Safety and Efficiency of Method of Exosome Inhalation in COVID-19 Associated Pneumonia
Safety and Efficiency of Method of Exosome Inhalation in COVID-19 Associated Pneumonia
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.
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).
Inclusion Criteria:

 -  Ability to understand the study objectives and risks and provide signed and dated
 informed consent;

 -  COVID-19 infection (by PCR or antibody test or high probability of COVID-19 by CT);

 -  Pneumonia requiring hospitalization, and oxygen saturation of <93%, need for
 noninvasive ventilation. The confirmed volume of lung damage by CT;

 -  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;