COVID-19EXO: Evaluation of Safety and Efficiency of Method of Exosome Inhalation in SARS-CoV-2 Associated Pneumonia.

• Sponsor: State-Financed Health Facility "Samara Regional Medical Center Dinasty" (Other)
• Overall Status: Completed
• CT.gov ID: NCT04491240
• Collaborator: Clinics of the Federal State Budgetary Educational Institution SSMU (Other), Samara Regional Clinical Hospital V.D. Seredavin (Other)

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Covid19; SARS-CoV-2 PNEUMONIA; COVID-19	Drug: EXO 1 inhalation; Drug: EXO 2 inhalation; Drug: Placebo inhalation	Phase 1/Phase 2

Detailed Description

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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention 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.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 (Participant, Care Provider)
• Masking Description: Two main groups will be provided with exosomes in a specially provided solution, the third group (control) will receive the same solution without exosomes. Due to exosomes are nanoparticles and requires special methods and devices to be detected the hospital staff and patients have no way to check which group receives exosomes.
• Primary Purpose: Other
• Official Title: The Protocol of Evaluation of Safety and Efficiency of Method of Exosome Inhalation in SARS-CoV-2 Associated Two-Sided Pneumonia
• Actual Study Start Date: Jul 20, 2020
• Actual Primary Completion Date: Oct 1, 2020
• Actual Study Completion Date: Oct 20, 2020

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Non-serious and Serious Adverse Events During Trial [30 days after clinic discharge]

   Safety assessment such as adverse events will be registered. Adverse events will be monitored during all trial

2. Number of Participants With Non-serious and Serious Adverse During Inhalation Procedure [after each inhalation during 10 days]

   Safety assessments such as adverse events during the inhalation procedures will be registered.

Secondary Outcome Measures

1. Time to Clinical Recovery (TTCR) [from first inhalation until discharge from the clinic, up to 30 days]

   Measure and compare time to clinical recovery compared to placebo. Time to clinical recovery calculated by the number of days the patient has hospitalized.

2. SpO2 Concentration [10 days during inhalation]

   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.

3. C-reactive Protein [At the begining of inhalation (day 1) and on next day of last inhalation (day 11)]

   Blood biochemistry C reactive protein level in serum.

4. Lactic Acid Dehydrogenase (LDH) [At the beginning of inhalation (day 1) and on next day of last inhalation (day 11)]

   Lactic Acid Dehydrogenase (LDH) level in serum

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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;

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Medical Centre Dinasty	Samara		Russian Federation	443095

Sponsors and Collaborators

• State-Financed Health Facility "Samara Regional Medical Center Dinasty"
• Clinics of the Federal State Budgetary Educational Institution SSMU
• Samara Regional Clinical Hospital V.D. Seredavin

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 6, 2020

More Information

Publications

None provided.

• Responsible Party: State-Financed Health Facility "Samara Regional Medical Center Dinasty"
• ClinicalTrials.gov Identifier: NCT04491240
• Other Study ID Numbers: COVID-19 EXO
• First Posted: Jul 29, 2020
• Last Update Posted: Nov 4, 2020
• Last Verified: Oct 1, 2020

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by State-Financed Health Facility "Samara Regional Medical Center Dinasty": Covid-19; SARS-CoV-2; exosomes; MSC
• Additional relevant MeSH terms: COVID-19; Pneumonia

