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Table 1 Everolimus in liver transplantation

From: Evaluating the efficacy, safety and evolution of renal function with early initiation of everolimus-facilitated tacrolimus reduction in de novo liver transplant recipients: Study protocol for a randomized controlled trial

Study Participants Study design and duration EVR dosing Efficacy Renal function Safety
Early conversion (≤3 months after transplantation)
Levy et al. [20] N = 119 recipients Prospective, randomized; 36 months 1, 2, or 4 mg/day 32.1, 26.7, and 25.8 for EVR 1, 2, and 4 mg/day at 1 year after immunosuppression was initiated; 39.3, 30.0, and 29.0 for EVR 1, 2, and 4 mg/day at 3 years after immunosuppression was initiated Change in CrCl (mL/min) from baseline at 1 year post-conversion: EVR 1, 2, and 4 mg/day vs placebo: −20.2, −43.0, and −36.9 vs −36.9 • CMV disease: 3.3, 3.6, 6.7, and 9.7 (placebo vs EVR 1, 2, and 4 mg/day, respectively, P = NS for all comparisons)
 • n = 28 (EVR 1.0 mg) + CNI
 • n = 30 (EVR 2.0 mg) + CNI
 • n =31 (EVR 4.0 mg) + CNI
 • n =30 (placebo) + CNI
• Thrombocytopenia: 10.0, 14.3, 20.0, and 19.4
• Leukopenia: 0, 14.3, 6.7, and 6.5
Masetti et al. [21] N = 78 recipients Prospective, randomized; 12 months Initial dose: 2.0 mg/day, C0 → 6–10 ng/mL post- CsA withdrawal: C0 → 8–12 ng/mL until Month 6, and C0 → 6–10 ng/mL thereafter 5.7 vs 7.7 at 40–87 days vs at 41–240 days after transplant (NS) Change in GFR (mL/min/1.73 m2) 1 year after conversion: EVR vs CsA: +5.9 vs −14.8 (P < 0.001) EVR vs CsA
• Inferior limb edema: 9.6 vs 0
 • n = 52 (EVR)
 • n = 26 (CsA) • Incisional hernia: 46.1 vs 26.9
• Biliary complications (stenosis/leak): 21.1 vs 30.8
• Infections: 46.1 vs 46.1
• CMV: 19.2 vs 23.1
(P = NS for all comparisons)
Fischer et al. [22] N = 203 recipients on CNI without corticosteroids Prospective, randomized; 12 months Initial dose of 1.5 mg b.i.d.; target C0 → 5–12 ng/mL in patients on treatment with TAC; C0 → 8–12 ng/mL in patients on treatment with CsA EVR vs CNI control at 11 months: 17.7 vs 15.3 EVR vs CNI: change in GFR (mL/min/1.73 m2)11 months after conversion from baseline (MDRD): 2.0 ± 23.2 vs −2.8 ± 23.1; LS mean difference ± SE: −7.778 ± 3.338 (P = 0.021)a EVR vs CNI
• Wound complications: 2 vs 3.9
 • n = 101 (EVR) • Incisional hernia: 11.9 vs 9.8
 • n = 102 (CNI continuation)
• Wound dehiscence: 0 vs 1
• Wound hemorrhage: 1 vs 0
• Infections and infestations: 73.3 vs 59.8
• Anemia: 18.8 vs 10.8
• Leukopenia: 20.8 vs 9.8b
• Thrombocytopenia: 7.9 vs 6.9 (P = NS for anemia and thrombocytopenia)
Sterneck et al. [23] N = 81 recipients from Fischer et al. [22] Prospective, randomized; 35 months Same as Fischer et al. [22] EVR vs CNI control at 35 months: 24.4 vs 15.8 (P = NS) Change in GFR 35 months after conversion: difference in eGFR between EVR and CNI (CG): −10.5 mL/min (P = 0.096) and Nankivell formula: −10.5 mL/min (P = 0.015) EVR vs CNI
• Peripheral edema: 22.0 vs 5.0 (P = 0.048)
• Neoplasms:17.1 vs 19.8 (P = 0.587)
 • n = 41 (EVR ± corticosteroids)
 • n = 40 (CNI ± corticosteroids) • Incisional hernia: 24.4 vs 15.0 (P = 0.404)
• Anemia: 4.9 vs 5.0 (P = 1.000)
De Simone et al. [24] N = 719 recipients Prospective, randomized; 12 months EVR + TAC-WD: initial dose of 1.0 mg b.i.d. ≤24 hours of randomization and C0 3–8 ng/mL until Month 4 post-Tx. Target C0 increased to 6–10 ng/mL. EVR + rTAC: initial dose of 1.0 mg b.i.d. ≤24 hours of randomization and C0 3–8 ng/mL maintained throughout the study. Recruitment to EVR + TAC-WD arm was terminated early. EVR + rTAC vs TAC-C: 4.1 vs 10.7, P = 0.005 Change in GFR (mL/min/1.73 m2) 1 year after conversion: adjusted mean difference in eGFR change for EVR + rTAC vs TAC-C: 8.50 ± 2.12; P < 0.001) EVR + rTAC vs TAC-C:
 • n = 245 (EVR + rTAC) • Edema: 17.6 vs 10.8 (RR 1.63; 95% CI: 1.03, 2.56)
 • n = 231 (EVR + TAC-WD)
• Wound complications: 11.0 vs 7.9 (RR 1.40; 95% CI: 0.80, 2.45)
 • n = 243 (TAC-C)
       • Incisional hernia: 2.9 vs 1.2 (RR 2.30, 95% CI: 0.60, 8.77)
• Leukopenia: 11.8 vs 5.0 (RR 2.38, 95% CI: 1.24, 4.55)
