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Mesenchymal Stromal Cells For Acute Respiratory Distress Syndrome (STAT)

Primary Purpose

Respiratory Distress Syndrome, Adult

Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Human Mesenchymal Stromal Cells
Cell Reconstitution Media
Sponsored by
Michael A. Matthay
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Respiratory Distress Syndrome, Adult focused on measuring Human Mesenchymal Stromal Cells, Acute Respiratory Distress Syndrome

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients will be eligible for inclusion if they meet all of the below criteria within 14 days of initial ICU admission. Criteria 1-3 must all be present within a 24-hour time period and at the time of enrollment:

Acute onset (defined below) of:

  1. A need for positive pressure ventilation by an endotracheal or tracheal tube with a PaO2/FiO2 ratio <250 mmHg and ≥5 cm H2O positive end-expiratory airway pressure (PEEP), as per the Berlin Criteria.
  2. Bilateral infiltrates consistent with pulmonary edema (defined below) on the frontal chest radiograph, or bilateral ground glass opacities on a chest CT scan.
  3. No clinical evidence of left atrial hypertension as a primary explanation for the bilateral pulmonary infiltrates.
  4. If the cause of ARDS is trauma, additional inclusion criteria will include ONE of the following relevant risk factors for developing ARDS:

    1. Hypotension (systolic blood pressure[SBP] < 90 mmHg) in the field or in the first 24 h after injury, or
    2. Transfusion of 3 units of blood products in the first 24 hours following injury, or
    3. Meets the new Critical Administration Threshold (CAT) criteria with at least 3 units of blood in one hour, or
    4. Blunt or penetrating torso trauma, or
    5. Long bone fractures, or
    6. The highest level of institutional trauma activation

Exclusion Criteria:

  1. Age less than 18 years
  2. Greater than 72 hours since first meeting ARDS criteria per the Berlin definition of ARDS
  3. Greater than 14 days since initial ICU admission
  4. Inability to administer study product within 14 days of ICU admission
  5. PaO2/FiO2 ≥ 250 mmHg after consent obtained and before study product is administered
  6. Unable to obtain informed consent/no surrogate available
  7. Pregnant or lactating
  8. In custody of law enforcement officials
  9. Burns > 20% of total body surface area
  10. WHO Class III or IV pulmonary hypertension
  11. History of cancer treatment in the last 2 years except for non-melanotic skin cancers
  12. Underlying medical condition for which 6-month mortality is estimated to be > 50%
  13. Moribund patient not expected to survive 24 hours
  14. Advanced chronic liver disease (Child-Pugh Score > 12)
  15. Severe chronic respiratory disease with the use of home oxygen
  16. Severe traumatic brain injury - defined as:

    1. A patient who has undergone intracranial neurosurgical intervention for monitoring or therapy (intracranial pressure monitoring, external ventricular drain, craniotomy), or
    2. Intracranial injury by head CT (does not include patients with minimal subarachnoid injury and/or minor skull fracture), or
    3. Post-resuscitation Glasgow Coma Score (GCS) < 9 assessed after sedation interruption, or
    4. Non-survivable head injury as assessed by neurosurgery
  17. Evidence of anoxic brain injury
  18. History of stroke within the last 3 years
  19. No intent/unwillingness to follow lung protective ventilation strategy
  20. Currently receiving extracorporeal life support (ECLS) or high-frequency oscillatory ventilation (HFOV)
  21. Anticipated extubation within 24 hours of enrollment
  22. Clinical evidence of left atrial hypertension as measured by a pulmonary arterial wedge pressure > 18mmHg or left ventricular failure measured by an echocardiogram with a left ventricular ejection fraction less than 40%. Clinical judgement will determine if either of these measurements needs to be carried out.

Sites / Locations

  • University of California Davis Medical Center
  • Zuckerberg San Francisco General Hospital and Trauma Center
  • University of California San Francisco
  • Oregon Health & Science University
  • Vanderbilt University Medical Center
  • Memorial Hermann Hospital - Texas Medical Center
  • Harborview Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Human Mesenchymal Stromal Cells

Cell Reconstitution Media

Arm Description

A single dose of 10 million cells/kg predicted body weight (PBW) Allogeneic Bone Marrow-Derived Human Mesenchymal Stromal Cells will administered intravenously over approximately 60-80 minutes.

A single dose of cell reconstitution media (1:1 mix of 5% human serum albumin and 10% Dextran 40) will administered intravenously over approximately 60-80 minutes.

