Clinical trial NCT04276987: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Coronavirus
Keywords: mesenchymal stem cells
exosome
nebulization
SARS-CoV-2
novel coronavirus pneumonia
Lead sponsor: Ruijin Hospital
Sponsor class: OTHER
Collaborators: name: Shanghai Public Health Clinical Center
name: Wuhan Jinyintan Hospital, Wuhan, China
name: Shanghai AbelZeta Ltd.
First posted: 2020-02-19
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).

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.

Primary outcomes:
measure: Adverse reaction (AE) and severe adverse reaction (SAE)
timeFrame: Up to 28 days
measure: Time to clinical improvement (TTIC)
timeFrame: Up to 28 days
Secondary outcomes:
measure: Number of patients weaning from mechanical ventilation
timeFrame: Up to 28 days
measure: Duration (days) of ICU monitoring
timeFrame: Up to 28 days
measure: Duration (days) of vasoactive agents usage
timeFrame: Up to 28 days
measure: Duration (days) of mechanical ventilation supply
timeFrame: Up to 28 days
measure: Number of patients with improved organ failure
timeFrame: Up to 28 days
measure: Rate of mortality
timeFrame: Up to 28 days
Other outcomes:
measure: Sequential organ failure assessment (SOFA) score
timeFrame: Every day for 28 days
measure: Lymphocyte Count (10E9/L)
timeFrame: Day0, Day3, Day7, Day14, Day21, Day28, indicated time points can be added if available
measure: C-reactive protein (CRP) (mg/L)
timeFrame: Day0, Day3, Day7, Day14, Day21, Day28, indicated time points can be added if available
measure: Lactate dehydrogenase (U/L)
timeFrame: Day0, Day3, Day7, Day14, Day21, Day28, indicated time points can be added if available
measure: D-dimer (mg/L)
timeFrame: Day0, Day3, Day7, Day14, Day21, Day28, indicated time points can be added if available
measure: pro-type B natriuretic peptide (pro-BNP) (pg/ml)
timeFrame: Day0, Day3, Day7, Day14, Day21, Day28, indicated time points can be added if available
measure: IL-1β (pg/ml)
timeFrame: Day0, Day3, Day7, Day14, Day21, Day28, indicated time points can be added if available
measure: IL-2R (ng/L)
timeFrame: Day0, Day3, Day7, Day14, Day21, Day28, indicated time points can be added if available
measure: IL-6 (ng/L)
timeFrame: Day0, Day3, Day7, Day14, Day21, Day28, indicated time points can be added if available
measure: IL-8 (ng/L)
timeFrame: Day0, Day3, Day7, Day14, Day21, Day28, indicated time points can be added if available
measure: Chest imaging
timeFrame: Day0, Day3, Day7, Day14, Day21, Day28, indicated time points can be added if available
measure: Time to SARS-CoV-2 RT-PCR negativity
timeFrame: Up to 28 days
Locations:
city: Shanghai
country: China
facility: Ruijin Hospital Shanghai Jiao Tong University School of Medicine
state: Shanghai
Study officials:
affiliation: Ruijin Hospital, Medical School of Shanghai Jiaotong University Shanghai, China
name: Jie-ming Qu, MD.,PhD.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.