Table 2.
List of registered, ongoing, clinical trials using mesenchymal stem/stromal cells (MSCs) as a therapy to treat COVID-19.
| Clinical trials number | Participants | MSC source | Outcomes |
|---|---|---|---|
| NCT04371393 (USA) | Target: N = 300 | MSCs (Remestemcel-L) at 2 × 106 cells/kg administered twice during first week (second infusion 4 days following first) plus standard care vs. placebo (Plasma-Lyte) (second infusion 4 days following first) plus standard care | - All-cause mortality - SAEs - No. of days off mechanical ventilation - Resolution/improvement of ARDS - Length of stay - Clinical improvement scale - Hs-CRP, IL-6, IL-8, TNF-α |
| NCT03042143 (Northern Ireland)—REALIST trial | Target: N = 75 | Single infusion of human umbilical cord derived CD362 enriched MSCs at maximum tolerable dose from phase I (dose escalation pilot study) plus standard care vs. placebo (Plasma-Lyte) plus standard care | - Oxygenation index - SAEs - SOFA - Respiratory compliance - P/F ratio - Driving pressure - Extubation and reintubation - Ventilation free days - Length of ICU/hospital stay - Mortality |
| NCT04444271 (Pakistan) | Target: N = 20 | Bone marrow derived MSCs at 2 × 106 cells/kg on day 1 and 7 plus standard care vs. saline injection plus standard care | - Survival - No. oxygen support days - Time to negative nCoV test - CT scan - No. days to discharge |
| NCT04416139 (Mexico) | Target: N = 10 | Umbilical cord derived MSCs from De bank Laboratory at 1 × 106 cells/kg (no control group—data compared to controls treated in a previous trial) | - PaO2/FiO2 ratio - HR and RR - Body temperature - Leukocyte, lymphocyte, and platelet counts - PCT, fibrinogen, D-dimer, ferritin - CRP, TNF-α, IL-1, IL-10, IL-6, IL-17 - VEGF - T-cell analysis (CD4+ and CD8+) - NK and dendritic cells - SAEs - CT scan - nCoV-test |
| NCT04429763 (Colombia)—CELMA | Target: N = 30 | Umbilical cord derived MSCs at 1 × 106 cells/kg plus standard care vs. placebo (not stated) plus standard care control | - NEWS scale - Time to hospital discharge - Respiratory function - Inflammatory markers - Hematological and renal assessments |
| NCT04315987 (Brazil) | Target: N = 90 | NestaCell MSCs at 2 × 107 cells/kg on days 1, 3, 5, and 7 plus standard care vs. placebo (not stated) on days 1, 3, 5, and 7 plus standard care | - Change in clinical condition - Mortality - SpO2 - PaO2/FiO2 ratio - T-cell analysis (CD4+ and CD8+) - SAEs - Blood count and cardiac, hepatic, and renal profiles |
| NCT04366323 (Spain) | Target: N = 26 | Allogenic and expanded adipose tissue derived MSCs at 8 × 106 cells × 2 (no control group) | - Safety of administration (SAEs) - Efficacy of administration |
| NCT04456361 (Mexico) | Target: N = 9 | Wharton's jelly derived MSCs at 1 × 108 cells/kg (no control group) | - SpO2 - PaO2/FiO2 ratio - Ground glass opacity and pneumonia infiltration - LDH, CRP, D-dimer, and Ferritin |
| NCT04366271 (Spain) | Target: N = 106 | Undifferentiated allogenic umbilical cord MSCs (dose not stated) vs. standard care | - Mortality due to lung involvement - All-cause mortality - Days without mechanical ventilation - Days without vasopressors - Negative nCoV-test - SAEs |
| NCT04252118 (China) | Target: N = 20 | MSCs (source not stated) at 3 × 107 cells at day 0, 3, and 6 vs. standard care | - CT scan - SAEs - Pneumonia evaluation - Mortality - T-cell analysis (CD4+ and CD8+) - AAT, CRP, and CK |
| NCT04313322 (Jordan) | Target: N = 5 | Wharton's jelly derived MSCs at 1 × 106 cells/kg for 3 doses, spaced 3 days apart (No control group) | - Alleviations of symptoms - CT scan - Negative nCoV-test |
