Mesenchymal Stem Cell for Acute Respiratory Distress Syndrome Due for COVID-19 (COVID-19)

• ClinicalTrials.gov Identifier: NCT04416139
• Recruitment Status: Unknown
• First Posted: June 4, 2020
• Last Update Posted: June 4, 2020
• Sponsor: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
• Information provided by (Responsible Party): Martín Iglesias, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

Tracking Information

• First Submitted Date: May 30, 2020
• First Posted Date: June 4, 2020
• Last Update Posted Date: June 4, 2020
• Actual Study Start Date: May 1, 2020
• Estimated Primary Completion Date: April 30, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 3, 2020)

• Functional Respiratory changes: PaO2 / FiO2 ratio [ Time Frame: Three weeks ]
  To describe the clinical changes secondary to IV administration of AMSCa, in patients with bilateral COVID-19 pneumonia complicated by severe SIRA, with the evaluation of the PaO2 / FiO2 ratio.
• Clinical cardiac changes: Heart rate per minute [ Time Frame: Three weeks ]
  To describe the clinical changes secondary to IV administration of AMSCa, in patients with bilateral COVID-19 pneumonia complicated by severe SIRA, with the evaluation of the heart rate per minute.
• Clinical Respiratory Changes: Respiratory rate per minute [ Time Frame: Three weeks ]
  To describe the clinical changes secondary to IV administration of AMSCa, in patients with bilateral COVID-19 pneumonia complicated by severe SIRA, with the evaluation of the respiratory rate per minute.
• Changes in body temperature [ Time Frame: Three weeks ]
  To describe the clinical changes secondary to IV administration of AMSCa, in patients with bilateral COVID-19 pneumonia complicated by severe SIRA, with the evaluation of the fever curve in degrees centigrade.

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

Current Secondary Outcome Measures (submitted: June 3, 2020)

• General biochemical changes in Leukocytes [ Time Frame: Three weeks ]
  To assess the effect of the proposed treatment on the total Leukocytes
• General biochemical changes on lymphocytes [ Time Frame: Three weeks ]
  To assess the effect of the proposed treatment on absolute lymphocytes
• General biochemical changes on platelets [ Time Frame: Three weeks ]
  To assess the effect of the proposed treatment on total platelets
• General biochemical changes on fibrinogen [ Time Frame: Three weeks ]
  To assess the effect of the proposed treatment on serum fibrinogen
• General biochemical changes on pocalcitonin [ Time Frame: Three weeks ]
  To assess the effect of the proposed treatment on procalcitonin
• General biochemical changes on ferritin [ Time Frame: Three weeks ]
  To assess the effect of the proposed treatment on ferritin
• General biochemical changes on D-dimer [ Time Frame: Three weeks ]
  To assess the effect of the proposed treatment on D-dimer
• Changes on inflammatory C-reactive protein [ Time Frame: Three weeks ]
  To assess the anti-inflammatory effect of the proposed treatment with assessment of the levels of C-reactive protein
• Cahnges on Inflammatory cytokine TNFa [ Time Frame: Three weeks ]
  To assess the anti-inflammatory effect of the proposed treatment with assessment of the levels of TNFa in plasma.
• Changes on Inflammatory cytokine IL10 [ Time Frame: Three weeks ]
  To assess the anti-inflammatory effect of the proposed treatment with assessment of the levels of IL10 in plasma.
• Changes on Inflammatory cytokine IL1 [ Time Frame: Three weeks ]
  To assess the anti-inflammatory effect of the proposed treatment with assessment of the levels of IL1 in plasma.
• Changes on Inflammatory cytokine IL6 [ Time Frame: Three weeks ]
  To assess the anti-inflammatory effect of the proposed treatment with assessment of the levels of IL6 in plasma.
• Changes on Inflammatory cytokine IL 17 [ Time Frame: Three weeks ]
  To assess the anti-inflammatory effect of the proposed treatment with assessment of the levels of IL17 in plasma
• Changes on VEGF [ Time Frame: Three weeks ]
  To assess the anti-inflammatory effect of the proposed treatment with assessment of the levels of VEGF in plasma
• Radiological Changes [ Time Frame: Three weeks ]
  Assess the radiological evolution of the proposed treatment through simple chest CT
• Immunological changes on T cell [ Time Frame: Three weeks ]
  Evaluate immune system improvement with mass cytometry to analyze patients' immune cells: regulatory T cells
• Immunological changes on Dendritic cells [ Time Frame: Three weeks ]
  Evaluate immune system improvement with mass cytometry to analyze patients' immune cells: dendritic cells
• Immunological changes on CD4+ T [ Time Frame: Three weeks ]
  Evaluate immune system improvement with mass cytometry to analyze patients' immune cells: CD4 + T
• Immunological changes on CD8+ T [ Time Frame: Three weeks ]
  Evaluate immune system improvement with mass cytometry to analyze patients' immune cells: CD8 + T
• Immunological changes on NK cell [ Time Frame: Three weeks ]
  Evaluate immune system improvement with mass cytometry to analyze patients' immune cells: NK cells
• Adverse events [ Time Frame: Three weeks ]
  Evaluate the safety of the proposed treatment (allergic reactions and / or infection)
• RNA detection by SARS-Cov2 PCR [ Time Frame: Three weeks ]
  To assess the negativization of the SARS-Cov2 PCR RNA detection test

