Treatment With Human Umbilical Cord-derived Mesenchymal Stem Cells for Severe Corona Virus Disease 2019 (COVID-19)

Study Overview
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Brief Summary
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COVID-19 caused clusters of severe respiratory illness and was associated with 2% mortality. No specific anti-viral treatment exists. The mainstay of clinical management is largely symptomatic treatment, with organ support in intensive care for seriously ill patients. Cellular therapy, using mesenchymal stem cells has been shown to reduce nonproductive inflammation and affect tissue regeneration and is being evaluated in patients with ARDS. This clinical trial is to inspect the safety and efficiency of mesenchymal stem cells (MSCs) therapy for severe COVID-19.

Detailed Description
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The Corona Virus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) infection has unprecedentedly spread in the worldwide and been declared as a pandemic by the world health organization. COVID-19 is characterized by sustained cytokines production and hyper-inflammation, can cause clusters of severe respiratory illness with a fatality rate around 2-5%. There are currently no prophylactic vaccine and no specific antiviral treatment agents available recommended for COVID-19. Therefore, it is urgent to find a safe and effective therapeutic approach to COVID-19. During the last decade, the promising features of mesenchymal stem cells (MSCs), including their regenerative properties and ability to differentiate into diverse cell lineages, have generated great interest among researchers whose work has offered intriguing perspectives on cell-based therapies for various diseases. These findings seem to highlight that the beneficial effect of MSC-based treatment could be principally due by the immunomodulation and regenerative potential of these cells. MSCs could significantly reduce the pathological changes of lung and inhibit the cell-mediated immune inflammatory response induced by influenza virus in animal model . MSCs has been shown to reduce nonproductive inflammation and affect tissue regeneration and is being evaluated in patients with ARDS. Our phase I preliminary data of parallel assignment study(NCT04252118) showed that three doses of MSCs was safe in patients with COVID-19. Randomized control trial is needed to assess efficacy and safety. The investigators will do a prospective, double-blind, multicentre, randomised trial to assess treatment with three intravenous doses of MSCs compared with placebo. 90 severe COVID-19 patients will be recruited in China. 60 patients will receive i.v. transfusion 3 times of MSCs (4.0*10E7 cells per time) and the standard of care as the treated group. In addition, the 30 patients will receive placebo and standard of care as control group. Change in lesion proportion (%) of full lung volume from baseline to day 10, day28 and 90, change in consolidation/ ground-glass lesion proportion (%) of full lung volume from baseline to day 10, 28 and 90, time to clinical improvement in 28 days, mMRC (Modified Medical Research Council) dyspnea scale, 6-minute walk test, maximum vital capacity (VCmax), Diffusing Capacity (DLCO), oxygen saturation, oxygenation index, duration of oxygen therapy, side effects, immunological characteristics (immune cells, inflammatory factors, etc.) will be evaluated during the 90 days follow up.

Official Title
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A Phase II, Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy and Safety of Human Umbilical Cord-derived Mesenchymal Stem Cells in the Treatment of Severe COVID-19 Patients

Conditions
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Corona Virus Disease 2019(COVID-19)

Intervention / Treatment
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* Biological: UC-MSCs
* Biological: Saline containing 1% Human serum albumin（solution without UC-MSCs）


