Mesenchymal Stromal Cells for the Treatment of SARS-CoV-2 Induced Acute Respiratory Failure (COVID-19 Disease)

Phase 1

Completed

Conditions: COVID-19
Sars-CoV2
Acute Respiratory Distress Syndrome

Interventions: Other: Supportive Care
Biological: Mesenchymal Stromal Cells

Registration Number: NCT04345601

Lead Sponsor: Baylor College of Medicine

Brief Summary: \*\*\*At this time, we are only enrolling at Houston Methodist Hospital (HMH)/Baylor College of Medicine (BCM) and are not shipping cells outside of BCM/HMH.\*\*\*

This is a study for patients who have respiratory infection caused by SARS-CoV-2 that have not gotten better. Because there is no standard treatment for this infection, patients are being asked to volunteer for a gene transfer research study using mesenchymal stem cells (MSCs).

Stem cells are cells that do not yet have a specific function in the body. Mesenchymal stem cells (MSCs) are a type of stem cell that can be grown from bone marrow (the spongy tissue inside of bones). Stem cells can develop into other types of more mature (specific) cells, such as blood and muscle cells.

The purpose of this study is to see if MSCs versus controls can help to treat respiratory infections caused by SARS-CoV-2.

Detailed Description: Earlier, a healthy donor provided blood cells to generate MSCs. These cells were grown and frozen for later use.

Before being treated, the patient will receive a series of standard medical tests: These tests are done to assess the patient's eligibility to receive the cells.

* Physical exam and history

* SARS-CoV-2 test

* Blood tests

* Chest X-ray or chest CT Scan

* A urine pregnancy test, when applicable

The patient will be randomly assigned to a study group. We'll use a computer to put the patient into study group A (study drug) or group B (control) by chance (randomized). Patients randomized to the control group, will receive the standard treatment for their respiratory infection.

On the day that the patient is scheduled to receive the cells they will be pre-medicated with Benadryl and Tylenol. The patient will then receive an intravenous (into the vein) infusion of 1 x 10\^8 cells/kg of MSCs. The patient will be monitored closely for two hours after the infusion. The patient will receive a second infusion at the same dose within 3-5 days of the initial infusion (at the discretion of the investigator) if there is no improvement in respiratory parameters or if there is a worsening of Acute respiratory distress syndrome (ARDS).

The patient will receive standard medical tests when getting the infusion(s) and afterwards. As part of the research study, the patient will be evaluated daily for 7 days and then weekly at weeks 2, 3, and 4. The evaluations that will be done at these visits include:

* Physical exam and history

* SARS-CoV-2 test

* Blood tests

* Chest X-ray or chest CT Scan

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 28

Inclusion Criteria

18 years or older
Confirmed SARS-CoV2 infection real-time reverse transcription polymerase chain reaction (RT-PCR) assay
Moderate OR severe ARDS, based on the degree of impairment of oxygenation as defined by the ratio of arterial oxygen tension to fraction of inspired oxygen (PaO2/FiO2):
1. Moderate ARDS: PaO2/FiO2 100-200 mmHg OR
2. Severe ARDS: PaO2/FiO2 ≤100 mmHg
If on invasive or noninvasive (BiPAP) mechanical ventilator, PEEP ≥5 cm H2O
Bilateral opacities present on chest radiograph or computed tomographic (CT) scan, that are not fully explained by pleural effusions, lung collapse, or lung nodules.

Exclusion Criteria

Currently receiving extracorporeal membrane oxygenation (ECMO)
Severe chronic respiratory disease requiring use of home oxygen
Pregnant or lactating
Known hypersensitivity to dimethyl sulfoxide (DMSO)
Unstable hemodynamics as deemed by the treating physician/investigator including but not limited to unstable, ventricular tachycardia or new cardiac arrythmia requiring cardioversion.
Uncontrolled bacterial or fungal co-infection
Any end-stage organ disease or condition, which in the opinion of the Investigator, makes the patient an unsuitable candidate for treatment
Inability to obtain informed consent (from patient or legally appropriate proxy)
Presence of any contraindication to receiving prophylactic low dose unfractionated or low molecular weight heparin.
Respiratory failure not fully explained by cardiac failure or fluid overload.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Control Group	Supportive Care	Patients randomized to the control arm will receive supportive care or treatment designated by their treating physicians.
Safety Run In	Mesenchymal Stromal Cells	The study will first enroll and treat six patients with MSCs for safety run in. If no more than 2 treatment-related severe adverse events (tSAEs) are observed, the study will enroll and randomize additional patients in a ratio of 1:1 to receive either MSCs or routine/supportive care.
Mesenchymal stromal cells	Mesenchymal Stromal Cells	Patients randomized to the MSC arm will be administered an intravenous infusion of MSCs at a dose of 1 x 10\^8. A second infusion will be allowed if the patient does not have improvement in respiratory parameters per discretion of the investigator, or ARDS clinically worsens, within 3-5 days following the initial infusion.

