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Table 4 The investigated outcomes of the ongoing clinical trials using MSCs and MSC-derived exosomes to treat COVID-19 patients

From: Potential application of mesenchymal stem cells and their exosomes in lung injury: an emerging therapeutic option for COVID-19 patients

Clinical trial identifier Primary Outcome Measure Secondary Outcome Measure
#NCT04348461 1. Efficacy of the administration assessed by survival rate [time frame, 28 days]
2. Safety of the administration by adverse event rate [time frame, 6 months].
N.A.
NCT04467047 1. Overall survival [time frame, 60 days]
2. Assessment of overall survival at 30 days post-intervention
Changes on inflammatory CRP, hospital stay, oxygenation index (PaO2/FiO2), evaluation of functional respiratory changes: PaO2/FiO2 ratio, Improvement in Liao’s score (2020), radiological improvement [time frame, 60 days], COVID19 PCR negativity [time frame, 28 days].
NCT04473170 Adverse reactions incidence, rate of mortality within 28-days, time to clinical improvement on a seven-category ordinal scale [time frame, day 0–28] 1. Assessment of the immune response profile. Immune response profile characterized according the biomarkers: CD3, CD4, CD8, CD11c, CD14, CD16, CD19, CD20, CD25, CD27, CD28, CD38, CD45, CD45RA, CD45RO, CD56, CD57, CD66b, CD123, CD127, CD161, CD294, CCR4, CCR6, CCR7, CXCR3, CXCR5, HLA-DR, IgD, and TCRγδ, for the identification of immune cells and subsets analysis; and the humoral Immune profile: IgG, IgA, IgM levels [time frame, Days 0, 14, and 28].
2. Assessment of acute-phase serum markers. Complete Blood Counts (CBC), acute-phase proteins and Inflammatory markers: CRP, ESR, LDH, procalcitonin (PCT), ceruloplasmin, haptoglobin, alpha 1 antitrypsin, IL-6, ferritin C3, PT, fibrinogen and D-dimer [time frame, days 0, 14, and 28].
NCT04349540 Comparison of inflammatory/immunological biomarkers < 72 h after development of oxygen requirement [time frame, 72 h] 1. Overall survival at 30 and 100 days after development of oxygen requirement, those on immunosuppression.
2. Survival in SCT patients who are vs are not ongoing immunosuppression [time frame, days 30, and 100].
3. Proportion of patients requiring mechanical ventilation [time frame, day 30].
4. Incidence of secondary HLH (as defined by HS score) [time frame, day 30].
#ChiCTR2000029990 Improved respiratory system function (blood oxygen saturation) recovery time N.A.
NCT04466098 Incidence of grade 3–5 infusional toxicities and predefined hemodynamic or respiratory adverse events related to the infusion of MSCs [time frame, within 6 h of the start of the infusion]. 1. Incidence of a reduction in one or more biomarkers of inflammation by day 7 [time frame, day 7 after first infusion]
2. Trend changes in PaO2:FiO2 ratio, mean airway pressure, in peak pressure, plateau pressure, PEEP [time frame, on the day of screening and on days 3, 7 and 14 after first infusion].
3. Incidence of mortality [time frame, 28 days after first infusion].
4. Incidence of mortality [time frame, 100 days after first infusion].
5. Number of ICU-free days [time frame, 28 days after first infusion]
6. Number of days alive and ventilator-free composite score 3 [time frame, 28 days after first infusion].
7. Change in acute lung injury (ALI) score 2 [time frame, baseline and day 28 after first infusion].
8. Incidence of serious adverse events [time frame, 28 days after first infusion]
9. Number of days alive off supplemental oxygen [time frame, 100 days after first infusion].
NCT04445220 Safety and tolerability as measured by incidence of IP-related serious adverse events [time frame, outcomes and serious adverse events through Day 180]. N.A.
