Everolimus Versus Mycophenolate Mofetil De Novo After Lung Transplantation: A Prospective, Randomized, Open-Label Trial

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The role of mammalian target of rapamycin (mTOR) inhibitors in de novo immunosuppression after lung transplantation is not well defined. We compared Everolimus versus mycophenolate mofetil in an investigator-initiated single-center trial in Hannover, Germany. A total of 190 patients were randomly assigned 1:1 on day 28 posttransplantation to mycophenolate mofetil (MMF) or Everolimus combined with cyclosporine A (CsA) and steroids. Patients were followed up for 2 years. The primary endpoint was freedom from bronchiolitis obliterans syndrome (BOS). The secondary endpoints were incidence of acute rejections, infections, treatment failure and kidney function. BOS-free survival in intention-to-treat (ITT) analysis was similar in both groups (p = 0.174). The study protocol was completed by 51% of enrolled patients. The per-protocol analysis shows incidence of bronchiolitis obliterans syndrome (BOS): 1/43 in the Everolimus group and 8/54 in the MMF group (p = 0.041). Less biopsy-proven acute rejection (AR) (p = 0.005), cytomegalovirus (CMV) antigenemia (p = 0.005) and lower respiratory tract infection (p = 0.003) and no leucopenia were seen in the Everolimus group. The glomerular filtration rate (GFR) decreased in both groups about 50% within 6 months. Due to a high withdrawal rate, the study was underpowered to prove a difference in BOS-free survival. The dropout rate was more pronounced in the Everolimus group. Secondary endpoints indicate potential advantages of Everolimus-based protocols but also a potentially higher rate of drug-related serious adverse events.

Key words

clinical research/practice
lung transplantation/pulmonology
pharmacology
immunosuppression/immune modulation
clinical trial
immunosuppressant
calcineurin inhibitor: cyclosporine A (CsA)
antiproliferative agent: mycophenolate mofetil (MMF)
mechanistic target of rapamycin (mTOR)
bronchiolitis obliterans (BOS)

Abbreviations

AR
acute rejection
BOS
bronchiolitis obliterans syndrome
CF
cystic fibrosis
CI
confidence interval
CMV
cytomegalovirus
COPD
chronic obstructive pulmonary disease
CsA
cyclosporine A
DLTx
double-long transplantation
GFR
glomerular filtration rate
HUS
hemolytic–uremic syndrome
ICU
intensive care unit
IPF
idiopathic pulmonary fibrosis
ITT
intention to treat
LTx
lung transplantation
MMF
mycophenolate mofetil
mTOR
mammalian target of rapamycin
Re-LTx
recurrent lung transplantation
SLTx
single-lung transplantation
TMA
thrombotic microangiopathy

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