Covid-19 living Data

Umbilical cord mesenchymal stem cell infusion vs Standard care/Placebo (RCT)

Hospitalized patients

FOREST PLOTS -2022-04-03

Studies description

Trial NCT04457609
Publication Dilogo IH, Stem Cells Transl Me (2021) (published paper)
Dates: 2020-05-01 to 2020-10-10
Funding: Public/non profit (Ministry of Research and Technology/National Research and Innovation Agency Republic of Indonesia.)
Conflict of interest: No

Methods
	RCT Blinding: triple blinding
	Location : Multicenter / Indonesia Follow-up duration (days): *
Inclusion criteria	18-95 years critically ill patients intubated severe pneumonia pneumonia on chest x-ray and/or ground-glass opacity on thorax computed tomography (CT) scan postive RT-PCR bronchoalveolar lavage respiratory failure that progressed into ARDS, defined as the partial pressure of oxygen in arterial blood(PaO2)/the fraction of inspired oxygen (FiO2) lower than 300 mmHg supported by mechanical ventilation shock, such as septic shock (persistent hypotension following fluid resuscitation and requiring vasopressor to maintain mean arterial pressure of ≥65 mmHg and serum lactate of >2 mmol/L) multiple organ failure and monitored in the ICU leukopenia and lymphopenia in peripheral blood and differential count informed consent by subjects or family members
Exclusion criteria	History of malignancy pregnant or showed a positive pregnancy test history of or currently taking part in another clinical trial in the last 3 months
Interventions
	Treatment UC-MSC 1*10^6/kg IV, once-off
	Control Placebo
Participants
	Randomized participants : Placebo=20 UC-MSC=20
	Characteristics of participants N= 40 Mean age : NR 30 males Severity : Mild: n=0 / Moderate: n=0 / Severe: n=0 Critical: n=40
Primary outcome
	In the register Clinical improvement:Presence of dyspnea, presence of sputum, fever, ventilation status, blood pressure, heart rate, respiratory rate, oxygen saturation [Time Frame: 15 days]
	In the report mortality rate and length of ventilator usage
Documents avalaible	Protocol Yes. In English Statistical plan NR Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	*
General comment	This study is pending author reply. Time points outcomes were not clearly reported. In addition to the available version of the publication, the study registry and protocol were used in data extraction and risk of bias assessment. The study achieved the target sample size specified in the trial registry. There is no change from the trial registration in the intervention and control treatments. The registry primary outcome does not reflect the reported primary outcome. Some outcomes from the registry are not reported in the paper (e.g. clincal improvement).Some outcomes (e.g. mortality) are reported in the paper, but were not pre-specified in the trial registry. In the registry, the primary outcome is clinical improvement in the presence of dyspnea, presence of sputum, fever, ventilation status, blood pressure, heart rate, respiratory rate, and oxygen saturation. The follow-up time of study participants is unclear.

Trial NCT04355728
Publication Lanzoni G, Stem Cells Transl Me (2021) (published paper)
Dates: 2020-04-25 to 2020-07-21
Funding: Mixed (Ugo Colombo; Simkins Family Foundation; Fondazione Silvio Tronchetti Provera; Barilla Group & Family; Diabetes Research Institute Foundation; The Cure Alliance; NABTU; NCATS)
Conflict of interest: No

Methods
	RCT Blinding:
	Location : Single center / USA Follow-up duration (days): 60
Inclusion criteria	Patient currently hospitalized Aged ≥ 18 years Willing and able to provide written informed consent, or with a legal representative who can provide informed consent Peripheral capillary oxygen saturation (SpO2) ≤ 94% at room air, or requiring supplemental oxygen at screening PaO2/FiO2 ratio < 300 mmHg Bilateral infiltrates on frontal chest radiograph or bilateral ground glass opacities on a chest CT scan
Exclusion criteria	PaO2/FiO2 ≥ 300 at the time of enrollment A previous MSC infusion not related to this trial History of Pulmonary Hypertension (WHO Class III/IV) History of left atrial hypertension or decompensated left heart failure Pregnant or lactating patient Unstable arrhythmia Patients with previous lung transplant Patients currently receiving chronic dialysis Patients currently receiving Extracorporeal Membrane Oxygenation (ECMO) Presence of any active malignancy (except non-melanoma skin cancer) Any other irreversible disease or condition for which 6-month mortality is estimated to be greater than 50% Moderate to severe liver disease (AST and ALT >5 X ULN) Severe chronic respiratory disease with a PaCO2 > 50 mm Hg or the use of home oxygen Baseline QT prolongation Moribund patient not expected to survive > 24 hours
Interventions
	Treatment UC-MSC 100 +/- 20x10^6 in a 50 mL vehicle solution containing human serum albumin and heparin, infused at days 0 and 3
	Control Placebo
Participants
	Randomized participants : UC-MSC=12 Placebo=12
	Characteristics of participants N= 24 Mean age : NR 13 males Severity : Mild: n=0 / Moderate: n=0 / Severe: n=13 Critical: n=11
Primary outcome
	In the register Incidence of pre-specified infusion associated adverse events [ Time Frame: Day 5 ] Incidence of Severe Adverse Events [ Time Frame: 90 days ]
	In the report Safety, as defined by the occurrence of pre-specified infusion associated AEs, occurring within 6 hours from each infusion; Cardiac arrest or death within 24 h post infusion; Incidence of AEs
Documents avalaible	Protocol Yes. In English Statistical plan NR Data-sharing willing stated in the publication:
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the pre-print article, the trial registry and supplementary appendix as well as responses from contact with authors were used in data extraction and assessment of risk of bias. The study protocol was referenced in the paper but no date was provided to determine its prospective or retrospective nature and aid in the risk of bias assessment for the domain 'Selection of Reported Result'. There were no substantive differences between the pre-print article and the trial registry in population, procedures and interventions. There were some differences between the pre-print article and trial registry in secondary laboratory outcomes. On February 12th, 2021, we received additional information from authors on this study. This study was updated with data from contact with authors on March 30th, 2021.