Study Results

Participant Flow

Arm/Group Title	EXO-1	EXO-2	Placebo
Arm/Group Description	Participants (n=10) in this group will receive standard therapy and exosomes of the first type. EXO 1 inhalation: Twice a day during 10 days inhalation of 3 ml special solution contained 0.5-2x10^10 of nanoparticles (exosomes) of the first type.	Participants (n=10) in this group will receive standard therapy and exosomes of the second type. EXO 2 inhalation: Twice a day during 10 days inhalation of 3 ml special solution contained 0.5-2x10^10 of nanoparticles (exosomes) of the second type.	Participants (n=10) in this group will receive standard therapy and inhalation placebo solution. Placebo inhalation: Twice a day during 10 days inhalation of 3 ml special solution free of nanoparticles (exosomes).
Period Title: Overall Study
STARTED	10	10	10
COMPLETED	10	10	10
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	EXO-1	EXO-2	Placebo	Total
Arm/Group Description	Participants (n=10) in this group will receive standard therapy and exosomes of the first type. EXO 1 inhalation: Twice a day during 10 days inhalation of 3 ml special solution contained 0.5-2x10^10 of nanoparticles (exosomes) of the first type.	Participants (n=10) in this group will receive standard therapy and exosomes of the second type. EXO 2 inhalation: Twice a day during 10 days inhalation of 3 ml special solution contained 0.5-2x10^10 of nanoparticles (exosomes) of the second type.	Participants (n=10) in this group will receive standard therapy and inhalation placebo solution. Placebo inhalation: Twice a day during 10 days inhalation of 3 ml special solution free of nanoparticles (exosomes).	Total of all reporting groups
Overall Participants	10	10	10	30
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	10 100%	10 100%	10 100%	30 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	47.9	52.5	53.3	51.23
Sex: Female, Male (Count of Participants)
Female	6 60%	8 80%	5 50%	19 63.3%
Male	4 40%	2 20%	5 50%	11 36.7%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
Russia	10 100%	10 100%	10 100%	30 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Non-serious and Serious Adverse Events During Trial
Description	Safety assessment such as adverse events will be registered. Adverse events will be monitored during all trial
Time Frame	30 days after clinic discharge

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	EXO-1	EXO-2	Placebo
Arm/Group Description	Participants (n=10) in this group will receive standard therapy and exosomes of the first type. EXO 1 inhalation: Twice a day during 10 days inhalation of 3 ml special solution contained 0.5-2x10^10 of nanoparticles (exosomes) of the first type.	Participants (n=10) in this group will receive standard therapy and exosomes of the second type. EXO 2 inhalation: Twice a day during 10 days inhalation of 3 ml special solution contained 0.5-2x10^10 of nanoparticles (exosomes) of the second type.	Participants (n=10) in this group will receive standard therapy and inhalation placebo solution. Placebo inhalation: Twice a day during 10 days inhalation of 3 ml special solution free of nanoparticles (exosomes).
Measure Participants	10	10	10
Number of participants with serious adverse events during trial	0 0%	0 0%	0 0%
Number of participants with non-serious adverse events during trial	0 0%	0 0%	0 0%

2. Primary Outcome

Title	Number of Participants With Non-serious and Serious Adverse During Inhalation Procedure
Description	Safety assessments such as adverse events during the inhalation procedures will be registered.
Time Frame	after each inhalation during 10 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	EXO-1	EXO-2	Placebo
Arm/Group Description	Participants (n=10) in this group will receive standard therapy and exosomes of the first type. EXO 1 inhalation: Twice a day during 10 days inhalation of 3 ml special solution contained 0.5-2x10^10 of nanoparticles (exosomes) of the first type.	Participants (n=10) in this group will receive standard therapy and exosomes of the second type. EXO 2 inhalation: Twice a day during 10 days inhalation of 3 ml special solution contained 0.5-2x10^10 of nanoparticles (exosomes) of the second type.	Participants (n=10) in this group will receive standard therapy and inhalation placebo solution. Placebo inhalation: Twice a day during 10 days inhalation of 3 ml special solution free of nanoparticles (exosomes).
Measure Participants	10	10	10
Temperature increase	0 0%	0 0%	0 0%
Bronchospasm	0 0%	0 0%	0 0%
allergic reaction in the form of swelling Quincke, rash, seizures, etc.	0 0%	0 0%	0 0%
Other	0 0%	0 0%	0 0%

3. Secondary Outcome

Title	Time to Clinical Recovery (TTCR)
Description	Measure and compare time to clinical recovery compared to placebo. Time to clinical recovery calculated by the number of days the patient has hospitalized.
Time Frame	from first inhalation until discharge from the clinic, up to 30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	EXO-1	EXO-2	Placebo
Arm/Group Description	Participants (n=10) in this group will receive standard therapy and exosomes of the first type. EXO 1 inhalation: Twice a day during 10 days inhalation of 3 ml special solution contained 0.5-2x10^10 of nanoparticles (exosomes) of the first type.	Participants (n=10) in this group will receive standard therapy and exosomes of the second type. EXO 2 inhalation: Twice a day during 10 days inhalation of 3 ml special solution contained 0.5-2x10^10 of nanoparticles (exosomes) of the second type.	Participants (n=10) in this group will receive standard therapy and inhalation placebo solution. Placebo inhalation: Twice a day during 10 days inhalation of 3 ml special solution free of nanoparticles (exosomes).
Measure Participants	10	10	10
Mean (Standard Deviation) [days]	13.8 (1.55)	14.8 (2.35)	14.1 (1.37)