Outcomes

Primary Outcome Measures

Change in oxygenation index (OI)
Change in OI from baseline over the 36 hours following the infusion of study product

Secondary Outcome Measures

Acute Lung Injury Score (LIS)
LIS over 7 days, or on the last day of positive pressure ventilation prior to day 7. The LIS is a composite 4-point scoring system including the PaO2/FiO2, PEEP, lung compliance, and the extent of infiltrates on the chest X-ray. Each of the four components is categorized from 0 to 4, where a higher number is worse. The total Lung Injury Score is obtained by dividing the aggregate sum by the number of components used.
Pulmonary Dead Space Fraction
Pulmonary Dead Space at day 1, 2, 3 and 7. The dead-space fraction is calculated as: (PaCO2 - PeCO2) ÷ PaCO2
Chest radiograph assessment of pulmonary edema (RALE score)
RALE score at day 1, 2, 3 and 7. To calculate RALE, each radiographic quadrant is scored for extent of consolidation (0-4) and density of opacification (1-3). The product of the consolidation and density scores for each of the four quadrants is summed. The RALE score ranges from 0 (best) to 48 (worst).
Ventilator free-days
Ventilator free-days over 7, 14 and 28 days
Duration of assisted ventilation over 28 days
Duration of assisted ventilation over 28 days in the survivors
Percentage of patients achieving pressure support ventilation for 2 hours
Percentage of patients achieving pressure support ventilation equal to 5 cm H2O with positive end-expiratory pressure (PEEP) equal to 5 cm H2O for 2 hours
Occurrence of Infection
Superficial incisional/wound infections, deep incisional wound infections, and organ/space infections, and ventilator associated pneumonia (all during the 14 days after enrollment)
Sequential Organ Failure Assessment (SOFA) over 7 days
SOFA score at 3 and 7 days. The score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems which are added up. Each score ranges from 0 to 4. SOFA score ranges from 0 (best) to 24 (worst).
All-cause hospital mortality
All-cause hospital mortality at 14, 28 and 60 days
Glasgow Outcome Score (GCS)
Glasgow Outcome Score at hospital discharge. The GCS is a scale to evaluate level of consciousness in patients with acute brain injury. The scale assesses 3 functions: Eye Opening, Verbal Response, and Motor Response. GCS scores range from 15 (best) to 3 (worst)
Percentage of patients occurred any thromboembolic events
Thromboembolic events are measured by ultrasound of the deep venous system or CT-angiography of the chest ordered for clinical purposes/by treating clinicians
Plasma angiopoietin-2
Change in levels of plasma angiopoietin-2 from baseline compared to 6, 24, 48 and 72 hours
Plasma Receptor for Advanced Glycation Endproducts (RAGE)
Change in levels of plasma RAGE from baseline compared to 6, 24, 48 and 72 hours
Plasma interleukin-6
Change in levels of plasma interleukin-6 from baseline compared to 6, 24, 48 and 72 hours
Plasma interleukin-8
Change in levels of plasma interleukin-8 from baseline compared to 6, 24, 48 and 72 hours
Plasma Soluble tumor necrosis factor 1 (sTNF-1)
Change in levels of plasma sTNF-1 from baseline compared to 6, 24, 48 and 72 hours
Plasma protein C
Change in levels of plasma protein C from baseline compared to 6, 24, 48 and 72 hours
Plasma lipoxin A4
Change in levels of plasma lipoxin A4 from baseline compared to 6, 24, 48 and 72 hours
Plasma Resolvin D1
Change in levels of plasma Resolvin D1 from baseline compared to 6, 24, 48 and 72 hours
Plasma angiopoietin-1
Change in levels of plasma angiopoietin-1 from baseline compared to 6, 24, 48 and 72 hours
Plasma keratinocyte growth factor (KGF)
Change in levels of plasma KGF from baseline compared to 6, 24, 48 and 72 hours
Urine microalbumin
Change in levels of urine microalbumin from baseline compared to 24 and 48 hours
Total protein in min-bronchoalveolar lavage (mBAL)
Change in total protein levels in from baseline to day 2
Tolerability of the hMSCs - incidence of pre-specified infusion-associated events and unexpected severe adverse events
Tolerability of the hMSCs, defined as the incidence of pre-specified infusion-associated events and unexpected severe adverse events in ARDS patients treated with human MSCs

