RAPID REVIEW

Should Mesenchymal Stem Cell Therapy be used in the treatment of COVID-19?

Namnama P. Villarta-De Dios1 and Evelyn S. Osio-Salido2

1Department of Pediatrics, Amang Rodriguez Memorial Medical Center

2Division of Rheumatology, Department of Medicine, College of Medicine and Philippine General Hospital, University of the Philippines Manila

This rapid review summarizes the available evidence on the efficacy and safety of mesenchymal stem cell therapy

(MSC) in treating patients with COVID-19. This may change as new evidence emerges.

KEY FINDINGS

There is some short-term benefit from the use of mesenchymal stem cell therapy for severe COVID-19 in a low- quality, small randomized controlled trial (RCT). Further studies, ideally with good quality RCTs, are needed to confirm benefit and safety.

•Mesenchymal stem cells (MSCs) are non-hematopoietic adult stem cells that are able to self-renew and differentiate into various cells of any cell lineage. MSCs have the ability to migrate (homing) to damaged tissue for repair and regeneration, as well as signal other cells to help in tissue repair. It can effect cellular differentiation, consequently shifting the immune system from Th1 to Th2 responses.1,2

•A recent review showed improved disease-associated parameters in experimental acute respiratory distress syndrome (ARDS).3

•We found three studies (one case report, one prospective cohort, and one small randomized controlled trial) reporting the effects of MSC on COVID-19. Based on low-quality evidence, it appeared that human umbilical cord blood-derived MSC, given after failure to improve with standard treatment, had beneficial effects in terms of earlier onset of clinical improvement among individuals with severe or critical COVID-19. However, 28-day clinical improvement and mortality were not significantly different compared to standard treatment. There was no reported adverse reaction.

•There are 52 registered and ongoing clinical trials to investigate the efficacy and safety of mesenchymal stem cells as treatment for COVID-19.

•Mesenchymal stem cell therapy is not included in any of the existing guidelines for the treatment of COVID-19.

Disclaimer: The aim of these rapid reviews is to retrieve, appraise, summarize and update the available evidence on COVID-related health technology. The reviews have not been externally peer- reviewed; they should not replace individual clinical judgement and the sources cited should be checked. The views expressed represent the views of the authors and not necessarily those of their host institutions. The views are not a substitute for professional medical advice.

Copyright Claims: This review is an intellectual property of the authors and of the Institute of Clinical Epidemiology, National Institutes of Health-UP Manila and Asia-Pacific Center for Evidence Based Healthcare Inc.

BACKGROUND

One of the major challenges with the COVID-19 pandemic is the lack of a proven effective and safe antiviral treatment. The scientific community is in a race to find pharmacologic agents that can save the lives of those with severe or critical illness. In COVID-19, severe disease is attributed to uncontrolled viral replication and cellular destruction, hyperactivity of the inflammatory response (cytokine storm), and hypercoagulability.4 Several anti- inflammatory drugs are currently under investigation to suppress the state of hyper-inflammation.

Mesenchymal stem cells are a group of non-hemato- poietic adult stem cells that are able to self-renew and differentiate into different cells of mesoderm (chondrocytes, osteocytes, and adipocytes), ectoderm, and endoderm cell lineages. They were first isolated in 1974 and have been isolated from the bone marrow, adipose tissue, the umbilical cord, fetal liver, muscle, and lung and can multiply in vitro.1

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Mesenchymal stem cell therapy is actively being investigated as treatment for many degenerative and inflammatory diseases like cancer, osteoarthritis, acute myocardial infarction, amyotrophic lateral sclerosis, inflammatory bowel disease (Crohn’s disease), systemic lupus erythematosus, and steroid-resistant graft versus host disease. This form of therapy is not recognized as mainstream treatment but is considered as an Advanced Therapy Medicinal Product.5

The usefulness of MSC in the treatment of inflammatory diseases has been attributed to its ability to migrate (homing) to damaged tissue for repair and regeneration. Specific receptors or ligands expressed by damaged tissues facilitate trafficking, adhesion, and infiltration of MSCs to the injured site. MSCs secrete extracellular vesicles with paracrine factors and significantly regulate proliferation, antioxidant activity, and cellular differentiation. The signal stimulates macrophages, endothelial cells, and resident stem cells to help the tissue repair process.6

MSC also has immune modulation and anti- inflammatory effects, anti-apoptotic activity, and it can stimulate neo-angiogenesis. Through its effect on cellular differentiation, it can inhibit the proliferation and function of immune cells (B and T lymphocytes, dendritic cells, natural killer cells, monocytes, neutrophils, and macrophages), leading to a shift of the immune system from Th1 toward Th2 responses.2,6 MSCs secrete anti-microbial peptides, LL-37 and Lipocalin-2, which likely play a role in facilitating bacterial clearance.5

MSC has been shown to attenuate acute lung injury from influenza in a pig model and to alleviate inflammation and mortality associated with Japanese encephalitis virus in a mouse model. It has enhanced immune reconstitution in people with human immunodeficiency virus.7 There are improved disease-associated parameters in experimental acute respiratory distress syndrome (ARDS).3

There are many concerns about MSC as a form of treatment and efforts are underway to address them. Some of these concerns are standard nomenclature (mesenchymal stem cell versus mesenchymal stromal cell), good manufacturing standards, and quality control. The US FDA requires that the cultured cells be “minimally” manipulated to avoid procedures “that might alter the biological features of the cells.” These conditions of “minimal manipulation” need to be specified. There are reports of inadequate cell culture protocols, use of supplemented cell culture media, enzymatic treatment, and long-term cell expansion that are known to change the quality of MSCs. There may be heterogeneity in the quality of the human MSC product that is affected not only by the isolation and culture methods, but also by the age, genetic traits, and medical history of the donor. There have been note of discrepancies between the results of in vitro studies and clinical trials. Lastly, there is the potential for harm: (1) pro-tumorigenic effects, (2) immunosuppressed state, and (3) differentiation

into undesirable tissue (for example, MSC transplanted into heart tissue differentiating into noncardiac cells).5  Therefore, this form of treatment must be thoroughly studied first before clinical use.

Unfortunately, clinical trials that investigate the efficacy and safety of mesenchymal stem cell for COVID-19 patients are still limited. This rapid review summarizes the available evidence on the efficacy and safety of mesenchymal stem cell therapy in the management of patients with COVID-19.


METHODS

A literature search was done during the period May 1-4, 2020. Search words were terms and derivatives of the following: “coronavirus infections,” “coronavirus,” “novel coronavirus,” “NCOV,” "COVID-19,” severe acute respiratory syndrome coronavirus,” “SARS 2,” “SARS COV 2,” and “mesenchymal cell (Appendix 1).” Utilized websites included Pubmed, Google scholar, MedRxiv, clinical trials. gov, and WHO ITCRP websites. The articles were selected based on the following inclusion criteria:

•Population: COVID-19 patients of any age, with any co-morbidities, any severity

•Intervention: mesenchymal stem cell, any dose, any duration

•Comparator: placebo, any active control, no intervention

•Outcomes: clinical improvement, mortality, intensive care unit confinement, viral detection

•Study designs: meta-analysis, systematic review, randomized controlled trials (RCTs), non-randomized studies, observational studies (e.g. cohort, case-control, cross-sectional, case report, case series)

Critical appraisal was done using Painless Evidence- Based Medicine for clinical trials; Newcastle-Ottawa scale for observational cohort, and JBI Critical Appraisal checklist for case series.8,9,10


RESULTS

Characteristics of Included Studies

There were four studies that fulfilled the inclusion criteria. One was a systematic review which found no study fitting its inclusion requirements.11 The other three studies12-14 were all done in China. Details of the included studies are in Table 1.


Critical Appraisal

The overall level of methodological quality of the included studies was very low. The case report of Liang et al. and the pilot study of Leng et al both had high risk of bias.9,10 In the pilot study of Leng et al, there was no randomization of included subjects, no standardized timing of administration of MSC, incomplete description of the baseline characteristics of the included subjects, absence of

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Table 1. Characteristics of Included Studies

No.