• Thrombocytopenia: 5.3 vs 1.7
• Anemia: 7.8 vs 8.3 (RR 0.93, 95% CI: 0.51, 1.71)
Saliba et al. [25] Same as De Simone et al. [24] Prospective, randomized; 24 months Same as De Simone et al. [24] 6.1 vs 13.3; −7.2% (97.5% CI: −13.5, −0.9; P = 0.010). EVR + rTAC vs TAC-C at 24 months) Change in GFR (mL/min/1.73 m2) 24 months after conversion: EVR + rTAC vs TAC-C: mean difference in eGFR change: +6.7 (97.5% CI: +1.9, +11.4; P = 0.002) EVR + rTAC vs TAC-C:
• Peripheral edema: 22.4 vs 14.9 (P = 0.036)
• Wound complications: 11.0 vs 8.3 (P = 0.36)
• Incisional hernia: 9.8 vs 7.9 (P = 0.52)
• Thrombocytopenia: 8.2 vs 2.9 (P = 0.016)
• Anemia: 9.8 vs 10.3 (P = 0.88)
• CMV: 4.9 vs 5.4 (P = 0.84)
• Viral infection: 18.4 vs 18.2 (P = 1.000)
Late conversion (>3 months after transplantation)
Bilbao et al. [26] N = 25 recipients. Retrospective; mean of 10 ± 9 months In refractory rejection: initial dose 0.5 mg/12 hours (C0 → 5 ng/mL). For CNI-related adverse events: 0.5 mg once/twice a day. For malignancy: 0.5 mg/day, C0 < 3 ng/mL    • Mucositis: 4
All converted to EVR • Sepsis (graft-vs-host disease): 4
Casanovas et al. [27] N = 35 recipients. All converted to EVR Prospective, single-arm; mean of 134 months Initial dose 0.25 mg/12 hours for the first 4 days. Target C0 3–5 ng/mL    Anemia, leukopenia, and thrombocytopenia: 11.4
Castroagudin et al. [28] N = 21 recipients (chronic renal dysfunction). All converted to EVR Prospective, single-arm; median of 19.8 months 0.75 mg b.i.d., C0 → 3–8 ng/mL   Change in GFR (mL/min/1.73 m2) 1 year after conversion: +7.65 (P = 0.016 vs baseline)  
De Simone et al. [29] N = 40 recipients Prospective, single-arm 12 months 1.5 mg/day (C0 → 3–8 ng/mL) tBPAR: 15 Change in CrCl (mL/min) 1-year post conversion: 4.03±12.6 (-10.6-52.5) • Oral ulcers/stomatitis: 22.5
• Lower urinary tract infection: 5
• Pruritis and acne:7.5 each
De Simone et al. [30] N = 145 recipients Prospective, randomized; 12 months Initial dose of 3 mg/day b.i.d on day 1. After week 2: EVR C0 → 3–8 ng/mL with concomitant CNI or C0 → 6–12 ng/mL if CNI was eliminated EVR vs CNI: 4.2 vs 1.4 Change in CrCl (mL/min) 6 months post-conversion: EVR: +1.0; controls: +2.3 (NS) EVR vs CNI
• Mouth ulcers: 26.4 vs 0.0 (P < 0.01)
 • n = 72 (EVR therapy with CNI reduction or discontinuation)
• Infections: 31.9 vs 21.9 (15.3 vs 1.4 suspected to be drug-related)
 • n = 73 (CNI continuation)
• Rash/dry skin/eczema: 6.9 vs 0.0 (P = 0.028)
• Leukopenia: 12.5 vs 5.5
• Thrombocytopenia: 5.6 vs 1.4
• Anemia: 9.7 vs 4.1
Saliba et al. [31] N = 240 maintenance recipients. All received EVR Retrospective; 12 months Introduced at mean 2.4 mg/day (Month 1: C0 → 7.3 ng/mL, Month 12 C0 → 8.1 ng/mL) C0 → 8.8 ng/mL at Month 12 in monotherapy cohort BPAR: 1.6 Change in GFR mL/min/1.73 m2; (CG method) 1 year after conversion (overall vs baseline): +4.2 (P = 0.007) chronic renal failure (subpopulation vs baseline): +8.6 (P = 0.02) • Edema: 16.3
• Stomatitis/mouth ulcers: 14.2
• Bacterial infection:12.5
• Rash: 18.8
• Anemia: 12.9
• Leukopenia: 9.2
• Thrombocytopenia: 6.3
Vallin et al. [32] N = 94 recipients. Retrospective; mean 12 ± 7 months Initial dose of 0.75–1.5 mg b.i.d. C0 adjusted to 3–8 ng/mL 9   • Edema: 7
All received EVR • Mucositis: 15
• Infection: 3
• Dermatitis: 19
  1. aBetween-group difference (calculated as CNI group minus everolimus group) at Month 11 after baseline; results based on analysis of covariance model. bTreatment group differences with an exploratory P value of ≤0.05. P values are included where available. b.i.d., twice daily; BPAR, biopsy-proven acute rejection; C0, trough level; CG, Cockcroft-Gault; CI, confidence interval; CMV, cytomegalovirus; CNI, calcineurin inhibitor; CrCl, creatinine clearance; CsA, cyclosporine A; eGFR, estimated glomerular filtration rate; EVR, everolimus; GFR, glomerular filtration rate; LS, least square; MDRD, modification of diet in renal disease; NS, nonsignificant; RR, relative risk; rTAC, reduced tacrolimus; SE, standard error; TAC, tacrolimus; TAC-C, standard tacrolimus; TAC-WD, tacrolimus withdrawal; Tx, transplantation.