Evaluation of Safety and Efficiency of Method of Exosome Inhalation in SARS-CoV-2 Associated Pneumonia.

Study Overview
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Brief Summary
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Coronavirus is an acute viral disease with prevailing upper respiratory tract infections caused by the RNA-containing virus of the genus Betacoronavirus of the Coronaviridae family. Most patients with severe COVID-19 develop pneumonia in the first week of the disease. As the infection progresses, the infiltration increases, and the affected areas increases. Excessive and uncontrolled immune system response with rapidly developing fatal cytokine storm plays the main role in the pathogenesis of acute respiratory distress syndrome (ARDS) due to SARS-CoV-2 infection. According to available data, exosomes can regulate inflammation and regenerative processes due to the change in the concentration of anti-inflammatory cytokines and switch the immune cell to regenerative secretome. Inhalation of exosomes may reduce inflammation and damage to the lung tissue and stimulate the regenerative processes. This protocol has been developed based on the literature, information about the ongoing tests NCT04276987 (A Pilot Clinical Study on Inhalation of Mesenchymal Stem Cells Exosomes Treating Severe Novel Coronavirus Pneumonia) and NCT04384445 (Organicell Flow for Patients With COVID-19), Patent No 271036826 of 2019. A method for obtaining and concentrating microRNA-containing exosomal multi-potent mesenchymal-stromal cells for use in cosmetic and pharmaceutical products to stimulate regenerative processes and slow down aging.

Detailed Description
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COVID-19 is an infectious disease caused by the most recently discovered coronavirus. This new virus and disease were unknown before the outbreak began in Wuhan, China, in December 2019. COVID-19 is now a pandemic affecting many countries worldwide. Globally, as of 1:09 pm CEST, 27 July 2020, there have been 16 096 741 confirmed cases of COVID-19, including 646 384 deaths, reported to WHO. The main and rapidly achievable target of SARS-CoV-2 is lung type II alveolar cells (AT2), which determines the development of diffuse alveolar damage. In the pathogenesis of ARDS due to COVID-19, the main role is played by an over-response of the immune system with rapidly developing severe life-threatening cytokine release syndrome (cytokine storm). Cytokine release syndrome threatens the emergence and progression of ARDS. The key components of the pathogenesis of ARDS also include disruption of cell cytotoxicity mechanisms, excessive activation of cytotoxic lymphocytes and macrophages with a massive release of proinflammatory cytokines (FNO-α, IL-1, IL-2, IL-6, IL-8, IL-10), granulocytic colony-stimulating factor, monocytic chemoattractive protein 1), and inflammatory markers (CRP, serum ferritin), infiltration of internal organs and tissues by activated T-lymphocytes and macrophages, resulting in a hyperinflammatory reaction. Such severe lesions can lead to death or severe lung damage, including long rehabilitation after discharge. Experimental studies have demonstrated that mesenchymal stem cells (MSCs) may significantly reduce lung inflammation and pathological impairment resulting from different types of lung injury. Many researchers connect the anti-inflammatory effect of MSC with their secretome which includes MSC derived exosomes. It is highly likely that MSC exosomes have the same therapeutic effect on inoculation pneumonia as MSCs themselves. Moreover, exosomes show a strong effect of regenerative stimulation on different wounds so the regenerative effect can be extended on patients with COVID-19 pneumonia. The purpose of this protocol is to explore the safety and efficiency of aerosol inhalation of the exosomes in the treatment of severe patients hospitalized with novel coronavirus pneumonia (NCP).

Official Title
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The Protocol of Evaluation of Safety and Efficiency of Method of Exosome Inhalation in SARS-CoV-2 Associated Two-Sided Pneumonia

Conditions
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Covid19, SARS-CoV-2 PNEUMONIA, COVID-19