NCT04447833 The incidence of TRAEIs [time frame, From drug administration to day 10 post-infusion]. TRAEIs:
• → New ventricular tachycardia, ventricular fibrillation or asystole within 10 days after infusion
• → New cardiac arrhythmia requiring cardioversion within 10 days after infusion
• → Clinical scenario consistent with transfusion incompatibility or transfusion-related infection, thromboembolic events (e.g.. pulmonary embolism), cardiac arrest or death within 10 days after infusion
1. Safety; All-cause mortality [time frame, 60 days post-infusion, 6 months, 1, 2, 3, 4, and 5 years post-infusion].
2. Changes in leucocytes [time frame, baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion, 6 months, 1, 2, 3, 4, and 5 years post-infusion].
3. Changes in Trombocytes [time frame, baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion, 6 months, 1, 2, 3, 4, and 5 years post-infusion].
4. Changes in plasma concentration of C-reactive protein (CRP) [time frame, baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion, 6 months, 1, 2, 3, 4, and 5 years post-infusion].
5. Changes in plasma concentration of prothrombin complex (PK) [time frame, baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion, 6 months, 1, 2, 3, 4, and 5 years post-infusion].
6. Changes in plasma concentration of Creatinine [time frame, baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion, 6 months, 1, 2, 3, 4, and 5 years post-infusion].
7. Changes in plasma concentration of Aspartate amino transferase (ASAT) [time frame, Baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion, 6 months, 1, 2, 3, 4, and 5 years post-infusion].
8. Changes in plasma concentration of Alanine amino transferase (ALAT) [time frame, Baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion, 6 months, 1, 2, 3, 4, and 5 years post-infusion].
9. Changes in plasma concentration of N-terminal pro-brain natriuretic peptide (NT-proBNP) [time frame, baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion, 6 months, 1, 2, 3, 4, and 5 years post-infusion].
10. Changes in blood pressure [time frame, baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion, 6 months, 1, 2, 3, 4, and 5 years post-infusion].
11. Changes in body temperature [time frame, baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion, 6 months, 1, 2, 3, 4, and 5 years post-infusion].
12. Efficacy; changes in pulmonary compliance [time frame, baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion].
13. Efficacy; changes in driving pressure (plateau pressure—PEEP) [time frame, baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion].
14. Efficacy; changes in oxygenation (PaO2/FiO2) [time frame, baseline (pre-infusion), day 1, 2, 3, 4, 7, and 10 post-infusion].
15. Efficacy; duration of ventilator support [time frame, baseline (pre-infusion), day 1, 2, 3, 4, 7, 10 and 60 post-infusion].
16. Efficacy; pulmonary bilateral infiltrates [time frame, baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion, 6 months, 1, 2, 3, 4, and 5 years post-infusion].
17. Efficacy; sequential organ failure assessment (SOFA) score [time frame, baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion, end of ICU].
18. Efficacy; hospital stay [time frame, day 60 post-infusion].
19. Lung function [time frame, day 60 post-infusion, 6 months, 1, 2, 3, 4, and 5 years post-infusion].
20. Lung fibrosis [time frame, baseline (pre-infusion), day 1, 3, 7 and 10 post-infusion, 6 months, 1, 2, 3, 4, and 5 years post-infusion].
21. 6 min walk test [time frame, 6 months, 1, 2, 3, 4, and 5 years post-infusion].
22. Changes in quality of life [time frame, 6 months, 1, 2, 3, 4, and 5 years post-infusion].
23. Blood biomarkers [time frame, baseline (pre-infusion), day 1, 2, 3, 4, 7 and 10 post-infusion, 6 months, 1, 2, 3, 4, and 5 years post-infusion].
24. Sensitization test [time frame, baseline (pre-infusion), day 60 post-infusion]. Sensitization tests (test for donor-specific antibodies) against KI-MSC-PL-205 donor.
NCT04457609 Clinical improvement: presence of dyspnea, presence of sputum, fever, ventilation status, blood pressure, heart rate, respiratory rate, oxygen saturation [time frame, 15 days]. Leukocyte, lymphocytes, CO2, HCO3, blood base excess level, blood oxygen partial pressure, O2 saturation, blood PH level, CRP, SGOT/SGPT (AST/ALT), ureum/creatinine, eGFR, sodium, potassium, chloride, procalcitonin, albumin, bilirubin, D-dimer level, fibrinogen, troponin, NT proBNP level [time frame, 15 days].
