Repair of acute respiratory distress syndrome by stromal cell administration (REALIST) trial: A phase 1 trial

Abstract

Background: Mesenchymal stromal cells (MSCs) may be of benefit in acute respiratory distress syndrome (ARDS) due to immunomodulatory, reparative, and antimicrobial actions. ORBCEL-C is a population of CD362 enriched umbilical cord-derived MSCs. The REALIST phase 1 trial investigated the safety and feasibility of ORBCEL-C in patients with moderate to severe ARDS.

Methods: REALIST phase 1 was an open label, dose escalation trial in which cohorts of mechanically ventilated patients with moderate to severe ARDS received increasing doses (100, 200 or 400 × 106 cells) of a single intravenous infusion of ORBCEL-C in a 3 + 3 design. The primary safety outcome was the incidence of serious adverse events. Dose limiting toxicity was defined as a serious adverse reaction within seven days. Trial registration clinicaltrials.gov NCT03042143.

Findings: Nine patients were recruited between the 7th January 2019 and 14th January 2020. Study drug administration was well tolerated and no dose limiting toxicity was reported in any of the three cohorts. Eight adverse events were reported for four patients. Pyrexia within 24 h of study drug administration was reported in two patients as pre-specified adverse events. A further two adverse events (non-sustained ventricular tachycardia and deranged liver enzymes), were reported as adverse reactions. Four serious adverse events were reported (colonic perforation, gastric perforation, bradycardia and myocarditis) but none were deemed related to administration of ORBCEL-C. At day 28 no patients had died in cohort one (100 × 106), three patients had died in cohort two (200 × 106) and one patient had died in cohort three (400 × 106). Overall day 28 mortality was 44% (n = 4/9).

Interpretation: A single intravenous infusion of ORBCEL-C was well tolerated in patients with moderate to severe ARDS. No dose limiting toxicity was reported up to 400 × 106 cells.

Conflict of interest statement

EG receives funding by the Wellcome Trust Health Innovation Challenge Fund [reference 106939/Z/15/Z] for the described work. COK, DMcA, JL, JS & AK are investigators on the grant funding this work from Wellcome Trust Health Innovation Challenge Fund [reference 106939/Z/15/Z]. DMcA, COK & MC are investigators on a grant received from the Northern Ireland Health and Social Care Research and Development Division to fund an additional COVID-19 cohort during phase 2 of this study. JL reports consulting fees from Baxter Healthcare and GlaxoSmithKline, provision of medicolegal reports to the Irish Clinical Indemnity Scheme, participation in DSMB for other clinical trials and is named on a patent for InspireShield, a device to reduce COVID-19 spread. AK reports grants received from MRC UK (MR/R025096/1 and MR/S009426/1) and a HORIZON 2020 MSC individual fellowship. MSH is supported by a NIHR Clinician Scientist Fellowship (CS-2016–16–011). GDP is supported by the 10.13039/100005622Health Research (NIHR) Applied Research Collaboration (ARC) West Midlands and is a director of research for the Intensive Care Society. GC reports grants from Health Research Board (Ireland) Emerging Clinician Scientist Award and the United States Department of defense Discovery Award. DMcA reports grants from NIHR, Innovate UK, MRC and Novavax as an investigator in ARDS and COVID-19 studies. DMcA reports consultancy fees unrelated to this work from Bayer, GlaxoSmithKline, Boehringer Ingelheim, Novartis and Eli Lilly. DMcA reports payments from GlaxoSmithKline as an educational seminar speaker. DMcA is a member of the DSMB for Vir Biotechnology, Inc and Faron Pharmaceuticals. DMcA has a patent for a novel treatment for inflammatory disease. DMcA is a director of research for the Intensive Care Society and Director of the EME programme for MRC/NIHR. DMcA reports a spouse who has received consultancy fees from INSMED and from the California Institute for Regenerative unrelated to this clinical trial. COK has received consultancy fees from INSMED, unrelated to this work, and fees for participation in grant panels for the Californian Institute of Regenerative Medicine, unrelated to this clinical trial. COK reports a spouse who has received grants from NIHR, Innovate UK, MRC and Novavax. COK reports a spouse who has received consultancy fees unrelated to this work from Bayer, GlaxoSmithKline, Boehringer Ingelheim, Novartis and Eli Lilly. COK reports a spouse who has received payments from GlaxoSmithKline as an educational seminar speaker. COK reports a spouse who is a member of the DSMB for Vir Biotechnology, Inc and Faron Pharmaceuticals. COK reports a spouse who has a patent for a novel treatment for inflammatory disease. COK reports a spouse who is a director of research for the Intensive Care Society and Director of the EME programme for MRC/NIHR. All other authors report no declarations of interest. The views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research (NIHR), or the Department of Health and Social Care.

© 2021 The Author(s).

Figures

Fig. 1

Consort diagram.

Fig. 2

Pulmonary (Oxygenation Index, P/F ratio, Respiratory Compliance, Driving pressure) and non-pulmonary organ function (SOFA score) outcomes Mean (SD) are provided for each dose cohort (dose 1: 100 × 10 6; dose 2: 200 × 10 6; dose 3: 400 × 10 6) at day 0 (baseline), day 4, day 7 and day 14. (A) Oxygenation index (B) P/F Ratio (C) Respiratory Compliance (D) Driving Pressure (E) SOF A Score.

Fig. 3

Plasma biological markers of systemic inflammatory response (IL-6, IL-8 and IL-18), markers of epithelial injury (Surfactant protein-D [SP-D]) and endothelial activation/injury (ICAM-1 and Angiopoietin 2 [Ang-2]). Mean (SD) are provided for each dose cohort (dose 1: 100 × 10 6; dose 2: 200 × 106; dose 3: 400 × 106) at day 0 (baseline), day 4, day 7 and day 14. A) IL-6 B) IL-8 C) IL-18 D) Ang-2 E) ICAM F) SP-D.