Primary Outcome Measures

Name	Time	Method
Proportion of Participants With Treatment-related Serious Adverse Events (tSAEs)	28 days post cell infusion	Treatment-related serious adverse events (tSAE) are those directly related to the investigational infusion product. Adverse event grading will be per NCI Common Terminology Criteria for Adverse Events(CTCAE), vs 5. Rate of tSAEs in patients treated with MSCs will be reported as proportion and its 95% confidence interval.
Number of Participants With Improvement by at Least Two Categories on a Six Category Ordinal Scale at Day 14	14 days post cell infusion	Change by at least two categories on a six-category ordinal scale as improvement at day 14 post-randomization per protocol defined criteria. The six-category ordinal scale ranges from 6 to 1 with a higher score indicating a worse clinical outcome as follows: 6 ꞊ death; 5 ꞊ hospitalization, requiring extracorporeal membrane oxygenation (ECMO) and/or invasive mechanical ventilation (IMV); 4 ꞊ hospitalization, requiring non-invasive mechanical ventilation (NIV) and/or High-flow nasal cannula (HFNC) therapy; 3 = hospitalization, requiring supplemental oxygen (but not NIV/HFNC); 2 = hospitalization, not requiring supplemental oxygen; 1 = hospital discharge.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Progression to Mechanical Ventilation or ECMO	28 days post cell infusion	Participants not receiving mechanical ventilation at baseline who progress to requiring mechanical ventilation.
Number of Oxygenation Free Days at Day 28	28 days post cell infusion	Number of oxygen support-free days through Day 28
Duration of Hospital Stay	from the date of on study to the time of hospital discharge, death, or last follow-up, whichever occurred first. Up to 35 days.	Duration of hospital stay is calculated from the date of on study to the time of hospital discharge, death, or last follow-up, whichever occurred first. It does not reflect the entire hospitalization time.
Duration of Mechanical Ventilation and/or ECMO	28 days post cell infusion	Number of days requiring invasive mechanical ventilation and/or ECMO (ventilation/ECMO free days at day 28)
Overall Survival	28 days post cell infusion	Probability of overall survival is calculated using Kaplan-Meier survival curves per protocol. Overall survival time is defined as days from the date of randomization or date of infusion if received MSCs to the date of death or the date of the last follow-up for censoring.
Clinical Status Determined by 6-point Ordinal Scale at Day 28	28 days post cell infusion	Clinical status at day 28 as determined by 6-point ordinal scale as follows: 6 ꞊ death; 5 ꞊ hospitalization, requiring extracorporeal membrane oxygenation (ECMO) and/or invasive mechanical ventilation (IMV); 4 ꞊ hospitalization, requiring non-invasive mechanical ventilation (NIV) and/or High-flow nasal cannula (HFNC) therapy; 3 = hospitalization, requiring supplemental oxygen (but not NIV/HFNC); 2 = hospitalization, not requiring supplemental oxygen; 1 = hospital discharge. The six-category ordinal scale ranges from 6 to 1 with a higher score indicating a worse clinical outcome.
Severity of Acute Respiratory Distress Syndrome (ARDS) at Day 14	14 days post cell infusion	ARDS is divided into 3 groups based on the degree of hypoxemia: mild (partial pressure of oxygen in the arterial blood(PaO2)/fraction of inspired oxygen(FIO2) 201-300 mm Hg), moderate (PaO2/FIO2: 101-200 mm Hg), and severe (PaO2/FIO2 ≤ 100 mm Hg) and ventilator settings with a positive end-expiratory pressure (PEEP) or continuous positive airway pressure (CPAP) ≥5 cm water (H2O).
Duration of ICU Stay	from the date of admission or data of on study if the patient was admitted to ICU before enrollment to the time of ICU discharge, death, or last follow-up, whichever occurred first. Up to 35 days.	The number of days a participant spent in ICU. Duration of ICU stay is calculated from the date of admission or data of on study if the patient was admitted to ICU before enrollment to the time of ICU discharge, death, or last follow-up, whichever occurred first.
All-cause Mortality	28 days post cell infusion	Number and percentage of deaths (all-cause) until Day 28