Measure leukemia inhibiting factor, IL-6, IL-10, ferritin, CXCR3, CD4, CD8, CD56 [time frame, 7 days].
Radiologic Improvement from chest X-ray/CT Scan [time frame, 15 days].
NCT04397471 Determine feasibility of recruiting healthy volunteers in a clinically useful timeframe. [time frame, 3 or more participants recruited in 1 month].
Manufacture a cell-based product suitable for clinical use [time frame, successfully opening the next phase of the trial in approx. 2 months].
Establishment of a robust process of production [time frame, successfully opening the next phase of the trial in approx. 2 months].
Production of stability data to be used in the MHRA dossier for the COMET clinical trial. [time frame, successfully opening the next phase of the trial in approx. 2 months]
Production of cell-based products to be administered to COVID-19 patients with severe pneumonitis. [time frame, successfully opening the next phase of the trial in approx. 2 months].
Analysis of cells for understanding production, manufacture and related research. [time frame, Successfully opening the next phase of the trial in approx. 2 months].
NCT04461925 Changes of oxygenation index PaO2/FiO2, most conveniently the P/F ratio [time frame, up to 28 days].
Changes in length of hospital stay [time frame, up to 28 days].
Changes in mortality rate [time frame, up to 28 days].
Changes of С-reactive protein (CRP, mg/L) [time frame, At baseline, Day 1, Week 1, Week 2, Week 4, Week 8].
Evaluation of pneumonia improvement [time frame, at baseline, Day 1, Week 1, Week 2, Week 4, Week 8].
Duration of respiratory symptoms (difficulty breathing, dry cough, fever, etc.) [time frame, at baseline, day 1, week 1, week 2, week 4, week 8].
Peripheral blood count recovery time [time frame, at baseline, day 1, week 1, week 2, week 4, week 8].
NCT04428801 Tolerability and acute safety of cell infusion by assessment of the total number of AEs/SAEs related and non-related with the medication [time frame, 6 months].
The overall proportion of subjects who develop any AEs/SAEs related and non-related with the AdMSC infusions as compared to the control group [time frame, 6 months].
COVID-19 incidence rates in both the study and control groups [time frame, 6 months].
1. The proportion of subjects who are infected by SARS-Cov-2 measured by PCR or other nuclear level-based SARS-Cov-2 testing in respiratory tract specimens (oropharyngeal samples) collected by oropharyngeal swab using the CDC standard method. [time frame, 6 months].
2. The proportion of subjects who are infected by SARS-Cov-2 virus develop symptoms including mild, classic, severe and critical sever cases between study group and control group. [time frame, 6 months].
3. Change of proportion of subjects who are infected by SARS-Cov-2 and develop IgM/IgG antibodies against SARS-Cov-2 between study group and control group. [time frame, 6 months].
4. Change of lymphocyte count in white blood cell counts, PaO2 arterial blood gas from the baseline [time frame, 6 months].
5. Compare the proportion of subjects who develop severe COVID-19 pneumonia cases, mortality rates, C-reactive protein (CRP), D-dimer (mg/L), procalcitonin (μg)/L, pro-type B natriuretic peptide (pro-BNP) (pg/mL), bilirubin, creatinine for both study and control groups [time frame, 6 months].
6. Change in blood test values for cytokine panels (IL-1β, IL-6, IL-8, IL-10, TNFα) from the baseline [time frame, 6 months].
7. Change in blood test values for cytokine panels (IL-1β, IL-6, IL-8, IL-10, TNFα) from the baseline [time frame, 6 months]
8. The proportion of subjects from SARS-CoV-2 RT-PCR positive to negativity in respiratory tract specimens (oropharyngeal samples) collected by oropharyngeal swab using the CDC standard method. as compared to control group [time frame, 6 months].
