Extracellular Vesicles From Mesenchymal Cells in the Treatment of Acute Respiratory Failure

Pneumonia Clinical Trial

Official title:

Extracellular Vesicles From Mesenchymal Cells in the Treatment of Acute Respiratory Failure Associated With SARS-CoV-2 and Other Etiologies: a Clinical Trial, Randomized, Double-blind.

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06002841
• Other study ID #: EVs_2023
• Status: Not yet recruiting
• Phase: Phase 1/Phase 2
• Start date: February 1, 2024
• Est. completion date: June 1, 2025

Study information

• Verified date: August 2023
• Source: D'Or Institute for Research and Education
• Contact: Carolina Nonaka, phD
• Phone: +55 (71) 3281-6970
• Email: carolina.nonaka[@]hsr.com.br
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a phase I/II, randomized, double-blind, placebo-controlled clinical trial that will evaluate the safety and potential efficacy of therapy with extracellular vesicles (EVs) obtained from mesenchymal stromal cells (MSCs), patients with moderate to severe acute respiratory distress syndrome due to COVID-19 or other etiology. Participants will be allocated to receive EVs obtained from MSCs or placebo (equal volume of Plasma-Lyte A). Blinding will cover the participants, the multidisciplinary intensive care team and the investigators.

Description:

The studied population will consist of 15 patients diagnosed with acute respiratory failure syndrome admitted to the intensive care unit of Hospital São Rafael. This research aims to assess the safety and potential effectiveness of intravenous therapy using extracellular vesicles derived from mesenchymal cells in patients with moderate to severe acute respiratory distress syndrome. The treatment group will receive intravenous administration of extracellular vesicles obtained from mesenchymal cells, while the control group will receive a placebo.

EV group: will consist of 10 participants who will receive two infusions of 25 mL of the investigational product (Plasma-Lyte A solution containing EVs obtained from MSCs), intravenously, at intervals of 48 h.

Placebo group: will consist of 5 participants who will receive an equal volume of Plasma-Lyte A, intravenously, following the same schedule as the IV group: two infusions with an interval of 48 hours.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 15
• Est. completion date: June 1, 2025
• Est. primary completion date: June 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age >= 18 years old;

• Chest CT radiological image with ground-glass opacities or chest X-ray with - bilateral infiltrates characteristic of pulmonary edema;

• In invasive mechanical ventilation with PEEP 5 cm H2O and PaO2/FiO2<250mmHg;

• Respiratory failure not explained by cardiac causes or fluid overload.

Exclusion Criteria:

• Unable to provide informed consent;

• Pregnancy or breastfeeding;

• Patients with active malignancy who have received chemotherapy in the last 2 years;

• Life expectancy of less than 6 months or in exclusive palliative care;

• Severe liver failure, with a Child-Pugh score > 12;

• Previous renal failure: patients already undergoing dialysis or patients with GFR < 30ml/min/1.73 m2

• Clinical or radiological suspicion of tuberculosis;

• Chronic respiratory failure;

• Use of ECMO;

• Moribund (high probability of death within the next 48 hours).

Related Conditions & MeSH terms

• Acute Lung Injury
• Acute Respiratory Distress Syndrome (ARDS)
• Pneumonia
• Respiratory Distress Syndrome
• Respiratory Distress Syndrome, Newborn
• Respiratory Insufficiency
• Severe Acute Respiratory Syndrome
• Severe Acute Respiratory Syndrome (SARS)
• Syndrome

Intervention

Biological:
• intravenous treatment with EVs
intravenous treatment with extracellular vesicles
• intravenous treatment with placebo solution
intravenous treatment with placebo solution (without extracellular vesicles)

Locations

Country	Name	City	State
Brazil	Hospital São Rafael	Salvador	Bahia

Sponsors (4)

Lead Sponsor	Collaborator
D'Or Institute for Research and Education	Hospital Sao Rafael, Oswaldo Cruz Foundation, Rio de Janeiro State Research Supporting Foundation (FAPERJ)

Country where clinical trial is conducted

Brazil, 

References & Publications (19)

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Cruz FF, Borg ZD, Goodwin M, Sokocevic D, Wagner DE, Coffey A, Antunes M, Robinson KL, Mitsialis SA, Kourembanas S, Thane K, Hoffman AM, McKenna DH, Rocco PR, Weiss DJ. Systemic Administration of Human Bone Marrow-Derived Mesenchymal Stromal Cell Extracellular Vesicles Ameliorates Aspergillus Hyphal Extract-Induced Allergic Airway Inflammation in Immunocompetent Mice. Stem Cells Transl Med. 2015 Nov;4(11):1302-16. doi: 10.5966/sctm.2014-0280. Epub 2015 Sep 16. — View Citation

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de Castro LL, Xisto DG, Kitoko JZ, Cruz FF, Olsen PC, Redondo PAG, Ferreira TPT, Weiss DJ, Martins MA, Morales MM, Rocco PRM. Human adipose tissue mesenchymal stromal cells and their extracellular vesicles act differentially on lung mechanics and inflammation in experimental allergic asthma. Stem Cell Res Ther. 2017 Jun 24;8(1):151. doi: 10.1186/s13287-017-0600-8. — View Citation

