Table 1 Everolimus in kidney transplantation

B156 Nashan et al. [9]

N = 111 de novo patients

EVR (3 mg/day) + basiliximab + steroids with either full-dose CsA (C0 125–250 ng/mL) or reduced-dose CsA (C0 50–100 ng/mL)

3-year, phase II, open-label, multicentre, randomised, parallel-group study

• Efficacy failure was significantly lower in the reduced-dose CsA group vs. the full-dose CsA group at month 6 (3.4 % vs. 15.1 %; p = 0.046), month 12 (8.6 % vs. 28.3 %; p = 0.012), and month 36 (17.2 % vs. 35.8 %; p = 0.032)

• Mean CrCL (mL/min) was higher in the reduced-dose CsA group vs. the full-dose CsA group at month 6 (59.7 vs. 51.1; p = 0.009), month 12 (60.9 vs. 53.5; p = 0.007), and month 36 (56.6 vs. 51.7; p = 0.436)

B201

N = 588 de novo patients

3-year, randomised, multicentre, parallel-group study; 1-year, double-blind, double-dummy and 2-year, open-label

• At months 12 and 36, efficacy failure rates were similar for all groups (p = NS)

• At month 36, creatinine values were higher in the EVR groups, requiring a protocol amendment that recommended lower CsA exposure

• Incidence of CMV infection was significantly lower at month 12 (p = 0.001) and month 36 (p = 0.0001) in the EVR groups vs. the MMF group

Vitko et al. [10]

Vitko et al. [11]

EVR 1.5 mg/day or EVR 3 mg/day or MMF 2 g/day; all with standard CsA and steroids

B251

Lorber et al. [12]

N = 583 de novo patients

EVR 1.5 mg/day or EVR 3 mg/day or MMF 2 g/day; all with standard CsA and steroids

3-year, randomised, multicentre, parallel-group, study; 1-year, double-blind, double-dummy, and 2-year, open-label

• At months 12 and 36, primary efficacy failure rates were similar for all the arms (p = NS)

• Incidence of antibody-treated acute rejection was significantly lower at month 12 (p = 0.01) and month 36 for the EVR 1.5 arm vs. the MMF arm (p = 0.014)

• In a subgroup analysis, CsA dose reduction in the EVR arms resulted in improved renal function

A2306

Vitko et al. [13]

Tedesco-Silva et al. [14]

N = 237 de novo patients

EVR 1.5 mg/day or EVR 3 mg/day; both with low-dose CsA ± steroids

1-year, multicentre, randomised, open-label, parallel-group study

• Median serum creatinine levels were similar for both the EVR arms (month 6, 133 vs. 132 μmol/L; month 12, 131 vs. 130 μmol/L)

• At month 6 and month 12, efficacy failure rates were similar for both arms (p = NS)

A2307

Vitko et al. [13]

Tedesco-Silva et al. [14]

N = 256 de novo patients

EVR 1.5 mg/day or EVR 3 mg/day; both with low-dose CsA + basiliximab induction ± steroids

1-year, multicentre, randomised, open-label, parallel-group study

• Median serum creatinine levels were similar for both the EVR arms (month 6, 130 μmol/L in both arms; month 12, 129 vs. 128 μmol/L)

• At month 6 and month 12, efficacy failure rates were similar for both arms (p = NS)

US09

Chan et al. [15]

N = 92 de novo patients

Low-dose tacrolimus vs. standard-dose tacrolimus; both with EVR 1.5 mg/day + steroids + basiliximab

6-month, prospective, multicentre, open-label, randomised, parallel-group, exploratory study

• No significant difference in mean serum creatinine between EVR with either low- or standard-dose tacrolimus treatment groups at 6 months (112 vs. 127 μmol/L; p = 0.114)

• Mean eGFR rate was high and comparable between the EVR with low- or standard-dose tacrolimus groups (75.3 vs. 72.5 mL/min, p = 0.466)

• BPAR and efficacy failure rates were low and comparable for both treatment arms

A2309

Tedesco-Silva et al. [16]

Cibrik et al. [17]

N = 833 de novo patients

EVR (1.5 mg/day, C0 3–8 ng/mL or 3 mg/day, C0 6–12 ng/mL) + reduced CsA vs. MPA + standard CsA

24-month, phase IIIb, multicentre, randomised, open-label, non-inferiority study

• At month 24, composite efficacy failure rates were 32.9 %, 26.9 %, and 27.4 % in the EVR 1.5 mg, EVR 3 mg, and MPA groups, respectively

