Top

Published in:

Open Access 01-12-2022 | Acute Respiratory Distress-Syndrome | Study protocol

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

Authors: 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, Cecilia O’Kane

Published in: Trials | Issue 1/2022

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

Available only for authorised users

Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012;307(23) https://doi.org/10.1001/jama.2012.5669.

Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, et al. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA. 2016;315(8):788–800. https://doi.org/10.1001/jama.2016.0291.CrossRefPubMed

Herridge MS, Tansey CM, Matte A, Tomlinson G, Diaz-Granados N, Cooper A, et al. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med. 2011;364(14):1293–304. https://doi.org/10.1056/NEJMoa1011802.CrossRefPubMed

Bienvenu OJ, Friedman LA, Colantuoni E, Dinglas VD, Sepulveda KA, Mendez-Tellez P, et al. Psychiatric symptoms after acute respiratory distress syndrome: a 5-year longitudinal study. Intensive Care Med. 2018;44(1):38–47. https://doi.org/10.1007/s00134-017-5009-4.CrossRefPubMed

Tzotzos SJ, Fischer B, Fischer H, Zeitlinger M. Incidence of ARDS and outcomes in hospitalized patients with COVID-19: a global literature survey. Crit Care. 2020;24(1):516. https://doi.org/10.1186/s13054-020-03240-7.CrossRefPubMedPubMedCentral

Agus A, Hulme C, Verghis RM, McDowell C, Jackson C, O'Kane CM, et al. Simvastatin for patients with acute respiratory distress syndrome: long-term outcomes and cost-effectiveness from a randomised controlled trial. Crit Care. 2017;21(1):108. https://doi.org/10.1186/s13054-017-1695-0.CrossRefPubMedPubMedCentral

MacSweeney RM, McAuley DF. Acute respiratory distress syndrome. Lancet. 2016;388(10058):2416–30. https://doi.org/10.1016/S0140-6736(16)00578-X.CrossRef

Griffiths MJD, McAuley DF, Perkins GD, Barrett N, Blackwood B, Boyle A, et al. Guidelines on the management of acute respiratory distress syndrome. BMJ Open Resp Res. 2019;6(1):e000420. https://doi.org/10.1136/bmjresp-2019-000420.CrossRefPubMedPubMedCentral

Shaw TD, McAuley DF, O'Kane CM. Emerging drugs for treating the acute respiratory distress syndrome. Expert Opin Emerg Drugs. 2019;24(1):29–41. https://doi.org/10.1080/14728214.2019.1591369.CrossRefPubMed

10.

Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, et al. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med. 2021;384(8):693–704. https://doi.org/10.1056/NEJMoa2021436.CrossRefPubMed

11.

Angus DC, Derde L, Al-Beidh F, et al. Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial. JAMA. 2020;324(13):1317–29.CrossRef

12.

Investigators RC. Interleukin-6 receptor antagonists in critically ill patients with Covid-19. N Engl J Med. 2021;384(16):1491–502. https://doi.org/10.1056/NEJMoa2100433.CrossRef

13.

RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021;397(10285):1637–45.CrossRef

14.

Gorman E, Millar J, McAuley D, O’Kane C. Mesenchymal stromal cells for acute respiratory distress syndrome (ARDS), sepsis, and COVID-19 infection: optimizing the therapeutic potential. Expert Rev of Respir Med. 2021;15(3):301–24. https://doi.org/10.1080/17476348.2021.1848555.CrossRef

15.

Mushahary D, Spittler A, Kasper C, Weber V, Charwat V. Isolation, cultivation, and characterization of human mesenchymal stem cells. Cytometry. 2018;93(1):19–31. https://doi.org/10.1002/cyto.a.23242.CrossRefPubMed

16.

Huang Z, Liu H, Zhang X, Wen G, Zhu C, Zhao Y, et al. Transcriptomic analysis of lung tissues after hUC-MSCs and FTY720 treatment of lipopolysaccharide-induced acute lung injury in mouse models. Int Immunopharmacol. 2018;63:26–34. https://doi.org/10.1016/j.intimp.2018.06.036.CrossRefPubMed

17.

