Multiple Dosing of Mesenchymal Stromal Cells in Patients With ARDS (COVID-19)

Phase 2

Completed

Conditions: ARDS (Moderate or Severe)
COVID-19 Pneumonia
Acute Respiratory Distress Syndrome

Interventions: Other: Placebo
Biological: Mesenchymal stromal cells

Registration Number: NCT04466098

Lead Sponsor: Masonic Cancer Center, University of Minnesota

Brief Summary: This is a multi-center, randomized, placebo controlled, interventional phase 2A trial to evaluate the safety profile and potential efficacy of multi-dosing of mesenchymal stromal cells (MSC) for patients with SARS-CoV-2 associated Acute Respiratory Distress Syndrome (ARDS). After informed consent, treatment assignment will be made by computer-generated randomization to administer either MSC or vehicle placebo control with a 2:1 allocation to the MSC: placebo arm.

Detailed Description: MSCs are adult, non-hematopoietic precursor cells derived from a variety of tissues (e.g., bone marrow, adipose tissue, and placenta) and have been used as therapy in multiple conditions, especially in immune-mediated inflammatory diseases, such as graft versus-host disease (GVHD) and systemic lupus erythematosus (SLE) with evidence of benefit.

In preclinical models, MSC are effective in ameliorating acute lung injury due to their ability to secrete paracrine factors that regulate lung endothelial and epithelial permeability, including growth factors, anti-inflammatory cytokines, and antimicrobial peptides. Based on the promising pre-clinical preliminary data and intriguing results in patients with COVID-19 associated pneumonia and ARDS as well as an established safety profile of MSC generally and in ARDS in particular, the researchers propose multiple dosing of MSCs as a study treatment to ameliorate the severity and duration of SARS-CoV-2 associated pneumonia and ARDS potentially improve survival.

Patients will receive study agent (MSC or placebo) within 48 hours of enrollment. Three doses will be administered unless a severe infusion adverse event occurs that is related to the MSC infusion. Doses will be repeated approximately every 48-72 hours with the aim of completing 3 doses within 7 days of the first dose. All patients will receive standard of care treatments for ARDS.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 8

Inclusion Criteria

Age 18-80 years
Meets 'Berlin Criteria' for diagnosis of moderate to severe ARDS for a minimum of 4 hours
Less than 48 hours on a ventilator after meeting criteria for diagnosis of ARDS
SARS-CoV-2 (proven by RT-PCR assay) with radiographic infiltrates
PaO2/FiO2 < 250
Positive end-expiratory airway pressure (PEEP) >5 cm H20
Elevated C-reactive protein (above laboratory upper limit of normal)
Meets organ function requirements, including left ventricular ejection fraction (LVEF) >35% ( as defined below)
Off other investigational agents directed against inflammatory cytokines 48 hours prior to enrollment; agents directed against the replication of SARS-CoV-2 [e.g., Remdesivir] are permitted
Voluntary informed consent in person or virtually by the patient or patient surrogate considering the face to face limitations during the COVID-19 pandemic and, given the nature of the study population, which frequently requires mechanical ventilation with sedation, surrogate consent will likely occur in a substantial proportion of the study population (this will remain a valid consent until the patient is fully alert, and aware, and can provide a second consent to continue participation in the study).
Adequate organ function is defined as:
- Renal: Calculated estimated glomerular filtration rate >30 mL/min/1.73 m2 (on chemistry panel)
- Hepatic: Bilirubin <3x upper limit of normal (ULN) and AST, ALT and alkaline phosphatase <5x ULN
- Cardiac: Absence of uncontrolled arrhythmia and LVEF >35%

