Gorman Ellen A, Rynne Jennifer, Gardiner Hannah J, Rostron Anthony J, Bannard-Smith Jonathan, Bentley Andrew M, Brealey David, Campbell Christina, Curley Gerard, Clarke Mike, Dushianthan Ahilanadan, Hopkins Phillip, Jackson Colette, Kefela Kallirroi, Krasnodembskaya Anna, Laffey John G, McDowell Cliona, McFarland Margaret, McFerran Jamie, McGuigan Peter, Perkins Gavin D, Silversides Jonathan, Smythe Jon, Thompson Jacqui, Tunnicliffe William S, Welters Ingeborg D M, Amado-Rodríguez Laura, Albaiceta Guillermo, Williams Barry, Shankar-Hari Manu, McAuley Daniel F, O'Kane Cecilia M
Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom.
Centre for Inflammation Research, The University of Edinburgh, Edinburgh, United Kingdom.
Am J Respir Crit Care Med. 2023 Aug 1;208(3):256-269. doi: 10.1164/rccm.202302-0297OC.
Mesenchymal stromal cells (MSCs) may modulate inflammation, promoting repair in coronavirus disease (COVID-19)-related acute respiratory distress syndrome (ARDS). We investigated the safety and efficacy of ORBCEL-C (CD362 [cluster of differentiation 362]-enriched, umbilical cord-derived MSCs) in COVID-19-related ARDS. In this multicenter, randomized, double-blind, allocation-concealed, placebo-controlled trial (NCT03042143), patients with moderate to severe COVID-19-related ARDS were randomized to receive ORBCEL-C (400 million cells) or placebo (Plasma-Lyte 148). The primary safety and efficacy outcomes were the incidence of serious adverse events and oxygenation index at Day 7, respectively. Secondary outcomes included respiratory compliance, driving pressure, Pa:Fi ratio, and Sequential Organ Failure Assessment score. Clinical outcomes relating to duration of ventilation, lengths of ICU and hospital stays, and mortality were collected. Long-term follow-up included diagnosis of interstitial lung disease at 1 year and significant medical events and mortality at 2 years. Transcriptomic analysis was performed on whole blood at Days 0, 4, and 7. Sixty participants were recruited (final analysis: = 30 received ORBCEL-C, = 29 received placebo; 1 participant in the placebo group withdrew consent). Six serious adverse events occurred in the ORBCEL-C group and three in the placebo group (risk ratio, 2.9 [95% confidence interval, 0.6-13.2]; = 0.25). Day 7 mean (SD) oxygenation index did not differ (ORBCEL-C, 98.3 [57.2] cm HO/kPa; placebo, 96.6 [67.3] cm HO/kPa). There were no differences in secondary surrogate outcomes or in mortality at Day 28, Day 90, 1 year, or 2 years. There was no difference in the prevalence of interstitial lung disease at 1 year or significant medical events up to 2 years. ORBCEL-C modulated the peripheral blood transcriptome. ORBCEL-C MSCs were safe in subjects with moderate to severe COVID-19-related ARDS but did not improve surrogates of pulmonary organ dysfunction.
间充质基质细胞（MSCs）可能调节炎症反应，促进冠状病毒病（COVID-19）相关急性呼吸窘迫综合征（ARDS）的修复。我们研究了ORBCEL-C（富含CD362[分化簇362]的脐带间充质基质细胞）在COVID-19相关ARDS中的安全性和有效性。在这项多中心、随机、双盲、分配隐藏、安慰剂对照试验（NCT03042143）中，中度至重度COVID-19相关ARDS患者被随机分配接受ORBCEL-C（4亿个细胞）或安慰剂（平衡液148）。主要安全性和有效性结局分别为第7天严重不良事件的发生率和氧合指数。次要结局包括呼吸顺应性、驱动压、动脉血氧分压与吸入氧浓度比值（Pa:Fi）以及序贯器官衰竭评估评分。收集了与通气时间、重症监护病房（ICU）住院时间、住院时间和死亡率相关的临床结局。长期随访包括1年时间质性肺疾病的诊断以及2年时的重大医疗事件和死亡率。在第0天、第4天和第7天对全血进行转录组分析。招募了60名参与者（最终分析：30名接受ORBCEL-C，29名接受安慰剂；安慰剂组1名参与者撤回同意）。ORBCEL-C组发生6例严重不良事件，安慰剂组发生3例（风险比，2.9[95%置信区间，0.6 - 13.2]；P = 0.25）。第7天的平均（标准差）氧合指数无差异（ORBCEL-C，98.3[57.2]cm H₂O/kPa；安慰剂，96.6[67.3]cm H₂O/kPa）。在第28天、第90天、1年或2年时，次要替代结局或死亡率均无差异。1年时间质性肺疾病的患病率或2年内的重大医疗事件均无差异。ORBCEL-C调节外周血转录组。ORBCEL-C间充质基质细胞在中度至重度COVID-19相关ARDS患者中是安全的，但并未改善肺器官功能障碍的替代指标。