Devaney J, Horie S, Masterson C, Elliman S, Barry F, O'Brien T, et al. Human mesenchymal stromal cells decrease the severity of acute lung injury induced by E. coli in the rat. Thorax. 2015;70(7):625–35. https://doi.org/10.1136/thoraxjnl-2015-206813.CrossRefPubMed

18.

Krasnodembskaya A, Samarani G, Song Y, Zhuo H, Su X, Lee JW, et al. Human mesenchymal stem cells reduce mortality and bacteremia in gram-negative sepsis in mice in part by enhancing the phagocytic activity of blood monocytes. Am J Physiol Lung Cell Mol Physiol. 2012;302(10):L1003–13. https://doi.org/10.1152/ajplung.00180.2011.CrossRefPubMedPubMedCentral

19.

McIntyre LA, Moher D, Fergusson DA, Sullivan KJ, Mei SHJ, Lalu M, et al. Efficacy of mesenchymal stromal cell therapy for acute lung injury in preclinical animal models: a systematic review. PLoS One. 2016;11(1):e0147170. https://doi.org/10.1371/journal.pone.0147170.CrossRefPubMedPubMedCentral

20.

Masterson C, Devaney J, Horie S, O'Flynn L, Deedigan L, Elliman S, et al. Syndecan-2-positive, bone marrow-derived human mesenchymal stromal cells attenuate bacterial-induced acute lung injury and enhance resolution of ventilator-induced lung injury in rats. Anesthesiology. 2018;129(3):502–16. https://doi.org/10.1097/ALN.0000000000002327.CrossRefPubMed

21.

Wilson JG, Liu KD, Zhuo H, Caballero L, McMillan M, Fang X, et al. Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. Lancet Resp Med. 2015;3(1):24–32. https://doi.org/10.1016/S2213-2600(14)70291-7.CrossRef

22.

Matthay MA, Calfee CS, Zhuo H, Thompson BT, Wilson JG, Levitt JE, et al. Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial. Lancet Resp Med. 2019;7(2):154–62. https://doi.org/10.1016/S2213-2600(18)30418-1.CrossRef

23.

Khan RS, Newsome PN. A comparison of phenotypic and functional properties of mesenchymal stromal cells and multipotent adult progenitor cells. Front Immunol. 2019;10 https://doi.org/10.3389/fimmu.2019.01952.

24.

Bellingan G, Jacono F, Bannard-Smith J, Brealey D, Meyer N, Thickett D, et al. Safety and efficacy of multipotent adult progenitor cells in acute respiratory distress syndrome (MUST-ARDS): a multicentre, randomised, double-blind, placebo-controlled phase 1/2 trial. Intensive Care Med. 2022;48(1):36–44. https://doi.org/10.1007/s00134-021-06570-4.CrossRefPubMed

25.

Zheng G, Huang L, Tong H, Shu Q, Hu Y, Ge M, et al. Treatment of acute respiratory distress syndrome with allogeneic adipose-derived mesenchymal stem cells: a randomized, placebo-controlled pilot study. Respir Res. 2014;15(1):39. https://doi.org/10.1186/1465-9921-15-39.CrossRefPubMedPubMedCentral

26.

Yip HK, Fang WF, Li YC, Lee FY, Lee CH, Pei SN, et al. Human umbilical cord-derived mesenchymal stem cells for acute respiratory distress syndrome. Crit Care Med. 2020;48(5):e391–9.CrossRef

27.

Sánchez-Guijo F, García-Arranz M, López-Parra M, Monedero P, Mata-Martínez C, Santos A, et al. Adipose-derived mesenchymal stromal cells for the treatment of patients with severe SARS-CoV-2 pneumonia requiring mechanical ventilation. Proof Concept Study EClinicalMedicine. 2020;25:100454. https://doi.org/10.1016/j.eclinm.2020.100454.CrossRefPubMed

28.

