Normothermic ex-vivo preservation with the portable Organ Care System Lung device for bilateral lung transplantation (INSPIRE): a randomised, open-label, non-inferiority, phase 3 study

BACKGROUND: Severe primary graft dysfunction (PGD) of grade 3 (PGD3) is a common serious complication following lung transplantation. We aimed to assess physiological donor lung preservation using the Organ Care System (OCS) Lung device compared with cold static storage. METHODS: In this non-inferiority, randomised, controlled, open-label, phase 3 trial (INSPIRE) recipients were aged 18 years or older and were registered as standard criteria primary double lung transplant candidates. Eligible donors were younger than 65 years old with a ratio of partial pressure of oxygen in arterial blood to the fraction of inspired oxygen of more than 300 mm Hg. Transplant recipients were randomly assigned (1:1) with permuted blocks, stratified by centre, to receive standard criteria donor lungs preserved in the OCS Lung device (OCS arm) or cold storage at 4 degrees C (control arm). The composite primary effectiveness endpoint was absence of PGD3 within the first 72 h after transplant and 30-day survival in the per-protocol population, with a stringent 4% non-inferiority margin. Superiority was tested upon meeting non-inferiority. The primary safety endpoint was the mean number of lung graft-related serious adverse events within 30 days of transplant. We did analyses in the per-protocol and intention-to-treat populations. This trial is registered with ClinicalTrials.gov, number NCT01630434. FINDINGS: Between Nov 17, 2011, and Nov 24, 2014, we randomly assigned 370 patients, and 320 (86%) underwent transplantation (n=151 OCS and n=169 control); follow-up was completed in Nov 24, 2016. The primary endpoint was met in 112 (79.4%) of 141 patients (95% CI 71.8 to 85.8) in the OCS group compared with 116 (70.3%) of 165 patients (62.7 to 77.2) in the control group (non-inferiority point estimate -9.1%; 95% CI -infinity to -1.0; p=0.0038; and superiority test p=0.068). Patient survival at day 30 post-transplant was 135 (95.7%) of 141 patients (95% CI 91.0-98.4) in the OCS group and 165 patients (100%; 97.8-100.0) in the control group (p=0.0090) and at 12 months was 126 (89.4%) of 141 patients (83.1-93.9) for the OCS group compared with 146 (88.1%) of 165 patients (81.8-92.8) for the control group. Incidence of PGD3 within 72 h was reported in 25 (17.7%) of 141 patients in the OCS group (95% CI 11.8 to 25.1) and 49 (29.7%) of 165 patients in the control group (22.8 to 37.3; superiority test p=0.015). The primary safety endpoint was met (0.23 lung graft-related serious adverse events in the OCS group compared with 0.28 events in the control group [point estimate -0.045%; 95% CI -infinity to 0.047; non-inferiority test p=0.020]). In the intention-to-treat population, causes of death at 30 days and in hospital were lung graft failure or lung infection (n=2 for OCS vs n=7 for control), cardiac causes (n=4 vs n=1), vascular or stroke (n=3 vs n=0), metabolic coma (n=0 vs n=2), and generalised sepsis (n=0 vs n=1). INTERPRETATION: The INSPIRE trial met its primary effectiveness and safety endpoints. Although no short-term survival benefit was reported, further research is needed to see whether the reduced incidence of PGD3 within 72 h of a transplant might translate into earlier recovery and improved long-term outcomes after lung transplantation. FUNDING: TransMedics Inc.

• Warnecke, G.
• Van Raemdonck, D.
• Smith, M. A.
• Massard, G.
• Kukreja, J.
• Rea, F.
• Loor, G.
• De Robertis, F.
• Nagendran, J.
• Dhital, K. K.
• Moradiellos Diez, F. J.
• Knosalla, C.
• Bermudez, C. A.
• Tsui, S.
• McCurry, K.
• Wang, I. W.
• Deuse, T.
• Leseche, G.
• Thomas, P.
• Tudorache, I.
• Kuhn, C.
• Avsar, M.
• Wiegmann, B.
• Sommer, W.
• Neyrinck, A.
• Schiavon, M.
• Calabrese, F.
• Santelmo, N.
• Olland, A.
• Falcoz, P. E.
• Simon, A. R.
• Varela, A.
• Madsen, J. C.
• Hertz, M.
• Haverich, A.
• Ardehali, A.