4. Secondary Outcome

Title	SpO2 Concentration
Description	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.
Time Frame	10 days during inhalation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	EXO-1	EXO-2	Placebo
Arm/Group Description	Participants (n=10) in this group will receive standard therapy and exosomes of the first type. EXO 1 inhalation: Twice a day during 10 days inhalation of 3 ml special solution contained 0.5-2x10^10 of nanoparticles (exosomes) of the first type.	Participants (n=10) in this group will receive standard therapy and exosomes of the second type. EXO 2 inhalation: Twice a day during 10 days inhalation of 3 ml special solution contained 0.5-2x10^10 of nanoparticles (exosomes) of the second type.	Participants (n=10) in this group will receive standard therapy and inhalation placebo solution. Placebo inhalation: Twice a day during 10 days inhalation of 3 ml special solution free of nanoparticles (exosomes).
Measure Participants	10	10	10
Day 1	93.8	94.5	94
Day 2	94.8	95.3	96
Day 3	95.3	95.5	96
Day 4	95.5	96	96.5
Day 5	96	96.5	97.3
Day 6	96	97	97
Day 7	96.8	97.5	97.5
Day 8	97.3	97.3	98.3
Day 9	97.3	97.8	98.5
Day 10	97.8	98.5	98.8

5. Secondary Outcome

Title	C-reactive Protein
Description	Blood biochemistry C reactive protein level in serum.
Time Frame	At the begining of inhalation (day 1) and on next day of last inhalation (day 11)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	EXO-1	EXO-2	Placebo
Arm/Group Description	Participants (n=10) in this group will receive standard therapy and exosomes of the first type. EXO 1 inhalation: Twice a day during 10 days inhalation of 3 ml special solution contained 0.5-2x10^10 of nanoparticles (exosomes) of the first type.	Participants (n=10) in this group will receive standard therapy and exosomes of the second type. EXO 2 inhalation: Twice a day during 10 days inhalation of 3 ml special solution contained 0.5-2x10^10 of nanoparticles (exosomes) of the second type.	Participants (n=10) in this group will receive standard therapy and inhalation placebo solution. Placebo inhalation: Twice a day during 10 days inhalation of 3 ml special solution free of nanoparticles (exosomes).
Measure Participants	10	10	10
Day 1	78.3	75.4	61.5
Day 11	5.04	5.83	8.29

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	EXO-1
	Comments	The study results were statistically processed using STATA version 9.0, Statistica for Windows version 6.0. Changes from the beginning of inhalation and after were compared using the T-test for depended group criterion, data between the main group and the control group were compared using the non-parametric method, box-plot. The data in the table presented as a Mean with full range (min-max). The difference calculated as Mean difference with 95% confidence interval and Standard Deviation (SD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.020875
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	73.29000
	Confidence Interval	(2-Sided) 95%; 13.97687 to 132.6031
	Parameter Dispersion	Type: Standard Deviation; Value: 82.91404
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	EXO-2
	Comments	The study results were statistically processed using STATA version 9.0, Statistica for Windows version 6.0. Changes from the beginning of inhalation and after were compared using the T-test for depended group criterion, data between the main group and the control group were compared using the non-parametric method, box-plot. The data in the table presented as a Mean with full range (min-max). The difference calculated as Mean difference with 95% confidence interval and Standard Deviation (SD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.000953
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	69.56000
	Confidence Interval	(2-Sided) 95%; 36.88502 to 102.2350
	Parameter Dispersion	Type: Standard Deviation; Value: 45.67648
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments	The study results were statistically processed using STATA version 9.0, Statistica for Windows version 6.0. Changes from the beginning of inhalation and after were compared using the T-test for depended group criterion, data between the main group and the control group were compared using the non-parametric method, box-plot. The data in the table presented as a Mean with full range (min-max). The difference calculated as Mean difference with 95% confidence interval and Standard Deviation (SD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002233
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	53.21000
	Confidence Interval	(2-Sided) 95%; 24.69923 to 81.72077
	Parameter Dispersion	Type: Standard Deviation; Value: 39.85531
	Estimation Comments

