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Mesenchymal stromal cell therapy for COVID-19 acute respiratory distress syndrome: a double-blind randomised controlled trial

Bone Marrow Transplantation (2024)Cite this article

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Abstract

Mesenchymal stromal cells (MSC) have immunomodulatory and tissue-regenerative properties and have shown promising results in acute respiratory distress syndrome (ARDS) of multiple causes, including COVID-19. We conducted a randomised (1:1), placebo-controlled, double-blind clinical trial to assess the efficacy and safety of one bone marrow-derived MSC infusion in twenty patients with moderate to severe ARDS caused by COVID-19. The primary endpoint (increase in PaO2/FiO2 ratio from baseline to day 7, MSC 83.3 versus placebo 57.6) was not statistically significant, although a clinical improvement at day 7 in the WHO scale was observed in MSC patients (5, 50% vs 0, 0%, p = 0.033). Median time to discontinuation of supplemental oxygen was also shorter in the experimental arm (14 versus 23 days, p = 0.007), resulting in a shorter hospital stay (17.5 versus 28 days, p = 0.042). No significant differences were observed for other efficacy or safety secondary endpoints. No infusion or treatment-related serious adverse events occurred during the one-year follow-up. This study did not meet the primary endpoint of PaO2/FiO2 increase by day 7, although it suggests that MSC are safe in COVID-19 ARDS and may accelerate patients’ clinical recovery and hospital discharge. Larger studies are warranted to elucidate their role in ARDS and other inflammatory lung disorders.

Trial Registration: EudraCT Number: 2020-002193-27, registered on July 14th, 2020, https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-002193-27/ES. NCT number: NCT04615429, registered on November 4th, 2020, https://clinicaltrials.gov/ct2/show/NCT04615429.

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Fig. 1: CONSORT flow diagram COVID-AT study.
Fig. 2: Evolution of clinical status of patients treated with MSC as compared with placebo.
Fig. 3: Inflammatory and severity biomarkers.

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Data availability

The de-identified participant data will be available to other researchers, for scientific purposes, upon request to the corresponding author, with approval from the COVID-AT Steering Committee.

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Acknowledgements

We would like to acknowledge the generous contribution of volunteer donors of bone marrow for MSC production. In addition, we would also like to recognize the valuable and selfless dedication of all healthcare professionals who helped looking after COVID-19 patients, and contributed to generate scientific evidence, despite the difficulties imposed by the pandemic and its several waves.

Funding

This study was partly funded by the “Transferencia Nominativa COVID-19” of the Consejería de Sanidad de la Comunidad de Madrid, by the Fundación ACS and by the “Proyecto Mascarillas Boticaria”. These parties did not participate in the conduct of the study or the preparation of this manuscript.

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Author notes

  1. These authors contributed equally: María E. Martínez-Muñoz, Concepción Payares-Herrera.

Authors and Affiliations

  1. Department of Haematology and GMP Cellular Therapy Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain

    María E. Martínez-Muñoz, Isabel Salcedo, Trinidad Martín-Donaire, Rocío Sánchez, Rocío Zafra, Miguel García-Berciano & Rafael F. Duarte

  2. Instituto de Investigación Sanitaria Puerta de Hierro Segovia Arana, Madrid, Spain

    María E. Martínez-Muñoz, Concepción Payares-Herrera, Isabel Salcedo, Rosalía Alonso, Trinidad Martín-Donaire, Rocío Sánchez, Rocío Zafra, Miguel García-Berciano, Antonio Ramos-Martínez, Piedad Ussetti, Cristina Avendaño-Solà & Rafael F. Duarte

  3. Department of Clinical Pharmacology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain

    Concepción Payares-Herrera & Cristina Avendaño-Solà

  4. Intensive Care Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain

    Inés Lipperheide, Manuel Pérez-Torres & Juan J. Rubio

  5. Department of Pneumology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain

    Rosa Malo de Molina, Andrea Trisán-Alonso & Piedad Ussetti

  6. Department of Internal Medicine and Infectious Diseases, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain

    Antonio Ramos-Martínez

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Contributions

MEMM, CPH, IL, RMM, IS, RA, CAS and RFD: Conception and design. MEMM, CPH, IS, and RA: Collection and/or assembly of data. MEMM, CPH, IS, RA, CAS and RFD: data analysis and interpretation. MEMM, CPH and RFD: manuscript writing. IL, RMM, ATA, MPT, AR, PU and JJR: Provision of study material or patients and clinical follow-up. TMD, RS, RZ, MGB: MSC manufacture. CAS: sponsor’s regulatory responsibilities. IL and RFD: funding acquisition. All authors critically reviewed the manuscript and accepted the final version.

Corresponding author

Correspondence to Rafael F. Duarte.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

This trial adhered to the Declaration of Helsinki and received ethics approval with the title “Ensayo clínico doble ciego, aleatorizado, controlado, para evaluar la eficacia de las células mesenquimales estromales alogénicas en pacientes con síndrome de distrés respiratorio agudo debido a COVID-19 (COVID-AT)”, on June 3rd 2020, from the local research ethics committee “Comité de Ética de la Investigación con medicamentos del HUPHM”, with approval number 82-20. Informed consent was obtained prior to performing any study procedures from all patients or their representatives (witnessed oral consent, documented in writing).

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Martínez-Muñoz, M.E., Payares-Herrera, C., Lipperheide, I. et al. Mesenchymal stromal cell therapy for COVID-19 acute respiratory distress syndrome: a double-blind randomised controlled trial. Bone Marrow Transplant (2024). https://doi.org/10.1038/s41409-024-02230-5

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