Title/Author

Study design

Country

Population

Intervention

Comparison

Outcomes

Group(s)

Group(s)

 

 

 

 

 

 

1 Shu et al 202012

RCT,

China

Confirmed COVID-19

Human umbilical

Standard

Death, 28-day

 

 

open-label

 

with severe disease*

cord

therapy*,

 

 

Treatment

 

 

whose symptoms

mesenchymal

n=29

Worsened to critical

 

of Severe

 

 

were not alleviated

stem cells

 

Median time to clinical

 

COVID-19

 

 

after 7-10 days of

infusion group,

 

 

with human

 

 

standard therapy

2 x 106 cells/kg

 

improvement**, days

 

Umbilical Cord

 

 

 

weight over an

 

 

 

Mesenchymal

 

 

Exclusion: any kind of

hour (hUC-MSCs

 

Days to clinical improvement

 

Stem Cells

 

 

cancer, severe liver

group) and

 

Age <65 years

 

 

 

 

disease, known allergy

standard therapy*,

 

Age >65 years

 

 

 

 

or hypersensitivity

n=12

 

Day 7

 

 

 

 

to hUC-MSCs, and

 

 

 

 

 

 

other conditions that

 

 

Symptom relief

 

 

 

 

the clinician deems

 

 

Without Oxygen supplement

 

 

 

 

inappropriate for the

 

 

D28 clinical improvement

 

 

 

 

patient to participate.

 

 

2

Liang B 202013

Case report

China

Critical COVID-19

Standard treatment None

ICU confinement

 

 

 

 

with multi-organ

pre-hUCMSC*

 

Virus detection

 

Clinical

 

 

failure

Plus allogenic

 

 

 

remission of

 

 

 

hUCMSCs

 

 

 

a critically ill

 

 

 

produced under

 

 

 

COVID-19

 

 

 

GMP condition

 

 

 

patient treated

 

 

 

administered

 

 

 

by human

 

 

 

intravenously for

 

 

 

umbilical cord

 

 

 

three times (5×107

 

 

 

mesenchymal

 

 

 

cells each time) on

 

 

 

stem cells

 

 

 

D12, 15, 18 illness

 

 

3 Leng Z 2020 14

Non-

China

10 patients with

Standard therapy*

Standard

Primary safety data – infusional

 

 

randomized

 

confirmed COVID-19

plus MSC 1 × 106

therapy*,

and allergic reactions, secondary

 

Transplantation

trial

 

with no response to

cells/ kilogram of

placebo

infection and life-threatening

 

of ACE2-

 

 

standard therapy

weight infused

infusion

adverse events

 

Mesenchymal

 

 

Excluded- cancer,

in 40 min, n=7

n=3 severe

Primary efficacy data – cytokine

 

Stem Cells

 

 

critical COVID,

patients

COVID

levels, plasma C-reactive protein,

 

Improves the

 

 

participation in clinical

1 - critically severe

 

oxygen saturation

 

Outcome of

 

 

trial within 3 months

4 - severe

 

Secondary efficacy outcomes –

 

Patients with

 

 

 

2 - common

 

total lymphocyte count and

 

COVID-19

 

 

 

 

 

subpopulations, chest CT,

 

Pneumonia

 

 

 

 

 

respiratory rate, patient symptoms

*standard treatment:

Shu et al: antiviral and glucocorticoids for all patients, additional antibiotics, vasopressors, oxygen for some

Liang et al: lopinavir/ritonavir, inhalational interferon-α, 1 dose of oseltamivir, intravenous moxifloxacin, Xuebijing, methylprednisolone, immunoglobulins

Leng et al: not specified

**clinical improvement: defined as a two point-difference on a seven-category ordinal scale

blinding, and short period of observation for outcomes.10 In the RCT conducted by Shu et al, there was insufficient description of the randomization process, no mention of allocation concealment, no blinding, and a short period of observation for outcomes. The risk of bias for this study was low.11 Leng did not clearly describe what the standard treatment was for the included patients. (Appendix 2)

Aside from these validity issues, applicability of the results to the Philippine setting is a logistical issue because of the high level of expertise required and the cost of the treatment.


Effectiveness Outcomes

Liang et al 2020 reported their experience in treating a 65-year old woman with critical COVID-19. The patient,

who was on an invasive tracheal cannula to assist respiration, improved remarkably and was stable enough to be transferred out of the ICU two days after completing three infusions of human UC-derived MSC. The tracheal cannula was removed after the second infusion. In addition, the throat swab turned negative for the virus two days after the last infusion.

Leng et al 2020 found that significant differences in IL-10 (p=0.0282) and TNF-α (p=0.0269) before-after serum level ratios were observed between the control group and the MSC group. The serum levels of chemokines like IP- 10 and growth factor VEGF were both increased, though not significantly. All 7 patients in the intervention group recovered or were discharged from the hospital in 1-3 days after MSC infusion, while in the control group, one died, one had ARDS, and one had stable severe disease.

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Shu et al described that none of 12 patients given hUC-MSC had clinical deterioration, while 4 of the 29 in the control group deteriorated (RR 0.65, 95% CI 0.10, 4.04) and three of them died (RR 0.84, 95% CI 0.14,

4.92). These were not statistically significant (p=0.667 and p=0.553, respectively). There was a significantly shorter length of hospital stay in the hUC-MSC group, in both ≤65 years (hUC-MSC: median 6 days, IQR 3 and 7 days, control: median 12 days, IQR 7.5 and 12.5 days) and >65 years old groups (hUC-MSC: median 13 days, IQR 11.75 and 14 days, control: median 23 days, IQR 18.5 and 29 days). On Day 7 post-infusion, 58% of the hUC-MSC group compared to 17% in the control group had symptom relief (RR 3.38, 95% CI [1.33, 8.57]). In addition, in the treatment group 66.66% were off oxygen supplementation compared to 10.34% in the control group (RR 6.44 [95% CI 2.05, 20.2]).

In the hUC-MSC treatment group, clinical symptoms of weakness and fatigue, shortness of breath, and low oxygen saturation improved beginning on the third day of stem cells infusion, and reached a significant difference on day 7 (p=0.02). Reduction in CRP and IL-6 and increase in lymphocyte count were significant beginning at Day 3 post-infusion and improvement in oxygen saturation significant from Day 7 post-infusion (p<0.001). Resolution of lung inflammation seen on CT imaging was also faster at 1 week and 2 weeks. However, on Day 28, over-all clinical improvement (RR 1.06, 95% CI [0.85, 1.33]) and mortality (RR 0.81, 95% CI [0.093, 6.99]) were not significantly different between the MSC and the control groups.


Safety Outcomes

Leng et al did not observe any infusion reactions or hypersensitivity during the course of hospitalization. Liang and Shu did not report the presence or absence of any adverse reactions during the short observation period of two weeks.

There are 52 registered and ongoing clinical trials investigating the efficacy and safety of MSC as treatment for COVID-19. (Appendix 3)


Recommendations from Other Guidelines

Mesenchymal stem cell therapy is not included in any guideline for the treatment of COVID-19.


CONCLUSION

There is insufficient evidence to support the use of MSC at the present time. Low-quality evidence suggests that human umbilical cord blood-derived MSC, when given to severe and critical COVID-19 patients after failure to

improve with standard treatment, may afford some beneficial effect in terms of earlier onset of clinical improvement. Outcomes for 28-day clinical improvement and mortality are not significantly different compared to standard treatment. There is no reported adverse reaction.

The efficacy and safety of MSC for COVID-19 need to be confirmed through randomized controlled trials, several of which are ongoing.


Declaration of Conflict of Interest

No conflict of interest.

REFERENCES

1.Wei X, Yang X, Han ZP, Qu FF, Shao L, Shi YF. Mesenchymal stem cells: a new trend for cell therapy. Acta Pharmacol Sin. 2013;34(6): 747–54.

2.Zhao RC. Stem cell-based therapy for coronavirus disease 2019. Stem Cells Dev. 2020; 29(11):679-81.

3.Lopes-Pacheco M, Robba C, Rocco PRM, Pelosi P. Current understanding of the therapeutic benefits of mesenchymal stem cells in acute respiratory distress syndrome. Cell Biol Toxicol. 2020; 36(1):83–102.

4.Jin Y, Yang H, Wangquan J, Wu W, Chen S, Zhang W, et al. Virology, epidemiology, pathogenesis, and control of COVID-19. Viruses. 2020; 12(4):372).

5.Lukomska B, Stanaszek L, Zuba-Surma E, Legosz P, Sarzynska S, Drela K. Challenges and controversies in human mesenchymal stem cell therapy. Stem Cells Int. 2019; 2019:9628536.

