A Pilot Clinical Study on Inhalation of Mesenchymal Stem Cells Exosomes Treating Severe Novel Coronavirus Pneumonia

• ClinicalTrials.gov Identifier: NCT04276987
• Recruitment Status: Completed
• First Posted: February 19, 2020
• Last Update Posted: September 7, 2020
• Sponsor: Ruijin Hospital
• Collaborators: Shanghai Public Health Clinical Center; Wuhan Jinyintan Hospital, Wuhan, China; Cellular Biomedicine Group Ltd.
• Information provided by (Responsible Party): Ruijin Hospital

Tracking Information

• First Submitted Date: February 16, 2020
• First Posted Date: February 19, 2020
• Last Update Posted Date: September 7, 2020
• Actual Study Start Date: February 15, 2020
• Actual Primary Completion Date: May 31, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 18, 2020)

• Adverse reaction (AE) and severe adverse reaction (SAE) [ Time Frame: Up to 28 days ]
  Safety evaluation within 28 days after first treatment, including frequency of adverse reaction (AE) and severe adverse reaction (SAE)
• Time to clinical improvement (TTIC) [ Time Frame: Up to 28 days ]
  Efficiency evaluation within 28 days, including time to clinical improvement (TTIC)

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 18, 2020)

• Number of patients weaning from mechanical ventilation [ Time Frame: Up to 28 days ]
  Number of patients weaning from mechanical ventilation within 28 days
• Duration (days) of ICU monitoring [ Time Frame: Up to 28 days ]
  Duration (days) of ICU monitoring within 28 days
• Duration (days) of vasoactive agents usage [ Time Frame: Up to 28 days ]
  Duration (days) of vasoactive agents using within 28 days
• Duration (days) of mechanical ventilation supply [ Time Frame: Up to 28 days ]
  Duration (days) of mechanical ventilation supply among survivors
• Number of patients with improved organ failure [ Time Frame: Up to 28 days ]
  Number of patients with improved organ failure within 28 days, including cardiovascular system, coagulation system, liver, kidney and other extra-pulmonary organs
• Rate of mortality [ Time Frame: Up to 28 days ]
  Rate of mortality within 28 days

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: February 21, 2020)

• Sequential organ failure assessment (SOFA) score [ Time Frame: Every day for 28 days ]
  Records of daily sequential organ failure assessment (SOFA) score (From 0 to 24 points, higher scores mean a worse outcome)
• Lymphocyte Count (10E9/L) [ Time Frame: Day0, Day3, Day7, Day14, Day21, Day28, indicated time points can be added if available ]
  Records of Blood routine test
• C-reactive protein (CRP) (mg/L) [ Time Frame: Day0, Day3, Day7, Day14, Day21, Day28, indicated time points can be added if available ]
• Lactate dehydrogenase (U/L) [ Time Frame: Day0, Day3, Day7, Day14, Day21, Day28, indicated time points can be added if available ]
• D-dimer (mg/L) [ Time Frame: Day0, Day3, Day7, Day14, Day21, Day28, indicated time points can be added if available ]
  Coagulation function
• pro-type B natriuretic peptide (pro-BNP) (pg/ml) [ Time Frame: Day0, Day3, Day7, Day14, Day21, Day28, indicated time points can be added if available ]
  Records of heart failure
• IL-1β (pg/ml) [ Time Frame: Day0, Day3, Day7, Day14, Day21, Day28, indicated time points can be added if available ]
  Record of serum cytokine
• IL-2R (ng/L) [ Time Frame: Day0, Day3, Day7, Day14, Day21, Day28, indicated time points can be added if available ]
  Record of serum cytokine
• IL-6 (ng/L) [ Time Frame: Day0, Day3, Day7, Day14, Day21, Day28, indicated time points can be added if available ]
  Record of serum cytokine
• IL-8 (ng/L) [ Time Frame: Day0, Day3, Day7, Day14, Day21, Day28, indicated time points can be added if available ]
  Record of serum cytokine
• Chest imaging [ Time Frame: Day0, Day3, Day7, Day14, Day21, Day28, indicated time points can be added if available ]
  Computed tomography or X-ray
• Time to SARS-CoV-2 RT-PCR negativity [ Time Frame: Up to 28 days ]
  Time to SARS-CoV-2 RT-PCR negativity in respiratory tract specimens

Original Other Pre-specified Outcome Measures (submitted: February 18, 2020)

