A randomized trial of everolimus-based quadruple therapy vs standard triple therapy early after lung transplantation

Jens Gottlieb, Claus Neurohr, Joachim Müller-Quernheim, Hubert Wirtz, Bjoern Sill, Heinrike Wilkens, Vasiliki Bessa, Christoph Knosalla, Martina Porstner, Carmen Capusan, Martin Strüber, Jens Gottlieb, Claus Neurohr, Joachim Müller-Quernheim, Hubert Wirtz, Bjoern Sill, Heinrike Wilkens, Vasiliki Bessa, Christoph Knosalla, Martina Porstner, Carmen Capusan, Martin Strüber

Abstract

Calcineurin inhibitor (CNI) therapy after lung transplantation increases risk of kidney failure. Early everolimus-based quadruple low CNI immunosuppression may improve renal function without compromising efficacy or safety. A prospective, randomized, open-label, 12-month multicenter trial was conducted at 8 German sites. Patients 3-18 months after lung transplantation were randomized (1:1), stratified by baseline estimated glomerular filtration rate (eGFR). In the quadruple low CNI regimen, patients received everolimus (target trough level 3-5 ng/mL) with reduced CNI (tacrolimus 3-5 ng/mL or cyclosporine 25-75 ng/mL) and a cell cycle inhibitor plus prednisone. In the standard triple CNI regimen, patients received tacrolimus (target trough level >5 ng/mL) or cyclosporine (>100 ng/mL) and a cell cycle inhibitor plus prednisone. Of the 180 patients screened, 130 were randomized: 67 in the quadruple low CNI group and 63 in the standard triple CNI group. The primary endpoint (eGFR after 12 months) demonstrated superiority of the quadruple low CNI regimen: 64.5 mL/min vs 54.6 mL/min for the standard triple group (least squares mean, analysis of covariance; P < .001). Key efficacy parameters (biopsy-proven acute rejection, chronic lung allograft dysfunction, and death) and safety endpoints were similar between both groups. Quadruple low CNI immunosuppression early after lung transplantation was demonstrated to be efficacious and safe. Clinical trials registry: ClinicalTrials.gov NCT01404325.

Keywords: clinical research/practice; cyclosporine A (CsA); everolimus; immunosuppressant - calcineurin inhibitor; immunosuppressant - mechanistic target of rapamycin; immunosuppressant - mechanistic target of rapamycin (mTOR); immunosuppression/immune modulation; lung transplantation/pulmonology; rejection; tacrolimus.

© 2019 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.

Figures

Figure 1
Figure 1
Study design. AZA, azathioprine; CNI, calcineurin inhibitor; EC‐MPS, enteric‐coated mycophenolate sodium; MMF, mycophenolate mofetil; CsA, cyclosporine; TAC, tacrolimus; LTx, lung transplantation; W, week; M, month
Figure 2
Figure 2
CONSORT diagram. CLAD, chronic lung allograft dysfunction; CNI, calcineurin inhibitor; CONSORT, Consolidated Standards of Reporting Trials; eGFR, estimated glomerular filtration rate
Figure 3
Figure 3
Mean unadjusted eGFR, CKD‐EPI according to treatment group (last observation carried forward method). Vertical bars indicate standard deviation. BL, baseline; CKD‐EPI, Chronic Kidney Disease Epidemiology Collaboration; CNI, calcineurin inhibitor; eGFR, estimated glomerular filtration rate; D, day; M, month

