Mesenchymal Stem Cell Therapy for SARS-CoV-2-related Acute Respiratory Distress Syndrome

Study Overview
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Brief Summary
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Acute Respiratory Distress Syndrome (ARDS) is the major cause of death in the COVID-19 pandemic. In this trial, the safety and efficacy of Mesenchymal Stem Cells (MSC) for the treatment of ARDS in COVID-19 patients will be assessed.

Detailed Description
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Acute respiratory distress syndrome (ARDS) is the major cause of death in the COVID 19 infection pandemic. It is a devastating clinical condition, caused by an acute and diffuse lung injury that requires management in the intensive care unit. It is caused by uncontrolled inflammation that leads to severe pulmonary alveolar damage and capillary membrane leakage, and progressive respiratory failure. There is no effective treatment for ARDS and the only supportive care strategies are the mainstay of therapy. Mesenchymal stem cells (MSCs) have high regenerative and immunomodulatory capacities. In preclinical research, ARDS, MSCs modulate the inflammatory response, augment tissue repair, enhance pathogen clearance, and reduce the severity of the injury, pulmonary dysfunction, and apoptosis. Moreover, many studies have shown that the anti-inflammatory effects of MSCs can significantly reduce virus (e.g., Influenza)-induced lung injury and mortality in animals. Since 2014 clinical trials are using MSC from variable sources [bone marrow (BM), fat, and umbilical cord (UC)] in the treatment of ARDS. Some of the clinical trials are ongoing and the final reports are not reported. In all final reports, the safety of the application of MSC has been documented and most of them implied improvement in mortality and decrease of morbidity. Moreover, experimental studies have demonstrated that MSCs or their extracellular vesicles (MSCs-EVs) significantly reduced lung inflammation and pathological impairment resulting from different types of lung injury. Also, macrophage phagocytosis, bacterial killing, and the outcome are improved. It is highly likely that MSCs-EVs have the same therapeutic effect on inoculation pneumonia as MSCs themselves. Critically ill coronavirus documented cases suspicious to ARDS (mild or moderate) will be enrolled in the study. Our previous experiment (IRCT20200217046526N1) showed the safety of 3 injections of MSCs in patients with COVID-19. This multi-center trial will recruit 60 patients. All patients in all groups will receive conventional therapy for virus treatment and supportive care for ARDS. The patients allocated randomly to three groups: Control (n=20). Patients will conventional therapy for virus treatment and supportive care for ARDS will be used as control. Intervention Group1 (n=20). Patients will receive two doses of MSCs 100×10e6 (±10%), at Day 0 and Day 2 intravenously. Intervention Group 2 (n=20). Patients will receive two doses of MSCs 100×10e6 (±10%), at Day 0 and Day 2 plus two doses of extracellular vesicles (EVs) on Day 4 and Day 6 intravenously. The clinical symptoms, pulmonary imaging, side effects, 28-days mortality inflammatory factors, etc. will be evaluated during the 28 days follow up.

Official Title
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Mesenchymal Stem Cell Therapy for Acute Respiratory Distress Syndrome in Coronavirus Infection: A Phase 2-3 Clinical Trial

Conditions
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Covid-19

Intervention / Treatment
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* Biological: Cell therapy protocol 1
* Biological: Cell therapy protocol 2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmation of 2019-nCoV infection by RT-PCR Diagnosis of ARDS according to the Berlin definition of ARDS Requiring supplemental oxygen Pneumonia that is judged by chest radiograph or CT PaO2/oxygen absorption concentration (FiO2) ≤ 300MMHG Pulmonary imaging shows that the focused progress > 50% in 24-48 hours Mild to Moderate 2019-nCoV pneumonia/ stay in the ICU <48 hours SOFA score between 2-3 point Exclusion Criteria: Severe allergies or allergies after 1st injection to stem cell preparations and their components Patients with a malignant tumor, other serious systemic diseases, and psychosis Co-Infection of HIV, tuberculosis, influenza virus, adenovirus, and other respiratory infection viruses Patients with a previous history of pulmonary embolism Be thought by researchers to be inappropriate to participate in this clinical study (Expected deaths within 48 hours, uncontrolled infections) Liver or kidney SOFA score of more than 3 points; combined with other organ failures (need organ support), Stage 4 severe chronic kidney disease or requiring dialysis (i.e. estimated glomerular filtration rate (eGFR) < 30) Pulmonary obstructive pneumonia, severe pulmonary interstitial fibrosis, alveolar proteinosis, allergic alveolitis, and other known viral pneumonia or bacterial pneumonia Continuous use of immunosuppressive agents or organ transplants in the past 6 months In vitro life support (ECMO, ECCO2R, RRT) Pregnant or lactating women Uncontrolled underlying disease

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Two MSC infusion<br>Intervention Group1(n=20). Patients will receive two doses of MSCs 100×10e6 (±10%) intravenously plus Conventional treatment. | Biological: Cell therapy protocol 1<br>* Cell therapy protocol 1(n=20). Patients will receive two doses of MSCs 100×10e6 (±10%) at Day 0 and Day 2 plus Conventional treatment.<br>|
| Experimental: Two MSC infusion Plus two EVs infusion<br>Intervention Group 2 (n=20). Patients will receive two doses of MSCs 100×10e6 (±10%), intravenously plus two doses of EVs plus Conventional treatment | Biological: Cell therapy protocol 2<br>* Patients will receive two doses of MSCs 100×10e6 (±10%)at Day 0 and Day 2, intravenously plus two doses of EVs at Day 4 and Day 6 plus conventional treatment.<br>|
| No Intervention: Control<br>Control (n=20). Patients will conventional therapy for virus treatment and supportive care for ARDS will be used as control. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events assessment | Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | From baseline to day 28 | 
| Blood oxygen saturation | Evaluation of Pneumonia Improvement | From baseline to day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intensive care unit-free days | Number of days | Up to day 8 | 
| Clinical symptoms | Improvement of clinical symptoms including duration of fever, respiratory distress, pneumonia, cough, sneezing | From baseline to day 14 | 
| Respiratory efficacy | increase in PaO2/FiO2 ratio from baseline to day 7 | From baseline to day 7 | 
| Biomarkers concentrations in plasma | Biochemical examination | At baseline, 7, 14, 28 days after the first intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, Acute Respiratory Distress Syndrome, 2019 Novel Coronavirus Pneumonia