Trial NCT04333368, EudraCT 2020-001287-28
Publication Monsel A, Crit Care (2022) (published paper)
Dates: 2020-04-06 to 2020-10-29
Funding: Public/non profit (French Ministry of Health and the French National Research Agency)
Conflict of interest: No

Methods
	RCT Blinding: triple blinding
	Location : Multicenter / France Follow-up duration (days): 28
Inclusion criteria	Age > 18 years reverse transcriptase–polymerase chain reaction -confirmed SARS–CoV-2 infection Berlin criteria-defined acute respiratory distress syndrome for < 96 h respiratory support (invasive or non-invasive mechanical ventilation, and/or high-flow nasal oxygenation) with positive end-expiratory pressure equivalent ≥ 5 cm H2O.
Exclusion criteria	Age < 18 years acute respiratory distress syndrome present for > 96 h pulmonary fibrosis pulmonary hypertension (WHO classification class III or IV) pulmonary embolism within the previous 3 months extracorporeal membrane oxygenation or life support immunocompromised status including use of immunosuppressive medications pregnancy or breastfeeding treatment for cancer in the past 2 years underlying medical condition with life expectancy < 6 months moderate-to-severe liver disease (Child–Pugh score > 12) severe chronic lung disease with the use of home oxygen and/or partial arterial pressure of carbon dioxide > 50 mm Hg patients not committed to full support (i.e., had do not resuscitate or limit life support orders) participation in another trial of COVID-19 therapeutics.
Interventions
	Treatment UC-MSC Three intravenous infusions of 10^6 UC-MSCs/kg (maximum dose set at 80 × 10^6 cells per infusion) or placebo on D1, D3 ± 1 and D5 ± 1.
	Control Placebo
Participants
	Randomized participants : UC-MSC=22 Placebo=25
	Characteristics of participants N= 47 Mean age : NR 37 males Severity : Mild: n=0 / Moderate: n=0 / Severe: n=14 Critical: n=31
Primary outcome
	In the register Respiratory efficacy evaluated by the increase in PaO2/FiO2 ratio from baseline to day 7 in the experimental group compared with the placebo group
	In the report Respiratory improvement assessed as the partial pressure of oxygen to fractional inspired oxygen (PaO2/FiO2)-ratio change between baseline (D0) and D7 post-randomization.
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Low
General comment	“In addition to the published article, the supplementary materials including protocol and study registry were used in data extraction and risk of bias assessment. There is no change from the trial registration in the intervention and control treatments. The registry primary outcome reflects the reported primary outcome. Some outcomes from the registry are not reported in the paper (but these are not relevant to our review). Adverse events reported separately for before and after Day 14, so only those up to Day 14 were extracted due to potential patient overlap. The study (n=47) did not achieve the target sample size (n=60) specified in the trial registry."