9. Quantifying viral RNA in stool for baseline and final follow-up. [time frame, 6 months].
NCT04416139 Functional Respiratory changes: PaO2/FiO2 ratio, Changes in body temperature, cardiac changes: Heart rate per minute, respiratory rate [time frame, 3  weeks]. General biochemical changes in leukocytes, lymphocytes, platelets, fibrinogen, pocalcitonin, ferritin, D-dimer, C-reactive protein, Inflammatory cytokine TNFa, IL10, IL1, IL6, IL 17, VEGF, radiological changes (CT), immunological changes on T cell, dendritic cells, CD4+ T, CD8+ T, NK cell, RNA detection by SARS-Cov2 PCR, and adverse events [time frame, 3  weeks].
NCT04429763 Clinical deterioration or death [time frame, 4 weeks]. N.A.
NCT04444271 Overall survival [time frame, 30 days post-intervention]. 1. Clinical improvement [time frame, 30 days].
2. Time of COVID19 PCR negativity [time frame, day 1, 3, 7, 10, 14].
3. Radiological improvement (day 15 and day 30 assessment) [time frame, day 15 and day30].
4. Days required to discharge from hospital [time frame, 30 days post-admission].
NCT04456361 Oxygen saturation [time frame, baseline, and at days 2, 4, and 14 post-treatment]. Oxygen pressure in inspiration, ground-glass opacity, pneumonia infiltration, LDH, CRP, D-dimer ferritin [time frame, Baseline, and at days 4 and 14 post-treatment].
NCT04366271 Mortality due to lung involvement due to SARS-CoV-2 infection at 28 days of treatment [time frame, 28 days]. 1. Mortality due to lung involvement due to SARS-CoV-2 infection at 14 days of treatment [time frame, 14 days].
2. Mortality from any cause at 28 days [time frame, 28 days].
3. Days without mechanical respirator and without vasopressor treatment for 28 days [time frame, 28 days].
4. Patients alive without mechanical ventilation and without vasopressors on day 28 [time frame, 28 days].
5. Patients alive and without mechanical ventilation on day 14 [time frame, 14 days].
6. Patients alive and without mechanical ventilation on day 28 [time frame, 28 days].
7. Patients alive and without vasopressors on day 28 [time frame, 28 days].
8. Days without vasopressors for 28 days [time frame, 28 days].
9. Patients cured at 15 days [time frame, 15 days].
10. Incidence of treatment-emergent adverse events [time frame, 1 year].
NCT04371393 Number of all-cause mortality [time frame, 30 days]. 1. Number of days alive off mechanical ventilatory support [time frame, 60 days].
2. Number of adverse events [time frame, 30 days].
3. Number of participants alive at day 7, 14, 60, 90.
4. Number of participants with resolution and/or improvement of ARDS on days 7, 14, 21, and 30.
5. Change from baseline of the severity of ARDS on days 7, 14, 21, and 30.
6. Length of stay [time frame, 12 months]
7. Clinical improvement scale on days 7, 14, 21 and 30; change CRP concentration on days 7, 14, 21, and 30.
8. Change in IL-6 and IL-8 inflammatory marker level on days 7, 14, 21 and 30; change in TNF-alpha inflammatory marker level on days 7, 14, 21, and 30.
NCT04313322 Clinical outcome, CT Scan, RT-PCR results [time frame, 3 weeks]. RT-PCR results [time frame, 8 weeks].
NCT04452097 1 Incidence of infusion-related adverse events [time frame, day 3].
2 Incidence of any treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs) [time frame, day 28].
Selection of an appropriate dose of the hUC-MSC product for the following phase 2 study [time frame, Day 28].
NCT04315987 Change in clinical condition [time frame, 10 days]. 1. Rate of mortality, respiratory rate, hypoxia, PaO2/FiO2 ratio, changes of blood oxygen, side effects [time frame, 10 days].
2. CD4+ and CD8+ T cell count [time frame, days 1, 2, 4, 6 and 8].
3. Complete blood count, cardiac, hepatic, and renal profiles; [time frame, days 1, 2, 4, 6, and 8].
NCT04252118 (preliminary for NCT04288102) Size of lesion area by chest radiograph or CT [time frame, at baseline, day 3, 6, 10, 14, 21, 28]
Side effects in the MSCs treatment group [time frame, at baseline, day 3, 6, 10, 14, 21, 28, 90 and 180].
1. Improvement of clinical symptoms including duration of fever and respiratory [time frame, at baseline, day 3, 6, 10, 14, 21, 28].
