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
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
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DOI：
10.1016/s2213-2600(18)30136-x
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发表时间：
2018-05-01
影响因子：
76.2
通讯作者：
Ardehali, Abbas
中科院分区：
文献类型：
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作者：
Warnecke, Gregor;Van Raemdonck, Dirk;Ardehali, Abbas
研究背景严重的原发性肺移植功能障碍（PGD）3级（PGD 3）是肺移植术后常见的严重并发症。我们的目的是评估生理供体肺保存使用的器官护理系统（OCS）肺设备相比，冷静态storage.Methods在这个非劣效性，随机，对照，开放标签，3期试验（INSPIRE）收件人年龄为18岁或以上，并注册为标准标准的主要双肺移植候选人。符合条件的供体年龄小于65岁，动脉血中氧分压与吸入氧分数的比值大于300 mm Hg。移植受者被随机分配（1：1），按中心分层，接受保存在OCS肺装置（OCS组）或4 ℃冷藏（对照组）中的标准供体肺。复合主要有效性终点为符合方案人群中移植后前72小时内PGD 3缺失和30天生存率，严格的非劣效性界值为4%。在符合非劣效性的情况下检验优效性。主要安全性终点是移植后30天内肺移植相关严重不良事件的平均数量。我们在符合方案和意向治疗人群中进行了分析。该试验注册于ClinicalTrials.gov，编号NCT 01630434。结果在2011年11月17日至2014年11月24日期间，我们随机分配了370例患者，其中320例（86%）接受了移植（n=151例OCS和n=169例对照）;随访于2016年11月24日完成。112例患者达到主要终点（79.4%）141例患者（95% CI 71.8至85.8），而116（70.3%）165例患者（62.7 - 77.2）（非劣效性点估计值-9.1%; 95% CI -无穷大至-1.0; p=0.0038;优效性检验p=0.068）。移植后30天的患者存活率为135（95.7%）141例患者（95% CI 91.0-98.4），OCS组和165例患者（100%;对照组97.8-100.0）（p=0.0090），12个月时为126 OCS组141例患者中的89.4%（83.1-93.9），对照组165例患者中的146例（88.1%）（81.8-92.8）。OCS组141例患者中有25例（17.7%）（95% CI 11.8 - 25.1）和对照组165例患者中有49例（29.7%）（22.8 - 37.3;优效性检验p=0.015）报告了72小时内PGD 3的发生率。达到了主要安全性终点（OCS组发生0.23起肺移植物相关严重不良事件，对照组发生0.28起事件[点估计值-0.045%; 95% CI -8至0.047;非劣效性检验p=0.020]）。在意向治疗人群中，30天和住院期间的死亡原因是肺移植失败或肺部感染（OCS组n=2 vs对照组n=7），心脏原因（n=4 vs n=1），血管性或卒中（n=3 vs n=0），代谢性昏迷（n=0 vs n=2）和全身性脓毒症（n=0 vs n=1）。解释INSPIRE试验达到了其主要有效性和安全性终点。虽然没有短期生存益处的报道，但需要进一步的研究来确定移植后72小时内PGD 3发生率的降低是否可能转化为肺移植后早期恢复和长期结局的改善。版权所有（C）2018 Elsevier Ltd.保留所有权利。
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 -8 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. Copyright (C) 2018 Elsevier Ltd. All rights reserved.