Mesenchymal Stromal Cells For Acute Respiratory Distress Syndrome

Michael A. Matthay120 enrolled

Overview

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).

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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

120

Conditions

Respiratory Distress Syndrome, Adult

Interventions

Human Mesenchymal Stromal CellsBIOLOGICAL

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.

Cell Reconstitution MediaBIOLOGICAL

300 mL of reconstitution media (1:1 mix of 5% human serum albumin and 10% Dextran 40)

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (7)

University of California Davis Medical Center

Sacramento, California, United States

Zuckerberg San Francisco General Hospital and Trauma Center

San Francisco, California, United States

University of California San Francisco

San Francisco, California, United States

Oregon Health & Science University

Outcomes

Primary Outcomes

Change in Oxygenation Index (OI)

Change in OI from baseline over the 36 hours (6, 12, 18, 24, 30, 36 hours) following the initiation of the study product infusion. Lower values are considered better.

Time frame: 36 hours

Secondary Outcomes

Acute Lung Injury Score (LIS)

Changes in the 4-point acute lung injury (LIS) score from the baseline to days 1, 2, 3 and 7, 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

Pulmonary Dead Space Fraction

Pulmonary Dead Space at day 1, 2, 3 and 7. The dead-space fraction is calculated as: (PaCO2 - PeCO2) ÷ PaCO2

Time frame: 7 days

Change of Chest Radiograph Assessment of Pulmonary Edema (RALE Score)

Changes of RALE score at day 1, 2, 3 and 7 from baseline RALE score. 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

Ventilator Free-days (VFD) Over 14 Days

Ventilator free-days over 14 days. Defined as the number of days from the time of initiating unassisted breathing to day 14 after study product administration, assuming survival for at least two consecutive calendar days after initiating unassisted breathing and continued unassisted breathing to day 14. If a patient returns to assisted breathing and subsequently achieves unassisted breathing to day 14, VFDs will be counted from the end of the last period of assisted breathing to day 14.

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.