Hashemian S-MR, Aliannejad R, Zarrabi M, Soleimani M, Vosough M, Hosseini S-E, et al. Mesenchymal stem cells derived from perinatal tissues for treatment of critically ill COVID-19-induced ARDS patients: a case series. Stem Cell Res Ther. 2021;12(1):91. https://doi.org/10.1186/s13287-021-02165-4.CrossRefPubMedPubMedCentral

29.

Xu X, Jiang W, Chen L, Xu Z, Zhang Q, Zhu M, et al. Evaluation of the safety and efficacy of using human menstrual blood-derived mesenchymal stromal cells in treating severe and critically ill COVID-19 patients: An exploratory clinical trial. Clin Transl Med. 2021;11(2):e297. https://doi.org/10.1002/ctm2.297.CrossRefPubMedPubMedCentral

30.

Singh S, Chakravarty T, Chen P, Akhmerov A, Falk J, Friedman O, et al. Allogeneic cardiosphere-derived cells (CAP-1002) in critically ill COVID-19 patients: compassionate-use case series. Basic Res Cardiol. 2020;115(4):36. https://doi.org/10.1007/s00395-020-0795-1.CrossRefPubMedPubMedCentral

31.

Feng Y, Huang J, Wu J, Xu Y, Chen B, Jiang L, et al. Safety and feasibility of umbilical cord mesenchymal stem cells in patients with COVID-19 pneumonia: a pilot study. Cell Prolif. 2020;53(12):e12947. https://doi.org/10.1111/cpr.12947.CrossRefPubMedPubMedCentral

32.

Meng F, Xu R, Wang S, Xu Z, Zhang C, Li Y, et al. Human umbilical cord-derived mesenchymal stem cell therapy in patients with COVID-19: a phase 1 clinical trial. Signal Transduct Target Ther. 2020;5(1):172. https://doi.org/10.1038/s41392-020-00286-5.CrossRefPubMedPubMedCentral

33.

Shi L, Huang H, Lu X, Yan X, Jiang X, Xu R, et al. Effect of human umbilical cord-derived mesenchymal stem cells on lung damage in severe COVID-19 patients: a randomized, double-blind, placebo-controlled phase 2 trial. Signal Transduct Target Ther. 2021;6(1):58. https://doi.org/10.1038/s41392-021-00488-5.CrossRefPubMedPubMedCentral

34.

Lanzoni G, Linetsky E, Correa D, Messinger Cayetano S, Alvarez RA, Kouroupis D, et al. Umbilical cord mesenchymal stem cells for COVID-19 acute respiratory distress syndrome: a double-blind, phase 1/2a, randomized controlled trial. Stem Cells Transl Med. 2021;10(5):660–73. https://doi.org/10.1002/sctm.20-0472.CrossRefPubMedPubMedCentral

35.

Dilogo IH, Aditianingsih D, Sugiarto A, Burhan E, Damayanti T, Sitompul PA, et al. Umbilical cord mesenchymal stromal cells as critical COVID-19 adjuvant therapy: a randomized controlled trial. Stem Cells Transl Med. 2021;10(9):1279–87. https://doi.org/10.1002/sctm.21-0046.CrossRefPubMedPubMedCentral

36.

Mesoblast Ltd Press Release, GlobalNewsWire. http://www.globenewswire.com/news-release/2021/04/29/2220310/0/en/Remestemcel-L-Reduces-Mortality-in-Patients-Less-Than-65-Years-Old-With-Moderate-Severe-COVID-19-ARDS-Topline-60-Day-Results-From-Randomized-Controlled-Trial.html. Accessed 16 Feb 2022.

37.

Gibson PG, Qin L, Puah SH. COVID-19 acute respiratory distress syndrome (ARDS): clinical features and differences from typical pre-COVID-19 ARDS. Med J Aust. 2020;213(2):54–6.e1.CrossRef

38.