| NCT04336254 (China) | Target: N = 20 | Allogenic human dental pulp MSCs at 3 × 107 cells at day 1, 4, and 7 vs. saline control at day 1, 4, and 7 | - TTCI - CT scan - Immune function markers - Time for negative nCoV-test - Blood count and classification - SpO2 - RR - Body temperature - SAEs - CRP |
| NCT04346368 (China) | Target: N = 20 | Bone marrow derived MSCs at 1 × 106 cells/kg at day 1 vs. standard care | - PaO2/FiO2 ratio - SAEs - Clinical outcome - No. days in hospital - CT scan - Changes in viral load - T-cell analysis (CD4+ and CD8+) - Mortality - CRP |
| NCT04288102 (China) | Target: N = 100 | Umbilical cord derived MSCs at 4 × 107 at day 0, 3, and 6 vs. saline control at day 0, 3, and 6 | - Pneumonia evaluation - Time to clinical improvement - PaO2/FiO2 ratio - Days on oxygen therapy - SpO2 - 6-min walk test - Lymphocyte counts - Cytokine/chemokine assessment - SAEs - All-course mortality |
| NCT04273646 (China) | Target: N = 48 | Umbilical cord derived MSCs at 0.5 × 106 cells/kg at day 1, 3, 5, and 7 plus standard care vs. saline control at day 1, 3, 5, and 7 plus standard care | - Pneumonia evaluation - SAEs - Survival - Organ failure assessment - CRP and Procalcitonin - Lymphocyte count - T-cell analysis (CD3+, CD4+, and CD8+) - CD4+/CD8+ ratio |
| NCT04339660 (China) | Target: N = 30 | Umbilical cord derived MSCs at 1 × 106 cells/kg vs. saline control | - TNF-α, IL-1β, IL-6, TGF-β, IL-8, PCT, CRP - SpO2 - Mortality - CT scan - Blood count recovery time - Duration of respiratory symptoms - Negative nCoV-test |
| NCT04382547 (Belarus) | Target: N = 40 | Allogenic pooled olfactory mucosa derived MSCs (dose not stated) vs. standard care control | - nCoV-test - SAEs |
| NCT04457609 (Indonesia) | Target: N = 40 | Umbilical cord derived MSCs at 1 × 106 cells/kg with Oseltamivir and Azithromycin vs. standard care with Oseltamivir and Azithromycin | - Clinical improvement markers - General laboratory outcomes - PCT, bilirubin, D-dimer, and fibrinogen - Troponin and NT-proBNP - LIF, IL-6, IL-10, ferritin, CXCR3 - T-cell analysis (CD4+, CD8+, and CD56+) - VEGF - CT scan |
| NCT04352803 (USA) | Target: N = 20 | Autologous adipose derived MSCs at 0.5 × 106 cells/kg vs. standard care control | - SAEs - Progression and time to/on mechanical ventilation - Length of hospital stay - All-cause mortality |
| NCT04490486 (USA) | Target: N = 21 | Umbilical cord derived MSCs at 1 × 108 cells on day 0 and 3 vs. 1% human serum albumin in Plasmalyte A on day 0 and 3 | - SAEs - Inflammatory markers - COVID-19 viral load - SOFA score - Electrolyte levels - LDH - No. ICU discharges - Vasoactive agent use - Mortality - Immune markers - CT scan |
| NCT04522986 (Japan) | Target: N = 6 | Adipose derived MSCs at 1 × 108 cells once a week for 4 weeks (no control group) | - SAEs |
| NCT04461925 (Ukraine) | Target: N = 30 | Placenta derived MSCs at 1 × 106 cells/kg once every 3 days for 3 infusions vs. standard care control | - PaO2/FiO2 ratio - Length of hospital stay - Mortality - CRP - CT scan - Duration of respiratory symptoms - Blood count recovery time |
| NCT04362189 (USA) | Target: N = 100 | Allogenic adipose tissue derived MSCs (Hope Biosciences) at 1 × 106 cells/dose at day 0, 3, 7, and 10 vs. saline control at day 0, 3, 7, and 10 | - IL-6, CRP, TNF-α, and IL-10 - Oxygenation - RTRA - ECG assessment - Routine blood assessments - Cardiac, hepatic, and renal assessment - Blood count - Platelets, Prothrombin time, D-dimer, and INR - Immune markers - SAEs - Chest X-ray - CT scan - Negative nCoV-test |
| NCT04371601 (China) | Target: N = 60 | Umbilical cord derived MSCs at 1 × 106 cells/kg once every 4 days for 4 infusions vs. standard care control | - PaO2/FiO2 ratio - TNF-α and IL-6 - Immune markers - CRP and calcitonin |