• Mean eGFR rate (MDRD; mL/min/1.73 m²) at month 24 was 52.2, 49.4, and 50.5 in the three arms, respectively

ZEUS (2418)

Budde et al. [18]

Budde et al. [19]

N = 300 de novo patients

After initial immunosuppression with CsA + EC-MPS + steroids, patients at 4.5 months post transplant are randomised (1:1) to either continue the same regimen or switch to EVR (C0 6–10 ng/mL) + EC-MPS + steroids

12-month, phase IV, prospective, multicentre, open-label, randomised study with additional 48-month follow-up

• Adjusted mean cGFR was significantly higher at month 12 (+9.8 mL/min/1.73 m²; p < 0.0001) and at 5 years (+5.3 mL/min/1.73 m²; p <0.001) in the EVR group vs. the CsA group

CALLISTO (A2420)

Albano et al. [20]

Dantal et al. [21]

N = 139 de novo patients

Immediate EVR treatment (day 1 post transplant; C0 3–8 ng/mL) vs. delayed EVR (week 5; C0 3–8 ng/mL). All patients also received low CsA, anti-IL-2 receptor induction therapy, and steroids

12-month, prospective, multicentre, open-label study

• Primary composite efficacy failure at month 3 occurred in 55.4 % patients in the immediate EVR group vs. 63.5 % in the delayed group (p = 0.387) while at month 12 the rates were 64.6 % and 66.2 %, respectively (p = 0.860)

• At month 12, median eGFR values were 48 and 49 mL/min/1.73 m² in the immediate EVR and delayed EVR groups, respectively

• Incidence of DGF and wound healing complications were similar between the treatment groups

CERTES (A2419)/LATAM (A2423)

Novoa et al. [22]

N = 119; A2419 de novo patients

N = 51; A2423 de novo patients

Initial treatment with EVR (C0 3–8 ng/mL) + CsA + basiliximab induction + steroids; randomisation (1:1) at 3 months to either continue the same regimen with CsA reduction (C2 300–500 ng/mL in A2419 and 350–450 ng/mL in A2423) or to start CsA elimination (by month 4 in A2419 and by month 6 in A2423) with EVR (C0 8–12 ng/mL)

12-month, multicentre, prospective, randomised, open-label study

• At month 12, eGFR rates were significantly higher in the CsA-elimination group vs. the CsA-minimisation group (68.3 vs. 63.6 mL/min/1.73 m², p = 0.0289)

• Post randomisation, the incidence of efficacy failure (BPAR, graft loss, death, loss to follow-up) at 12 months was comparable in the two groups: 18.9 % in the CNI-elimination group vs. 17.5 % in the CNI-minimisation group (p = NS)

ASSET (A2426)

Langer et al. [23]

N = 228 de novo patients

EVR (C0 3–8 mg/mL) with tacrolimus (C0 4–7 ng/mL) up to month 3; from month 4 either continue the same low-tacrolimus dose or start very low-tacrolimus dose (C0 1.5–3 ng/mL)

12-month, open-label, randomised study

• At month 12, mean eGFR was higher in the very low-tacrolimus group vs. the low-tacrolimus group (difference: 5.3 mL/min/1.73 m²; p = NS)

• Incidence of BPAR from month 4 to month 12 was non-inferior (p = 0.0014) for the very low-tacrolimus group vs. the low-tacrolimus group (2.7 % vs. 1.1 %)

• The incidence of NODM from month 4 to month 12 was numerically lower in the very low-tacrolimus group vs. the low-tacrolimus group (2.7 % vs. 8.6 %; p = 0.086).

APOLLO (DE02)

Budde et al. [24]

Budde et al. [25]

N = 93 maintenance patients (≥6 months post transplant)

EVR (C0 6–10 ng/mL) + EC-MPS ± steroids vs. standard CNI (CsA C0 80–150 ng/mL or tacrolimus C0 5–10 ng/mL) + EC-MPS ± steroids

12-month, open-label, prospective, multicentre study with follow-up at month 60

• Mean time post transplant was 83.5 months with EVR vs. 70.1 months with CNI

• Adjusted mean eGFR values (Nankivell, mL/min/1.73 m²) were numerically higher with EVR vs. CNI at month 12 (61.6 vs. 58.8; p = NS) and at month 60 (63.0 vs. 57.9; p = NS)

• Using the MDRD formula, adjusted eGFR at month 12 was significantly higher (+4.9 mL/min/1.73 m²) with EVR vs. CNI (p = 0.030)

• At month 60, for patients who remained on the study drug, mean eGFR was significantly higher with EVR vs. CNI (71.6 vs. 60.6; p = 0.005)