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, aged at 18 years (including) -75 years old Hospitalized Laboratory confirmation of SARS-CoV-2 infection by reverse-transcription polymerase chain reaction (RT-PCR) from any diagnostic sampling source Pneumonia that is judged by computed tomography In accordance with any one of the following : 1)dyspnea (RR ≥ 30 times / min), 2)finger oxygen saturation ≤ 93% in resting state, 3)arterial oxygen partial pressure (PaO2) / oxygen absorption concentration (FiO2) ≤ 300MMHG, 4)pulmonary imaging shows that the focus progress > 50% in 24-48 hours Interstitial lung damage is judged by computed tomography. Exclusion Criteria: Pregnancy, lactation and those who are not pregnant but do not take effective contraceptives measures; Patients with malignant tumor, other serious systemic diseases and psychosis; Patients who are participating in other clinical trials; Inability to provide informed consent or to comply with test requirements. Co-Infection of HIV, tuberculosis, influenza virus, adenovirus and other respiratory infection virus. Invasive ventilation Shock Combined with other organ failure( need organ support) Interstitial lung damage caused by other reasons ( in 2 weeks) The pulmonary imaging revealed the interstitial damage of lungs before the COVID-19 confirmed.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, double-blind, placebo-controlled study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Human Umbilical Cord-Mesenchymal Stem Cells (UC-MSCs)<br>Participants will receive standard of care plus 3 does of UC-MSCs | Biological: UC-MSCs<br>* 3 does of UC-MSCs(4.0*10E7 cells per time) intravenously at Day 0, Day 3, Day 6.<br>|
| Placebo Comparator: Placebo<br>Participants will receive standard of care plus 3 does of placebo | Biological: Saline containing 1% Human serum albumin（solution without UC-MSCs）<br>* 3 does of placebo（intravenously at Day 0, Day 3, Day 6）<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in lesion proportion (%) of full lung volume from baseline to day 28. | Evaluation of Pneumonia Improvement | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in lesion proportion (%) of full lung volume from baseline to day 10 and 90 | Evaluation of Pneumonia Improvement | Day 10, Day 90 | 
| Change in consolidation lesion proportion (%) of full lung volume from baseline to day 10, 28 and 90. | Evaluation of Pneumonia Improvement | Day 10, Day 28, Day 90 | 
| Change in ground-glass lesion proportion (%) of full lung volume from baseline to day 10, 28 and 90. | Evaluation of Pneumonia Improvement | Day 10, Day 28, Day 90 | 
| Pulmonary fibrosis - related morphological features in CT scan at day 90 a. cord-like shadow b. honeycomb-like shadows c. interlobular septal thickening d. intralobular interstitial thickening e. pleural thickening | Evaluation of Pneumonia Improvement | Day 90 | 
| Lung densitometry: Change in total voxel 'weight' in lesion area voxel 'weight'=voxel density (in HU) × voxel volume (in voxel) | Evaluation of Pneumonia Improvement | Day 10, Day 28, Day 90 | 
| Lung densitometry: volumes histogram of lung density distribution (<-750, -750 -300, -300 50, >50) at day 10, 28 and 90. | Evaluation of Pneumonia Improvement | Day 10, Day 28, Day 90 | 
| Time to clinical improvement in 28 days. | Clinical improvement defined as a one-point deduction from baseline in a 6 ordinal scale: Not hospitalized; Hospitalized, not requiring supplemental oxygen; Hospitalized, requiring supplemental oxygen; Hospitalized, on non-invasive ventilation or high flow oxygen devices; Hospitalized, on invasive mechanical ventilation or ECMO; Death. | Day 28 | 
| Oxygenation index( PaO2/FiO2) | Evaluation of Pneumonia Improvement | Day 6, Day 10, Day 28 | 
| Duration of oxygen therapy(days) | Evaluation of Pneumonia Improvement | Day 28, Day 90 | 
| Blood oxygen saturation | Evaluation of Pneumonia Improvement | Day 6, Day 10, Day 28 | 
| 6-minute walk test | Evaluation of Pneumonia Improvement | Day 28, Day 90 | 
| Maximum vital capacity (VCmax) | Evaluation of Pneumonia Improvement | Baseline, Day 10, Day 14, Day 21, Day 28, Day 90 | 
| Diffusing Capacity (DLCO) | Evaluation of Pneumonia Improvement | Baseline, Day 10, Day 14, Day 21, Day 28, Day 90 | 
| mMRC (Modified Medical Research Council) dyspnea scale | Evaluation of Pneumonia Improvement No limitation of activities, discharged from hospital =Score 1; Hospitalized, no oxygen therapy=Score 2; Oxygen by mask or nasal prongs-Score 3; Non-invasive ventilation or high-flow oxygen=Score 4; Mechanical ventilation or ECMO=Score 5; Death=Score 6. | Day 28, Day 90 | 
| Changes of absolute lymphocyte counts and subsets from baseline to day 6, 10, 28 and 90. | Marker of Immunological function | Day 6, Day 10, Day 28, Day 90 | 
| Changes of cytokine/chemokine levels from baseline to day 6, 10, 28 and 90. | Marker of Immunological function | Day 6, Day 10, Day 28, Day 90 | 
| Adverse events | Safety endpoints | Day 0 through Day 90 | 
| Serious adverse events | Safety endpoints | Day 0 through Day 90 | 
| All-cause mortality | Safety endpoints | Day 0 through Day 90 |