• Sequential organ failure assessment (SOFA) score [ Time Frame: Every day for 28 days ]
  Records of daily sequential organ failure assessment (SOFA) score
• Lymphocyte Count (10E9/L) [ Time Frame: Day0, Day3, Day7, Day14, Day21, Day28, indicated time points can be added if available ]
  Records of Blood routine test
• C-reactive protein (CRP) (mg/L) [ Time Frame: Day0, Day3, Day7, Day14, Day21, Day28, indicated time points can be added if available ]
• Lactate dehydrogenase (U/L) [ Time Frame: Day0, Day3, Day7, Day14, Day21, Day28, indicated time points can be added if available ]
• D-dimer (mg/L) [ Time Frame: Day0, Day3, Day7, Day14, Day21, Day28, indicated time points can be added if available ]
  Coagulation function
• pro-type B natriuretic peptide (pro-BNP) (pg/ml) [ Time Frame: Day0, Day3, Day7, Day14, Day21, Day28, indicated time points can be added if available ]
  Records of heart failure
• IL-1β (pg/ml) [ Time Frame: Day0, Day3, Day7, Day14, Day21, Day28, indicated time points can be added if available ]
  Record of serum cytokine
• IL-2R (ng/L) [ Time Frame: Day0, Day3, Day7, Day14, Day21, Day28, indicated time points can be added if available ]
  Record of serum cytokine
• IL-6 (ng/L) [ Time Frame: Day0, Day3, Day7, Day14, Day21, Day28, indicated time points can be added if available ]
  Record of serum cytokine
• IL-8 (ng/L) [ Time Frame: Day0, Day3, Day7, Day14, Day21, Day28, indicated time points can be added if available ]
  Record of serum cytokine
• Chest imaging [ Time Frame: Day0, Day3, Day7, Day14, Day21, Day28, indicated time points can be added if available ]
  Computed tomography or X-ray
• Time to SARS-CoV-2 RT-PCR negativity [ Time Frame: Up to 28 days ]
  Time to SARS-CoV-2 RT-PCR negativity in respiratory tract specimens

Descriptive Information

• Brief Title: A Pilot Clinical Study on Inhalation of Mesenchymal Stem Cells Exosomes Treating Severe Novel Coronavirus Pneumonia
• Official Title: A Pilot Clinical Study on Aerosol Inhalation of the Exosomes Derived From Allogenic Adipose Mesenchymal Stem Cells in the Treatment of Severe Patients With Novel Coronavirus Pneumonia
• Brief Summary: In December 2019, a novel coronavirus infectious disease characterized by acute respiratory impairment due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) broke out in Wuhan city of Hubei province in China. So far no specific antiviral therapy can be available for patients with SARS-CoV-2 infection. Although symptomatic and supportive care, even with mechanical ventilation or extracorporeal membrane oxygenation (ECMO), are strongly recommended for severe infected individuals, those with advancing age and co-morbidities such as diabetes and heart disease remain to be at high risk for adverse outcomes. This pilot clinical trial will be performed to explore the safety and efficiency of aerosol inhalation of the exosomes derived from allogenic adipose mesenchymal stem cells (MSCs-Exo) in severe patients with novel coronavirus pneumonia (NCP).

Detailed Description

Since December 2019, SARS-CoV-2 infection has become a worldwide urgent public health event, especially in China. As of February 13, 2020, over 63,000 cases have been confirmed with over 10,200 severe cases in mainland of China. There is currently no vaccine or specific antiviral treatment existing for SARS-CoV-2 infection. Although symptomatic and supportive care are recommended for severe infected individuals, those with advancing age and co-morbidities such as diabetes and heart disease remain to be at high risk for adverse outcomes, with mortality of ~10%. Therefore, it is urgent to find a safe and effective therapeutic approach to patients with severe coronavirus disease-19(COVID-19) characterized by an severe acute respiratory impairment.

Experimental studies have demonstrated that mesenchymal stem cells (MSCs) or their exosomes (MSCs-Exo) significantly reduced lung inflammation and pathological impairment resulting from different types of lung injury. In addition, macrophage phagocytosis, bacterial killing and outcome are improved. It is highly likely that MSCs-Exo have the same therapeutic effect on inoculation pneumonia as MSCs themselves.

Although human bone marrow MSCs have been safely administered in patients with ARDS and septic shock (phase I/II trials), it seems safer to deliver MSCs-Exo rather than live MSCs. The intravenous administration of MSCs may result in aggregating or clumping in the injured microcirculation and carries the risk of mutagenicity and oncogenicity, which do not exist by treating with nebulized MSCs-Exo. Another advantage of MSCs-Exo over MSCs is the possibility of storing them for several weeks/months allowing their safe transportation and delayed therapeutic use.

The purpose of this single-arm design, open label, combined interventional clinical trial, therefore, is to explore the safety and efficiency of aerosol inhalation of the exosomes derived from allogenic adipose mesenchymal stem cells (MSCs-Exo) in the treatment of severe patients hospitalized with novel coronavirus pneumonia (NCP).