Trial NCT04288102
Publication Shi L, eBioMedicine (2022) (published paper)
Dates: 2020-03-05 to 2021-03-31
Funding: Public/non profit (The National Key R&D Program of China; The Innovation Groups of the National Natural Science Foundation of China; The National Science and Technology Major Project)
Conflict of interest: No

Methods
	RCT Blinding: double blinding
	Location : Multicenter / China Follow-up duration (days): 90
Inclusion criteria	severe COVID-19 diagnosed after onset of disease chest computed tomography (CT) imaging confirmed pneumonia combined with lung damage. The illness severity of COVID-19 was evaluated in accordance with Guidelines issued by the National Health Commission of China (version 7.0). Briefly, patients with any of the following conditions but without invasive ventilation, shock or other organ failure (need organ support therapy) were considered as severe cases: dyspnoea (respiratory rate ≥ 30 times/min) oxygen saturation of 93% or lower on room air arterial oxygen partial pressure (PaO2)/fraction of inspired oxygen (FiO2) ≤ 300 mmHg pulmonary imaging showing that the foci progressed by > 50% in 24-48 hours.
Exclusion criteria	Shock or COVID-19 combined with any one of other organ failures, those who received invasive ventilation, or patients with any malignant tumour, pregnancy or breastfeeding, or co-infection of other pathogens
Interventions
	Treatment hUC-MSC 4.0x10^7 MSCs in a volume of 100 mL, infused on days 0, 3 and 6.
	Control Placebo
Participants
	Randomized participants : hUC-MSC=66 Placebo=35
	Characteristics of participants N= 101 Mean age : NR 56 males Severity : Mild: n=24 / Moderate: n=75 / Severe: n=1 Critical: n=0
Primary outcome
	In the register Change in lesion proportion (%) of full lung volume from baseline to day 28
	In the report change in the total lesion proportion (%) of the whole lung volume from baseline to day 28, as measured by chest CT
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published/pre-print article, the trial registry, study protocol, supplementary materials and statistical analysis plan were used in data extraction and assessment of risk of bias. Originally planned as a Phase 1 study, the study progressed to Phase 2 with an expanded sample size due to satisfactory assessment of safety. The study exceeded its original and amended sample sizes. Changes were made to primary outcome measure in the trial registry both during and after study conduct, but this is reported along with the reasons in the pre-print article. Some outcomes from the registry/protocol are not reported in the paper (e.g., time to clinical improvement). This study was updated on March 19th, 2021 using data from the published manuscript (Signal Transduction). This study was updated on March 22nd, 2022 using 1-year follow-up data from the published manuscript (eBioMedicine)

Trial ChiCTR2000031494
Publication Shu L, Stem Cell Res Ther (2020) (published paper)
Dates: 12/02/2020 to 25/03/2020
Funding: Public/non profit (National Natural Science Foundation of China; Key Research and Development Project of Jiangsu Province)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Single center / China Follow-up duration (days): 28
Inclusion criteria	Report: In general, patients with severe COVID-19 whose clinical symptoms were not significantly alleviated under standard treatment for 7 to 10 days were recommended for participation in this pilot study. Registry: (1) Aged 18 to 90 years old, male or female (2) Patients with a definite diagnosis of new type of coronavirus pneumonia (3) Expected survival time > 10 days (4) Serology: HIV antibody negative hepatitis B surface antigen, e antigen negative hepatitis C antibody negative female patients with negative pregnancy test ALT, AST <=2.5 ULN for patients with liver metastases, ALT, AST <=5 ULN ALP <=2.5 ULN serum urea nitrogen and creatinine <=1.5 ULN serum total bilirubin <1.5 times the upper limit of normal (6) Patients or their legal representatives can understand and voluntarily sign informed consent.
Exclusion criteria	Report: Exclusion criteria included the following: any kind of cancer, severe liver disease, known allergy or hypersensitivity to hUC-MSCs, and other conditions that the clinician deemed inappropriate for participation. Registry: 1. With any autoimmune disease 2. with malignant tumors 3. Participated in other clinical studies within three months before entering the group 4. Severe allergic history, allergic to T cell therapy products or other biological agents 5. Pregnant, planning to become pregnant or lactating women 6. Patients with severe systemic diseases who are not suitable for entering the study, including but not limited to severe liver dysfunction, severe coagulation disorders, severe mental diseases, etc. 7. Previously received other stem cell therapy, had received CIK cell therapy within two months 8. Researchers believe that other conditions should not be included in this trial
Interventions
	Treatment hUC-MSC 2 x 10^6 cells/kg IV in 100 mL of normal saline once off.
	Control Standard care
Participants
	Randomized participants : hUC-MSC=12 Standard care=29
	Characteristics of participants N= 41 Mean age : NR 24 males Severity : Mild: n=3 / Moderate: n=28 / Severe: n=10 Critical: n=0
Primary outcome
	In the register Chest Imaging; Lung Function; ADL
	In the report Incidence of progression from severe to critical illness and the time to a clinical improvement of two points on a seven-category ordinal scale
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication:
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	"In addition to the published article, the study registry was used in data extraction and risk of bias assessment. This is a report on a single centre pilot study. The target sample size of 18 specified in the registry was not achieved for the intervention arm. There is no change from the trial registration in the intervention and control treatments. The inclusion and exclusion criteria in the registry and report do not match. The primary outcome and all secondary outcomes from the report are not specified in the trial registry."