References

    1. Chambers DC, Yusen RD, Cherikh WS, et al. The Registry of the International Society for Heart and Lung Transplantation: thirty‐fourth Adult Lung And Heart‐Lung Transplantation Report‐2017; Focus Theme: allograft ischemic time. J Heart Lung Transplant. 2017;36(10):1047‐1059.
    1. Munshi L, Keshavjee S, Cypel M. Donor management and lung preservation for lung transplantation. Lancet Respir Med. 2013;1(4):318‐328.
    1. Afshar K. Future direction of immunosuppression in lung transplantation. Curr Opin Organ Transplant. 2014;19(6):583‐590.
    1. Scheffert JL, Raza K. Immunosuppression in lung transplantation. J Thorac Dis. 2014;6(8):1039‐1053.
    1. Nankivell BJ, PʼNg CH, OʼConnell PJ, Chapman JR. Calcineurin inhibitor nephrotoxicity through the lens of longitudinal histology: comparison of cyclosporine and tacrolimus eras. Transplantation. 2016;100(8):1723‐1731.
    1. Barraclough K, Menahem SA, Bailey M, Thomson NM. Predictors of decline in renal function after lung transplantation. J Heart Lung Transplant. 2006;25(12):1431‐1435.
    1. Hornum M, Burton CM, Iversen M, Hovind P, Hilsted L, Feldt‐Rasmussen B. Decline in 51Cr‐labelled EDTA measured glomerular filtration rate following lung transplantation. Nephrol Dial Transplant. 2007;22(12):3616‐3622.
    1. Mason DP, Solovera‐Rozas M, Feng J, et al. Dialysis after lung transplantation: prevalence, risk factors and outcome. J Heart Lung Transplant. 2007;26(11):1155‐1162.
    1. Hellemons ME, Bakker SJ, Postmus D, et al. Incidence of impaired renal function after lung transplantation. J Heart Lung Transplant. 2012;31(3):238‐243.
    1. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351(13):1296‐1305.
    1. Carrero JJ, Hecking M, Chesnaye NC, Jager KJ. Sex and gender disparities in the epidemiology and outcomes of chronic kidney disease. Nat Rev Nephrol. 2018;14(3):151‐164.
    1. Tedesco‐Silva H, Felipe C, Ferreira A, et al. Reduced incidence of cytomegalovirus infection in kidney transplant recipients receiving everolimus and reduced tacrolimus doses. Am J Transplant. 2015;15(10):2655‐2664.
    1. Brennan DC, Legendre C, Patel D, et al. Cytomegalovirus incidence between everolimus versus mycophenolate in de novo renal transplants: pooled analysis of three clinical trials. Am J Transplant. 2011;11(11):2453‐2462.
    1. Kobashigawa J, Ross H, Bara C, et al. Everolimus is associated with a reduced incidence of cytomegalovirus infection following de novo cardiac transplantation. Transpl Infect Dis. 2013;15(2):150‐162.
    1. Strueber M, Warnecke G, Fuge J, et al. Everolimus versus mycophenolate mofetil de novo after lung transplantation: a prospective, randomized, open‐label trial. Am J Transplant. 2016;16(11):3171‐3180.
    1. Rittà M, Costa C, Solidoro P, et al. Everolimus‐based immunosuppressive regimens in lung transplant recipients: impact on CMV infection. Antiviral Res. 2015;113:19‐26.
    1. Ghassemieh B, Ahya VN, Baz MA, et al. Decreased incidence of cytomegalovirus infection with sirolimus in a post hoc randomized, multicenter study in lung transplantation. J Heart Lung Transplant. 2013;32(7):701‐706.
    1. Tedesco Silva H Jr, Cibrik D, Johnston T, et al. Everolimus plus reduced‐exposure CsA versus mycophenolic acid plus standard‐exposure CsA in renal‐transplant recipients. Am J Transplant. 2010;10(6):1401‐1413.
    1. De Simone P, Nevens F, De Carlis L, et al. Everolimus with reduced tacrolimus improves renal function in de novo liver transplant recipients: a randomized controlled trial. Am J Transplant. 2012;12(11):3008‐3020.
    1. Eisen HJ, Kobashigawa J, Starling RC, et al. Everolimus versus mycophenolate mofetil in heart transplantation: a randomized, multicenter trial. Am J Transplant. 2013;13(5):1203‐1216.
    1. Glanville AR, Aboyoun C, Klepetko W, et al. European and Australian Investigators in Lung Transplantation . Three‐year results of an investigator‐driven multicenter, international, randomized open label de novo trial to prevent BOS after lung transplantation. J Heart Lung Transplant. 2015;34(1):16‐25.
    1. Gullestad L, Iversen M, Mortensen SA, et al. Everolimus with reduced calcineurin inhibitor in thoracic transplant recipients with renal dysfunction: a multicenter, randomized trial. Transplantation. 2010;8(7):864‐872.
    1. Gullestad L, Mortensen S‐A, Eiskjær H, et al. Two‐year outcomes in thoracic transplant recipients after conversion to everolimus with reduced calcineurin inhibitor within a multicenter, open‐label, randomized trial. Transplantation. 2010;90(12):1581‐1589.
    1. Levey AS, Stevens LA, Schmid CH, et al.; CKD‐EPI (Chronic Kidney Disease Epidemiology Collaboration) . A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604‐612.
    1. Verleden GM, Raghu G, Meyer KC, Glanville AR, Corris P. A new classification system for chronic lung allograft dysfunction. J Heart Lung Transplant. 2014;33(2):127‐133.
    1. Hoek FJ, Kemperman FA, Krediet RT. A comparison between cystatin C, plasma creatinine and the Cockcroft and Gault formula for the estimation of glomerular filtration rate. Nephrol Dial Transplant. 2003;18(10):2024‐2031.
    1. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med. 1999;130(6):461‐470.
    1. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31‐41.
    1. Nankivell BJ, Borrows RJ, Fung CL, O'Connell PJ, Chapman JR, Allen RD. Calcineurin inhibitor nephrotoxicity: longitudinal assessment by protocol histology. Transplantation. 2004;78(4):557‐565.
    1. Snell GI, Valentine VG, Vitulo P, et al.; RAD B159 Study Group . Everolimus versus azathioprine in maintenance lung transplant recipients: an international, randomized, double‐blind clinical trial. Am J Transplant. 2006;6(1):169‐177.
    1. Borrows R, Chusney G, Loucaidou M, et al. Mycophenolic acid 12‐h trough level monitoring in renal transplantation: association with acute rejection and toxicity. Am J Transplant. 2006;6(1):121‐128.
    1. Boudjema K, Camus C, Saliba F, et al. Reduced‐dose tacrolimus with mycophenolate mofetil vs. standard‐dose tacrolimus in liver transplantation: a randomized study. Am J Transplant. 2011;11(5):965‐976.
    1. Treede H, Glanville AR, Klepetko W, et al.; European and Australian Investigators in Lung Transplantation . Tacrolimus and cyclosporine have differential effects on the risk of development of bronchiolitis obliterans syndrome: results of a prospective, randomized international trial in lung transplantation. J Heart Lung Transplant. 2012;31(8):797‐804.
    1. Degen DA, Janardan J, Barraclough KA, et al. Predictive performance of different kidney function estimation equations in lung transplant patients. Clin Biochem. 2017;50(7–8):385‐393.

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