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

Ellen Gorman, Manu Shankar-Hari, Phil Hopkins, William S Tunnicliffe, Gavin D Perkins, Jonathan Silversides, Peter McGuigan, Anna Krasnodembskaya, Colette Jackson, Roisin Boyle, Jamie McFerran, Cliona McDowell, Christina Campbell, Margaret McFarland, Jon Smythe, Jacqui Thompson, Barry Williams, Gerard Curley, John G Laffey, Mike ClarkeDaniel F McAuley, Cecilia M O'Kane

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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.

Original languageEnglish
Article number101167
JournalEClinicalMedicine - published by THE LANCET
Volume41
Early online date24 Oct 2021
DOIs
Publication statusPublished - Nov 2021

Bibliographical note

Funding Information:
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 Health 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.

Funding Information:
The trial was funded by the Wellcome Trust Health Innovation Challenge Fund [reference 106939/Z/15/Z] and sponsored by the Belfast Health and Social Care Trust. The funder had no role in the study design, conduct or analysis.

Funding Information:
The trial was funded by the Wellcome Trust Health Innovation Challenge Fund [reference 106939/Z/15/Z] and sponsored by the Belfast Health and Social Care Trust. The funder had no role in the study design, conduct or analysis.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 Health 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.The trial was funded by the Wellcome Trust Health Innovation Challenge Fund [Reference 106939/Z/15/Z]. DFM and CO'K conceived the study. All authors made a substantial contribution to the protocol development and conduct of the study. CC and CMcD are the trial statisticians and have verified the data included in this report. EG and COK have verified the biomarker data included in this report. EG and COK prepared the first draft of the manuscript and all authors have contributed to the writing of the report and have reviewed and approved the final version. The authors would like to acknowledge all patients and their legal representatives who participated in the REALIST trial; clinical research teams at each clinical site who participated in patient recruitment, data collection and patient follow up; clinical teams at each site who provided clinical care to patients involved in the study; pharmacy and cell therapy facility staff at each clinical site for oversight and management of the study drugs; staff at NHSBT involved in the manufacture and distribution of ORBCEL-C; staff at Victoria Pharmaceuticals involved in the manufacture and distribution of placebo; staff at Northern Ireland Clinical Trials Unit for support in conduct of the trial; staff at Queen's University, Belfast and Belfast Health and Social Care Trust who supported laboratory analysis; members of the data monitoring and ethics committee (Professor John Norrie, Professor Mervyn Singer and Professor Sam Janes); members of the trial steering committee (Professor Charles Hinds, Professor John Simpson, Professor Mike Grocott, Mr Barry Williams and Professor John Laffey). Data will be available to researchers on request subject to sponsor approval.

Publisher Copyright:
© 2021 The Author(s)

ASJC Scopus subject areas

  • General Medicine

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