6.Saeedi P, Halabian R, Imani Fooladi AA. A revealing review of mesenchymal stem cells therapy, clinical perspectives and modification strategies. Stem Cell Investig. 2019; 6:34.

7.Al-Anazi K, Al-Anazi W, Al-Jasser A.  The rising role of mesenchymal stem cells in the treatment of various infectious complications.  DOI:  http://dx.doi.org/10.5772/intechopen.

91475.  IntechOpen  [Internet]. [cited 2020 May 1].  Available from:  https://www.intechopen.com/books/advanced-biometric- technologies/liveness-detection-in-biometrics

8.Timonera M, Aw M, Lim SG, Dans A, Dans L. Evaluation of articles on therapy. In: Dans A, Dans L, Silvestre MA (editors). Painless Evidence-based Medicine, 2nd edition. USA: Wiley; 2017.

9.Wells GA, Shea B, O'Connell D, Peterson J, Welch V, Losos M, et al. Newcastle-Ottawa Scale [Internet]. [cited 2020 May 1]. Available from: http://www.ohri.ca/programs/clinical_epidemiology/ oxford.htm

10.JBI Critical Appraisal Checklist for Case Series [Internet]. [cited 2020 May 1]. Available from: http://joannabriggs.org/research/ critical-appraisal-tools.html

11.Rada G, Corbalan J, Rojas P. Cell-based therapies for COVID-19: a living systematic review. medRxiv. 2020; 2020.04.24.20078667.

12.Shu L, Niu C, Li R, Huang T, Wang Y, Ji N, et al. Treatment of severe COVID-19 with human umbilical cord mesenchymal stem cells. April 29, 2020:1–21.

13.Liang S, Jiao HL, Chi LK, Shi XY, Liang AM, Tian Y, et al. Clinical remission of a critically ill COVID-19 patient treated by human umbilical cord mesenchymal stem cells. Chinese J Tissue Eng Res. 2020; 16(49):9179–85.

14.Leng Z, Zhu R, Hou W, Feng Y, Yang Y, Han Q, et al. Transplantation of ACE2-mesenchymal stem cells improves the outcome of patients with covid-19 pneumonia. Aging Dis. 2020; 11(2):216–28.

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APPENDICES

Appendix 1. Literature Search

Database

Search strategy / search terms

Date and time of search

Results

Yield

Eligible

 

 

 

Medline

"Coronavirus Infections"[MeSH] OR

May 1, 2020 12:10 PM

21

1

 

"Coronavirus"[MeSH] OR coronavirus OR

 

 

 

 

novel coronavirus OR NCOV OR "COVID-19"

 

 

 

 

[Supplementary Concept] OR covid19 OR covid 19

 

 

 

 

OR covid-19 OR "severe acute respiratory syndrome

 

 

 

 

coronavirus 2" [Supplementary Concept] OR severe

 

 

 

 

acute respiratory syndrome coronavirus 2 OR SARS2

 

 

 

 

OR SARS 2 OR SARS COV2 OR SARS COV 2 OR

 

 

 

 

SARS-COV-2

 

 

 

 

“mesenchymal cell”

 

 

 

Google Scholar

“COVID-19” and “MESENCHYMAL STEM CELL”

May 1, 2020 10:30 AM

9

0

ResearchGate

“COVID-19” and “MESENCHYMAL STEM CELL”

May 1, 2020 11:28 AM

6

2

Trial Registries

 

 

 

 

ClinicalTrials.gov

 

 

 

 

Chinese Clinical Trial Registry

“MESENCHYMAL STEM CELL”

May 4, 2020 1:00 AM

13

0

EU Clinical Trials Register

“COVID-19” and “MESENCHYMAL STEM CELL”

May 4, 2020 1:10 AM

1

0

Republic of Korea - Clinical Research

“COVID-19” and “MESENCHYMAL STEM CELL”

May 4, 2020 1:15 AM

0

—

Information Service

 

 

 

 

Japan Primary Registries Network /

“COVID-19” and “MESENCHYMAL STEM CELL”

May 4, 2020 1:18 AM

0

—

NIPH Clinical Trials Search

 

 

 

 

ICTRP Database (COVID-19 trials)

“MESENCHYMAL”

May 4, 2020 3:28 PM

37

0

Other databases

 

 

 

 

chinaxiv.org

“COVID-19” and “MESENCHYMAL STEM CELL”

May 1, 2020 10:55 PM

1

1

MedRxiv.org

“COVID-19” and “MESENCHYMAL STEM CELL”

May 1, 2020 11:05 PM

1

1

*standard treatment:

Shu et al: antiviral and glucocorticoids for all patients, additional antibiotics, vasopressors, oxygen for some

Liang et al: lopinavir/ritonavir, inhalational interferon-α, 1 dose of oseltamivir, intravenous moxifloxacin, Xuebijing, methylprednisolone, immunoglobulins

Leng et al: not specified

**clinical improvement: defined as a two point-difference on a seven-category ordinal scale

Appendix 2. Critical appraisal

Evaluation of Articles on therapy (Timonera M et al, 2017)

Appraisal Criteria

Shu L et al, 2020. Treatment of Severe COVID-19 with human Umbilical

 

Cord Mesenchymal Stem Cells.

Directness

YES

Randomization

UNCLEAR. “Randomization” was mentioned but not explicitly described.

Allocation concealment

NOT STATED

Similar baseline characteristics at the start of the trial

YES. Baseline characteristics did not show any statistically significant

 

differences between groups. There was noted clinical difference in number

 

of days from onset of illness to randomization (MSC: median 11.5 days,

 

IQR 6, 20 days versus control: median 14 days, IQR 10,18 days)

Blinding of patients

NO

Blinding of caregivers to treatment assignment

NO

Blinding of outcome assessors blinded to treatment assignment

NO

Analysis of patients in their original grouping

YES

Adequate follow-up rate

YES

Risk of Bias

High

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Newcastle-Ottawa Quality Assessment Scale for Cohort Studies (2019)

Journal

Leng et al 2020. Transplantation of ACE2- Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19

 

Pneumonia. 2020;11(2): 216-228.

 

Criterion

NPVD

EOS

Selection

1) Representativeness of the exposed cohort

1) Representativeness of the exposed cohort

 

a. Truly representative of the average ___ (describe) in the

a. Truly representative of the average ___ (describe) in the

 

community

community

 

b. Somewhat representative of the average ___ (describe)

b. Somewhat representative of the average ___ (describe)

 

in the community

in the community

 

c. Selected group of users (e.g. nurses, volunteers)

c. Selected group of users (e.g. nurses, volunteers)

 

d. No description of the derivation of the cohort

d. No description of the derivation of the cohort

 

2) Selection of the non-exposed cohort

2) Selection of the non-exposed cohort

 

a. Drawn from the same community as the exposed

a. Drawn from the same community as the exposed

 

cohort

cohort

 

b. Drawn from a different source

b. Drawn from a different source

 

c. No description of the derivation of the cohort

c. No description of the derivation of the cohort

 

3) Ascertainment of exposure

3) Ascertainment of exposure

 

a. Secure record

a. Secure record

 

b. Structured interview

b. Structured interview

 

c. Written self-report

c. Written self-report

 

d. No description

d. No description

 

4) Demonstration that outcome of interest was not present

4) Demonstration that outcome of interest was not present

 

at start of study

at start of study

 

a. Yes           b. No

a. Yes           b. No

Comparability 1) Comparability of cohorts on the basis of the design

1) Comparability of cohorts on the basis of the design

(maximum of 2

or analysis

or analysis

stars allotted in

a. Study controls for ____ (select the most important factor)

a. Study controls for ____ (select the most important factor)

this category)

b. Study controls for any additional factor (This criteria

b. Study controls for any additional factor (This criteria

 

could be modified to indicate specific control for a

could be modified to indicate specific control for a

 

second important factor.)

second important factor.)

Outcome

1) Assessment of outcome

1) Assessment of outcome

 

a. Independent blind assessment stated in the paper, or

a. Independent blind assessment stated in the paper, or

 

confirmation of the outcome by reference to secure

confirmation of the outcome by reference to secure

 

records (x-rays, medical records, etc.)

records (x-rays, medical records, etc.)

