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

Gregor Warnecke, Dirk Van Raemdonck, Michael A. Smith, Gilbert Massard, Jasleen Kukreja, Federico Rea, Gabriel Loor, Fabio De Robertis, Jayan Nagendran, Kumud K. Dhital, Francisco Javier Moradiellos Díez, Christoph Knosalla, Christian A. Bermudez, Steven Tsui, Kenneth McCurry, I. Wen Wang, Tobias Deuse, Guy Lesèche, Pascal Thomas, Igor Tudorache & 16 others Christian Kühn, Murat Avsar, Bettina Wiegmann, Wiebke Sommer, Arne Neyrinck, Marco Schiavon, Fiorella Calebrese, Nichola Santelmo, Anne Olland, Pierre Emanuel Falcoz, Andre R. Simon, Andres Varela, Joren C. Madsen, Marshall Hertz, Axel Haverich, Abbas Ardehali

Research output: Contribution to journalArticle

29 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)357-367
Number of pages11
JournalThe Lancet Respiratory Medicine
Volume6
Issue number5
DOIs
StatePublished - May 1 2018

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Lung Transplantation
Equipment and Supplies
Lung
Transplants
Prostaglandins D
Control Groups
Tissue Donors
Safety
Survival
Primary Graft Dysfunction
Arm
Oxygen
Population
Organ Preservation
Partial Pressure
Incidence
Coma
Blood Vessels
Cause of Death
Sepsis

PubMed: MeSH publication types

  • Clinical Trial, Phase III
  • Equivalence Trial
  • Journal Article
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

Cite this

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. / Warnecke, Gregor; Van Raemdonck, Dirk; Smith, Michael A.; Massard, Gilbert; Kukreja, Jasleen; Rea, Federico; Loor, Gabriel; De Robertis, Fabio; Nagendran, Jayan; Dhital, Kumud K.; Moradiellos Díez, Francisco Javier; Knosalla, Christoph; Bermudez, Christian A.; Tsui, Steven; McCurry, Kenneth; Wang, I. Wen; Deuse, Tobias; Lesèche, Guy; Thomas, Pascal; Tudorache, Igor; Kühn, Christian; Avsar, Murat; Wiegmann, Bettina; Sommer, Wiebke; Neyrinck, Arne; Schiavon, Marco; Calebrese, Fiorella; Santelmo, Nichola; Olland, Anne; Falcoz, Pierre Emanuel; Simon, Andre R.; Varela, Andres; Madsen, Joren C.; Hertz, Marshall; Haverich, Axel; Ardehali, Abbas.

In: The Lancet Respiratory Medicine, Vol. 6, No. 5, 01.05.2018, p. 357-367.

Research output: Contribution to journalArticle

Warnecke, G, Van Raemdonck, D, Smith, MA, Massard, G, Kukreja, J, Rea, F, Loor, G, De Robertis, F, Nagendran, J, Dhital, KK, Moradiellos Díez, FJ, Knosalla, C, Bermudez, CA, Tsui, S, McCurry, K, Wang, IW, Deuse, T, Lesèche, G, Thomas, P, Tudorache, I, Kühn, C, Avsar, M, Wiegmann, B, Sommer, W, Neyrinck, A, Schiavon, M, Calebrese, F, Santelmo, N, Olland, A, Falcoz, PE, Simon, AR, Varela, A, Madsen, JC, Hertz, M, Haverich, A & Ardehali, A 2018, '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', The Lancet Respiratory Medicine, vol. 6, no. 5, pp. 357-367. https://doi.org/10.1016/S2213-2600(18)30136-X
Warnecke, Gregor ; Van Raemdonck, Dirk ; Smith, Michael A. ; Massard, Gilbert ; Kukreja, Jasleen ; Rea, Federico ; Loor, Gabriel ; De Robertis, Fabio ; Nagendran, Jayan ; Dhital, Kumud K. ; Moradiellos Díez, Francisco Javier ; Knosalla, Christoph ; Bermudez, Christian A. ; Tsui, Steven ; McCurry, Kenneth ; Wang, I. Wen ; Deuse, Tobias ; Lesèche, Guy ; Thomas, Pascal ; Tudorache, Igor ; Kühn, Christian ; Avsar, Murat ; Wiegmann, Bettina ; Sommer, Wiebke ; Neyrinck, Arne ; Schiavon, Marco ; Calebrese, Fiorella ; Santelmo, Nichola ; Olland, Anne ; Falcoz, Pierre Emanuel ; Simon, Andre R. ; Varela, Andres ; Madsen, Joren C. ; Hertz, Marshall ; Haverich, Axel ; Ardehali, Abbas. / 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. In: The Lancet Respiratory Medicine. 2018 ; Vol. 6, No. 5. pp. 357-367.
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title = "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",
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.",
author = "Gregor Warnecke and {Van Raemdonck}, Dirk and Smith, {Michael A.} and Gilbert Massard and Jasleen Kukreja and Federico Rea and Gabriel Loor and {De Robertis}, Fabio and Jayan Nagendran and Dhital, {Kumud K.} and {Moradiellos D{\'i}ez}, {Francisco Javier} and Christoph Knosalla and Bermudez, {Christian A.} and Steven Tsui and Kenneth McCurry and Wang, {I. Wen} and Tobias Deuse and Guy Les{\`e}che and Pascal Thomas and Igor Tudorache and Christian K{\"u}hn and Murat Avsar and Bettina Wiegmann and Wiebke Sommer and Arne Neyrinck and Marco Schiavon and Fiorella Calebrese and Nichola Santelmo and Anne Olland and Falcoz, {Pierre Emanuel} and Simon, {Andre R.} and Andres Varela and Madsen, {Joren C.} and Marshall Hertz and Axel Haverich and Abbas Ardehali",
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TY - JOUR

T1 - Normothermic ex-vivo preservation with the portable Organ Care System Lung device for bilateral lung transplantation (INSPIRE)

T2 - a randomised, open-label, non-inferiority, phase 3 study

AU - Warnecke, Gregor

AU - Van Raemdonck, Dirk

AU - Smith, Michael A.

AU - Massard, Gilbert

AU - Kukreja, Jasleen

AU - Rea, Federico

AU - Loor, Gabriel

AU - De Robertis, Fabio

AU - Nagendran, Jayan

AU - Dhital, Kumud K.

AU - Moradiellos Díez, Francisco Javier

AU - Knosalla, Christoph

AU - Bermudez, Christian A.

AU - Tsui, Steven

AU - McCurry, Kenneth

AU - Wang, I. Wen

AU - Deuse, Tobias

AU - Lesèche, Guy

AU - Thomas, Pascal

AU - Tudorache, Igor

AU - Kühn, Christian

AU - Avsar, Murat

AU - Wiegmann, Bettina

AU - Sommer, Wiebke

AU - Neyrinck, Arne

AU - Schiavon, Marco

AU - Calebrese, Fiorella

AU - Santelmo, Nichola

AU - Olland, Anne

AU - Falcoz, Pierre Emanuel

AU - Simon, Andre R.

AU - Varela, Andres

AU - Madsen, Joren C.

AU - Hertz, Marshall

AU - Haverich, Axel

AU - Ardehali, Abbas

PY - 2018/5/1

Y1 - 2018/5/1

N2 - 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.

AB - 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.

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