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Repair of acute respiratory distress syndrome by stromal cell administration (REALIST): a structured study protocol for an open-label dose-escalation phase 1 trial followed by a randomised, triple-blind, allocation concealed, placebo-controlled phase 2 trial

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Ellen Gorman, Manu Shankar-Hari, Phil Hopkins, William S. Tunnicliffe, Gavin D. Perkins, Jonathan Silversides, Peter McGuigan, Colette Jackson, Roisin Boyle, Jamie McFerran, Cliona McDowell, Christina Campbell, Margaret McFarland, Jon Smythe, Jacqui Thompson, Barry Williams, Gerard Curley, John G. Laffey, Mike Clarke, Daniel F. McAuley & 1 more Cecilia O’Kane

Original languageEnglish
Article number401
JournalTrials
Volume23
Issue number1
DOIs
PublishedDec 2022

Bibliographical note

Funding Information: The authors would like to acknowledge the support of the Wellcome Trust Health Innovation Challenge Fund [Reference 106939/Z/15/Z], the Research and Development Division of the Public Health Agency (Northern Ireland), members of the DMEC (Professor John Norrie, Professor Mervyn Singer and Professor Sam Janes) and members of the TSC (Professor Charles Hinds, Professor John Simpson, Professor Mike Grocott, Mr Barry Williams and Professor John Laffey). Funding Information: The authors would like to acknowledge the support of the Wellcome Trust Health Innovation Challenge Fund [Reference 106939/Z/15/Z], the Research and Development Division of the Public Health Agency (Northern Ireland), members of the DMEC (Professor John Norrie, Professor Mervyn Singer and Professor Sam Janes) and members of the TSC (Professor Charles Hinds, Professor John Simpson, Professor Mike Grocott, Mr Barry Williams and Professor John Laffey). DFM and CO’K conceived the study. All authors made a substantial contribution to the protocol development. All authors have read and approved the manuscript. The Wellcome Trust Health Innovation Challenge Fund [Reference 106939/Z/15/Z] and the Research and Development Division of the Public Health Agency (Northern Ireland) will provide research costs for the REALIST study. The funders have no role in the study design, data acquisition, data analysis or manuscript preparation. Orbsen Therapeutics Ltd. have granted a non-exclusive, trial-specific licence to the Cellular and Molecular Therapies Division of the National Health Service Blood and Transplant Service to manufacture REALIST ORBCEL-C to GMP standards for the REALIST trial. Orbsen Therapeutics Ltd. have no role in the study design, data acquisition, data analysis or manuscript preparation. The investigator team will have full access to the final trial dataset. The trial will be reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines. The results of the trial will be published when data on the primary outcome are available. Long-term data and mechanistic data will also be reported though may form the basis of separate publications. Publications will be published in peer-reviewed open access journals (in keeping with the Wellcome Trust open access policy). A lay person’s summary of the principal findings of the results will be sent to all patients involved in the study at their request. 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 and JS are investigators on the grant funding this work from Wellcome Trust Health Innovation Challenge Fund [reference 106939/Z/15/Z]. DMcA, COK and 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 the REALIST trial . 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. 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. Publisher Copyright: © 2022, The Author(s).

King's Authors

Abstract

Background: Mesenchymal stromal cells (MSCs) may be of benefit in ARDS due to immunomodulatory and reparative properties. This trial investigates a novel CD362 enriched umbilical cord derived MSC product (REALIST ORBCEL-C), produced to Good Manufacturing Practice standards, in patients with moderate to severe ARDS due to COVID-19 and ARDS due to other causes. Methods: Phase 1 is a multicentre open-label dose-escalation pilot trial. Patients will receive a single infusion of REALIST ORBCEL-C (100 × 106 cells, 200 × 106 cells or 400 × 106 cells) in a 3 + 3 design. Phase 2 is a multicentre randomised, triple blind, allocation concealed placebo-controlled trial. Two cohorts of patients, with ARDS due to COVID-19 or ARDS due to other causes, will be recruited and randomised 1:1 to receive either a single infusion of REALIST ORBCEL-C (400 × 106 cells or maximal tolerated dose in phase 1) or placebo. Planned recruitment to each cohort is 60 patients. The primary safety outcome is the incidence of serious adverse events. The primary efficacy outcome is oxygenation index at day 7. The trial will be reported according to the Consolidated Standards for Reporting Trials (CONSORT 2010) statement. Discussion: The development and manufacture of an advanced therapy medicinal product to Good Manufacturing Practice standards within NHS infrastructure are discussed, including challenges encountered during the early stages of trial set up. The rationale to include a separate cohort of patients with ARDS due to COVID-19 in phase 2 of the trial is outlined. Trial registration: ClinicalTrials.gov NCT03042143. Registered on 3 February 2017. EudraCT Number 2017-000584-33

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