 

b. Record linkage (e.g. identified through ICD codes on

b. Record linkage (e.g. identified through ICD codes on

 

database records)

database records)

 

c. Self-report (i.e. no reference to original medical records

c. Self-report (i.e. no reference to original medical records

 

or x-rays to confirm the outcome)

or x-rays to confirm the outcome)

 

d. No description

d. No description

 

2) Was follow-up long enough for outcomes to occur

2) Was follow-up long enough for outcomes to occur

 

a. Yes           b. No

a. Yes           b. No

 

3) Adequacy of follow-up of cohorts

3) Adequacy of follow-up of cohorts

 

a. Complete follow-up — all subjects accounted for

a. Complete follow-up — all subjects accounted for

 

b. Subjects lost to follow-up unlikely to introduce bias —

b. Subjects lost to follow-up unlikely to introduce bias —

 

small number lost <20%

small number lost <20%

 

c. Follow-up rate < 80%

c. Follow-up rate < 80%

 

d. No description or unclear

d. No description or unclear

Joanna Briggs Institute Critical Appraisal Checklist for Case Reports

Reviewers: NPVD and EOS    Date: 23 May 2020

Journal: Liang et al 2020. Clinical remission of a critically ill COVID-19 patient treated by human umbilical cord mesenchymal stem cells.

 

 

Yes

No Unclear N/A

1.

Were patient’s demographic

 

characteristics clearly described?

 

 

 

 

2.

Was the patient’s history clearly

 

described and presented as a timeline?

 

 

 

 

3.

Was the current clinical condition of the

 

patient on presentation clearly described?

 

 

 

 

4.

Were diagnostic tests or assessment

 

methods and the results clearly described?

 

 

 

 

5.

Was the intervention(s) or treatment

 

procedure(s) clearly described?

 

 

 

 

 

 

Yes

No Unclear N/A

6.

Was the post-intervention clinical

 

condition clearly described?

 

 

 

 

7.

Were adverse events (harms)

 

or unanticipated events

 

 

 

 

 

identified and described?

 

 

 

 

7.

Does the case report provide

 

takeaway lessons?

 

 

 

 

Overall appraisal:  Include    Exclude    Seek further info

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Appendix 3. Characteristics of Registered and Ongoing Clinical Trials

 

 

 

 

 

 

 

 

 

Start and

 

 

 

 

 

 

No.

Clinical Trial ID / Title

Status

estimated primary

Study design

Country

Population

Intervention Group(s)

Comparison Group(s)

Outcomes

 

 

 

completion date

 

 

 

 

 

 

1

ChiCTR2000030173

Not

Feb 17, 2020 to

Interventional

China

Patients with signs

Umbilical cord mesenchymal

Conventional treatment

Pulmonary function; Novel coronavirus pneumonic nucleic acid test

 

 

Recruiting

Apr 17, 2020

study (Parallel)

 

and symptoms and

cells (Nt=30)

(Nc=30)

 

 

 

 

 

 

 

confirmed COVID-19;

 

 

 

 

 

 

 

 

 

informed consent

 

 

 

2

ChiCTR2000030116

Recruiting

Feb 1, 2020 to

Interventional

China

Patients 5-7 days in the

Different stem cell doses

Different stem cell

Time to leave ventilator on day 28 after receiving MSCs infusion

 

 

 

Aug 31, 2020

study (Dose

 

ICU, with ARDS needing

 

doses

 

 

 

 

 

comparison)

 

intubation, primary disease

 

 

 

 

 

 

 

 

 

caused by NCoV infection;

 

 

 

 

 

 

 

 

 

imaging shows bilateral lung

 

 

 

 

 

 

 

 

 

lesions, informed consent

 

 

 

3

ChiCTR2000030138

Not

Feb 24, 2020 to

Interventional

China

Patients with confirmed

Intravenous hUCMSC

Routine treatment +

Clinical index

 

 

Recruiting

May 31, 2020

study (Parallel)

 

COVID-19 (RT-PCR and

 

placebo

 

 

 

 

 

 

 

imaging of pneumonia);

 

 

 

 

 

 

 

 

 

informed consent

 

 

 

4

ChiCTR2000030088

Not

Mar 1, 2020 to

Interventional

China

Confirmed critical cases of

Wharton's Jelly mesenchymal

Saline

Nucleic acid of the novel coronavirus is negative;CT scan of ground glass shadow

 

 

Recruiting

Dec 31, 2020

study (Parallel)

 

NCoV pneumonia

stem cells (1x106/kg)

 

disappeared

5

ChiCTR2000030020

Recruiting

Feb 6, 2020 to

Case Series

China

Confirmed critical cases of

Mesenchymal stem cell therapy

—

Coronavirus nucleic acid markers negative rate (primary); trough and peak of FEV1

 

 

 

Feb 5, 2022

 

 

NCoV pneumonia or COVID

 

 

(secondary)

 

 

 

 

 

 

suspect based on panel

 

 

 

6

ChiCTR2000029990

Recruiting

Jan 1, 2020 to

Interventional

China

Patients with confirmed

Mesenchymal stem cell

Saline

Improved respiratory system function (blood oxygen saturation) recovery time

 

 

 

Mar 31, 2020

study (Parallel)

 

COVID-19 (RT-PCR and

 

 

(primary)

 

 

 

 

 

 

imaging of pneumonia);

 

 

 

 

 

 

 

 

 

moderate to severe cases

 

 

 

 

 

 

 

 

 

of NCoV pneumonia;

 

 

 

 

 

 

 

 

 

informed consent

 

 

 

7

ChiCTR2000030261

Not

Feb 28, 2020 to

Interventional

China

Patients with confirmed

Inhaled mesenchymal

—­

Lung CT (primary), nucleic acid, Leukocytes and lymphocytes in blood routine

 

 

Recruiting

May 31, 2020

study (Parallel)

 

COVID-19 (symptoms, RT-

stem cell exosomes

 

(secondary)

 

 

 

 

 

 

PCR, exposure within 14

 

 

 

 

 

 

 

 

 

days from symptoms onset)

 

 

 

8

ChiCTR2000029580

Recruiting

Jan 1, 2020 to

Interventional

China

Confirmed critical cases of

Ruxolitinib combined with

Routine treatment

Safety

 

 

 

Dec 31, 2020

study (Parallel)

 

NCoV pneumonia or COVID

mesenchymal stem cell

 

 

 

 

 

 

 

 

suspect; informed consent

 

 

 

9

ChiCTR2000030866

Recruiting

Feb 1, 2020 to

Open-label,

China

Confirmed critical cases of

Intravenous infusion

—

Mortality in serious and critical patients (primary)

 

 

 

Dec 31, 2020

observational

 

NCoV pneumonia or COVID

of MSC based on

 

 

 

 

 

 

study

 

suspect; informed consent

conventional treatments

 

 

10

ChiCTR2000030835

Recruiting

Feb 14, 2020 to

Single arm

China

Confirmed critical cases

Routine Treatment plus

Routine Treatment +

Serious Adverse Events (primary)

 

 

 

Feb 14, 2021

interventional

 

of NCoV pneumonia.

High dose MSC

Low dose MSC

DRP (secondary)

 

 

 

 

study

 

Severe pneumonia.

(2x106/kg per infusion)

(1x106/kg per infusion)

 

 

 

 

 

 

 

Informed consent

 

 

 

11

ChiCTR2000030224

Not

Feb 14, 2020 to

Interventional

China

Critical and severe patients

mesenchymal stem cells

Nomral saline

SP02; lesions of lung CT; temperature; Blood routine; Inflammatory biomarkers;

 

 

Recruiting

May 31, 2020

study (Parallel)

 

 

 

 

 

12

ChiCTR2000031319

Not

Apr 1, 2020 to

Randomized

China

Patients with confirmed

Routine treatment plus IV

Routine treatment plus

TTCI

 

 

Recruiting

Jul 31, 2020

Clinical Trial

 

COVID-19 (symptoms,

human dental pulp stem cells

placebo

 

 

 

 

 

 

 

RT-PCR and imaging of

 

 

 

pneumonia); severe cases of NCoV pneumonia; informed consent

13 ChiCTR2000031430

Recruiting Mar 14, 2020 to

Non-randomized China

Patients with confirmed

 

Dec 31, 2021

case control

COVID-19. High-

 

 

study

resolution CT indicates

 

 

 

interstitial injures in

 

 

 

the lungs (honeycomb

 

 

 

shadows or grid shadows).