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Coronavirus

Intervention

Biological: MSCs-derived exosomes

5 times aerosol inhalation of MSCs-derived exosomes (2.0*10E8 nano vesicles/3 ml at Day 1, Day 2, Day 3, Day 4, Day 5).

Study Arms

Experimental: MSCs-derived Exosomes Treatment Group

Conventional treatment and aerosol inhalation of MSCs-derived exosomes treatment participants will receive conventional treatment and 5 times aerosol inhalation of MSCs-derived exosomes (2.0*10E8 nano vesicles/3 ml at Day 1, Day 2, Day 3, Day 4, Day 5).

Intervention: Biological: MSCs-derived exosomes

• Publications *: Zhu YG, Shi MM, Monsel A, Dai CX, Dong X, Shen H, Li SK, Chang J, Xu CL, Li P, Wang J, Shen MP, Ren CJ, Chen DC, Qu JM. Nebulized exosomes derived from allogenic adipose tissue mesenchymal stromal cells in patients with severe COVID-19: a pilot study. Stem Cell Res Ther. 2022 May 26;13(1):220. doi: 10.1186/s13287-022-02900-5.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 3, 2020): 24
• Original Estimated Enrollment (submitted: February 18, 2020): 30
• Actual Study Completion Date: July 31, 2020
• Actual Primary Completion Date: May 31, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1.Willingness of study participant to accept this treatment arm, and signed informed consent; 2.Male or female, aged at 18 years (including) to 75 years old; 3.Patients with confirmed novel coronavirus pneumonia; 4.Confirmation of SARS-CoV-2 infection by reverse-transcription polymerase chain reaction (RT-PCR) from respiratory tract or blood specimens; 5.Diagnostic criteria of "Severe" or " Critical":

1. Severe, comply with any of the following:

   1. Respiratory distress, Respiratory rate (RR) ≥ 30 times/min
   2. Pulse oxygen saturation (SpO2) at rest ≤ 93%
   3. Partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) ≤ 300mmHg

2. Critical, comply with any of the following:

   1. Respiratory failure, and requirement for mechanical ventilation
   2. Shock
   3. Other organ failure and requirement for ICU monitoring

Exclusion Criteria:

1. Allergic or hypersensitive to any of the ingredients;
2. Pneumonia caused by bacteria, mycoplasma, chlamydia, legionella, fungi or other viruses;
3. Obstructive HABP/VABP induced by lung cancer or other known causes;
4. Carcinoid syndrome;
5. History of long-term use of immunosuppressive agents;
6. History of epilepsy and requirement for continuous anticonvulsant treatment or anticonvulsant treatment received within the last 3 years;
7. History of severe chronic respiratory disease and requirement for long-term oxygen therapy;
8. Undergoing hemodialysis or peritoneal dialysis;
9. Estimated or actual rate of creatinine clearance < 15 ml/min;
10. History of moderate and severe liver disease (Child-Pugh score >12);

11. Expectation of receiving any of following medications during the study:

    1. Receiving continuous valproic acid or sodium valproate within the first 2 weeks prior to screening
    2. Receiving 5-transtryptamine reuptake inhibitors, tricyclic antidepressants, 5-HT1 receptor agonists or monoamine oxidase inhibitors within the first 2 weeks prior to screening
12. Incapable of understanding study protocol;
13. History of deep venous thrombosis or pulmonary embolism within the last 3 years;
14. Undergoing ECMO or high-frequency oscillatory ventilation support;
15. HIV, hepatitis virus, or syphilis infection;
16. Period of pregnancy or lactation, or planned pregnancy within 6 months;
17. Any condition of unsuitable for the study determined by investigators.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: China

Administrative Information

• NCT Number: NCT04276987
• Other Study ID Numbers: MEXCOVID
• Has Data Monitoring Committee: Not Provided

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

• Plan to Share IPD: Yes
• Plan Description: all IPD that underlie results in a publication
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Supporting Materials: Analytic Code
• Time Frame: Starting 6 months after publication

• Current Responsible Party: Ruijin Hospital
• Original Responsible Party: Same as current
• Current Study Sponsor: Ruijin Hospital
• Original Study Sponsor: Same as current

Collaborators

• Shanghai Public Health Clinical Center
• Wuhan Jinyintan Hospital, Wuhan, China
• Cellular Biomedicine Group Ltd.

Investigators

• Principal Investigator: Jie-ming Qu, MD.,PhD.; Ruijin Hospital, Medical School of Shanghai Jiaotong University Shanghai, China

• PRS Account: Ruijin Hospital
• Verification Date: September 2020