2. Time of nucleic acid turning negative, CD4+ and CD8+ T cell count, alanine aminotransferase, C-reactive protein, creatine kinase [time frame, at baseline, day 3, 6, 10, 14, 21, 28, 90 and 180].
3. Rate of mortality within 28-days [time frame, day 28].
NCT04288102 Change in lesion proportion (%) of full lung volume from baseline to day 28. [time frame, day 28]. 1. Change in lesion proportion (%) of full lung volume from baseline to day 10 and 90 [time frame, day 10, day 90].
2. Change in consolidation lesion proportion (%) of full lung volume from baseline to day 10, 28 and 90. [time frame, day 10, 28, and 90].
3. Change in ground-glass lesion proportion (%) of full lung volume from baseline to day 10, 28 and 90. [time frame, day 10, 28, and 90].
4. Pulmonary fibrosis-related morphological features in CT scan at day 90.
5. Lung densitometry [time frame, days 10, 28, and 90].
6. Lung densitometry: volumes histogram of lung density distribution (< − 750, − 750 to about − 300, − 300 to about 50, > 50) at day 10, 28 and 90. [time frame, days 10, 28, and 90].
7. Time to clinical improvement in 28 days. [time frame, day 28].
8. Oxygenation index (PaO2/FiO2) [time frame, days 6, 10, and 28]
9. Duration of oxygen therapy (days) [time frame, day 28 and 90].
10. Blood oxygen saturation [time frame, days 6, 10, and 28]
11. 6-min walk test [time frame, days 28 and 90].
12. Maximum vital capacity (VCmax) [time frame, baseline, days 10, 14, 21, 28, and 90].
13. Diffusing capacity (DLCO) [time frame, baseline, days 10, 14, 21, 28, and 90].
14. mMRC (Modified Medical Research Council) dyspnea scale [time frame, day 28, Day 90].
15. Changes of absolute lymphocyte counts and subsets, changes of cytokine/chemokine from baseline to day 6, 10, 28 and 90. [time frame, days 6, 10, 28, and 90].
16. Adverse events, serious adverse events, all-cause mortality [time frame, day 0 through Day 90].
NCT04302519 Improvement time of ground-glass shadow in the lungs [time frame, 14 days]. 1. Absorption of lung shadow absorption by CT scan-chest [time frame, 7, 14, 28 and 360 days]
2. Changes of blood oxygen [time frame, 3, 7 and 14 days]
NCT04273646 Pneumonia severity index [time frame, from baseline (0 w) to 12 week after treatment].
Oxygenation index (PaO2/FiO2) [time frame, from baseline (0 w) to 12 week after treatment].
1. Side effects [time frame, From Baseline (0 W) to 96 week after treatment].
2. Survival, sequential organ failure assessment [time frame, day 28].
3. C-reactive protein, procalcitonin, lymphocyte count, CD3+, CD4+ and CD8+ T cell count, CD4+/CD8+ratio [time frame, from baseline (0 W) to 12 week after treatment].
NCT04299152   1. Percentage of activated T cells, percentage of Th17 after therapy by flow cytometry [time frame, 4 weeks].
2. Chest imaging changes by computed tomography (CT) scan of the chest, quantification of the SARS-CoV-2 viral load by real time RT-PCR [time frame, 4 weeks].
NCT04269525 Oxygenation index [time frame, on the day 14 after enrollment]. 1. 28 day mortality rate.
2. Hospital stay [time frame, up to 6 months]
3. COVID-19 antibody test on the day 7, 14, and 28.
4. Improvement of lung imaging examinations on the day 7, 14, 28
5. White blood cell count, procalcitonin, lymphocyte count, IL-2, IL-4, IL-6, IL-10, TNF-α, γ-IFN, CRP, CD4+, CD8+, NK cells [time frame, on the day 7, 14, 28 after enrollment]
NCT04333368 Respiratory efficacy evaluated by the increase in PaO2/FiO2 ratio from baseline to day 7 in the experimental group compared with the placebo group [time frame, From baseline to day 7]. 1. Lung injury score, oxygenation index, in-hospital mortality, mortality, ventilator-free days, number of days between randomization and the first day the patient meets weaning criteria meets PaO2/FiO2 > 200 (out of a prone positioning session) [time frame, from baseline to day 28].