 

 

 

Informed consent

Conventional treatment

Conventional treatment

Electrocardiogram; St George's Respiratory Questionnaire Score; High resolution

regimen plus MSC treatment

regimen

CT for chest; Blood gas analysis; Percutaneous blood oxygen saturation; 6 min

 

 

walking distance; Pulmonary function VCmax; Blood routine; Liver and kidney

 

 

function; Cytokine analysis; Immunoglobulin; Lymphocyte subsets; Coagulation;

 

 

Myocardial enzymes; Serum ferritin; Procalcitonin; IL-6; Lactic acid; D-Dimer; CRP

14 EUCTR2019-002688-89-ES

Ongoing

Jul 26,

2019 to

Phase I/II

Spain

Patients with moderate

 

 

Jul 26,

2020

randomized

 

to severe ARDS. With

 

 

 

 

control

 

invasive mechanical

 

 

 

 

 

 

ventilation (included

 

 

 

 

 

 

COVID-19 patients)

HCR040, a drug whose

placebo

Adverse events, average stay in ICU (primary)

active substance is HC016

 

 

(allogeneic adipose-derived

 

 

adult mesenchymal stem cells)

 

 

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Should Mesenchymal Stem Cell Therapy be used in the treatment of COVID-19?

 

 

Should Mesenchymal Stem Cell Therapy be used in the treatment of COVID-19?

 

 

 

Start and

 

 

 

 

 

 

No.

Clinical Trial ID / Title

Status

estimated primary

Study design

Country

Population

Intervention Group(s)

Comparison Group(s)

Outcomes

 

 

 

completion date

 

 

 

 

 

 

15

EUCTR2020-001682-36-ES

Ongoing

Apr 14, 2020 to

Double-blind,

Spain

Patients with SARS-CoV-2

allogeneic mesenchymal stem

placebo

Patients weaned off mechanical ventilation in less than 7 days after IMP

 

 

 

Apr 14, 2021

placebo-

 

infection confirmed

cells (MSV®-allo)

 

administration. Survival rate at Day 28. (primary)

 

 

 

 

controlled phase

 

by molecular testing.

 

 

1. Time to recovery after MSV-allo administration

 

 

 

 

I/II

 

Admitted to ICU for

 

 

2. Time to normal imaging 3. Modification in the inflammatory response (labs) 3.

 

 

 

 

 

 

severe pneumonia.

 

 

Modification in leukocytes and lymphocyte populations. 5. Safety, tolerability and

 

 

 

 

 

 

 

 

 

immunogenicity profiles

16

EUCTR2020-001266-11-ES

Ongoing

Apr 16, 2020 to

Two-center,

Spain

COVID-19 (by RT-PCR) in

Allogeneic mesenchymal stromal

Placebo

Survival rate at Day 28. Days to normalization of body temp. Days until

 

 

 

Apr 16, 2021

randomized,

 

respiratory failure requiring

cells isolated from adipose tissue

 

patient was extubated. and laboratory (primary). Days ICU / hospitatlization /

 

 

 

 

control

 

mechanical ventilation

 

 

oxygen therapy.

17

IRCT20140911019125N6

Recruiting

Apr 4, 2020 to

Phase II single

Iran

Patients with COVID-19

Conventional medications

—

Pulmonary condition, RNA expression of COVID19 virus, Lymphocytes count,

 

 

 

Jul 10, 2020

arm, not

 

pneumonia

plus dental pulp mesenchymal

 

Study of clinical signs on Days 14 and 28.

 

 

 

 

randomized,

 

 

stem cells

 

 

 

 

 

 

community-

 

 

 

 

 

 

 

 

 

based, open label

 

 

 

 

 

18

IRCT20140528017891N8

Not

Mar 24, 2020 to

Phase III, parallel

Iran

Patients with acute form

Routine medication plus initial

Routine medication plus

Death, Pneumonia severity index, Oxygenation Index, CRP Procalcitonin,

 

 

Recruiting

Apr 13, 2020

RCT double blind

 

of COVID-19 confirmed

dose of 0.5–1 million / kg of

placebo

Lymphocyte count, CD3 +, CD4 + and CD8 + T cells count,

 

 

 

 

 

 

by RT-PCR and HRCT

MSC on Days 1, 3 and 6 (3 doses)

 

Improved pneumonia using CT scan up to Day 28

19

IRCT20200325046860N2

Trial ended

Mar 28, 2020 to

Phase I

Iran

Patients with confirmed

Conventional medications plus

Conventional

Respiratory function of patients (every 24 hours after MSC infusion)

 

 

 

Apr 29, 2020

 

 

COVID-19 pneumonia

MSC on Days 1, 3 and 6 (3 doses)

medications plus

 

 

 

 

 

 

 

(symptoms, chest CT). No

 

placebo

 

 

 

 

 

 

 

improvement in next 48 h.

 

 

 

20 IRCT20200217046526N1

Trial ended Mar 15, 2020 to

Phase I and II,

Iran

 

Apr 25, 2020

non-controlled

 

 

 

non-randomized

 

Confirmation of 2019- nCoV infection by RT- PCR Diagnosis of ARDS. Pneumonia via symptoms and imaging. Mild to Moderate 2019-nCoV pneumonia/ stay in the ICU <48 hours SOFA score between 2-3 point

Conventional medications plus — mesenchymal stem cells on Days 1, 3 and 6 (3 doses)

Adverse events assessed 24 hours after each intervention, on days 6, 7, 14 and 28 after the first intervention.

21

EUCTR2020-001364-29

Ongoing

Apr 20, 2020

Phase I/II

Spain

Severe COVID-19

Allogenic adipose tissue-derived

Hydroxychloroquine

Adverse Events and Serious Adverse Events. Reduction of the SARS-CoV-2 viral

 

 

 

 

 

 

pneumonia

mesenchymal stem cells (2 doses)

+ Azithromycin or

load by PCR on days 6 and 15.Mortality at day 15, 28. Proportion of patients

 

 

 

 

 

 

 

 

Lopinavir / ritonavir

in categories 5, 6 or 7 of the ordinal scale of 7 points on days 15 and 28 days.

 

 

 

 

 

 

 

 

+ Interferon β-1b +

Proportion of patients needing rescue therapy (Tocilizumab, corticosteroids, or

 

 

 

 

 

 

 

 

Hydroxychloroquine

therapies under investigation in clinical trials). Time to get an improvement in a

 

 

 

 

 

 

 

 

 

category since admission to the ordinal scale.

22

NCT04315987

Not yet

Apr 20

Single Group

Sao Paulo, Brazil

COVID-19 Pneumonia

NestCell®

none

Change in Clinical Condition

 

HOPE

recruiting

Jun 20

Assignment,

 

 

 

 

Rate of mortality, 10days

 

 

 

 

Open Label

 

 

 

 

Change of Clinical symptoms - respiratory rate, Hypoxia, PaO2 / FiO2 ratio, CD4+

 

 

 

 

 

 

 

 

 

and CD8+ T cell count

 

 

 

 

 

 

 

 

 

Changes of blood oxygen

 

 

 

 

 

 

 

 

 

Side effects in the treatment group

 

 

 

 

 

 

 

 

 

Complete blood count, cardiac, hepatic and renal profiles

23

NCT04252118

Recruiting

Jan 27, 2020

Non-Randomized

Beijing, China

COVID-19

MSCs

none

Size of lesion area by chest radiograph or CT

 

2020003D

 

Dec 21

Open Label

 

 

 

 

Side effects in the MSCs treatment group

 

 

 

 

 

 

 

 

 

Improvement of Clinical symptoms including duration of fever and respiratory

 

 

 

 

 

 

 

 

 

Time of nucleic acid turning negative

 

 

 

 

 

 

 

 

 

Rate of mortality within 28-days

 

 

 

 

 

 

 

 

 

CD4+ and CD8+ T celll count, ALT, CRP, Creatine kinase

24

NCT04366323

Not yet

Apr 20

Randomized

 

Sars-CoV2

Allogeneic, expanded adipose

 

Safety - Adverse Event Rate

 

AdiQure/COVID-19

recruiting

Oct 21

Parallel

 

 

tissue-derived MSC

 

Efficacy- Survival Rate

 

 

 

 

Open Label

 

 

 

 

 

25

NCT04313322

Recruiting

Mar 16, 2020

Single Group

Amman, Jordan

Use of Stem Cells for

WJ-MSCs

none

Clinical outcome

 

COVID-19

 

Sep 30, 2020

Assignment

 

COVID-19 Treatment

 

 

CT Scan

 

 

 

 

Open Label

 

 

 

 

RT-PCR results

26

NCT04336254

Recruiting

Apr 6, 2020

Randomized

Wuhan, Hubei,

COVID-19

allogeneic human dental

Intravenous saline

TTCI

 

2020K-G005 | hDPSC-

 

Mar 31, 2021

Parallel

China

 

pulp stem cells (BSH BTC &

injection (Placebo)

Lung lesion

 

CoVID-2019-02-2020

 

 

Assignment

 

 

Utooth BTC) |

 

Immune function

 

 

 

 

Triple blind

 

 

 

 

Time of SARS-CoV-2 clearance

 

 

 

 

 

 

 

 

 

Blood test, SPO2, C-reactive protein (mg/L)

 

 

 

 

 

 

 

 

 

RR, Body temperature

 

 

 

 

 

 

 

 

 

Side effects in the treatment group

94

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Should Mesenchymal Stem Cell Therapy be used in the treatment of COVID-19?

