Safety and Efficiency of Method of Exosome Inhalation in COVID-19 Associated Pneumonia (COVID-19EXO2)

• ClinicalTrials.gov Identifier: NCT04602442
• Recruitment Status: Unknown
• First Posted: October 26, 2020
• Last Update Posted: October 26, 2020
• Sponsor: Olga Tyumina
• Collaborators: Clinics of the Federal State Budgetary Educational Institution SSMU; Samara Regional Clinical Hospital V.D. Seredavin
• Information provided by (Responsible Party): Olga Tyumina, State-Financed Health Facility "Samara Regional Medical Center Dinasty"

Tracking Information

• First Submitted Date: October 21, 2020
• First Posted Date: October 26, 2020
• Last Update Posted Date: October 26, 2020
• Actual Study Start Date: October 1, 2020
• Estimated Primary Completion Date: August 1, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 23, 2020)

• Number of participants with non-serious and serious adverse events during trial [ Time Frame: through study, an average of 2 months ]
  Safety assessment such as adverse events will be registered. Adverse events will be monitored during all trial
• Number of participants with non-serious and serious adverse during inhalation procedure [ Time Frame: 10 days during inhalation procedures ]
  Safety assessments such as adverse events during the inhalation procedures will be registered.

• Original Primary Outcome Measures: Same as current
• Change History: No Changes Posted

Current Secondary Outcome Measures (submitted: October 23, 2020)

• Time to clinical recovery (TTCR) [ Time Frame: up to 2 months ]
  Measure and compare time to clinical recovery and clinical discharge compare to placebo.
• SpO2 concentration changes [ Time Frame: up to 2 months ]
  Concentration of SpO2 by Pulse oximetry device during procedures and compare to placebo.
• Chest Imaging Changes [ Time Frame: Three times. At diagnosis, 10-14 days after treatment and 30 days after clinic discharge ]
  Chest imaging changes for 30 days compared to placebo. Information on the percent of damaged lungs will be analyzed and reported.
• Blood biochemistry (CRP) [ Time Frame: Baseline, day 5, 10, 20 ]
  C-reactive protein (CRP, mg/L) concentration in the plasma will be measured. The result will be analyzed and compared in time.
• Procalcitonin concentration [ Time Frame: Baseline, day 5, 10, 20 ]
  Procalcitonin concentration in plasma (ng/mL) will be measured. The result will be analyzed and compared in time.
• Ferritin concentration [ Time Frame: Baseline, day 5, 10, 20 ]
  Ferritin concentration in plasma (ng/mL) will be measured. The result will be analyzed and compared in time.
• Creatinine concentration [ Time Frame: Baseline, day 5, 10, 20 ]
  Creatinine concentration (umol/L) in plasma will be measured. The result will be analyzed and compared in time.
• Urea concentration [ Time Frame: Baseline, day 5, 10, 20 ]
  Urea concentration (mmol/L) in plasma will be measured. The result will be analyzed and compared in time.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety and Efficiency of Method of Exosome Inhalation in COVID-19 Associated Pneumonia
• Official Title: The Extended Protocol of Evaluation of Safety and Efficiency of Method of Exosome Inhalation in COVID-19 Associated Two-Sided Pneumonia

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.

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 Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

The trial has three groups, each with 30 subjects (n=90). 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

Condition

• Covid19
• SARS-CoV-2 PNEUMONIA
• COVID-19

Intervention

• 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.
• 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.
• Drug: Placebo inhalation
  Twice a day during 10 days inhalation of 3 ml special solution free of nanoparticles (exosomes).

Study Arms

• Experimental: EXO-1
  Participants (n=30) in this group will receive standard therapy and exosomes of the first type.
  Intervention: Drug: EXO 1 inhalation
• Experimental: EXO-2
  Participants (n=30) in this group will receive standard therapy and exosomes of the second type.
  Intervention: Drug: EXO 2 inhalation
• Placebo Comparator: Placebo
  Participants (n=30) in this group will receive standard therapy and inhalation placebo solution.
  Intervention: Drug: Placebo inhalation

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: October 23, 2020): 90
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 30, 2021
• Estimated Primary Completion Date: August 1, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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;

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Russian Federation

Administrative Information

• NCT Number: NCT04602442
• Other Study ID Numbers: COVID-19 EXO Extended
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Olga Tyumina, State-Financed Health Facility "Samara Regional Medical Center Dinasty"
• Original Responsible Party: Same as current
• Current Study Sponsor: Olga Tyumina
• Original Study Sponsor: Same as current

Collaborators

• Clinics of the Federal State Budgetary Educational Institution SSMU
• Samara Regional Clinical Hospital V.D. Seredavin

• Investigators: Not Provided
• PRS Account: State-Financed Health Facility "Samara Regional Medical Center Dinasty"
• Verification Date: October 2020