| NCT04348461 (Spain) | Target: N = 100 | Allogenic expanded adipose tissue derived MSCs at 1.5 × 106 cells/kg vs. standard care control | - Efficacy of administration of MSCs - SAEs |
| NCT04452097 (USA) | Target: N = 9 | Umbilical cord derived MSCs (3 groups): - Low dose: 0.5 × 106 cells/kg - Middle dose: 1 × 106 cells/kg - High dose: 1.5 × 106 cells/kg |
- SAEs - TEAEs - Selection of appropriate dose for Phase II trial |
| NCT04494386 (USA) | Target: N = 60 | Umbilical cord lining derived MSCs at 1 × 106 cells/dose vs. saline control—either a single dose or 2 doses separated by 48 h | - DLT - SAEs - Berlin definition of ARDS - SpO2 and PaO2/FiO2 ratio - No. of VFDs - Blood count - Routine blood assessments - BUN and urinalysis - AAT |
| NCT04345601 (USA) | Target: N = 30 | MSCs (source not specified) at 1 × 108 cells vs. standard care control | - SAEs - Change to clinical status |
| NCT04377334 (Germany) | Target: N = 40 | Allogenic bone marrow derived MSCs (dose not stated) vs. standard care control | - Lung injury score - D-dimer - Pro-resolving lipid mediators - Phenotype of immune cells - Cytokine and chemokine analysis - Survival - Extubation - Lymphocyte subpopulation - Complement molecules - SARS-CoV-2 specific antibody |
| NCT04390139 (Spain) | Target: N = 30 | Wharton's jelly derived MSCs at 1 × 106 cells/kg on day 1 and 3 vs. placebo (not stated) on day 1 and 3 | - All-cause mortality - SAEs - Need for mechanical ventilation - No. of VFDs - PaO2/FiO2 ratio - SOFA index - APACHE II score - Duration of hospitalization - Immune response - Feasibility of MSCs - nCoV-test - LDH, D-dimer, and ferritin - Subpopulations of lymphocytes and immunoglobins - In vitro response of receptor lymphocytes |
| NCT04392778 (Turkey) | Target: N = 30 | MSCs (source not stated) at 3 × 106 cells/kg on day 0, 3, and 6 to COVID-19 patients with a ventilator vs. saline control on day 0, 3, and 6 to COVID-19 patients with a ventilator vs. standard care control to COVID-19 patients without a ventilator | - Clinical improvement - CT scan - Negative nCoV-test - Blood tests |
| NCT04467047 (Brazil) | Target: N = 10 | MSCs (source not stated) at 1 × 106 cells/kg (safety and feasibility study) | - Survival - CRP - Length of hospital stay - PaO2/FiO2 ratio - Liao's score (2020) - CT scan - Negative nCoV-test |
| NCT04398303 (USA) | Target: N = 70 | Allogenic umbilical cord derived MSCs at 1 × 106 cells/kg vs. MSC conditioned media at 100 ml vs. placebo (MEM-α) at 100 ml | - Mortality - No. of VFDs - No. of days on O2 therapy - No. of ICU-free days - Pulmonary function - Berlin criteria score |
| NCT04437823 (USA) | Target: N = 20 | Umbilical cord derived MSCs at 0.5 × 106 cells/kg on day 1, 3, and 5 vs. standard care control | - SAEs - CT scan - Negative nCoV-test - SOFA score - Mortality - Clinical respiratory changes |
| NCT04269525 (China) | Target: N = 16 | Umbilical cord derived MSCs at 3.3 × 107 cells on day 1, 3, 5, and 7 | - PaO2/FiO2 ratio - Mortality - Length of hospital stay - nCoV PCR and antibody-test - Lung imaging - WBC and lymphocyte count - PCT - IL-2, IL-4, IL-4, IL-6, IL-10, TNF-α, γ-IFN, and CRP - NK cells - T-cell analysis (CD4+, CD8+) |
| NCT04447833 (Sweden) | Target: N = 9 | Allogenic bone marrow derived MSCs at 1 × 106 cells/kg (n = 3) and 2 × 106 cells/kg (n = 6) | - SAEs - All-cause mortality - Leucocytes and thrombocytes - CRP - Prothrombin - Creatinine - AST and AAT - NT-proBNP - Blood pressure - Body temperature - Efficacy for MSC use - Lung function - 6-min walk test - Quality of life assessment - Blood biomarkers - Sensitisation test |