• 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: Mesenchymal Stem Cell for Acute Respiratory Distress Syndrome Due for COVID-19
• Official Title: Mesenchymal Stem Cells for the Treatment of Severe Acute Respiratory Distress Syndrome Due to COVID-19. Pilot Study

Brief Summary

Acute Respiratory Distress Syndrome (ARDS) is the main cause of death from COVID-19. One of the main mechanisms for ARDS is the violent storm of cytokines and chemokines, which cause uncontrolled fatal systemic inflammation by the immune system on the body, with additional multiple organ failure. Mortality in cases of severe ARDS caused by COVID 19 varies significantly between 50 and 90%, basically depending on the age of the patient and the presence of comorbidities.

The plasticity of Mesenchymal Stem Cells (MSC) regulates inflammation and immunity. MSC can promote and inhibit an immune response, depending on the dynamics of inflammation and depending on the activation force of the immune system, the types of inflammatory cytokines present, and the effects of immunosuppressants. Essentially, the state of inflammation determines the immunoregulatory fate of MSC. Thus, IV application of AMSCa has been shown to control the inflammatory response in various diseases, such as the graft-versus-host reaction and the ARDS caused by H5NI.

The objective of this study is to describe the clinical changes secondary to IV administration of MSC allogenic, in patients with bilateral COVID-19 pneumonia complicated by severe ARDS, with the evaluation of the PaO2 / FiO2 ratio, heart and respiratory rates, and the fever curve.

Five patients, of either sex, over 18 years of age, with bilateral pneumonia caused by COVID-19 and severe SIRA that has not improved with the standard management measures used at that time in the care center, will be included in the study. This treatment will be administered after discussing it with the relatives that it is a procedure considered as rescue and will be carried out with informed consent. 1x10(6) xKg will be applied IV.

The follow-up of the patient will be for three weeks. PaO2 / FiO2 data, fever, inflammatory markers and immunity will be evaluated. The results will be compared with the historical controls attended at INCMNSZ.

Detailed Description

Acute Respiratory Distress Syndrome (ARDS) is the main cause of death from COVID-19. One of the main mechanisms for ARDS is the storm of cytokines and chemokines, which cause uncontrolled fatal systemic inflammation. The SARS-CoV-2 virus infects cells that express the angiotensin II converting enzyme receptor (ACE2). This receptor is widely distributed on the surface of type II alveolar cells (AT2) and on the capillary endothelium. This is why the cytokine storm will trigger a violent attack by the immune system on the body, cause ARDS and multiple organ failure, and can ultimately lead to death. Mortality in cases of severe SIRA caused by COVID 19 varies significantly between 50 and 90%, basically depending on the age of the patient and the presence of comorbidities.

