Mesenchymal Stromal Cells For Acute Respiratory Distress Syndrome (STAT)

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

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).

Study Overview

• Status: Completed
• Conditions: Respiratory Distress Syndrome, Adult
• Intervention / Treatment: Biological: Human Mesenchymal Stromal Cells; Biological: Cell Reconstitution Media

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).

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Michael Matthay, MD; Phone Number: 415-353-1206; Email: michael.matthay@ucsf.edu
• Study Contact Backup: Name: Hanjing Zhuo, MPH; Phone Number: 415-502-7434; Email: hanjing.zhuo@ucsf.edu

Study Locations

• United States
  • California
    • Sacramento, California, United States, 95817
      • University of California Davis Medical Center
    • San Francisco, California, United States, 94143
      • University of California San Francisco
    • San Francisco, California, United States, 94110
      • Zuckerberg San Francisco General Hospital and Trauma Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Memorial Hermann Hospital - Texas Medical Center
  • Washington
    • Seattle, Washington, United States, 98112
      • Harborview Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Human Mesenchymal Stromal Cells; 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.	Biological: Human Mesenchymal Stromal Cells; 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.; Other Names: hMSCs
Experimental: Cell Reconstitution Media; 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.	Biological: Cell Reconstitution Media; 300 mL of reconstitution media (1:1 mix of 5% human serum albumin and 10% Dextran 40); Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in oxygenation index (OI)	Change in OI from baseline over the 36 hours following the infusion of study product	36 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	7 days
Pulmonary Dead Space Fraction	Pulmonary Dead Space at day 1, 2, 3 and 7. The dead-space fraction is calculated as: (PaCO2 - PeCO2) ÷ PaCO2	7 days
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).	7 days
Ventilator free-days	Ventilator free-days over 7, 14 and 28 days	28 days
Duration of assisted ventilation over 28 days	Duration of assisted ventilation over 28 days in the survivors	28 days
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	28 days
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)	14 days
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).	7 days
All-cause hospital mortality	All-cause hospital mortality at 14, 28 and 60 days	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)	60 days
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	60 days
Plasma angiopoietin-2	Change in levels of plasma angiopoietin-2 from baseline compared to 6, 24, 48 and 72 hours	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	72 hours
Plasma interleukin-6	Change in levels of plasma interleukin-6 from baseline compared to 6, 24, 48 and 72 hours	72 hours
Plasma interleukin-8	Change in levels of plasma interleukin-8 from baseline compared to 6, 24, 48 and 72 hours	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	72 hours
Plasma protein C	Change in levels of plasma protein C from baseline compared to 6, 24, 48 and 72 hours	72 hours
Plasma lipoxin A4	Change in levels of plasma lipoxin A4 from baseline compared to 6, 24, 48 and 72 hours	72 hours
Plasma Resolvin D1	Change in levels of plasma Resolvin D1 from baseline compared to 6, 24, 48 and 72 hours	72 hours
Plasma angiopoietin-1	Change in levels of plasma angiopoietin-1 from baseline compared to 6, 24, 48 and 72 hours	72 hours
Plasma keratinocyte growth factor (KGF)	Change in levels of plasma KGF from baseline compared to 6, 24, 48 and 72 hours	72 hours
Urine microalbumin	Change in levels of urine microalbumin from baseline compared to 24 and 48 hours	48 hours
Total protein in min-bronchoalveolar lavage (mBAL)	Change in total protein levels in from baseline to day 2	2 days
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	24 hours

Collaborators and Investigators

• Sponsor: Michael A. Matthay
• Collaborators: The University of Texas Health Science Center, Houston; United States Department of Defense; Oregon Health and Science University; Vanderbilt University Medical Center; University of Minnesota; Harborview Injury Prevention and Research Center
• Investigators: Principal Investigator: Michael Matthay, MD, University of California, San Francisco

Study record dates

Study Major Dates

• Study Start (Actual): November 26, 2019
• Primary Completion (Actual): September 30, 2023
• Study Completion (Actual): September 30, 2023

Study Registration Dates

• First Submitted: January 24, 2019
• First Submitted That Met QC Criteria: January 25, 2019
• First Posted (Actual): January 28, 2019

Study Record Updates

• Last Update Posted (Estimated): December 20, 2023
• Last Update Submitted That Met QC Criteria: December 19, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Acute Respiratory Distress Syndrome; Human Mesenchymal Stromal Cells
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Disease; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; Syndrome; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury
• Other Study ID Numbers: UCSF-hMSC-ARDS-P1P2-12

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: We do not have plan to share IPD data to other researchers.

Drug and device information, study documents

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