| NCT04491240 (Russia) | Target: N = 90 | Inhalation of MSC exosomes at 0.5–2 × 1010 nanoparticles for COVID-19 patients (n = 30) and SARS-CoV-2 pneumonia patients (n = 30) vs. inhalation of solution free placebo (n = 30)—inhalation twice a day for 10 days | - SAEs - TTCI - Blood gases - SpO2 - Chest imaging |
| NCT04333368 (France) | Target: N = 40 | Umbilical cord Wharton's jelly derived MSCs at 1 × 106 cells/kg at day 1, 3, and 5 vs. placebo (NaCl) control at day 1, 3, and 5 | - PaO2/FiO2 ratio - Lung injury score - Mortality - No. of VFDs - Use of sedatives - Use of neuromuscular blocking agent - ICU-acquired weakness - SAEs - Quality of life at 1 year - Cytokine analysis - Anti-HLA antibodies |
| NCT04466098 (USA) | Target: N = 30 | Thawed product containing MSCs (source not stated) at 300 × 106 cells 3 times separated by 48 h vs. placebo (dextran and human serum albumin) control 3 times separated by 48 h | - SAEs - Inflammatory markers - PaO2/FiO2 ratio - Mean airway, peak and plateau pressure - PEEP - Mortality - No. of ICU free days - No. of VFDs - Acute lung injury score - No. of days off O2 therapy |
| NCT04445220 (USA) | Target: N = 22 | Allogenic human MSCs at 2.5 × 106 cells (low dose) and 7.5 × 106 cells (high dose) vs. standard care control—patients with COVID-19 and acute kidney injury | - Safety and tolerability - SAEs |
| NCT04276987 (China) | Target: N = 30 | Allogenic adipose tissue derived MSC exosomes inhaled at 2 × 108 nano-vesicles on 5 consecutive days | - SAEs - TTCI - No. of patients weaning from mechanical ventilation - Vasoactive agent use - No. of days on mechanical ventilation - Mortality - SOFA score - Lymphocyte count - CRP, LDH, and D-dimer - NT-proBNP - IL-1β, IL-2R, IL-6, and IL-8 - Chest imaging - Negative nCoV-test |
| IRCT20140528017891N8 (Iran) | Target: N = 10 | Umbilical cord derived MSCs at 0.5–1 million cells/kg at 1st, 3rd, and 6th day vs. saline injection at 1st, 3rd, and 6th day plus standard care | - Mortality - Pneumonia severity index and CT scan - SpO2 supply - CRP and PCT - Lymphocyte count - T-cell analysis (CD3+, CD4+, and CD8+) |
| NCT04355728 (USA) | Target: N = 24 | Umbilical cord derived vs. standard care control | - Adverse events - 90 day survival post-infusion - No. of VFDs - Change in oxygenation index and plat-PEEP - SOFA and SIT scores - TnI, CRP, and D-dimer - WBC and platelet count - AA/EPA ratio - 25-Hydroxyl Vitamin D - Alloantibody levels |
| CHICTR2000030224 (China) | Target: N = NA | MSCs (source unknown): critical and severe group injected with MSCs vs. critical and severe control group injected with saline | - SpO2 - CT scan - Temperature - Routine blood markers - Inflammatory markers - Hepatic and renal function |
| ChiCTR2000030173 (China) | Target: N = NA | Umbilical cord derived vs. standard care control | - Pulmonary function - nCoV pneumonic nucleic acid test - Pulmonary CT and chest radiography |
| CHICTR2000030138 (China) | Target: N = NA | Umbilical cord derived vs. standard care plus saline injection control | - Clinical index |
| ChiCTR2000030088 (China) | Target: N = NA | Umbilical cord Wharton's jelly derived MSCs at 1 × 106 cells/kg vs. standard care and saline injection control | - nCoV pneumonic nucleic acid test - CT scan of ground glass shadow |
| CHICTR2000029990; TARGET N = NA (China) | Target: N = NA | MSCs (source unknown) vs. standard care and saline injection control | - Respiratory system function (O2 saturation) recovery time |
| ChiCTR2000029817 (NA) | Target: N = NA | Umbilical cord derived MSCs and NK cells: - High dose group: NK cells and MSCs at > 5 × 109; Once every 2 days, five times - Conventional dose group: NK cells and MSCs at > 3 × 109; once every 2 days, three times - Preventive dose group: NK cells and MSCs at > 3 × 109; one infusion |