EVEREST (IT02)

Salvadori et al. [26]

Ponticelli et al. [27]

N = 285 de novo patients

Standard EVR (C0 3–8 ng/mL) with low CsA (C2 350–500 ng/mL) vs. high EVR (C0 8–12 ng/mL) with very low CsA (C2 150–300 ng/mL)

6-month, multicentre, randomised, open-label, parallel-group study with follow-up at 12 months and an extension to 24 months

• Death-censored graft survival was significantly lower with standard EVR vs. the high EVR arm at month 6 (90.2 % vs. 97.9 %, p = 0.007) and at month 24 (87.4 % vs. 94.4 %, p = 0.048)

• No significant difference between groups at months 6 and 24 for mean serum creatinine levels and incidence of BPAR

A1202

Takahashi et al. [28]

N = 122 de novo patients

EVR (C0 3 to 8 ng/mL) + reduced-dose CsA vs. MMF (2 g/day) + standard-dose CsA. All patients receive basiliximab and steroids

12-month, phase III, multicentre, randomised, open-label, parallel-group, non-inferiority study

• 52 % reduction in CsA exposure was achieved in the EVR group at month 12

• At month 12, EVR with reduced CsA exposure was non-inferior to the MMF group for composite efficacy failure (11.5 % vs. 11.5 %)

• Median eGFR at month 12 was comparable between the EVR arm vs. the MMF arm (58.00 vs. 55.25 mL/min/1.73 m²; p = 0.063)

ASCERTAIN (A2413)

Holdaas et al. [29]

N = 398 maintenance patients

Patients ≥6 months post transplant and receiving CNI ± MPA/azathioprine ± steroid randomised to either continue the same regimen (control arm) or switch to a CNI-elimination (EVR C0 8–12 ng/mL), or a CNI-minimisation by 70–90 % (EVR C0 3–8 ng/mL) regimen

24-month, phase IV, multicentre, prospective, randomised, open-label, parallel-group study

• At month 24, mean mGFR was comparable for all the three arms (p = NS)

• Post-hoc analyses showed that patients with baseline CrCl >50 mL/min had a significantly greater increase in mGFR after CNI-elimination vs. the control arm (difference 11.4 mL/min/1.73 m², p = 0.017)

• Study drug discontinuation was significantly high in the CNI-elimination and CNI-minimisation arms vs. the control arm

SOCRATES (A2421)

Chadban et al. [30]

N = 126 de novo patients

Initial treatment with CsA + EC-MPS + steroids for the first 14 days post transplant then either continue the same regimen (control arm) or switch to + steroids + EC-MPS and CNI withdrawal, or EVR (C0 6–10 ng/mL) + CsA reduction + steroid and EC-MPS withdrawal

36-month, prospective, open-label, randomised controlled trial

• The steroid withdrawal arm was prematurely terminated due to the high rate of discontinuations

• At month 12, EVR with CNI-withdrawal was non-inferior to the control arm for mean eGFR (65.1 vs. 67.1 mL/min/1.73 m²; p = 0.026)

• Patients in the EVR with CNI-withdrawal group experienced a higher rate of BPAR vs. the control group (31 % vs. 13 %, p = 0.048)

MECANO (NL02)

Bemelman et al. [31]

N = 113 maintenance patients

Initial treatment with CsA + EC-MPS + steroids + basiliximab induction followed by randomisation at 6 months to start either CsA + MPA elimination, or MPA + CsA elimination, or EVR + CsA and MPA elimination; with steroids

24-month, prospective, open-label, randomised, multicentre study

• Post conversion, acute rejection rates were 3 % in the CsA group, 22 % in the MPA group, and 0 % in the EVR group (p <0.009)

• Mean serum creatinine values were significantly lower at the latest follow-up (14 ± 5 months after transplantation) in the EVR arm vs. the CsA group

CENTRAL (ASE01)

Mjörnstedt et al. [32]

N = 204 de novo patients

Initial treatment with CsA + EC-MPS + steroids + basiliximab induction followed by randomisation at 7 weeks post transplant to either continue the same regimen, or convert to EVR (C0 6–10 ng/mL) + EC-MPS

36-month, open-label, parallel-group study

• From week 7 to month 12, change in mGFR was significantly greater with EVR vs. the CsA arm (4.9 vs. 0.0 mL/min; p = 0.012; ANCOVA).

• No differences in graft or patient survival for both the groups

• The 12-month incidence of BPAR was significantly high in the EVR arm vs. the CsA arm (27.5 % vs. 11.0 %; p = 0.004)