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

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

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).

Study Overview

• Status: Completed
• Conditions: Coronavirus
• Intervention / Treatment: Biological: MSCs-derived exosomes

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
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200025
      • Ruijin Hospital Shanghai Jiao Tong University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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).	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).

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Other Outcome Measures

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

Collaborators and Investigators

• Sponsor: Ruijin Hospital
• Collaborators: Shanghai Public Health Clinical Center; Cellular Biomedicine Group Ltd.; Wuhan Jinyintan Hospital, Wuhan, China
• Investigators: Principal Investigator: Jie-ming Qu, MD.,PhD., Ruijin Hospital, Medical School of Shanghai Jiaotong University Shanghai, China

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 15, 2020
• Primary Completion (Actual): May 31, 2020
• Study Completion (Actual): July 31, 2020

Study Registration Dates

• First Submitted: February 16, 2020
• First Submitted That Met QC Criteria: February 18, 2020
• First Posted (Actual): February 19, 2020

Study Record Updates

• Last Update Posted (Actual): September 7, 2020
• Last Update Submitted That Met QC Criteria: September 3, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: SARS-CoV-2; mesenchymal stem cells; nebulization; exosome; novel coronavirus pneumonia
• Additional Relevant MeSH Terms: Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Coronavirus Infections; Pneumonia
• Other Study ID Numbers: MEXCOVID

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No