Gregor Warnecke1, Dirk Van Raemdonck2, Michael A Smith3, Gilbert Massard4, Jasleen Kukreja5, Federico Rea6, Gabriel Loor7, Fabio De Robertis8, Jayan Nagendran9, Kumud K Dhital10, Francisco Javier Moradiellos Díez11, Christoph Knosalla12, Christian A Bermudez13, Steven Tsui14, Kenneth McCurry15, I-Wen Wang16, Tobias Deuse17, Guy Lesèche18, Pascal Thomas19, Igor Tudorache20, Christian Kühn20, Murat Avsar20, Bettina Wiegmann21, Wiebke Sommer21, Arne Neyrinck2, Marco Schiavon6, Fiorella Calabrese6, Nichola Santelmo4, Anne Olland4, Pierre-Emanuel Falcoz4, Andre R Simon8, Andres Varela11, Joren C Madsen22, Marshall Hertz23, Axel Haverich21, Abbas Ardehali24. 1. Department of Cardiac, Thoracic, Transplantation, and Vascular Surgery, Hannover Medical School, Hannover, Germany; German Center for Lung Research (DZL; partner site), Hannover, Germany. Electronic address: warnecke.gregor@mh-hannover.de. 2. Department of Thoracic Surgery, University Hospital Leuven, Leuven, Belgium. 3. Department of General Thoracic Surgery, St Joseph's Medical Center, Phoenix, AZ, USA. 4. Department of Thoracic Surgery, Hospital of University of Strasbourg, Strasbourg, France. 5. Department of Thoracic Surgery, University of California San Francisco, San Francisco, CA, USA. 6. Department of Thoracic Surgery, University of Padua, Padua, Italy. 7. Department of Cardiothoracic Surgery, University of Minnesota, Minneapolis, MN, USA. 8. Department of Cardiothoracic Surgery, Royal Brompton and Harefield Hospital Trust, London, UK. 9. Department of Surgery, Division of Cardiac Surgery, University of Alberta Medical Center, Edmonton, AB, Canada. 10. Department of Cardiothoracic Surgery, St Vincent's Hospital, Sydney, NSW, Australia. 11. Department of Thoracic Surgery, University Hospital Puerta de Hierro, Madrid, Spain. 12. Department of Cardiothoracic and Vascular Surgery, German Heart Institute Berlin, Berlin, Germany; German Centre for Cardiovascular Research (DHZK; partner site), Berlin, Germany. 13. Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. 14. Cardiothoracic Surgery, Papworth Hospital Trust, Papworth, UK. 15. Cardiothoracic Surgery, The Cleveland Clinic Foundation, Cleveland, OH, USA. 16. Department of Cardiothoracic Surgery, Indiana University, Indianapolis, IN, USA. 17. Department Cardiovascular Surgery, University Hospital Eppendorf, Hamburg, Germany. 18. Department Thoracic and Vascular Surgery, Hospital Bichat, Paris, France. 19. Department of Thoracic Surgery, Lung Transplantation, and Diseases of the Esophagus, University Hospitals of Marseille, Marseille, France. 20. Department of Cardiac, Thoracic, Transplantation, and Vascular Surgery, Hannover Medical School, Hannover, Germany. 21. Department of Cardiac, Thoracic, Transplantation, and Vascular Surgery, Hannover Medical School, Hannover, Germany; German Center for Lung Research (DZL; partner site), Hannover, Germany. 22. Massachusetts General Transplant Center and Department of Cardiac Surgery, Massachusetts General Hospital, Boston, MA, USA. 23. Department of Respiratory Medicine, University of Minnesota, Minneapolis, MN, USA. 24. Department of Surgery, Division of Cardiothoracic Surgery, Ronald Reagan University of California, Los Angeles Medical Center, Los Angeles, CA, USA.
Abstract
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°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 -∞ 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 -∞ 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.
RCT Entities:
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°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 -∞ 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 -∞ 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.
Authors: Bradley W Ellis; Dmitry O Traktuev; Stephanie Merfeld-Clauss; Uryan Isik Can; Meijing Wang; Ray Bergeron; Pinar Zorlutuna; Keith L March Journal: Stem Cells Date: 2020-12-23 Impact factor: 6.277