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

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 NCT 01404325.

Viral load-guided immunosuppression after lung transplantation (VIGILung)—study protocol for a randomized controlled trial

“…The sample size calculation is based on the assumption of a mean decline in GFR of 15 between randomization and 12 months thereafter and a standard deviation of 20 in the control group. Two randomized trials [ 8 , 13 ] observed effect sizes of a similar magnitude. Compared to the control group, a mean decline in GFR of 5 in the experimental group (i.e., difference of 10 in GFR declines between the intervention groups) is regarded as clinically relevant.…”

“…The effect size assumed for the sample size calculation was derived from the observed glomerular filtration rate (GFR) changes within 12 months in two recent immunosuppressive trials including reduced calcineurin inhibitor strategies [8,13]. All endpoints will be assessed by predefined definitions [9,[14][15][16][17][18].…”

“…Guiding immunosuppression by an immune response assay in a prospective trial resulted in reductions in CNI doses of 13–25% within the first year after liver transplantation, with documented reductions in bacterial and fungal infections [ 6 ]. In lung transplant recipients, a CNI reduction of 50% has led to an improvement of GFR (CKD-EPI) by 10 ml/min/1.73 m 2 after 12 months in a recent randomized trial [ 8 ]. With the management of trough levels by TTV load, it is expected that a similar CNI dose reduction can be achieved.…”

Viral load Guided Immunosuppression after Lung Transplantation (VIGILung) – study protocol for a randomized controlled trial

“…The effect size assumed for the sample size calculation were derived from the observed glomerular ltration rate (GFR) changes within 12 months in two recent immunosuppressive trials including reduced calcineurin inhibitor strategies (8,14). All endpoints will be assessed by pre-de ned de nitions (9,(15)(16)(17)(18)(19).…”

“…Guiding immunosuppression by an immune response assay in a prospective trial resulted in reductions in CNI doses of 13%-25% within the rst year after liver transplantation, with documented reductions in bacterial and fungal infections (6). In lung transplant recipients, a CNI reduction of 50% has led to an improvement of GFR (CKD-EPI) by 10 ml/min/1.73 m² after 12 months in a recent randomized trial (8).…”