2. Cumulative use of sedatives, duration of use of sedatives, duration of use of neuromuscular blocking agents (other than used for intubation), use of neuromuscular blocking agents (other than used for intubation), ICU-acquired weakness and delirium, treatment-induced toxicity rate and adverse events up to day 28.
3. Quality of life at 1 year (EQ. 5D-3L quality of life questionnaire) [time frame, At 6 months and 12 months].
4. Measurements of plasmatic cytokines (IL1, IL6, IL8, TNF-alpha, IL10, TGF-beta, sRAGE, Ang2) level [time frame, At day 1, 3, 5, 7, and 14].
5. Anti-HLA antibodies plasmatic dosage [time frame, from baseline to day 14, and at 6 months].
NCT04276987 Adverse reaction (AE) and severe adverse reaction (SAE) Time to clinical improvement (TTIC) [time frame, up to 28 days]. Number of patients weaning from mechanical ventilation, duration (days) of ICU monitoring, vasoactive agents usage, mechanical ventilation supply, number of patients with improved organ failure and mortality rate within 28 days.
NCT04336254 Time to clinical improvement [time frame, 1–28 days]. Lung lesion, immune function (Th1 cytokines: IL-1β, IL-2, TNF-a, ITN-γ; Th2 cytokines: IL-4, IL-6, IL-10; immunoglobulins: IgA, IgG, IgM, and total IgE; Lymphocyte counts: CD3+, CD4+, CD8+, CD16+,CD19+, CD56+), time of SARS-CoV-2 clearance, blood test, SPO2, RR, body temperature, side effects in the treatment group, CRP [time frame, 1–28 days].
NCT04348435 Incidence of hospitalization for COVID-19, incidence of symptoms associated with COVID-19 [time frame, week 0 through week 26 (end of study)]. 1. Absence of upper/lower respiratory infection [time frame, week 0 through week 26].
2. Leukocyte differential, CRP, TNF alpha, IL-6, IL-10, glucose, calcium, albumin, total protein, sodium, total carbon dioxide, complete blood count (CBC) and complete metabolic profile (CMP) [time frame, weeks 0, 6, 14, 26].
NCT04352803 Incidence of unexpected adverse events, frequency of progression to mechanical ventilation, changes in length of mechanical ventilation, changes in length of weaning of mechanical ventilation, changes in length of hospital stay, changes in mortality rate [time frame, up to 28 days]. N.A.
NCT04366323 Safety of the administration assessed by adverse event rate [time frame, 12 months]
Efficacy of the administration by survival rate [time frame, 28 days]
N.A.
NCT04349631 Incidence of hospitalization for COVID-19 [time frame, week 0 through week 26 (end of study)]
Incidence of symptoms for COVID-19 [time frame, week 0 through week 26 (end of study)].
Absence of upper/lower respiratory infection [time frame, weeks 0 through 26]
CBC, CMP, and IL-10, 6, TNF-alpha [time frame, Weeks 0, 6, 14, 26].
NCT04346368 Changes of oxygenation index (PaO2/FiO2) [time frame, at baseline, 6 h, day 1, 3, week 1, week 2, week 4, month 6]
Side effects in the BM-MSCs treatment group [time frame, baseline through 6 months].
Clinical outcome, hospital stay, CT scan, changes in viral load, changes of CD4+, CD8+ cells count and concentration of cytokines, rate of mortality within 28-days, changes of C-reactive protein [time frame, From baseline to day 28].
NCT04382547 Number of cured patients [time frame, 3 weeks] Number of patients with treatment-related adverse events [time frame, 3 weeks].
NCT04366063 Adverse events assessment [time frame, from baseline to day 28].
Blood oxygen saturation [time frame, from baseline to day 14].