The plasticity of Mesenchymal Stem Cell (MSC) regulates inflammation and immunity. MSC can promote and inhibit an immune response, depending on the dynamics of inflammation and depending on the activation force of the immune system, the types of inflammatory cytokines present, and the effects of immunosuppressants. Essentially, the state of inflammation determines the immunoregulatory fate of MSC. Thus, IV application of MSC has been shown to control the inflammatory response in various diseases, such as the graft-versus-host reaction and the ARDS caused by H5NI.

MSC are negative for ACE2, therefore they have been used to decrease the cytokine storm present in COVID-19.

Two recent studies in China have used human allogeneic MSC to treat COVID-19 pneumonia. Both studies reveal a marked reversal of symptoms, even in critically serious cases. Lung function improved two days after MSC application and 10 days later they were discharged. Lymphocytes increased, PCR decreased, and cytokine-producing immune cells disappeared within 3 to 6 days. Regulatory immune cells increased. TNF alpha factor decreased and IL10 increased.

Taking into account the previous concepts together with the current global pandemic, and the high mortality existing among patients with bilateral pneumonia caused by COVID-19 and severe ARDS, the investigators propose intravenous infusion of mesenchymal stem cells from bank laboratory, with the purpose partially proven to decrease the systemic inflammatory process, offering it as a salvage treatment.

Five patients, of either sex, over 18 years of age, with bilateral pneumonia caused by COVID-19 and severe ARDS that has not improved in relation to the following parameters: a) Persistent PaO2 / FiO2 less than 150, b) persistent fever, c ) D-dimer increase of at least 50% of baseline and / or ferritin greater than 1000, after 48 h of hospital stay receiving the standard management measures used at that time in the care center, will be included in the study. Covid pneumonia should be confirmed by chest CT and RNA detection by positive SARS-Cov2 PCR. This treatment will be administered after discussing it with the relatives that it is a procedure considered as rescue and will be carried out with informed consent.

Their follow-up will be daily while they are hospitalized in the Intensive Care Unit and / or hospitalized, until their discharge from the hospital or until the third week after surgery. If the patient has already been discharged from the hospital, his last evaluation will be in the third week.

The main objective of this protocol is: To describe the clinical changes secondary to IV administration of MSC, in patients with bilateral COVID-19 pneumonia complicated by severe ARDS, with the evaluation of the PaO2 / FiO2 ratio, heart rate and respiratory rate, as well as of the fever curve daily.

The secondary objectives are:

a) To assess the effect of the proposed treatment on the general biochemical indicators (Leukocytes, absolute lymphocytes, absolute neutrophils, absolute monocytes, absolute eosinophils, absolute basophils, erythrocytes, hemoglobin, platelets, total bilirubin, albumin, amino-aspartate transferase, fibrinogen, procalcitonin, glomerular filtration, myoglobin, troponin, ferritin and D-dimer. Daily.

b. To assess the anti-inflammatory effect of the proposed treatment with assessment of the levels of cytokines, and C-reactive protein, TNFa, IL10, IL1, IL6, IL17, VEGF in plasma. These variables will be evaluated before treatment, upon discharge from the ICU, and / or from the Hospital.

c. Assess the radiological evolution of the proposed treatment through simple chest CT. These variables will be evaluated before treatment, upon discharge from the ICU, and / or from the Hospital.

d. Evaluate immune system improvement with mass cytometry to analyze patients' immune cells: regulatory T cells (CXCR3-), dendritic cells (DC, CXCR3-), CXCR3 + CD4 + T, CXCR3 + CD + T, and CXCRT3 + NK. These variables will be evaluated before treatment, upon discharge from the ICU, and / or from the Hospital.

e) Assess the safety of the proposed treatment (allergic reactions and / or infection) F. To assess the negativization of the RNA detection test by SARS-Cov2 PCR. These variables will be evaluated before treatment, upon discharge from the ICU, and / or from the Hospital.