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Kordelas L, Rebmann V, Ludwig AK, Radtke S, Ruesing J, Doeppner TR, Epple M, Horn PA, Beelen DW, Giebel B. MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease. Leukemia. 2014 Apr;28(4):970-3. doi: 10.1038/leu.2014.41. No abstract available. — View Citation

Lanyu Z, Feilong H. Emerging role of extracellular vesicles in lung injury and inflammation. Biomed Pharmacother. 2019 May;113:108748. doi: 10.1016/j.biopha.2019.108748. Epub 2019 Mar 14. — View Citation

Lasser C, Jang SC, Lotvall J. Subpopulations of extracellular vesicles and their therapeutic potential. Mol Aspects Med. 2018 Apr;60:1-14. doi: 10.1016/j.mam.2018.02.002. Epub 2018 Feb 16. — View Citation

Naji A, Eitoku M, Favier B, Deschaseaux F, Rouas-Freiss N, Suganuma N. Biological functions of mesenchymal stem cells and clinical implications. Cell Mol Life Sci. 2019 Sep;76(17):3323-3348. doi: 10.1007/s00018-019-03125-1. Epub 2019 May 4. — View Citation

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Sengupta V, Sengupta S, Lazo A, Woods P, Nolan A, Bremer N. Exosomes Derived from Bone Marrow Mesenchymal Stem Cells as Treatment for Severe COVID-19. Stem Cells Dev. 2020 Jun 15;29(12):747-754. doi: 10.1089/scd.2020.0080. Epub 2020 May 12. — View Citation

Shi MM, Yang QY, Monsel A, Yan JY, Dai CX, Zhao JY, Shi GC, Zhou M, Zhu XM, Li SK, Li P, Wang J, Li M, Lei JG, Xu D, Zhu YG, Qu JM. Preclinical efficacy and clinical safety of clinical-grade nebulized allogenic adipose mesenchymal stromal cells-derived extracellular vesicles. J Extracell Vesicles. 2021 Aug;10(10):e12134. doi: 10.1002/jev2.12134. Epub 2021 Aug 14. — View Citation

Silva JD, de Castro LL, Braga CL, Oliveira GP, Trivelin SA, Barbosa-Junior CM, Morales MM, Dos Santos CC, Weiss DJ, Lopes-Pacheco M, Cruz FF, Rocco PRM. Mesenchymal Stromal Cells Are More Effective Than Their Extracellular Vesicles at Reducing Lung Injury Regardless of Acute Respiratory Distress Syndrome Etiology. Stem Cells Int. 2019 Aug 21;2019:8262849. doi: 10.1155/2019/8262849. eCollection 2019. — View Citation

Tieu A, Lalu MM, Slobodian M, Gnyra C, Fergusson DA, Montroy J, Burger D, Stewart DJ, Allan DS. An Analysis of Mesenchymal Stem Cell-Derived Extracellular Vesicles for Preclinical Use. ACS Nano. 2020 Aug 25;14(8):9728-9743. doi: 10.1021/acsnano.0c01363. Epub 2020 Aug 4. — View Citation

Wiklander OP, Nordin JZ, O'Loughlin A, Gustafsson Y, Corso G, Mager I, Vader P, Lee Y, Sork H, Seow Y, Heldring N, Alvarez-Erviti L, Smith CI, Le Blanc K, Macchiarini P, Jungebluth P, Wood MJ, Andaloussi SE. Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J Extracell Vesicles. 2015 Apr 20;4:26316. doi: 10.3402/jev.v4.26316. eCollection 2015. — View Citation

Zhou T, He C, Lai P, Yang Z, Liu Y, Xu H, Lin X, Ni B, Ju R, Yi W, Liang L, Pei D, Egwuagu CE, Liu X. miR-204-containing exosomes ameliorate GVHD-associated dry eye disease. Sci Adv. 2022 Jan 14;8(2):eabj9617. doi: 10.1126/sciadv.abj9617. Epub 2022 Jan 12. — View Citation

Zhu YG, Feng XM, Abbott J, Fang XH, Hao Q, Monsel A, Qu JM, Matthay MA, Lee JW. Human mesenchymal stem cell microvesicles for treatment of Escherichia coli endotoxin-induced acute lung injury in mice. Stem Cells. 2014 Jan;32(1):116-25. doi: 10.1002/stem.1504. — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Measure administration of extracellular vesicles (EVs) up to 28 days	Measure as reported adverse events up to 28 days after treatment or placebo administration to evaluate safety of treatment	28 days
Secondary	All-cause mortality	at days 14 and 28 after randomization;	Day 14 and day 28
Secondary	Variation in the Ratio PaO2/FiO2	PaO2 (arterial partial pressure of oxygen)/FiO2 (fraction of inspired oxygen) on the day of randomization and at 24 hours, 48 hours and 7 days after the first infusion;	Baseline, day 01, day 02 and day 07
Secondary	Variation in the SOFA index	Variation in the SOFA index (Assessment of Sequential Organ Failure) at the time of randomization and during follow-up until discharge from the intensive care unit;	day 01, day 02, day 07, day 09, day 14 and day 29
Secondary	Exploratory laboratory analysis	variation in total and differential laboratory analysis.	30 days
Secondary	Duration of the period of hospitalization	from hospital time in the intensive care unit (ICU)	30 days
Secondary	Duration of the period of ICU ventilation	If applicable,will be measured the time of mechanical ventilation.	30 days