Gorman E, Shankar-Hari M, Hopkins P, Tunnicliffe WS, Perkins GD, Silversides J, et al. Repair of acute respiratory distress syndrome by stromal cell administration in COVID-19 (REALIST-COVID-19): a structured summary of a study protocol for a randomised, controlled trial. Trials. 2020;21(1):462. https://doi.org/10.1186/s13063-020-04416-w.CrossRefPubMedPubMedCentral

39.

Cook N, Hansen AR, Siu LL, Abdul Razak AR. Early phase clinical trials to identify optimal dosing and safety. Mol Oncol. 2015;9(5):997–1007. https://doi.org/10.1016/j.molonc.2014.07.025.CrossRefPubMed

40.

Krige A, Pattison N, Booth M, Walsh T. Co-enrolment to intensive care studies – a UK perspective. J Intensive Care Soc. 2013;14(2):103–6. https://doi.org/10.1177/175114371301400203.CrossRef

41.

Advisory Committee on the Safety of Blood Tissues and Organs. Donation of Starting Material for Cell-Based Advanced Therapies: a SaBTO Review 2014. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/326823/Cellular_Therapy.pdf. Accessed 22 Feb 2022.

42.

Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–7. https://doi.org/10.1080/14653240600855905.CrossRefPubMed

43.

Seeley E, McAuley DF, Eisner M, Miletin M, Matthay MA, Kallet RH. Predictors of mortality in acute lung injury during the era of lung protective ventilation. Thorax. 2008;63(11):994–8. https://doi.org/10.1136/thx.2007.093658.CrossRefPubMed

44.

Craig TR, Duffy MJ, Shyamsundar M, McDowell C, O'Kane CM, Elborn JS, et al. A randomized clinical trial of hydroxymethylglutaryl- coenzyme a reductase inhibition for acute lung injury (The HARP Study). Am J Resp Crit Care. 2011;183(5):620–6. https://doi.org/10.1164/rccm.201003-0423OC.CrossRef

45.

McAuley DF, Laffey JG, O'Kane CM, Perkins GD, Mullan B, Trinder TJ, et al. Simvastatin in the acute respiratory distress syndrome. N Engl J Med. 2014;371(18):1695–703. https://doi.org/10.1056/NEJMoa1403285.CrossRefPubMed

46.

Shyamsundar M, McKeown STW, O'Kane CM, Craig TR, Brown V, Thickett DR, et al. Simvastatin decreases lipopolysaccharide-induced pulmonary inflammation in healthy volunteers. Am J Resp Crit Care. 2009;179(12):1107–14. https://doi.org/10.1164/rccm.200810-1584OC.CrossRef

47.

Haslam PL, Baughman RP. Report of ERS Task Force: guidelines for measurement of acellular components and standardization of BAL. Eur Respir J. 1999;14(2):245–8. https://doi.org/10.1034/j.1399-3003.1999.14b01.x.CrossRefPubMed

48.

Smith CT, Hopkins C, Sydes M, Woolfall K, Clarke M, Murray G, et al. Good practice principles for sharing individual participant data from publicly funded clinical trials. Trials. 2015;16(S2) https://doi.org/10.1186/1745-6215-16-S2-O1.

49.

Schulz KF, Altman DG, Moher D, the CG. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMC Med. 2010;8(1):18.CrossRef

50.

Mendicino M, Bailey Alexander M, Wonnacott K, Puri Raj K, Bauer SR. MSC-based product characterization for clinical trials: an FDA perspective. Cell Stem Cell. 2014;14(2):141–5. https://doi.org/10.1016/j.stem.2014.01.013.CrossRefPubMed

51.

Couto PS, Shatirishvili G, Bersenev A, Verter F. First decade of clinical trials and published studies with mesenchymal stromal cells from umbilical cord tissue. Regen Med. 2019;14(4):309–19. https://doi.org/10.2217/rme-2018-0171.CrossRefPubMed

52.

