetil

SDC, Figure 1. Treatment regimens

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Figure S2. Measurements of creatinine clearance at 24 weeks (FAS)

Creatinine clearance was estimated using the Cockcroft–Gault formula Bas, basiliximab; FAS, full analysis set; Tac, tacrolimus

60 50 40 30 20 10 0

Least square mean (SE)

Tacrolimus BD 0.2mg/kg

(Arm 1)

49.8 (1.30) 53.7 (1.25)

55.1 (1.27)

57.0 (1.26) p=0.001

Tacrolimus QD 0.2mg/kg

(Arm 2)

Tacrolimus QD 0.3mg/kg

(Arm 3)

Tacrolimus QD 0.2mg/kg + basiliximab + CS bolus

(Arm 4)

Creatinine clearance was estimated using the Cockcroft–Gault formula FAS, full analysis set