The inclusion criteria are:

1. Comply with the informed consent procedure and sign the informed consent form.
2. Over 18 years
3. Of any gender
4. With SARS-Cov2 PCR RNA detection test, positive
5. With bilateral pneumonia caused by COVID-19
6. Severe ARDS with PaO2 / FiO2 less than 150
7. That it has not improved in relation to: a) Persistent PaO2 / FiO2 less than 150, b) persistent fever, c) increase in D-dimer at least 50% of the baseline and / or ferritin greater than 1000, after 48 hrs hospital stay receiving the standard management measures used at that time in the care center.
8. Lymphopenia less than 800 total lymphocytes
9. Increased D-dimer (> 1200 mg / dl)
10. CT compatible with bilateral pneumonia
11. SOFA under 11 With knowledge of the patient and / or their responsible relatives that it is a rescue treatment, in an experimental phase.

The bank mesenchymal cells will be donated by the CBCells Bio Technology Laboratory, at no cost to the patient or INCMNSZ.

1x106 x Kg of weight, diluted in 100 ml of saline, will be infused intravenously, to pass in 40 minutes. It will be monitored with monitors, Pao2 / Fio2, FC, FR, ECG. Additionally, fever and muscle contractures will be monitored, which will be recorded every hour for 24 hours and every 24 hours thereafter, up to three weeks after the application of MSC. The patient should continue with their indicated medical treatments, such as antibiotics and specific treatments in case of comorbidities.

The results will be compared with the historical controls attended at INCMNSZ Thus, the results obtained will give information to calculate the sample size in subsequent studies in which the usefulness of the procedure will be evaluated.

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

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

Mesenchymal Stem Cell from umbilical cord allogenic from de bank laboratory, will be applied IV to 5 patients con pneumonia bilateral due to COVID 19, complicated with acute respiratory distress syndrome. The clinical, biochemical, inflammatory and immune changes will be described and compare against historical cases treated in the Instituto Nacional de Ciencias Medicas y Nutrición Salvador Zubirán

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Covid 19

Intervention

Biological: Infusion IV of Mesenchymal Stem cells

Mesenchymal Stem cells from bank will be applied IV, at dose 1 million xKg in a single dose

Study Arms

• Active Comparator: Treated group
  Five patients, of any sex and age, with bilateral COVID-19 pneumonia, severe SIRA with PaO2 / FiO2 less than 150, lymphopenia less than 800 total lymphocytes, CT with bilateral pneumonia, SOFA less than 11 and that has not improved in relation to the following parameters: a) persistent PaO2 / FiO2 less than 150; b) persistent fever, c) increase in D-dimer of at least 50% of the baseline and / or ferritin greater than 1000, after 48 h of hospital stay receiving the standard management measures used at that time in the Care Center, will be included in the study. This treatment will be administered after discussing it with the relatives that it is a procedure considered as rescue and will be carried out with informed consent.
  Intervention: Biological: Infusion IV of Mesenchymal Stem cells
• No Intervention: Control Group
  The results obtained in the treated group will be compared against the historical controls treated in INCMNSZ, evaluating the same variables.

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: June 3, 2020): 10
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: May 1, 2021
• Estimated Primary Completion Date: April 30, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Bilateral pneumonia due to COVID-19
• With SARS-Cov2 PCR RNA detection test, positive
• Severe ARDS
• PaO2/FiO2 <150
• Leukocytes < 800
• Chest TAC with pneumonia bilateral
• persistant fever
• increase 50% D-Dimer, respect to basal value
• Ferritin > 1000
• SOFA < 11
• Medical treatment during 48 hr according to de Institutional Medical center
• With knowledge of the patient and / or his relatives responsible that it is a rescue treatment, in experimental phase.

Exclusion Criteria:

• Pneumonia or ARDS caused by COVID-19, mild and moderate.
• More than three organic failures
• Expectations of survival less than 48 hr in the opinion of the treating service
• Pneumonia or SIRA not caused by COVID-19
• Advance will of the patient to refuse rescue or experimental treatment.

Sex/Gender

• Sexes Eligible for Study: All

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

Administrative Information

• NCT Number: NCT04416139
• Other Study ID Numbers: SCI-3354-20-21-1
• Has Data Monitoring Committee: Yes

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: No

• Current Responsible Party: Martín Iglesias, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
• Original Responsible Party: Same as current
• Current Study Sponsor: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
• Verification Date: June 2020