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

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ClinicalTrials.gov Identifier: NCT04466098
Recruitment Status : Recruiting
First Posted : July 10, 2020
Last Update Posted : August 14, 2020
Sponsor:
Information provided by (Responsible Party):
Masonic Cancer Center, University of Minnesota

Tracking Information
First Submitted Date  ICMJE July 8, 2020
First Posted Date  ICMJE July 10, 2020
Last Update Posted Date August 14, 2020
Actual Study Start Date  ICMJE July 30, 2020
Estimated Primary Completion Date December 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 8, 2020)
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 ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 8, 2020)
  • Incidence of a reduction in one or more biomarkers of inflammation by day 7 [ Time Frame: Day 7 after first infusion ]
  • Trend changes in PaO2:FiO2 ratio [ Time Frame: On the day of screening and on days 3, 7 and 14 after first infusion ]
  • Trend changes in Mean Airway Pressure [ Time Frame: On the day of screening and on days 3, 7 and 14 after first infusion ]
  • Trend changes in peak pressure [ Time Frame: On the day of screening and on days 3, 7 and 14 after first infusion ]
  • Trend changes in plateau pressure [ 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) [ Time Frame: On the day of screening and on days 3, 7 and 14 after first infusion ]
  • Incidence of mortality [ Time Frame: 28 days after first infusion ]
  • Incidence of mortality [ Time Frame: 100 days after first infusion ]
  • Number of ICU-free days [ Time Frame: 28 days after first infusion ]
  • Number of days alive and ventilator free composite score 3 [ Time Frame: 28 days after first infusion ]
  • Change in acute lung injury (ALI) score 2 [ Time Frame: 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
  • 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 ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Multiple Dosing of Mesenchymal Stromal Cells in Patients With ARDS (COVID-19)
Official Title  ICMJE 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)
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
This is a randomized (2:1 ratio) placebo controlled trial.
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description:
Patients will be randomly assigned (2:1) to receive either 300 × 10^6 MSC or vehicle placebo control. Randomization will be stratified by risk (high versus standard risk based on the presence of preexisting co-morbidities), using permuted block sizes of 3. The allocation sequence will be accessed by each cell processing laboratory through ONCORE. Personnel in the cell processing laboratories are not masked to the treatment group, but patients, clinical staff, and investigators will be unaware of treatment assignment. To maintain masking of the investigators and clinicians, bags containing the study products and intravenous tubing had opaque coverings applied in the cell laboratories.
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Respiratory Distress Syndrome
  • ARDS (Moderate or Severe)
  • COVID-19 Pneumonia
Intervention  ICMJE
  • 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]
Study Arms  ICMJE
  • Experimental: Mesenchymal Stromal Cells
    Three fixed doses of MSC approximately 48 hours apart.
    Intervention: Biological: Mesenchymal stromal cells
  • Placebo Comparator: Placebo
    Three fixed doses of placebo control approximately 48 hours apart.
    Intervention: Other: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 8, 2020)
30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 1, 2021
Estimated Primary Completion Date December 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: David Ingbar, MD 612-624-0999 ingba001@umn.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04466098
Other Study ID Numbers  ICMJE 2020LS075
MT2020-12 ( Other Identifier: University of Minnesota Masonic Cancer Center )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Masonic Cancer Center, University of Minnesota
Study Sponsor  ICMJE Masonic Cancer Center, University of Minnesota
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: David Ingbar, MD Masonic Cancer Center, University of Minnesota
PRS Account Masonic Cancer Center, University of Minnesota
Verification Date August 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP