Menstrual Blood Stem Cells in Severe Covid-19

Study Overview
=================
Brief Summary
-----------------
In this randomized controlled trial (RCT), severe cases of COVID-19 infection will be treated with secretome of menstrual blood stem cells. The improvement in the clinical, laboratory and radiological manifestations will be evaluated in treated patients compared with the control group.

Detailed Description
-----------------
The devastating effect of severe acute respiratory syndrome coronavirus-2 (SARS COV-2) infection is caused by a robust cytokine storm that leads to lung tissue damage. Several studies have found that the severity of the disease is correlated with the release of excessive proinflammatory cytokines, such as IL-1, IL-6, IL-12, IFN-γ, and TNF-α, preferentially targeting lung tissue. This finding was confirmed by the high level of plasma cytokines found in the most severe COVID-19 patients associated with extensive lung damage. As a result, it is essential to find an effective treatment option to control the devastating cytokine storm of COVID-19 and regenerate the damaged lung. Although mesenchymal stem cells are a powerful tool for clinical applications, they have limits in terms of administration, safety, and variability of therapeutic response. It is interesting to note that the MSC secretome composed of cytokines, chemokines, growth factors, proteins, and extracellular vesicles could be a valid alternative to their use. It is not only easier to preserve, transfer and produce the secretome, but also safer to administer. Previous studies reported that the hypoxic condition of MSCs could enhance the release of their active soluble molecules known as Secretome-MSCs (S-MSCs), such as IL-10 and TGF-β that useful in alleviating inflammation. Moreover, they could also increase the expression of growth factors such as VEGF and PDGF that accelerate lung injury improvement. These active molecules could potentially serve as a biological therapeutic agent for treating the severe SARS-CoV-2 infection. According to recent studies, we successfully isolated the S-MSCs from their culture medium using tangential flow filtration (TFF) strategy with several molecular weight cut-off category. This study investigated the clinical outcomes of severe COVID-19 patients with several comorbidities treated with S-MSCs in Indonesia.

Official Title
-----------------
Safety and Efficacy Study of Allogeneic Human Menstrual Blood Stem Cells Secretome to Treat Severe Covid-19 Patients, Clinical Trial Phase I&II

Conditions
-----------------
Covid19, Cytokine Storm

Intervention / Treatment
-----------------
* Biological: Allogeneic human menstrual blood stem cells secretome
* Other: Intravenous saline injection


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients whose clinical and laboratory test results have a positive diagnosis of Covid-19. Patients who are willing to participate as subjects in the study by signing the informed content. Diagnosed with severe pneumonia of COVID: respiratory distress, RR >30 times/min; resting oxygen saturation of 90% or less; arterial partial pressure of oxygen / oxygen concentration ≤300mmHg; Pulmonary infiltration more than 50% in 24 to 48 hours SARS-CoV-2 nucleic acid test was positive. Exclusion Criteria: History of drug reactions or allergies Pneumonia caused by bacteria, Mycoplasma, Chlamydia, Legionella, fungi, or other viruses Airway obstruction due to lung cancer or unknown factors Carcinoid syndrome History of epilepsy and long-term use of anticonvulsant drugs during the last 3 years History of long-term use of immunosuppressive drugs History of chronic respiratory illness that requires long-term oxygen therapy The patient is on blood or peritoneal dialysis Creatinine clearance <15 ml / min Moderate to severe liver disease (Child-Pugh score> 12) History of deep vein thrombosis (DVT) or pulmonary embolism over the past 3 years Being under ECMO or high-frequency oscillatory ventilation support Diagnostic of HIV, hepatitis B, and syphilis Pregnant or lactating women Lack of consciousness and inability to provide informed consent by the patient

Ages Eligible for Study
-----------------
Minimum Age: 25 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Biological: allogeneic human menstrual blood stem cells secretome Intravenous injection of 5 ml menstrual blood stem cells secretome on day 1, day 2, day 3, day 4, and day 5, based on the routine treatment of COVID-19 Other: Intravenous saline injection (Placebo) Intravenous injection of 5ml of 0.9% saline on day 1, day 2, day 3, day 4, and day 5, based on the routine treatment of COVID-19
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Menstrual blood stem cell secretome group<br>Intravenous Allogeneic Menstrual Blood Stem Cells Secretome injection+Routine treatment | Biological: Allogeneic human menstrual blood stem cells secretome<br>* This COVID-19 Study intervention consists of Intravenous Allogeneic human menstrual blood stem cell (MenSC) secretome injection in addition to standard care. The MenSC were characterized as CD90+, CD73+, CD105+, and CD45-based on multiparameter flow cytometry.<br>|
| Placebo Comparator: Control group<br>Intravenous saline injection (Placebo)+Routine treatment | Other: Intravenous saline injection<br>* Intravenous saline injection in addition to standard care<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse reactions incidence | The proportion of participants with treatment-related Adverse Event as assessed by CTCAE v5.0. | Day 0 - 28 | 
| Time to clinical improvement | Days from administration of the Investigational Product for improvement | Day 0 - 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of serum CRP (mg/L) levels | To evaluate the anti-inflammatory effect of the proposed treatment an assessment of the inflammatory markers | Days 0, 5, 10, 14, and 28 | 
| Assessment of serum LDH (U/L) levels | To evaluate the anti-inflammatory effect of the proposed treatment an assessment of the inflammatory markers | Days 0, 5, 10, 14, and 28 | 
| Assessment of serum Ferritin (ng/ml) levels | To evaluate the anti-inflammatory effect of the proposed treatment an assessment of the inflammatory markers | Days 0, 5, 10, 14, and 28 | 
| Assessment of serum D-dimer (microgr/ml) levels | To evaluate the anti-inflammatory effect of the proposed treatment an assessment of the inflammatory markers | Days 0, 5, 10, 14, and 28 | 
| Immunological changes on CD4+ T and CD8+ T | Evaluate immune system improvement with flow cytometry to analyze patients' immune cells | Days 0, 5, 10, 14, and 28 | 
| Lung Involvement | Side effects measured by Chest Readiograph Side effects measured by Chest Readiograph | Day 0 - 28 | 
| Changes in Inflammatory cytokine IL 6 | To assess the anti-inflammatory effect of the proposed treatment an assessment of the levels of IL6 in plasma. | Days 0, 5, 10, 14, and 28 | 
| Changes in anti-Inflammatory cytokine IL10 | To assess the anti-inflammatory effect of the proposed treatment an assessment of the levels of IL10 in plasma. | Days 0, 5, 10, 14, and 28 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
menstrual blood stem cell, mesenchymal stem cells, secretome, covid-19