Full Information

First Posted
January 24, 2019
Last Updated
September 18, 2023
Sponsor
Michael A. Matthay
Collaborators
United States Department of Defense, Harborview Injury Prevention and Research Center, Oregon Health and Science University, Vanderbilt University Medical Center, The University of Texas Health Science Center, Houston, University of Minnesota
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1. Study Identification

Unique Protocol Identification Number
NCT03818854
Brief Title
Mesenchymal Stromal Cells For Acute Respiratory Distress Syndrome
Acronym
STAT
Official Title
A Phase 2b, Randomized, Double-blind, Placebo-controlled, Multi-center Clinical Trial of Allogeneic Bone Marrow-derived Human Mesenchymal Stromal Cells (hMSCs) for the Treatment of Acute Respiratory Distress Syndrome
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
November 26, 2019 (Actual)
Primary Completion Date
September 30, 2023 (Anticipated)
Study Completion Date
July 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Michael A. Matthay
Collaborators
United States Department of Defense, Harborview Injury Prevention and Research Center, Oregon Health and Science University, Vanderbilt University Medical Center, The University of Texas Health Science Center, Houston, University of Minnesota

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a Phase 2b, randomized, double-blind, placebo-controlled, multi-center study to assess the safety and efficacy of a single dose of Allogeneic Bone Marrow-derived Human Mesenchymal Stromal Cells (hMSCs) infusion in patients with Acute Respiratory Distress Syndrome (ARDS). This study is the extension of the Phase 1 pilot study (NCT01775774) and Phase 2a study (NCT02097641).
Detailed Description
This clinical study design is a randomized, double-blinded, placebo-controlled Phase 2b clinical trial using a 10 million cell/kg dose of human Mesenchymal Stromal Cells (hMSCs). Subjects will be randomized in a 1:1 randomization scheme to receive hMSCs or cell reconstitution media (1:1 mix of 5% human serum albumin and 10% Dextran 40) as the placebo; the study will enroll 120 patients who achieve a stable clinical baseline and receive study product (either hMSCs or the placebo). The Data and Safety Monitoring Board (DSMB) will review adverse outcomes and protocol compliance. A pre-specified interim review will occur after 60 subjects have been enrolled and received study product; enrollment will continue during the DSMB review. All pre-specified clinically important events and unexpected serious adverse events including death during hospitalization up to 60 days will be reported to the DSMB on an ongoing basis; the study will be stopped for a safety evaluation by the DSMB if they have any concerns or if three subjects have pre-specified clinically important events or unexpected serious adverse events except death since death will be common in this critically ill population due the nature of the underlying illness (e.g., ARDS).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Respiratory Distress Syndrome, Adult
Keywords
Human Mesenchymal Stromal Cells, Acute Respiratory Distress Syndrome