1. Intensive care unit-free days [time frame, up to day 8].
2. Clinical symptoms [time frame, from baseline to day 14].
3. Respiratory efficacy [time frame, from baseline to day 7].
4. Biomarkers concentrations in plasma [time frame, at baseline, 7, 14, 28 days after the first intervention].
NCT04437823 Safety and efficacy assessment of infusion associated adverse events [time frame, day 01 to day 30]
Chest radiograph or chest CT scan [time frame, day 01 to day 30].
COVID-19 Quantitative real time PCR, Sequential Organ Failure Assessment (SOFA) score, evaluation of organ function (each organ system is assigned a value for 0 (normal) to 4 (highest degree of dysfunction)), rate of mortality, clinical respiratory changes [time frame, day 01 to day 30].
NCT04339660 The immune function (TNF-α, IL-1β, IL-6, TGF-β, IL-8, PCT, CRP) [time frame, 4 weeks].
Blood oxygen saturation [time frame, 4 weeks].
Rate of mortality within 28-days, size of lesion area by chest imaging, CD4+ and CD8+ T cells count, peripheral blood count recovery time, duration of respiratory symptoms (fever, dry cough, difficulty breathing), COVID-19 nucleic acid negative time [time frame, at baseline, day 1, 2, 7, week 2, week 3, week 4].
NCT04392778 Clinical improvement [time frame, 3 months]. Lung damage improvement, SARS-Cov-2 viral infection laboratory test, blood test [time frame, 3 months].
NCT04371601 Changes of oxygenation index (PaO2/FiO2), blood gas test [time frame, 12 months]. Detection of TNF-α levels, IL-10 levels, immune cells that secret cytokines, including CXCR3+, CD4+, CD8+, NK+ cells, and regulatory T cells (CD4+ CD25+ FOXP3+ Treg cells). Changes of oxygenation index (PaO2/FiO2), blood gas test, changes of c-reactive protein and calcitonin [time frame, 1, 3, 6, 12 months].
NCT04355728 Incidence of pre-specified infusion associated adverse events [time frame, day 5].
Incidence of severe adverse events [time frame, 90 days].
1. Survival rate after 90 days post first infusion [time frame, 90 days].
2. Small Identification Test (SIT) scores [time frame, At baseline, day 18 and day 28].
3. CBC, CMP, D-dimer, and alloantibodies levels [time frame, Baseline, 28 days].
NCT04362189 Interleukin-6, C reactive protein, oxygenation, TNF alpha, IL-10 [time frame, day 0, 7. 10].
Return to room air (RTRA) [time frame, day 0, 3, 7, 10, 28].
1. CBC, CMP, D-dimer, INR, CD4+/CD8+ ratio, NK cells [time frame, screening, day 0, 7, 10].
2. CT scan [time frame, days 0 and 28].
3. PCR test for SARS-CoV-2 [time frame, day 0, 3, 7, 10].
NCT04390152 Intergroup mortality difference with treatment [time frame, 28 days]. 1. Number of patients with treatment-related adverse events [time frame, 6 months].
2. Difference in days of mechanical ventilation between groups [time frame, From ICU admission to 180 days].
3. Median reduction of days of hospitalization, reduction of days of oxygen needs [time frame, from hospital admission to 180 days].
4. Difference in APACHE II score between groups [time frame, baseline and 7 days]
5. CBC, CMP, LDH, IL-6, IL-10, TNF-alpha [time frame, baseline to 7 days].
NCT04377334 Lung injury score [time frame, day 10]. D-dimer, immune cell phenotype, pro-resolving lipid mediators, cytokines, chemokines day 0, 1, 2, 3, 10 and 15, survival (day 10 and 28), extubation (day 28), lymphocyte subpopulations, SARS-CoV-2-specific antibody titers and complement molecules (C5-C9) (day 0, 5 and 10).
NCT04331613 Adverse reaction (AE) and severe adverse reaction (SAE), changes of lung imaging examinations [time frame, Within 28 days after treatment]. CBC, CMP, IL-1beta, IL-2, IL-6, IL-8, lactate, procalcitonin, CRP, CK, and rate of all-cause mortality within 28 days.
NCT04390139 All-cause mortality at day 28 [time frame, day 28]. Safety, need for treatment with rescue medication, duration of mechanical ventilation, ventilator-free days, evolution of PaO2/FiO2 ratio, SOFA index, APACHE II score, duration of hospitalization, evolution of markers of immune response (leucocyte count, neutrophils), feasibility of MSC administration, LDH, ferritin.