- Time to disease recovery and time to negative nCoV test - Clearance rate and time of main symptoms - Transfer to ICU time - Routine blood tests - Biochemical indicators - Immune indices |
| CHICTR2000029816 (NA) | Target: N = NA | Umbilical cord derived MSCs (dose not stated) vs. standard care control | - Time to disease recovery and time to negative nCoV test - Clearance rate and time of main symptoms - Transfer to ICU time - Routine blood tests - Biochemical indicators - Immune indices |
| ChiCTR2000029580 (China) | Target: N = NA | Ruxolitinib and MSCs (source and dose not stated) vs. standard care control | - Safety |
| CHICTR2000029569 (China) | Target: N = NA | Umbilical cord derived blood mononuclear cells conditioned medium vs. standard care control | - PSI, CT, and X-Ray - Arterial blood gas - Assisted breathing time - Mortality - Disease evolution - Hospitalization days - Safety outcome index |
| EUCTR2020-001450-22-ES (Spain) | Target: N = NA | Allogenic umbilical cord derived MSCs (dose not stated) | - Mortality - Mechanical ventilation incidence - Need for vasopressors - Safety profile of MSCs - Neutrophils, monocytes and NK cells PCT, ferritin, D-dimer and hs-troponin - PCR test - B and T lymphocytes - Interleukins, Th1, 2&17, NLRP3, and HMGB1 |
| IRCT20200421047150N1 (Iran) | Target: N = NA | Umbilical card Wharton's jelly derived: three injections at 0.5–1 million cells/kg at 1st, 3rd, and 6th day. Control receiving standard care plus saline injection at 1st, 3rd, and 6th day | - Not stated |
| ACTRN12620000612910 (Australia) | Target: N = NA | Mesenchymoangioblast derived MSCs (CYP-001) at 2 × 106 cells/kg twice vs. ICU standard care control | - Not stated |
| NCT04361942 (Spain) | Target: N = 24 | Allogenic MSCs (source unknown) vs. placebo (not stated) | - Withdrawal of invasive mechanical ventilation - Mortality - Patients achieving a clinical response - Patients achieving a radiological response |
| EUCTR2020-001266-11-ES (Spain) | Target: N = 100 | Allogenic adipose tissue MSCs | - Efficacy and safety of administration of MSCs - Survival - Temperature - Withdrawal of mechanical ventilation - Patients transitioning to O2 therapy from mechanical ventilation - O2 therapy duration - Days in ICU - Duration of hospitalization - PaO2/FiO2 - Chest radiology - Routine blood markers - Inflammatory markers - Coagulation markers - Immune markers |
Source: https://clinicaltrials.gov/ct2/home and https://trialstreamer.robotreviewer.net/.
hs-CRP, high sensitivity C-reactive protein; IL-, Interleukin-; TNF-α, Tumor necrosis factor-α; SAE, Serious adverse event; HR, Heart rate; RR, Respiratory rate; PCT, Procalcitonin; VEGF, Vascular endothelial growth factor; RTRA, Return to room air; INR, International normalized ratio of blood coagulation; TEAE, treatment emergent serious adverse events; DLT, Dose limiting toxicity; VFD, Ventilator free days; BUN, Blood urea nitrogen; APACHE, Acute physiology and chronic health disease classification; AST, Aspartate aminotransferase; NEWS, National early warning score; LDH, Lactate dehydrogenase; AAT, Alanine aminotransferase; CK, Creatine kinase; TTCI, Time to clinical improvement; LIF, Leukemia inhibiting factor; PEEP, Positive end-expiratory pressure; SOFA, Sequential organ failure assessment; SIT, Small identification test; TnI, Troponin I; AA, Arachidonic acid; EPA, Eicosapentaenoic acid; nCoV, novel coronavirus; Polymerase chain reaction; NK, Natural killer; Th, T helper; NLRP3, NLR Family Pyrin Domain Containing 3; HMGB1, High mobility group box 1.