The 4Everlung trial was designed to evaluate the benefit of early everolimus (EVR)-based quadruple low immunosuppressive (IS) regimen on kidney function (RF) after LTx.

4EVERLUNG is a prospective, randomized, open-label, 12month multicenter trial conducted in 8 German sites. Eligible pts were randomized (1:1) 3-18 months after LTx. The quadruple regimen received EVR (C0-h 3-5 ng/mL) with reduced CNI (tacrolimus C0-h 3-5ng/mL or cyclosporine C0-h 25-75 ng/mL) and cell-cycle inhibitors plus prednisone, the triple regimen standard CNI (tacrolimus C0-h >8 ng/mL or CsA C0-h >100 ng/mL) with cell-cycle inhibitor and prednisone. Stratification of pts at randomization was done according to baseline glomerular filtration rate (GFR) values: ≥40 – 60 ml/min, >60 – 75 ml/min or >75 – 100 ml/min. Primary objective was the GFR calculated by CKD-EPI at 12 months. Outcomes on kidney function and efficacy from full analysis set (ITT) will be reported (NCT01404325). Overall, 180 pts were screened and 130 were randomized (median age 57 years, 63% male, 42% COPD/Emphysema). 67 pts were randomized to the quadruple low regimen and 63 pts to the triple standard CNI regimen. GFR was significantly improved in the quadruple low regimen at 1, 3, 6, 9 and 12 months after randomization with the primary endpoint being met at 12 months: GFR was 64.5 mL/min for the quadruple low regimen vs 54.6 mL/min for the triple standard regimen (absolute difference +9.9 mL/min, LS-mean, ANCOVA, p < 0.001). Pts with a baseline GFR of 40 to 60 mL/min showed the highest benefit with an absolute GFR difference of +13.1 mL/min. A composite of biopsy-proven rejection, graft loss or death was similar in both groups. Safety profiles were similar between both groups.

The 4EVERLUNG trial confirmed that an EVR-based quadruple-low CNI regimen is safe and efficacious early after LTx and led to improved kidney function in a clinically important range early after initiation in comparison to conventional dosed CNI-based triple immunosuppression.

CITATION INFORMATION: Gottlieb J., Neurohr C., Müller-Quernheim J., Wirtz H., Sill B., Wilkens H., Besa V., Knosalla C., Junge M., Capusan C., Strüber M. Superiority of Early Everolimus-Based Quadruple Immunosuppression versus Standard Triple Therapy after Lung Transplantation: 12 Months Results from Prospective 4EVERLUNG Study in Germany Am J Transplant. 2017;17 (suppl 3).

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