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

Multi-center, Randomized, Placebo Controlled, Interventional Phase 2A Clinical Trial Evaluating the Safety and Potential Efficacy of Multiple Dosing of Mesenchymal Stromal Cells in Patients With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Acute Respiratory Distress Syndrome; COVID-19 Pneumonia; ARDS (Moderate or Severe)
• Intervention / Treatment: Biological: Mesenchymal stromal cells; Other: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15261
      • University of Pittsburgh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Mesenchymal Stromal Cells; Three fixed doses of MSC approximately 48 hours apart.	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 Names: MSC
PLACEBO_COMPARATOR: Placebo; Three fixed doses of placebo control approximately 48 hours apart.	Other: Placebo; Dextran 40 + 5% human serum albumin [total volume 60 mL]

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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

Outcome Measure	Measure Description	Time Frame
Incidence of a reduction in one or more biomarkers of inflammation by day 7		Day 7 after first infusion
Trend changes in PaO2:FiO2 ratio		On the day of screening and on days 3, 7 and 14 after first infusion
Trend changes in Mean Airway Pressure		On the day of screening and on days 3, 7 and 14 after first infusion
Trend changes in peak pressure		On the day of screening and on days 3, 7 and 14 after first infusion
Trend changes in plateau pressure		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)		On the day of screening and on days 3, 7 and 14 after first infusion
Incidence of mortality		28 days after first infusion
Incidence of mortality		100 days after first infusion
Number of ICU-free days		28 days after first infusion
Number of days alive and ventilator free composite score 3		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	Baseline and Day 28 after first infusion
Incidence of serious adverse events		28 days after first infusion
Number of days alive off supplemental oxygen		100 days after first infusion

Collaborators and Investigators

• Sponsor: Masonic Cancer Center, University of Minnesota
• Investigators: Principal Investigator: David Ingbar, MD, Masonic Cancer Center, University of Minnesota

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 30, 2020
• Primary Completion (ACTUAL): February 25, 2022
• Study Completion (ANTICIPATED): December 1, 2023

Study Registration Dates

• First Submitted: July 8, 2020
• First Submitted That Met QC Criteria: July 8, 2020
• First Posted (ACTUAL): July 10, 2020

Study Record Updates

• Last Update Posted (ACTUAL): February 1, 2023
• Last Update Submitted That Met QC Criteria: January 31, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: SARS-CoV-2; COVID-19; Mesenchymal Stem Cells; MSC; cytokine storm; Mesenchymal Stromal Cells
• Additional Relevant MeSH Terms: Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Respiration Disorders; Pneumonia, Viral; Pneumonia; Lung Diseases; Disease; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; COVID-19; Syndrome; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury
• Other Study ID Numbers: 2020LS075; MT2020-12 (OTHER: University of Minnesota Masonic Cancer Center)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No