Phinney DG, Galipeau J. Manufacturing mesenchymal stromal cells for clinical applications: a survey of Good Manufacturing Practices at U.S. academic centers. Cytotherapy. 2019;21(7):782–92. https://doi.org/10.1016/j.jcyt.2019.04.003.CrossRefPubMed

53.

Kollerup Madsen B, Hilscher M, Zetner D, Rosenberg J. Adverse reactions of dimethyl sulfoxide in humans: a systematic review. F1000Res. 2018;7:1746.CrossRef

54.

National Institute for Health Research. DHSC issues guidance on the impact of COVID-19 on research funded or supported by NIHR 2020. https://www.nihr.ac.uk/news/dhsc-issues-guidance-on-the-impact-on-covid-19-on-research-funded-or-supported-by-nihr/24469. Accessed 22 Feb 2022.

55.

World Health Organisation. WHO Director-General’s opening remarks at the media briefing on COVID-19 11 March 2020. https://www.who.int/director-general/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19%2D%2D-11-march-2020. Accessed 22 Feb 2022.

56.

Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020;46(5):846–8. https://doi.org/10.1007/s00134-020-05991-x.CrossRefPubMed

57.

Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054–62. https://doi.org/10.1016/S0140-6736(20)30566-3.CrossRefPubMedPubMedCentral

58.

Chan MC, Kuok DI, Leung CY, Hui KP, Valkenburg SA, Lau EH, et al. Human mesenchymal stromal cells reduce influenza A H5N1-associated acute lung injury in vitro and in vivo. Proc Natl Acad Sci U S A. 2016;113(13):3621–6. https://doi.org/10.1073/pnas.1601911113.CrossRefPubMedPubMedCentral

59.

Loy H, Kuok DIT, Hui KPY, Choi MHL, Yuen W, Nicholls JM, et al. Therapeutic implications of human umbilical cord mesenchymal stromal cells in attenuating influenza A(H5N1) virus-associated acute lung injury. J Infect Dis. 2019;219(2):186–96. https://doi.org/10.1093/infdis/jiy478.CrossRefPubMed

60.

Gorman E, Shankar-Hari M, Hopkins P, Tunnicliffe WS, Perkins GD, Silversides J, et al. Repair of acute respiratory distress syndrome by stromal cell administration (REALIST trial): a phase 1 trial. EClinicalMedicine. 2021;41:101167. https://doi.org/10.1016/j.eclinm.2021.101167.CrossRefPubMedPubMedCentral

Title: 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
Authors: 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
Cecilia O’Kane
Publication date: 01-12-2022
Publisher: BioMed Central
Keywords: Acute Respiratory Distress-Syndrome
COVID-19
Published in: Trials / Issue 1/2022
Electronic ISSN: 1745-6215
DOI: https://doi.org/10.1186/s13063-022-06220-0

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Background

Methods

Discussion

Trial registration

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Discussion

Trial registration

Please log in to get access to this content

Other articles of this Issue 1/2022

Ocular Rosacea microBiome Study (ORBS)—sub-microbial versus antibiotic dosing of doxycycline versus placebo in treatment of symptomatic ocular rosacea: study protocol for a parallel-arm randomized clinical trial

Major adverse limb events in patients with femoro-popliteal and below-the-knee peripheral arterial disease treated with either sirolimus-coated balloon or standard uncoated balloon angioplasty: a structured protocol summary of the “SirPAD” randomized controlled trial

Cardiac magnetic resonance imaging versus computed tomography to guide transcatheter aortic valve replacement: study protocol for a randomized trial (TAVR-CMR)

The effects of synbiotic and/or vitamin D supplementation on gut-muscle axis in overweight and obese women: a study protocol for a double-blind, randomized, placebo-controlled trial

Internet-based cognitive therapy for women with antenatal depressive symptoms during the COVID-19 pandemic: protocol for a multi-center randomized controlled trial across China

A prospective randomised controlled trial of mechanical axis with soft tissue release balancing vs functional alignment with bony resection balancing in total knee replacement—a study using Stryker Mako robotic arm-assisted technology