Exclusion Criteria

Ventilator support of FiO2 >0·8 or PEEP >20 cm H2O and ongoing use of more than two vasopressors for 2 or more hours with any agent at doses shown below in the supine position.
- Norepinephrine >12 μg/min or 0.2 μg/kg per min
- Phenylephrine >150 μg/min or 3 μg/kg per min
- Epinephrine >10 ug/min or 0.2 μg/kg per min
- Vasopressin >0.04 units/min
Concurrent use of other investigational agents specifically for treatment of ARDS or inflammatory cytokines. (Note: Agents established to be efficacious and/or those used outside of formal trials are permitted as supportive data emerge)
Known ineligibility for use of a ventilator for a minimum of 7 days, as judged by the institution's Triage Team
Known allergy to MSC components: fetal calf serum, human albumin or DMSO
Active invasive malignant disease requiring chemotherapy/radiation
Other concurrent life-threatening disease (life expectancy <6 months) or eligible for hospice care
Known history of HIV infection on active treatment
Females who are pregnant or breastfeeding
Current mean arterial pressure (MAP) <60 mmHg while on 2 or more vasopressors at above doses for more than 2 hours
History of any significant cardiac (myocardial infarction within 12 months of screening visit or unstable angina), chronic ongoing hepatic, or renal disease (grade 3 or higher); diagnosis of congestive heart failure with hypoxemia primarily due to decompensated heart failure; diagnosis of severe chronic obstructive pulmonary disease (COPD) or interstitial lung disease requiring supplemental oxygen at home
Concurrent diagnosis of diffuse alveolar hemorrhage
Requiring continuous dialysis (unable to stop dialysis during study agent infusion)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Three fixed doses of placebo control approximately 48 hours apart.
Mesenchymal Stromal Cells	Mesenchymal stromal cells	Three fixed doses of MSC approximately 48 hours apart.

Primary Outcome Measures

Name	Time	Method
Incidence of Grade 3-5 Infusional Toxicities and Predefined Hemodynamic or Respiratory Adverse Events Related to the Infusion of MSC	Within 6 hours of the start of the infusion

Secondary Outcome Measures

Name	Time	Method
Change in Biomarkers of Inflammation From Day 0 to Day 7	Day 7 after first infusion	Mean (SD) represents the change on day 7 after treatment compared to pretreatment value for each biomarker of inflammation. (IL-1, IL-6, IL-8 and TNFa) Measured in pg/mL.
Trend Changes in PaO2:FiO2 Ratio	On the day of screening and on days 3, 7 and 14 after first infusion	Trend change was determined by evaluating PaO2:FiO2 ratios at prespecified time points and determining the slope of the line of best fit across data points for each patient, followed by taking the mean and SD across patients in each treatment group. Negative and positive slopes indicating decreasing or increasing values over time, respectively.
Trend Changes in Mean Airway Pressure	On the day of screening and on days 3, 7 and 14 after first infusion	Trend change was determined by evaluating mean airway pressure values at prespecified time points and determining the slope of the line of best fit across data points for each patient, followed by taking the mean and SD across patients in each treatment group. Negative and positive slopes indicating decreasing or increasing values over time, respectively.
Trend Changes in Peak Pressure	On the day of screening and on days 3, 7 and 14 after first infusion	Trend change was determined by evaluating peak pressure values at prespecified time points and determining the slope of the line of best fit across data points for each patient, followed by taking the mean and SD across patients in each treatment group. Negative and positive slopes indicating decreasing or increasing values over time, respectively.
Trend Changes in Plateau Pressure	On the day of screening (baseline) and on days 3, 7 and 14 after first infusion	Trend change was determined by evaluating plateau pressure values at prespecified time points and determining the slope of the line of best fit across data points for each patient, followed by taking the mean and SD across patients in each treatment group. Negative and positive slopes indicating decreasing or increasing values over time, respectively.
Trend Changes in Positive End-expiratory Airway Pressure (PEEP)	On the day of screening and on days 3, 7 and 14 after first infusion	Trend change was determined by evaluating Positive end-expiratory airway pressure (PEEP) values at prespecified time points and determining the slope of the line of best fit across data points for each patient, followed by taking the mean and SD across patients in each treatment group. Negative and positive slopes indicating decreasing or increasing values over time, respectively.
Incidence of Mortality	50 days after first infusion
Number of ICU-free Days	28 days after first infusion
Number of Days Alive and Ventilator Free	28 days after first infusion
Change in Acute Lung Injury (ALI) Score 2	Baseline and Day 28 after first infusion	Acute Lung Injury Score is a composite 4 point scoring system validated by the NHLBI ARDS Network that considers PaO2/FiO2, the level of positive end-expiratory airway pressure, respiratory compliance, and the extent of pulmonary infiltrates on the chest radiograph. Each criterion is scored from 0-4 based on the severity of the condition. The final score is calculated by dividing the total score by the number of criteria used. A score of 0 indicates no lung injury, and a score over 2.5 indicates Acute respiratory distress syndrome (ARDS). The scoring ranges from 0 to a maximum score of 3.
Incidence of Serious Adverse Events	28 days after first infusion
Number of Days Alive Off Supplemental Oxygen	100 days after first infusion

Trial Locations

Locations (2): University of Minnesota
🇺🇸
Minneapolis, Minnesota, United States
University of Pittsburgh
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Pittsburgh, Pennsylvania, United States