NCT04400032 Treatment-related adverse events [time frame, at time of infusion-12 months]. Number of participants alive and number of participants with ventilator-free by day 28.
NCT04398303 Mortality at day 30 [time frame, 30 days post-treatment]. Improvement in ventilator settings [time frame, 28–30 days post-treatment].
NCT04365101 Phase 1: frequency and severity of adverse events (AE), rate of clearance of SARS-CoV-2, clinical improvement [time frame, up to 12 months].
Phase 2: Time to clearance of SARS-CoV-2, clinical improvement by NEWS2 Score [time frame, up to 28 days].
Mortality rate and impact on sequential organ failure assessment (SOFA) score pulmonary clearance [time frame, up to 28 days].
NCT04393415 Clinical improvement [time frame, 2 weeks]. N.A.
NCT04397796 Adverse event and mortality rates [time frame, 30 days]
Ventilator-free days [time frame, 60 days].
1. Change in NEWS from baseline (NEWS of ≤ 2 [time frame, 30 days]).
2. SOFA score on days 8, 15, 22, and 29.
NCT03042143 Oxygenation index (OI) [time frame, day 7].
Incidence of serious adverse events (SAEs) [time frame, 28 days].
1. SOFA score [time frame, days 4, 7 and 14].
2. Respiratory compliance (Crs) [time frame, days 4, 7, and 14].
3. Oxygenation index [time frame, days 4, and 14].
4. Ventilation and pulmonar function [time frame, 28 and 90 days].
NCT04345601 Treatment-related serious adverse events [time frame, 28 days post cell infusion].
Change in clinical status at day 14 [time frame, 14 days post cell infusion].
N.A.
NCT04361942 Proportion of patients who have achieved withdrawal of invasive mechanical ventilation [time frame, 0–7 days].
Mortality rate [time frame, 28 days].
Proportion of patients who have achieved clinical response (0–7 days) and radiological responses (0–28 days).
NCT04333368 Respiratory efficacy evaluated by the increase in PaO2/FiO2 [time frame, from baseline to day 7]. 1. Lung injury score, Oxygenation index, In-hospital mortality, mortality, ventilator-free days, proportion of PaO2/FiO2 > 200, cumulative use and duration of sedatives and neuromuscular blocking agents, ICU-acquired weakness and delirium, treatment-induced toxicity rate and adverse events up to day 28.
2. Quality of life at one year (EQ. 5D-3L quality of life questionnaire) [time frame, at 6 months and 12 months]
3. Measurements of plasmatic cytokines (IL1, IL6, IL8, TNF-alpha, IL10, TGF-beta, sRAGE, Ang2) level [time frame, At day 1, 3, 5, 7 and 14].
4. Anti-HLA antibodies plasmatic dosage [time frame, from baseline to day 14, and at 6 months].
NCT04389450 Number of ventilator-free days [time frame, 28 days]. 1. All-cause mortality [time frame, 28 days]
2. Duration of mechanical ventilation [time frame, 8 weeks].
NCT04367077 Ventilator-free days, safety and tolerability as measured by the incidence of treatment-emergent adverse events [time frame, day 0–28]. 1. All-cause mortality [time frame, Day 60]
2. Ranked hierarchical composite outcome of alive and ventilator-free [time frame, Day 28].
3. Ventilator-free days [time frame, day 0–60].
  1. PEEP positive end-expiratory airway pressure, AEs/SAEs adverse events and severe adverse events, CRP C-reactive protein, LDH lactate dehydrogenase. APACHE II is a prognostic score based on 12 different items obtained in the first 24 h of ICU admission. It ranges from 0 to 71 points. A higher score is associated with higher mortality. TRAEIs, Pre-specified treatment-related adverse events of interest; NEWS2, National Early Warning Score 2 Score; NEWS: respiration rate, oxygen saturation, any supplemental oxygen, temperature, systolic blood pressure, heart rate, level of consciousness; SOFA, respiration, coagulation, liver, cardiovascular, central nervous system, and renal