6. Secondary Outcome

Title	Lactic Acid Dehydrogenase (LDH)
Description	Lactic Acid Dehydrogenase (LDH) level in serum
Time Frame	At the beginning of inhalation (day 1) and on next day of last inhalation (day 11)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	EXO-1	EXO-2	Placebo
Arm/Group Description	Participants (n=10) in this group will receive standard therapy and exosomes of the first type. EXO 1 inhalation: Twice a day during 10 days inhalation of 3 ml special solution contained 0.5-2x10^10 of nanoparticles (exosomes) of the first type.	Participants (n=10) in this group will receive standard therapy and exosomes of the second type. EXO 2 inhalation: Twice a day during 10 days inhalation of 3 ml special solution contained 0.5-2x10^10 of nanoparticles (exosomes) of the second type.	Participants (n=10) in this group will receive standard therapy and inhalation placebo solution. Placebo inhalation: Twice a day during 10 days inhalation of 3 ml special solution free of nanoparticles (exosomes).
Measure Participants	10	10	10
at Day 1	773	732	669
at Day 11	441	365	430

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	EXO-1
	Comments	The study results were statistically processed using STATA version 9.0, Statistica for Windows version 6.0. Changes from the beginning of inhalation and after were compared using the T-test for depended group criterion, data between the main group and the control group were compared using the non-parametric method, box-plot. The data in the table presented as a Mean with full range (min-max). The difference calculated as Mean difference with 95% confidence interval and Standard Deviation (SD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.008948
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	331.5200
	Confidence Interval	(2-Sided) 95%; 105.5938 to 557.4462
	Parameter Dispersion	Type: Standard Deviation; Value: 315.8230
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	EXO-2
	Comments	The study results were statistically processed using STATA version 9.0, Statistica for Windows version 6.0. Changes from the beginning of inhalation and after were compared using the T-test for depended group criterion, data between the main group and the control group were compared using the non-parametric method, box-plot. The data in the table presented as a Mean with full range (min-max). The difference calculated as Mean difference with 95% confidence interval and Standard Deviation (SD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.020921
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	366.6300
	Confidence Interval	(2-Sided) 95%; 69.77651 to 663.4835
	Parameter Dispersion	Type: Standard Deviation; Value: 414.9726
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments	The study results were statistically processed using STATA version 9.0, Statistica for Windows version 6.0. Changes from the beginning of inhalation and after were compared using the T-test for depended group criterion, data between the main group and the control group were compared using the non-parametric method, box-plot. The data in the table presented as a Mean with full range (min-max). The difference calculated as Mean difference with 95% confidence interval and Standard Deviation (SD)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004873
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	239.2000
	Confidence Interval	(2-Sided) 95%; 93.20037 to 385.1996
	Parameter Dispersion	Type: Standard Deviation; Value: 204.0934
	Estimation Comments

Adverse Events

Time Frame	During medical procedures and 1-month post-discharge from the clinic.
Adverse Event Reporting Description	Collection of information on unwanted reactions to inhalation after each inhalation, e.g. 1) temperature increase, 2) allergic reaction in the form of Quincke's disease, rash, seizures, etc.; 3) bronchospasm for inhalation.
Arm/Group Title	EXO-1		EXO-2		Placebo
Arm/Group Description	Participants (n=10) in this group will receive standard therapy and exosomes of the first type. EXO 1 inhalation: Twice a day during 10 days inhalation of 3 ml special solution contained 0.5-2x10^10 of nanoparticles (exosomes) of the first type.		Participants (n=10) in this group will receive standard therapy and exosomes of the second type. EXO 2 inhalation: Twice a day during 10 days inhalation of 3 ml special solution contained 0.5-2x10^10 of nanoparticles (exosomes) of the second type.		Participants (n=10) in this group will receive standard therapy and inhalation placebo solution. Placebo inhalation: Twice a day during 10 days inhalation of 3 ml special solution free of nanoparticles (exosomes).
All Cause Mortality
	EXO-1		EXO-2		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/10 (0%)
Serious Adverse Events
	EXO-1		EXO-2		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	EXO-1		EXO-2		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/10 (0%)
Immune system disorders
Allergic reactions	0/10 (0%)	0	0/10 (0%)	0	0/10 (0%)	0
Injury, poisoning and procedural complications
Temperature increase	0/10 (0%)	0	0/10 (0%)	0	0/10 (0%)	0
Respiratory, thoracic and mediastinal disorders
Bronchospasm	0/10 (0%)	0	0/10 (0%)	0	0/10 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.