 

 

 

Should Mesenchymal Stem Cell Therapy be used in the treatment of COVID-19?

 

 

 

Start and

 

 

 

 

 

 

 

 

No.

Clinical Trial ID / Title

Status

estimated primary

Study design

Country

Population

 

Intervention Group(s)

Comparison Group(s)

Outcomes

 

 

 

 

completion date

 

 

 

 

 

 

 

 

27

NCT04288102

Recruiting

Mar 5, 2020

Randomized

Wuhan, Hubei,

Corona Virus Disease

 

MSCs

Saline with 1% Human

Size of lesion area and severity of pulmonary fibrosis by chest CT

 

 

2020-013-D

 

Jul 31, 2020

Parallel

China

2019(COVID-19)

 

 

serum albumin

mMRC (Modified Medical Research Council) dyspnea scale

 

 

 

 

 

Assignment

 

 

 

 

 

Oxygenation Index(PaO2/FiO2)

 

 

 

 

 

Quadruple blind

 

 

 

 

 

Duration of oxygen therapy(days)

 

 

 

 

 

 

 

 

 

 

 

Duration of hospitalization(days)

 

 

 

 

 

 

 

 

 

 

 

Blood oxygen saturation

 

 

 

 

 

 

 

 

 

 

 

CD4+ T cell count and cytokine level

 

 

 

 

 

 

 

 

 

 

 

Side effects in the MSCs treatment group

 

 

 

 

 

 

 

 

 

 

 

6-minute walk test, Maximum vital capacity (VCmax), Diffusing Capacity (DLCO)

 

28

NCT04346368

Not yet

Apr 20

Randomized

Guangzhou,

Coronavirus Disease 2019

 

BM-MSCs

Placebo

Changes of Oxygenation Index (PaO2/FiO2)

 

 

SC-2020-01

recruiting

Dec 20

Parallel

Guangdong,

(COVID-19)

 

 

 

Side effects in the BM-MSCs treatment group

 

 

 

 

 

Assignment

China

 

 

 

 

Clinical outcome, Hospital stay

 

 

 

 

 

Single blind

 

 

 

 

 

CT Scan

 

 

 

 

 

(Participant)

 

 

 

 

 

Changes in viral load

 

 

 

 

 

 

 

 

 

 

 

Changes of CD4+, CD8+ cells count and concentration of cytokines,

 

 

 

 

 

 

 

 

 

 

 

Changes of C-reactive protein

 

 

 

 

 

 

 

 

 

 

 

Rate of mortality within 28-days

 

29

NCT04273646

Not yet

Apr 20, 2020

Randomized

Wuhan, Hubei,

2019 Novel Coronavirus

 

UC-MSC

Placebo

Pneumonia severity index

 

 

202001

recruiting

Feb 15, 2022

Parallel

China

Pneumonia | COVID-19

 

 

 

Oxygenation Index (PaO2/FiO2)

 

 

 

 

 

Assignment

 

 

 

 

 

Side effects in the UC-MSCs treatment group

 

 

 

 

 

Open Label

 

 

 

 

 

28-days survival

 

 

 

 

 

 

 

 

 

 

 

Sequential organ failure assessment

 

 

 

 

 

 

 

 

 

 

 

C-reactive protein, Procalcitonin, Lymphocyte count,CD3+, CD4+ and

 

 

 

 

 

 

 

 

 

 

 

CD8+ T cell count, CD4+/CD8+ratio

 

30

NCT04348435

Enrolling by

Apr 23, 2020

Randomized

Texas, United

COVID-19

 

HB-adMSCs

Placebos

Incidence of hospitalization for COVID-19

 

 

Allogeneic COVID-19 Protection

invitation

Apr 30, 2021

Parallel

States

 

 

 

 

Incidence of symptoms

 

 

 

 

 

Assignment

 

 

 

 

 

Absence of upper/lower respiratory infection

 

 

 

 

 

Quadruple blind

 

 

 

 

 

Laboratory tests, inflammatory markers

 

 

 

 

 

 

 

 

 

 

 

Cytokine levels- TNF alpha, IL-6, IL-10, SF-36, PHQ-9

 

31

NCT04366063

Recruiting

Apr 5, 2020

Randomized

Tehran, Iran

Covid-19

 

Cell therapy

 

Adverse Events assessment

 

 

991919 |

 

Dec 10, 2020

Parallel

 

 

 

 

 

Blood oxygen saturation

 

 

IRCT20200217046526N2

 

 

Assignment

 

 

 

 

 

Intensive care unit-free days

 

 

 

 

 

Open Label

 

 

 

 

 

Clinical symptoms

 

 

 

 

 

 

 

 

 

 

 

Respiratory efficacy

 

 

 

 

 

 

 

 

 

 

 

Biomarkers concentrations in plasma

 

32

NCT04382547

Not yet

May 11, 2020

Non-Randomized

Minsk, Belarus

COVID | Covid-19 |

 

Allogenic pooled

Standard treatment

Number of cured patients

 

 

IBCE_MSC2(Covid)

recruiting

Jun 30, 2021

Parallel

 

Coronavirus | Pneumonia

 

olfactory mucosa-derived

according to the

Number of patients with treatment-related adverse events

 

 

 

 

 

Assignment

 

| Pneumonia Viral |

 

mesenchymal stem cells

clinical protocols

 

 

 

 

 

 

Open Label

 

Pneumonia, Interstitial

 

 

 

 

 

 

 

 

 

 

 

| Sars-CoV2

 

 

 

 

 

33

NCT04339660

Recruiting

Feb 1, 2020

Randomized

Wuhan, Hubei,

COVID-19

 

UC-MSCs

Placebo

Cytokine levels- TNF, IL-1, IL-6, TGF, IL-8, TGF-beta

 

 

Pr20200402

 

Jun 30, 2020

Parallel

China

 

 

 

 

CRP, Peripheral blood count

 

 

 

 

 

Assignment

 

 

 

 

 

Blood oxygen saturation

 

 

 

 

 

Triple blind

 

 

 

 

 

Rate of mortality within 28-days

 

 

 

 

 

 

 

 

 

 

 

Size of lesion by chest imaging

 

 

 

 

 

 

 

 

 

 

 

CD4+ and CD8+ T cells count; Recovery time

 

 

 

 

 

 

 

 

 

 

 

Duration of respiratory symptoms (fever, dry cough, difficulty breathing, etc.)

