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.
Biological: Mesenchymal stromal cells
Thawed product containing MSC(300x10^6) in DMSO resuspended 1:1 with Dextran 40 + 5% human serum albumin [total volume 60 mL]
Other Name: MSC
Other: Placebo
Dextran 40 + 5% human serum albumin [total volume 60 mL]
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)
University of Minnesota
Minneapolis, Minnesota, United States
University of Pittsburgh
Pittsburgh, Pennsylvania, United States
David Ingbar, MD, Principal Investigator
Masonic Cancer Center, University of Minnesota