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

June 3, 2020 updated by: Martín Iglesias, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

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

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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

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

Enrollment (Anticipated)

10

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Mexico
      • Mexico City, Mexico, 14080
        • Recruiting
        • Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
        • Contact:
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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.
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
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Three weeks
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.
Three weeks
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.
Three weeks
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.
Three weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
General biochemical changes in Leukocytes
Time Frame: Three weeks
To assess the effect of the proposed treatment on the total Leukocytes
Three weeks
General biochemical changes on lymphocytes
Time Frame: Three weeks
To assess the effect of the proposed treatment on absolute lymphocytes
Three weeks
General biochemical changes on platelets
Time Frame: Three weeks
To assess the effect of the proposed treatment on total platelets
Three weeks
General biochemical changes on fibrinogen
Time Frame: Three weeks
To assess the effect of the proposed treatment on serum fibrinogen
Three weeks
General biochemical changes on pocalcitonin
Time Frame: Three weeks
To assess the effect of the proposed treatment on procalcitonin
Three weeks
General biochemical changes on ferritin
Time Frame: Three weeks
To assess the effect of the proposed treatment on ferritin
Three weeks
General biochemical changes on D-dimer
Time Frame: Three weeks
To assess the effect of the proposed treatment on D-dimer
Three weeks
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
Three weeks
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.
Three weeks
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.
Three weeks
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.
Three weeks
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.
Three weeks
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
Three weeks
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
Three weeks
Radiological Changes
Time Frame: Three weeks
Assess the radiological evolution of the proposed treatment through simple chest CT
Three weeks
Immunological changes on T cell
Time Frame: Three weeks
Evaluate immune system improvement with mass cytometry to analyze patients' immune cells: regulatory T cells
Three weeks
Immunological changes on Dendritic cells
Time Frame: Three weeks
Evaluate immune system improvement with mass cytometry to analyze patients' immune cells: dendritic cells
Three weeks
Immunological changes on CD4+ T
Time Frame: Three weeks
Evaluate immune system improvement with mass cytometry to analyze patients' immune cells: CD4 + T
Three weeks
Immunological changes on CD8+ T
Time Frame: Three weeks
Evaluate immune system improvement with mass cytometry to analyze patients' immune cells: CD8 + T
Three weeks
Immunological changes on NK cell
Time Frame: Three weeks
Evaluate immune system improvement with mass cytometry to analyze patients' immune cells: NK cells
Three weeks
Adverse events
Time Frame: Three weeks
Evaluate the safety of the proposed treatment (allergic reactions and / or infection)
Three weeks
RNA detection by SARS-Cov2 PCR
Time Frame: Three weeks
To assess the negativization of the SARS-Cov2 PCR RNA detection test
Three weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 1, 2020

Primary Completion (Anticipated)

April 30, 2021

Study Completion (Anticipated)

May 1, 2021

Study Registration Dates

First Submitted

May 30, 2020

First Submitted That Met QC Criteria

June 3, 2020

First Posted (Actual)

June 4, 2020

Study Record Updates

Last Update Posted (Actual)

June 4, 2020

Last Update Submitted That Met QC Criteria

June 3, 2020

Last Verified

June 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • SCI-3354-20-21-1

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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