Treprostinil Sodium Inhalation for Patients At High Risk for ARDS

ARDS is defined by acute hypoxemia, respiratory failure and the presence of bilateral lung
infiltrates. ARDS is a syndrome of inflammation and increased permeability that may coexist
with left atrial or pulmonary capillary hypertension. Several recent trials in ARDS/ALI
(Acute Lung Injury) have generated interest in the use of Prostacyclin (PGI2) and
prostacyclin analogs in improving oxygenation in ARDS/ALI. PGI2 is an arachidonic acid
metabolite naturally produced in the lung by endothelial cells, dendritic cells, smooth
muscle cells and fibroblasts. PGI2 is a potent selective pulmonary vasodilator and inhibitor
of platelet aggregation. The cellular effects include smooth muscle relaxation, inhibition of
cell migration, decreased dextran permeability in epithelial cell cultures in vitro,
decreased high tidal volume mechanical ventilation injury in mice and inhibition of
fibroblast adhesion and differentiation. PGI2 has broad anti-inflammatory activity,
inhibiting the production of Tumor necrosis factor alpha (TNFα), interleukin 1 beta (IL-1β),
interleukin 6 (IL-6) and granulocyte macrophage colony-stimulating factor (GMCSF) in human
alveolar macrophages.

The study objectives are:

1. To assess the feasibility of a randomized trial of treprostinil inhalation in patients
with acute hypoxemic respiratory failure not requiring positive pressure ventilation.

2. To evaluate the tolerability of inhaled treprostinil for patients with acute hypoxemic
respiratory failure

3. To assess the effect of treprostinil inhalation on oxygenation in patients with acute
hypoxic respiratory failure with, or at risk for, development of ARDS

4. To assess the effect of treprostinil inhalation on various biomarkers thought to be
related to the pathogenesis and/or clinical course of ARDS.

The hypothesis is: Treprostinil solution for inhalation (TYVASO) is safe and will improve
oxygenation and other secondary outcomes related to acute hypoxemic respiratory failure and
positive pressure ventilation initiation and duration, as well as exhibit effects on
ARDS-related pro-inflammatory and pro-fibrotic biomarkers.

Inclusion Criteria:

1. Adults age 18-75 years.

2. Acute onset need for 4 liters per minute (LPM) or more of supplemental oxygen to
maintain PaO2 > 60 mmHg or arterial O2 saturation > 90% by pulse oximetry.

3. Acute unilateral pulmonary infiltrate/s on chest radiograph with no clinical evidence
of left-sided heart failure. Bilateral infiltrates are acceptable as long as all other
inclusion/exclusion criteria are met.

Exclusion Criteria:

1. No consent/inability to obtain consent

2. Presence of pulmonary embolism

3. Known diffuse alveolar hemorrhage from vasculitis

4. Known pre-existing severe obstructive or restrictive lung disease (FEV 1 < 40%
predicted, total lung capacity (TLC) < 50 % predicted) or need for long-term
supplemental oxygen therapy

5. Known significant left ventricular systolic dysfunction with left ventricular ejection
fraction (LVEF) < 45% on echocardiogram.

6. Mean arterial pressure < 65 mmHg

7. Need for norepinephrine or dopamine dose > 12 mcg to maintain MAP > 65 mmHg

8. Severe chronic liver disease (Child-Pugh Score 11-15)

9. Moribund patient not expected to survive 24 hours

10. Corrected QT interval (QTc) interval > 500 ms on screening electrocardiogram

11. Pregnancy or breast feeding (Women of childbearing potential, defined as < 60 years of
age, will require pregnancy testing.)

12. Burns > 40% total body surface

13. Acute Neurological Disease (that may impair the ability to ventilate without
assistance)

14. Imminent need for intubation or non-invasive ventilation

15. Patient is Do Not Resuscitate/Do Not Intubate

16. Patient has a tracheotomy

17. Patient is currently receiving prostacyclin therapy [Epoprostenol (Flolan or Veltri),
Iloprost (Ventavis), Treprostinil (Orenitram, oral) (Remodulin, IV or SC)]

18. Patient has a language barrier