Mesenchymal Stromal Cells For Acute Respiratory Distress Syndrome

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).

Inclusion Criteria:

Patients will be eligible for inclusion if they meet all of the below criteria within 120
hours 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 <200 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 120 hours since initial ICU admission

4. Inability to administer study product within 120 hours of ICU admission

5. PaO2/FiO2 ≥ 200 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 (Childs-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.