 

 

 

 

 

 

 

 

 

 

 

COVID-19 nucleic acid negative time

 

34

NCT04349631

Enrolling by

May 7, 2020

Single Group

Texas, United

COVID-19

 

HB-adMSCs

none

Incidence of hospitalization for COVID-19

 

 

Protection Against COVID-19

invitation

Dec 31, 2020

Assignment

States

 

 

 

 

Incidence of symptoms for COVID-19

 

 

 

 

 

Open Label

 

 

 

 

 

absence of upper/lower respiratory infection

 

 

 

 

 

 

 

 

 

 

 

Laboratory tests

 

 

 

 

 

 

 

 

 

 

 

Cytokine levels- TNF alpha, IL-6, IL-10

 

 

 

 

 

 

 

 

 

 

 

C-reactive protein

 

 

 

 

 

 

 

 

 

 

 

SF-36, PHQ-9

 

35

NCT04352803

Not yet

Apr 20

Non-Randomized

 

Covid-19 Pneumonia |

 

Autologous Adipose MSC's

none

Safety - Incidence of unexpected adverse events

 

 

COVID-MSCIV

recruiting

Apr 26

Sequential

 

Cyotokine Storm

 

 

 

Efficacy - Frequency of progression to mechanical ventilation, Changes in length

 

 

 

 

 

Assignment Open

 

 

 

 

 

of mechanical ventilation, Changes in length of weaning of mechanical ventilation,

 

 

 

 

Label

 

 

 

 

 

Changes in length of hospital stay, Changes in mortality rate

 

36

NCT04302519

Not yet

Mar 5, 2020

Non-randomized

 

COVID-19

 

Dental pulp mesenchymal

none

Disappearance time of ground-glass shadow in the lungs

 

 

KT005HB001

recruiting

Jul 30, 2021

Single Group

 

 

 

stem cells

 

Absorption of Lung shadow absorption by CT Scan-Chest

 

 

 

 

 

Assignment

 

 

 

 

 

Changes of blood oxygen

 

 

 

 

 

Open Label

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

96

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Should Mesenchymal Stem Cell Therapy be used in the treatment of COVID-19?

 

 

 

Should Mesenchymal Stem Cell Therapy be used in the treatment of COVID-19?

 

 

 

Start and

 

 

 

 

 

 

 

 

No.

Clinical Trial ID / Title

Status

estimated primary

Study design

Country

Population

 

Intervention Group(s)

Comparison Group(s)

Outcomes

 

 

 

 

completion date

 

 

 

 

 

 

 

 

37

NCT04355728

Recruiting

Apr 25, 2020

Randomized

Miami, Florida,

COVID-19 ARDS

 

Umbilical Cord

Standard of Care

Incidence of pre-specified infusion associated adverse events

 

 

20200370

 

May 1, 2021

Parallel

United States

 

 

Mesenchymal Stem Cells

 

Incidence of Severe Adverse Events

 

 

 

 

 

Assignment

 

 

 

 

 

Survival rate after 90 days post first infusion

 

 

 

 

 

Single blind

 

 

 

 

 

Ventilator-Free Days | Change in Oxygenation Index (OI)

 

 

 

 

 

(Outcomes

 

 

 

 

 

Plat-PEEP

 

 

 

 

 

Assessor)

 

 

 

 

 

Sequential Organ Failure Assessment (SOFA) Scores

 

 

 

 

 

 

 

 

 

 

 

Small Identification Test (SIT) scores

 

 

 

 

 

 

 

 

 

 

 

Troponin I levels | C-Reactive Protein levels | Arachidonic Acid (AA).

 

 

 

 

 

 

 

 

 

 

 

Eicosapentaenoic Acid (EPA) Ratio, D-dimer levels, 25-Hydroxy Vitamin D levels,

 

 

 

 

 

 

 

 

 

 

 

Alloantibodies levels, Blood white cell count, Platelets count

 

38

NCT04371601

Active, not

Mar 1, 2020

Randomized

Fujian, China

COVID-19 Pneumonia

 

Oseltamivir

 

Changes of Oxygenation Index (PaO2/FiO2),blood gas Detection of TNF-α levels,

 

MSC-CoViD-2020

recruiting

Dec 31, 2022

Parallel

 

 

 

Hormones

 

IL-10 levels

 

 

 

 

 

Assignment Open

 

 

 

Oxygen therapy

 

Detection of immune cells that secret cytokines, including CXCR3+, CD4+, CD8+,

 

 

 

 

Label

 

 

 

mesenchymal stem cells

 

NK+ cells, and regulatory T cells (CD4 + CD25 + FOXP3 + Treg cells).

 

 

 

 

 

 

 

 

 

 

 

Changes of c-reactive protein and calcitonin

 

39

NCT04366271

Recruiting

May 7, 2020

Randomized

Madrid, Spain

COVID

 

Mesenchymal cells

Standard of care

Mortality due to lung involvement due to SARS-CoV-2 virus infection at 28 days

 

 

MESCEL-COVID19 |

 

May 31, 2021

Parallel

 

 

 

 

 

of treatment; 14 days of treatment

 

 

2020-001450-22

 

 

Assignment

 

 

 

 

 

Mortality from any cause at 28 days

 

 

 

 

 

Open Label

 

 

 

 

 

Days without mechanical respirator and without vasopressor treatment for 28 days

 

 

 

 

 

 

 

 

 

 

Patients alive without mechanical ventilation and without vasopressors on day 28

 

 

 

 

 

 

 

 

 

 

Patients alive and without mechanical ventilation on day 14, 28

 

 

 

 

 

 

 

 

 

 

 

Patients alive, without vasopressors on day 28

 

 

 

 

 

 

 

 

 

 

 

Days without vasopressors for 28 days

 

 

 

 

 

 

 

 

 

 

 

Cured at 15 days

 

 

 

 

 

 

 

 

 

 

 

Incidence of Treatment Adverse Events

 

40

NCT04293692

Withdrawn

Feb 24, 2020

Randomized

Wuhan, Hubei,

COVID-19

 

UC-MSCs

Placebo

Size of lesion area by chest imaging

 

 

Pr20200225

 

Feb 25, 2020

Parallel

China

 

 

 

 

Blood oxygen saturation

 

 

 

 

 

Assignment

 

 

 

 

 

Rate of mortality within 28-days

 

 

 

 

 

Triple blind

 

 

 

 

 

Sequential organ failure assessment

 

 

 

 

 

 

 

 

 

 

 

Side effects in the UC-MSCs treatment group

 

 

 

 

 

 

 

 

 

 

 

Electrocardiogram, the changes of ST-T interval mostly

 

 

 

 

 

 

 

 

 

 

 

Concentration of C-reactive protein

 

 

 

 

 

 

 

 

 

 

 

Immunoglobulin, CD4+ and CD8+ T cells count

 

 

 

 

 

 

 

 

 

 

 

Concentration of the blood cytokine (IL-1β, IL-6, IL-8,IL-10,TNF-α),

 

 

 

 

 

 

 

 

 

 

 

Concentration of the myocardial enzymes

 

41

NCT04362189

Not yet

May 15, 2020

Randomized

Houston, Texas,

COVID-19

 

HB-adMSC

Placebo

28-day mortality

 

 

Allogeneic Treatment COVID-19

recruiting

Oct 31, 2020

Parallel

United States

 

 

 

 

Invasive mechanical ventilation

 

 

 

 

 

Assignment

 

 

 

 

 

Leukocyte differential, C Reactive protein

 

 

 

 

 

Quadruple blind

 

 

 

 

 

TNF alpha, IL-6

 

 

 

 

 

 

 

 

 

 

 

Blood chemistry

 

 

 

 

 

 

 

 

 

 

 

NK cell surface antigen (CD3-CD54+)

 

 

 

 

 

 

 

 

 

 

 

CD4+/CD8+ ratio

 

 

 

 

 

 

 

 

 

 

 

IL-10, VEGF, D-dimer, Myoglobin, Troponin, Creatinine kinase, Serum ferritin

 

42

NCT04377334

Not yet

May 20

Randomized

Tuebingen,

ARDS | COVID-19

 

MSC

 

lung injury score

 

 

RESCOVID

recruiting

Feb 21

Parallel

Germany

 

 

 

 

D-dimers, phenotype, pro-resolving lipid mediators

 

 

 

 

 

Assignment

 

 

 

 

 

cytokines | chemokines

 

 

 

 

 

Open Label

 

 

 

 

 

Survival, extubation, lymphocyte subpopulations

 

 

 

 

 

 

 

 

 

 

 

SARS-CoV-2-specific antibody titers

 

 

 

 

 

 

 

 

 

 

 

Complement molecules (C5-C9)

 

43

NCT04348461

Not yet

Apr 6, 2020

Randomized

 

COVID | Respiratory

 

Allogeneic and expanded

 

Efficacy- Survival Rate

 

 

BALMYS-19

recruiting

Sep 30, 2020

Parallel

 

Distress Syndrome

 

adipose tissue-derived

 

Safety- Adverse Event Rate

 

 

 

 

 

Assignment

 

 

 

mesenchymal stromal cells

 

 

 

 

 

 

 

Quadruple blind

 

 

 

 

 

 

 

44

NCT04371393

Recruiting

Apr 30, 2020

Randomized

United States

Mesenchymal Stromal

 

Remestemcel-L

Placebo

Number of all-cause mortality

 

 

GCO 08-1078-0014

 

Apr 22

Parallel

 

Cells Remestemcel-L

 

 

 

Number of days alive off mechanical ventilatory

 

 

 

 

 

Assignment

 

 

 

 

 

Adverse events

 

 

 

 

 

Triple blind

 

 

 

 

 

Alive at day 7, 14, 60, 90

 

 

 

 

 

 

 

 

 

 

 

With resolution and/or improvement of ARDS

 

 

 

 

 

 

 

 

 

 

 

Change from baseline of the severity of ARDS

 

 

 

 

 

 

 

 

 

 

 

Length of stay

 

 

 

 

 

 

 

 

 

 

 

Clinical Improvement Scale

 

 

 

 

 

 

 

 

 

 

 

Change in serum hs-CRP, IL-6, IL-8, TNF-alpha

 

 

 

 

 

 

 

 

 

 

 

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Should Mesenchymal Stem Cell Therapy be used in the treatment of COVID-19?

