title: Three-year results of an investigator-driven multicenter, international, randomized open-label de novo trial to prevent BOS after lung transplantation.
abstract: BACKGROUND
  Chronic lung allograft dysfunction (CLAD), predominantly manifest as bronchiolitis obliterans syndrome (BOS), is the primary cause of morbidity and death after lung transplantation. We assessed the efficacy and safety of 2 de novo immunosuppression protocols to prevent BOS.
  
  
  METHODS
  This was a multicenter, prospective, international, randomized (1:1) open-label superiority study of de novo enteric-coated mycophenolate sodium (MPS) vs delayed-onset everolimus (RAD), both arms in combination with cyclosporine (CsA) monitored by 2-hour post-dose (C2) levels, and corticosteroids. Target C2 levels were lower in the RAD group because RAD is known to potentiate CsA nephrotoxicity. Cytolytic induction therapy was not used. Patients were stratified at entry for cystic fibrosis. Confirmation of anastomotic healing was required for randomization. Primary efficacy was freedom from BOS Grade 1 on intention-to-treat (ITT) analysis. Secondary efficacy parameters were patient and graft survival and severity of rejection. Treatment failure was defined by graft loss, patient death, drug cessation, or need for other therapy.
  
  
  RESULTS
  The 3-year freedom from BOS Grade 1 was 70% for MPS (n = 80) vs 71% for RAD (n = 84; p = 0.95 by log-rank) in ITT but was lower in the RAD arm of the per-protocol population (p = 0.03). The 3-year survival was 84% (MPS) vs 76% (RAD; p = 0.19 by log-rank). Thirteen patients switched from MPS vs 31 from RAD (p < 0.01). Days on MPS were greater than days on RAD (p < 0.01). Rejection events proven by biopsy specimen were more common on MPS (p = 0.02), as were leucopenia (p < 0.01), diarrhea (p < 0.01), and cytomegalovirus infection (p = 0.04). Venous thromboembolism was more frequent on RAD (p = 0.02). Creatinine at 3 years was 160 ± 112 μmol/1iter in MPS patients vs 152 ± 98 μmol/1iter in RAD patients (p = 0.67).
  
  
  CONCLUSIONS
  This 3-year ITT analysis found no significant difference between arms but was underpowered to accept the null hypothesis that RAD and MPS have equivalent efficacy in preventing BOS or death after lung transplantation.
authors.affiliation: Lung Transplant Unit, St.Vincent's Hospital, Sydney, New South Wales, Australia. Electronic address: Allan.Glanville@svha.org.au.
authors.forename: Allan R
authors.initials: AR
authors.lastname: Glanville
authors.affiliation: Lung Transplant Unit, St.Vincent's Hospital, Sydney, New South Wales, Australia.
authors.forename: Christina
authors.initials: C
authors.lastname: Aboyoun
authors.affiliation: Department of Thoracic Surgery, University of Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Klepetko
authors.affiliation: Department of Cardiovascular Surgery, University Heart Center, Hamburg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Reichenspurner
authors.affiliation: Department of Cardiovascular Surgery, University Heart Center, Hamburg, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Treede
authors.affiliation: University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Verschuuren
authors.affiliation: Division of Pulmonary Medicine and Lung Transplant Program, University Hospital, Zurich, Switzerland.
authors.forename: Annette
authors.initials: A
authors.lastname: Boehler
authors.affiliation: Division of Pulmonary Medicine and Lung Transplant Program, University Hospital, Zurich, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Benden
authors.affiliation: Department of Thoracic Medicine, The Prince Charles Hospital, Brisbane, Queensland, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Hopkins
authors.affiliation: Department of Respiratory Medicine, Newcastle University, Newcastle, United Kingdom.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Corris
mesh_terms: D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D001989:Bronchiolitis Obliterans / Q000209:etiology / Q000517:prevention & control*; D004359:Drug Therapy, Combination; D000068338:Everolimus; D005260:Female; D005500:Follow-Up Studies; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D016040:Lung Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D011183:Postoperative Complications / Q000209:etiology / Q000517:prevention & control*; D011446:Prospective Studies; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives*; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D000068338:Everolimus; D009173:Mycophenolic Acid; D020123:Sirolimus
keywords: BOS; CLAD; cyclosporine C(2) monitoring; everolimus; lung transplantation; mycophenolate sodium