Intervention / Treatment
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* Drug: EXO 1 inhalation
* Drug: EXO 2 inhalation
* Drug: Placebo inhalation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to understand the study objectives and risks and provide signed and dated informed consent; Confirmed COVID-19 infection (by PCR or antibody test); Pneumonia requiring hospitalization, and oxygen saturation of <94% indoors or a need for auxiliary oxygen. The confirmed volume of lung damage by CT: not less than 30% and not more than 80%; ability to proceed with inhalation by self; Exclusion Criteria: Severe respiratory failure at the time of screening due to COVID-19 pneumonia; Known to undergo medical resuscitation for 14 days before randomization; Any serious medical condition or deviation of the clinical laboratory parameter that, in the opinion of the researcher, prevents safe participation and completion of the study by the participant Confirmed uncontrolled active bacterial, fungal, viral or other infection (other than SARS-CoV-2). According to the researcher, the progression to death is inevitable and will occur within the next 24 hours, regardless of the therapy. The life expectancy of fewer than 28 days, taking into account a medical condition already existing that cannot be corrected, e.g. participants with the following conditions or suspicions: polyorganic insufficiency, poorly controlled neoplasms, terminal stage heart disease, cardiopulmonary cardiac arrest that required cardiopulmonary resuscitation, or electrical activity not accompanied by a pulse, or asystole within the last 30 days, terminal stage liver disease, terminal stage liver disease, or liver disease; Pregnancy or breastfeeding; Liver function failure (Class C for Child-Pugh), detected within 24 hours at screening (local laboratory); Absolute neutrophil count (ANC) <500 cells/µL at screening (local laboratory); Platelet count <50000 cells/µL at screening (based on laboratory data); Creatinine level ≥ 1.5 from the upper limit; Uncontrolled or untreated arrhythmia with clinical manifestations, myocardial infarction within the last 6 weeks or congestive heart failure (NYHA Degrees 3 or 4); Respiratory failure in the last 6 months or home use of oxygen in severe chronic respiratory disease (COPD); Quadriplegia; Primary immunodeficiency, tuberculosis, progressive multifocal leukoencephalopathy, aspergillosis or other invasive mold/fungal infection in anamnesis, or internal or bone marrow transplantation for 6 months before randomization; Known infection with hepatitis B or C viruses requiring therapy;

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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The trial has three groups, each with 10 subjects (n=30). All eligible study subjects will be randomized, double-blinded, to either the two treatment groups or placebo group.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EXO-1<br>Participants (n=10) in this group will receive standard therapy and exosomes of the first type. | Drug: EXO 1 inhalation<br>* Twice a day during 10 days inhalation of 3 ml special solution contained 0.5-2x10^10 of nanoparticles (exosomes) of the first type.<br>|
| Experimental: EXO-2<br>Participants (n=10) in this group will receive standard therapy and exosomes of the second type. | Drug: EXO 2 inhalation<br>* Twice a day during 10 days inhalation of 3 ml special solution contained 0.5-2x10^10 of nanoparticles (exosomes) of the second type.<br>|
| Placebo Comparator: Placebo<br>Participants (n=10) in this group will receive standard therapy and inhalation placebo solution. | Drug: Placebo inhalation<br>* Twice a day during 10 days inhalation of 3 ml special solution free of nanoparticles (exosomes).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Non-serious and Serious Adverse Events During Trial | Safety assessment such as adverse events will be registered. Adverse events will be monitored during all trial | 30 days after clinic discharge | 
| Number of Participants With Non-serious and Serious Adverse During Inhalation Procedure | Safety assessments such as adverse events during the inhalation procedures will be registered. | after each inhalation during 10 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Clinical Recovery (TTCR) | Measure and compare time to clinical recovery compared to placebo. Time to clinical recovery calculated by the number of days the patient has hospitalized. | from first inhalation until discharge from the clinic, up to 30 days | 
| SpO2 Concentration | The concentration of SpO2 by Pulse oximetry device during procedures in the groups. The measure was done before and after each inhalation (total 4 measures per day). The intraday SpO2 data of all patients in groups was calculated as Median with Inter-Quartile Range and presented in the table by days. | 10 days during inhalation | 
| C-reactive Protein | Blood biochemistry C reactive protein level in serum. | At the begining of inhalation (day 1) and on next day of last inhalation (day 11) | 
| Lactic Acid Dehydrogenase (LDH) | Lactic Acid Dehydrogenase (LDH) level in serum | At the beginning of inhalation (day 1) and on next day of last inhalation (day 11) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MSC, Covid-19, SARS-CoV-2, exosomes