 

 

Should Mesenchymal Stem Cell Therapy be used in the treatment of COVID-19?

 

 

 

Start and

 

 

 

 

 

 

No.

Clinical Trial ID / Title

Status

estimated primary

Study design

Country

Population

Intervention Group(s)

Comparison Group(s)

Outcomes

 

 

 

completion date

 

 

 

 

 

 

45

NCT04345601

Not yet

May 20

Single Group

Houston, Texas,

Sars-CoV2

Mesenchymal Stromal Cells

none

Incidence of unexpected adverse events

 

H-47561 MSC for COVID-19

recruiting

Feb 22

Assignment

United States

Acute Respiratory Distress

 

 

Improved oxygen saturations

 

 

 

 

Open Label

 

Syndrome

 

 

Decrease in oxygen supplementation by non-invasive or invasive interventions

 

 

 

 

 

 

COVID-19

 

 

Frequency of progression to mechanical ventilation or ECMO

 

 

 

 

 

 

 

 

 

Duration of mechanical ventilation, ICU stay, hospital stay

 

 

 

 

 

 

 

 

 

All-cause mortality at day 28

46

NCT04361942

Recruiting

Apr 20

Randomized

Valladolid, Spain

COVID-19 Pneumonia

Mesenchymal Stromal Cells

Placebo

Proportion of patients who have achieved withdrawal of invasive mechanical

 

TerCel_007 | 2020-001682-36

 

Dec 31, 2020

Parallel

 

 

 

 

ventilation

 

 

 

 

Assignment

 

 

 

 

Rate of mortality

 

 

 

 

Triple blind

 

 

 

 

Proportion of patients who have achieved clinical response

 

 

 

 

 

 

 

 

 

Proportion of patients who have achieved radiological responses

47

NCT03042143

Recruiting

Jan 7, 2019

Randomized

Belfast,

Acute Respiratory Distress

Human umbilical cord derived

Placebo

Oxygenation Index (OI)

 

16154DMcA-AS

 

Oct 22

Parallel

Northern

Syndrome

CD362 enriched MSCs

(Plasma-Lyte 148)

Incidence of Serious Adverse Events (SAEs)

 

 

 

 

Assignment

Ireland, United

 

 

 

Oxygenation Index | Sequential Organ Failure Assessment (SOFA) score

 

 

 

 

Quadruple blind

Kingdom

 

 

 

Respiratory compliance

 

 

 

 

 

 

 

 

 

Partial pressure of arterial oxygen to the fraction of inspired oxygen ratio (P/F ratio)

 

 

 

 

 

 

 

 

 

Driving Pressure

 

 

 

 

 

 

 

 

 

Extubation, reintubation

 

 

 

 

 

 

 

 

 

Ventilation free days at day 28, ICU and hospital stay, 28-& 90-day mortality

48

NCT04269525

Recruiting

Feb 6, 2020

Single Group

Wuhan, Hubei,

Viral

UC-MSCs

none

Oxygenation Index

 

2020002

 

Sep 30, 2020

Assignment

China

Pneumonia

 

 

28 day mortality

 

 

 

 

Open Label

 

 

 

 

Hospital stay

 

 

 

 

 

 

 

 

 

2019-nCoV nucleic acid test, Improvement of lung imaging, WBC, Lymphocyte

 

 

 

 

 

 

 

 

 

count and %, Procalcitonin

 

 

 

 

 

 

 

 

 

interleukin(IL)-2,IL-4IL-6IL-8, IL-10, TNF

 

 

 

 

 

 

 

 

 

interferon(IFN)

49

NCT04333368

Recruiting

Apr 6, 2020

Randomized

Paris, France

Severe Acute Respiratory

Umbilical cord Wharton's

NaCl 0.9%

Respiratory efficacy evaluated by the increase in PaO2/FiO2 ratio from baseline

 

APHP200395 | 2020-001287-28

 

Jul 31, 2021

Parallel

 

Syndrome Coronavirus 2

jelly-derived human

 

to day 7, Lung injury score, Oxygenation Index

 

 

 

 

Assignment

 

Severe Acute Respiratory

 

 

In-hospital mortality, Total mortality

 

 

 

 

Triple blind

 

Distress Syndrome

 

 

Ventilator-free days

 

 

 

 

 

 

 

 

 

Number of days between randomization and the first day the patient

 

 

 

 

 

 

 

 

 

meets weaning criteria/first day the patient meets PaO2/FiO2 > 200

 

 

 

 

 

 

 

 

 

(out of a prone positioning session), Cumulative use and duration of sedatives,

 

 

 

 

 

 

 

 

 

neuromuscular blockers

 

 

 

 

 

 

 

 

 

ICU-acquired weakness and delirium

 

 

 

 

 

 

 

 

 

Treatment-induced adverse events till D28

 

 

 

 

 

 

 

 

 

Quality of life at one year (EQ5D-3L)

 

 

 

 

 

 

 

 

 

Plasma cytokines (IL1, IL6, IL8, TNF-alpha, IL10, TGF-beta, sRAGE, Ang2)

 

 

 

 

 

 

 

 

 

Anti-HLA antibodies plasmatic dosage

50

NCT04299152

Not yet

May 10, 2020

Randomized

 

Severe Acute Respiratory

Stem Cell Educator-Treated

 

Number of Covid-19 patients unable to complete SCE Therapy

 

2020-TH-001

recruiting

Nov 10, 2020

Parallel

 

Syndrome (SARS)

Mononuclear Cells Apheresis

 

Percentage of activated T cells, Th17 after SCE

 

 

 

 

Assignment

 

Pneumonia

 

 

Chest CT imaging changes

 

 

 

 

Single blind

 

 

 

 

Quantification of SARS-CoV-2 viral load (real time RT-PCR)

51

NCT04341610

Not yet

Apr 20, 2020

Randomized

Copenhagen,

Respiratory Tract Diseases

Stem Cell Product

 

Changes in clinical critical treatment index

 

EudraCT number:

recruiting

Apr 30, 2021

Parallel

Denmark

 

 

 

Days of respirator use

 

2020-001330-36

 

 

Assignment,

 

 

 

 

Improvement of clinical symptoms, Mortality

 

 

 

 

Quadruple blind

 

 

 

 

CD4+ and CD8+ T cell count, Cytokine profile

 

 

 

 

 

 

 

 

 

CRP, WBC, Glomerular Filtration Rate, Duration of hospitalization

52

NCT04276987

Not yet

Feb 15, 2020

Single Group

 

Coronavirus

MSCs-derived exosomes

none

Adverse reaction

 

MEXCOVID

recruiting

Jul 31, 2020

Assignment

 

 

 

 

Severe adverse reaction

 

 

 

 

Open Label

 

 

 

 

Time to clinical improvement (TTIC)

 

 

 

 

 

 

 

 

 

# weaned from mechanical ventilation

 

 

 

 

 

 

 

 

 

Duration of ICU stay

Duration (days) of vasoactive agents usage

Duration (days) of mechanical ventilation

Number with improved organ failure

Rate of mortality

MSC- mesenchymal stem cell

100 ACTA MEDICA PHILIPPINA

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ACTA MEDICA PHILIPPINA 101

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