Treatment of Coronavirus COVID-19 Pneumonia (Pathogen SARS-CoV-2) With Cryopreserved Allogeneic P_MMSCs and UC-MMSCs

Study Overview
=================
Brief Summary
-----------------
Assessment of the clinical effects of infusions of cryopreserved allogeneic multipotent mesenchymal stem cells of the placenta and umbilical cord for COVID-19 patients with acute respiratory distress syndrome.

Detailed Description
-----------------
Currently, cell-based therapy and especially stem cell therapy has become a promising therapeutic field, in which many see opportunities to cure incurable diseases. Severe respiratory consequences of the COVID-19, the disease caused by the novel SARS-CoV-2 coronavirus, have prompted urgent need for novel therapies. Cell-based approaches, primarily using mesenchymal stem cells (MSCs), have demonstrated safety and efficacy in patients with the acute respiratory distress syndrome (ARDS) - common manifestation of cytokine storms, and the cause of death in many COVID-19 patients. Mesenchymal stem cells are a powerful immunomodulator, they secrete many anti-inflammatory biologically active substances (cytokines) that reduce the inflammatory process in the lungs. Also mesenchymal stem cells secrete numerous growth factors that contribute to the recovery of not only the affected lung tissue but also other organs.

Official Title
-----------------
Treatment of Coronavirus COVID-19 Pneumonia (Pathogen SARS-CoV-2) With Cryopreserved Allogeneic Multipotent Mesenchymal Stem Cells of the Placenta and Umbilical Cord

Conditions
-----------------
COVID-19 Pneumonia

Intervention / Treatment
-----------------
* Procedure: Placenta-Derived MMSCs; Cryopreserved Placenta-Derived Multipotent Mesenchymal Stromal Cells
* Drug: Antibiotics
* Drug: Hormones
* Drug: Anticoagulant Therapy
* Device: Оxygen therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female, aged at 18 years (including) - 75 years old. 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 X-ray imaging. In accordance with any one of the following: dyspnea (RR ≥ 30 times / min); finger oxygen saturation ≤ 93% in resting state; arterial oxygen partial pressure (PaO2) / oxygen absorption concentration (FiO2) ≤ 300MMHG (if possible); invasive ventilation< 48 h. Exclusion Criteria: Male or female, aged at <18 years and > 75 years old. 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, syphilis. Invasive ventilation > 48 h. Combined with other organ failure (need organ support).

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Experimental: stem cells therapy + treatment in according with approved by Ukrainian Health Ministry COVID-19 clinical protocol Experimental Group 1: Subjects with severe COVID-19 pneumonia shall be received three infusions of cryopreserved allogeneic P-MMSCs (1 million cells/kg body weight) at 2-days intervals: Day 1, Day 4, Day 7. Control Group: treatment in according with approved by Ukrainian MoH COVID-19 clinical protocol.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental group<br>On the basis conventional symptomatic treatment and supportive therapy, P-MMSCs were given at 1 million cells/kg body weight/ time, once every 3 days for a total of 3 times: Day 1, Day 4, Day 7. | Procedure: Placenta-Derived MMSCs; Cryopreserved Placenta-Derived Multipotent Mesenchymal Stromal Cells<br>* i/v infusions<br>* Other names: P-MMSCs;Drug: Antibiotics<br>* per os<br>* Other names: ceftriaxone and azithromycin capsules;Drug: Hormones<br>* a moderate amount of dexamethasone i/v<br>* Other names: dexamethasone;Drug: Anticoagulant Therapy<br>* Sub-Q<br>* Other names: Еnoxaparin;Device: Оxygen therapy<br>* Оxygen therapy, mechanical ventilation and other supportive therapies<br>* Other names: Оxygen insufflation;|
| Active Comparator: Control Group<br>Conventional symptomatic treatments such as antibacterial (ceftriaxone, azithromycin), anticoagulants, hormones, oxygen therapy, mechanical ventilation and other supportive therapies | Drug: Antibiotics<br>* per os<br>* Other names: ceftriaxone and azithromycin capsules;Drug: Hormones<br>* a moderate amount of dexamethasone i/v<br>* Other names: dexamethasone;Drug: Anticoagulant Therapy<br>* Sub-Q<br>* Other names: Еnoxaparin;Device: Оxygen therapy<br>* Оxygen therapy, mechanical ventilation and other supportive therapies<br>* Other names: Оxygen insufflation;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes of oxygenation index PaO2/FiO2, most conveniently the P/F ratio. | Improvement of pulmonary function. Arterial oxygen tension PaO2 (in mmHg)/fractional inspired oxygen FiO2 (expressed as a fraction, not a percentage), most conveniently the P/F ratio. The normal P/F ratio is   400-500 mmHg ( 55-65 kPa). P/F ratio <300mmHg - sign of Acute Respiratory Distress Syndrome (ARDS) | up to 28 days | 
| Changes in length of hospital stay | Length of Hospital Stay | up to 28 days | 
| Changes in mortality rate | Marker for efficacy of treatment | up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes of С-reactive protein (CRP, mg/L) | Infection biomarker. Serum CRP levels can be used for early diagnosis of pneumonia, patients with severe pneumonia had high CRP levels. | At baseline, Day 1, Week 1, Week 2, Week 4, Week 8 | 
| Evaluation of Pneumonia Improvement | CT assessment of pulmonary lesions and lung tissue changes | At baseline, Day 1, Week 1, Week 2, Week 4, Week 8 | 
| Duration of respiratory symptoms (difficulty breathing, dry cough, fever, etc.) | Indirect response to lung function | At baseline, Day 1, Week 1, Week 2, Week 4, Week 8 | 
| Peripheral blood count recovery time | Degree of infection | At baseline, Day 1, Week 1, Week 2, Week 4, Week 8 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Placenta-derived MMSCs, i/v infusions