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

Masonic Cancer Center, University of Minnesota8 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

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)

Outcomes

Primary Outcomes

Incidence of Grade 3-5 Infusional Toxicities and Predefined Hemodynamic or Respiratory Adverse Events Related to the Infusion of MSC

Time frame: Within 6 hours of the start of the infusion

Secondary Outcomes

Change in Biomarkers of Inflammation From Day 0 to Day 7

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.

Time frame: Day 7 after first infusion

Trend Changes in PaO2:FiO2 Ratio

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.

Time frame: On the day of screening and on days 3, 7 and 14 after first infusion

Trend Changes in Mean Airway Pressure

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.

Time frame: On the day of screening and on days 3, 7 and 14 after first infusion

Trend Changes in Peak Pressure

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.

Time frame: On the day of screening and on days 3, 7 and 14 after first infusion

Trend Changes in Plateau Pressure

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.

Time frame: On the day of screening (baseline) and on days 3, 7 and 14 after first infusion

Trend Changes in Positive End-expiratory Airway Pressure (PEEP)

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.

Time frame: On the day of screening and on days 3, 7 and 14 after first infusion

Incidence of Mortality

Time frame: 50 days after first infusion

Number of ICU-free Days

Time frame: 28 days after first infusion

Number of Days Alive and Ventilator Free

Time frame: 28 days after first infusion

Change in Acute Lung Injury (ALI) Score 2

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.

Time frame: Baseline and Day 28 after first infusion

Incidence of Serious Adverse Events

Time frame: 28 days after first infusion

Number of Days Alive Off Supplemental Oxygen

Time frame: 100 days after first infusion

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

Overview

Conditions

Interventions

Eligibility

Locations (2)

Outcomes

Primary Outcomes

Secondary Outcomes