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
For this Phase 2b trial, after informed consent is given, an assignment will be made by computer-generated randomization to administer either hMSCs therapy or placebo with a 1:1 allocation to the hMSCs:placebo arms.
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
120 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Human Mesenchymal Stromal Cells
Arm Type
Experimental
Arm Description
A single dose of 10 million cells/kg predicted body weight (PBW) Allogeneic Bone Marrow-Derived Human Mesenchymal Stromal Cells will administered intravenously over approximately 60-80 minutes.
Arm Title
Cell Reconstitution Media
Arm Type
Experimental
Arm Description
A single dose of cell reconstitution media (1:1 mix of 5% human serum albumin and 10% Dextran 40) will administered intravenously over approximately 60-80 minutes.
Intervention Type
Biological
Intervention Name(s)
Human Mesenchymal Stromal Cells
Other Intervention Name(s)
hMSCs
Intervention Description
Immediately prior to administration, the study product will be thawed and diluted 1:1 with reconstitution media (1:1 mix of 5% human serum albumin and 10% Dextran 40). Additional reconstitution media is added to a final product volume of 300 mL.
Intervention Type
Biological
Intervention Name(s)
Cell Reconstitution Media
Other Intervention Name(s)
Placebo
Intervention Description
300 mL of reconstitution media (1:1 mix of 5% human serum albumin and 10% Dextran 40)
Primary Outcome Measure Information:
Title
Change in oxygenation index (OI)
Description
Change in OI from baseline over the 36 hours following the infusion of study product
Time Frame
36 hours
Secondary Outcome Measure Information:
Title
Acute Lung Injury Score (LIS)
Description
LIS over 7 days, or on the last day of positive pressure ventilation prior to day 7. The LIS is a composite 4-point scoring system including the PaO2/FiO2, PEEP, lung compliance, and the extent of infiltrates on the chest X-ray. Each of the four components is categorized from 0 to 4, where a higher number is worse. The total Lung Injury Score is obtained by dividing the aggregate sum by the number of components used.
Time Frame
7 days
Title
Pulmonary Dead Space Fraction
Description
Pulmonary Dead Space at day 1, 2, 3 and 7. The dead-space fraction is calculated as: (PaCO2 - PeCO2) ÷ PaCO2
Time Frame
7 days
Title
Chest radiograph assessment of pulmonary edema (RALE score)
Description
RALE score at day 1, 2, 3 and 7. To calculate RALE, each radiographic quadrant is scored for extent of consolidation (0-4) and density of opacification (1-3). The product of the consolidation and density scores for each of the four quadrants is summed. The RALE score ranges from 0 (best) to 48 (worst).
Time Frame
7 days
Title
Ventilator free-days
Description
Ventilator free-days over 7, 14 and 28 days
Time Frame
28 days
Title
Duration of assisted ventilation over 28 days
Description
Duration of assisted ventilation over 28 days in the survivors
Time Frame
28 days
Title
Percentage of patients achieving pressure support ventilation for 2 hours
Description
Percentage of patients achieving pressure support ventilation equal to 5 cm H2O with positive end-expiratory pressure (PEEP) equal to 5 cm H2O for 2 hours
Time Frame
28 days
Title
Occurrence of Infection
Description
Superficial incisional/wound infections, deep incisional wound infections, and organ/space infections, and ventilator associated pneumonia (all during the 14 days after enrollment)
Time Frame
14 days
Title
Sequential Organ Failure Assessment (SOFA) over 7 days
Description
SOFA score at 3 and 7 days. The score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems which are added up. Each score ranges from 0 to 4. SOFA score ranges from 0 (best) to 24 (worst).
Time Frame
7 days
Title
All-cause hospital mortality
Description
All-cause hospital mortality at 14, 28 and 60 days
Time Frame
60 days
Title
Glasgow Outcome Score (GCS)
Description
Glasgow Outcome Score at hospital discharge. The GCS is a scale to evaluate level of consciousness in patients with acute brain injury. The scale assesses 3 functions: Eye Opening, Verbal Response, and Motor Response. GCS scores range from 15 (best) to 3 (worst)
Time Frame
60 days
Title
Percentage of patients occurred any thromboembolic events
Description
Thromboembolic events are measured by ultrasound of the deep venous system or CT-angiography of the chest ordered for clinical purposes/by treating clinicians
Time Frame
60 days
Title
Plasma angiopoietin-2
Description
Change in levels of plasma angiopoietin-2 from baseline compared to 6, 24, 48 and 72 hours
Time Frame
72 hours
Title
Plasma Receptor for Advanced Glycation Endproducts (RAGE)
Description
Change in levels of plasma RAGE from baseline compared to 6, 24, 48 and 72 hours
Time Frame
72 hours
Title
Plasma interleukin-6
Description
Change in levels of plasma interleukin-6 from baseline compared to 6, 24, 48 and 72 hours
Time Frame
72 hours
Title
Plasma interleukin-8
Description
Change in levels of plasma interleukin-8 from baseline compared to 6, 24, 48 and 72 hours
Time Frame
72 hours
Title
Plasma Soluble tumor necrosis factor 1 (sTNF-1)
Description
Change in levels of plasma sTNF-1 from baseline compared to 6, 24, 48 and 72 hours
Time Frame
72 hours
Title
Plasma protein C
Description
Change in levels of plasma protein C from baseline compared to 6, 24, 48 and 72 hours
Time Frame
72 hours
Title
Plasma lipoxin A4
Description
Change in levels of plasma lipoxin A4 from baseline compared to 6, 24, 48 and 72 hours
Time Frame
72 hours
Title
Plasma Resolvin D1
Description
Change in levels of plasma Resolvin D1 from baseline compared to 6, 24, 48 and 72 hours
Time Frame
72 hours
Title
Plasma angiopoietin-1
Description
Change in levels of plasma angiopoietin-1 from baseline compared to 6, 24, 48 and 72 hours
Time Frame
72 hours
Title
Plasma keratinocyte growth factor (KGF)
Description
Change in levels of plasma KGF from baseline compared to 6, 24, 48 and 72 hours
Time Frame
72 hours
Title
Urine microalbumin
Description
Change in levels of urine microalbumin from baseline compared to 24 and 48 hours
Time Frame
48 hours
Title
Total protein in min-bronchoalveolar lavage (mBAL)
Description
Change in total protein levels in from baseline to day 2
Time Frame
2 days
Title
Tolerability of the hMSCs - incidence of pre-specified infusion-associated events and unexpected severe adverse events
Description
Tolerability of the hMSCs, defined as the incidence of pre-specified infusion-associated events and unexpected severe adverse events in ARDS patients treated with human MSCs
Time Frame
24 hours

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients will be eligible for inclusion if they meet all of the below criteria within 14 days of initial ICU admission. Criteria 1-3 must all be present within a 24-hour time period and at the time of enrollment: Acute onset (defined below) of: A need for positive pressure ventilation by an endotracheal or tracheal tube with a PaO2/FiO2 ratio <250 mmHg and ≥5 cm H2O positive end-expiratory airway pressure (PEEP), as per the Berlin Criteria. Bilateral infiltrates consistent with pulmonary edema (defined below) on the frontal chest radiograph, or bilateral ground glass opacities on a chest CT scan. No clinical evidence of left atrial hypertension as a primary explanation for the bilateral pulmonary infiltrates. If the cause of ARDS is trauma, additional inclusion criteria will include ONE of the following relevant risk factors for developing ARDS: Hypotension (systolic blood pressure[SBP] < 90 mmHg) in the field or in the first 24 h after injury, or Transfusion of 3 units of blood products in the first 24 hours following injury, or Meets the new Critical Administration Threshold (CAT) criteria with at least 3 units of blood in one hour, or Blunt or penetrating torso trauma, or Long bone fractures, or The highest level of institutional trauma activation Exclusion Criteria: Age less than 18 years Greater than 72 hours since first meeting ARDS criteria per the Berlin definition of ARDS Greater than 14 days since initial ICU admission Inability to administer study product within 14 days of ICU admission PaO2/FiO2 ≥ 250 mmHg after consent obtained and before study product is administered Unable to obtain informed consent/no surrogate available Pregnant or lactating In custody of law enforcement officials Burns > 20% of total body surface area WHO Class III or IV pulmonary hypertension History of cancer treatment in the last 2 years except for non-melanotic skin cancers Underlying medical condition for which 6-month mortality is estimated to be > 50% Moribund patient not expected to survive 24 hours Advanced chronic liver disease (Child-Pugh Score > 12) Severe chronic respiratory disease with the use of home oxygen Severe traumatic brain injury - defined as: A patient who has undergone intracranial neurosurgical intervention for monitoring or therapy (intracranial pressure monitoring, external ventricular drain, craniotomy), or Intracranial injury by head CT (does not include patients with minimal subarachnoid injury and/or minor skull fracture), or Post-resuscitation Glasgow Coma Score (GCS) < 9 assessed after sedation interruption, or Non-survivable head injury as assessed by neurosurgery Evidence of anoxic brain injury History of stroke within the last 3 years No intent/unwillingness to follow lung protective ventilation strategy Currently receiving extracorporeal life support (ECLS) or high-frequency oscillatory ventilation (HFOV) Anticipated extubation within 24 hours of enrollment Clinical evidence of left atrial hypertension as measured by a pulmonary arterial wedge pressure > 18mmHg or left ventricular failure measured by an echocardiogram with a left ventricular ejection fraction less than 40%. Clinical judgement will determine if either of these measurements needs to be carried out.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michael Matthay, MD
Organizational Affiliation
University of California, San Francisco
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California Davis Medical Center
City
Sacramento
State/Province
California
ZIP/Postal Code
95817
Country
United States
Facility Name
Zuckerberg San Francisco General Hospital and Trauma Center
City
San Francisco
State/Province
California
ZIP/Postal Code
94110
Country
United States
Facility Name
University of California San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Facility Name
Oregon Health & Science University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
Vanderbilt University Medical Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Facility Name
Memorial Hermann Hospital - Texas Medical Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Harborview Medical Center
City
Seattle
State/Province
Washington
ZIP/Postal Code
98112
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
We do not have plan to share IPD data to other researchers.

Learn more about this trial

Mesenchymal Stromal Cells For Acute Respiratory Distress Syndrome

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