Treprostinil Sodium Inhalation for Patients At High Risk for ARDS

Study Overview
=================
Brief Summary
-----------------
Acute Respiratory Distress Syndrome (ARDS) is a rapidly progressing lung disease caused by a number of factors including pneumonia, sepsis and acute trauma that leads to reduced lung function and breathlessness. There are no pharmacological treatments approved for the treatment of ARDS. This pilot trial will study the safety and efficacy of Treprostinil sodium by inhalation for preventing the progression of acute hypoxemic respiratory failure to positive pressure ventilation and/or ARDS in patients at high risk.

Detailed Description
-----------------
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: To assess the feasibility of a randomized trial of treprostinil inhalation in patients with acute hypoxemic respiratory failure not requiring positive pressure ventilation. To evaluate the tolerability of inhaled treprostinil for patients with acute hypoxemic respiratory failure To assess the effect of treprostinil inhalation on oxygenation in patients with acute hypoxic respiratory failure with, or at risk for, development of ARDS 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.

Official Title
-----------------
Treprostinil Sodium Inhalation for Patients At High Risk for ARDS: Effect on Oxygenation and Disease-related Biomarkers

Conditions
-----------------
Respiratory Distress Syndrome, Adult

Intervention / Treatment
-----------------
* Drug: Treprostinil Inhalation Solution
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adults age 18-75 years. Acute onset need for 4 liters per minute (LPM) or more of supplemental oxygen to maintain Arterial partial pressure of oxygen (PaO2) > 60 mmHg or arterial O2 saturation > 90% by pulse oximetry. 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: No consent/inability to obtain consent Presence of pulmonary embolism Known diffuse alveolar hemorrhage from vasculitis 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 Known significant left ventricular systolic dysfunction with left ventricular ejection fraction (LVEF) < 45% on echocardiogram. Mean arterial pressure < 65 mmHg Need for norepinephrine or dopamine dose > 12 mcg to maintain mean arterial pressure (MAP) > 65 mmHg Severe chronic liver disease (Child-Pugh Score 11-15) Moribund patient not expected to survive 24 hours Corrected QT interval (QTc) interval > 500 ms on screening electrocardiogram Pregnancy or breast feeding (Women of childbearing potential, defined as < 60 years of age, will require pregnancy testing.) Burns > 40% total body surface Acute Neurological Disease (that may impair the ability to ventilate without assistance) Imminent need for intubation or non-invasive ventilation Patient is Do Not Resuscitate/Do Not Intubate Patient has a tracheotomy Patient is currently receiving prostacyclin therapy [Epoprostenol (Flolan or Veletri), Iloprost (Ventavis), Treprostinil (Orenitram, oral) (Remodulin, IV or SC)] Patient has a language barrier

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treprostinil inhalation solution<br>Treprostinil will be randomized 2:1 to placebo. Treprostinil (6 mcg per breath) will be administered every 4 hours. The dose will increase from 6 to12 breaths (maximum 72 mcg) over the first 20 hours, maintained for 7 days, and tapered down over 3 days. | Drug: Treprostinil Inhalation Solution<br>* Treprostinil inhalation solution administered as blinded marketed product<br>* Other names: TYVASO;|
| Placebo Comparator: Placebo<br>Placebo administration will be administered as above for the active arm | Drug: Placebo<br>* Supplied by the manufacturer and similar to the active drug but containing no Treprostinil<br>* Other names: Sterile saline solution;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Ratio of the Partial Pressure of Arterial Oxygen to the Fraction of Inspired Oxygen (PaO2/FiO2 Ratio) | PaO2/FiO2 ratio | Change in PaO2/FiO2 ratio from day 0 to day 2. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Ratio of Peripheral Oxygen Saturation to Fraction of Inspired Oxygen (SaO2/FiO2) | SaO2/FiO2 | 0-12 days | 
| Number of Days Not on a Ventilator | Ventilator-free days | 0-28 days post enrollment | 
| Number of Subjects Who Required Bi-level Positive Airway Pressure (BiPAP) or Continuous Positive Airway Pressure (CPAP) Via Face Mask | BiPAP / CPAP | 0-28 days | 
| Acute Respiratory Distress Syndrome (ARDS) Associated Biomarkers | Change in ARDS associated plasma biomarkers | Change from day 0 on days 3 and 7 | 
| Change in the Central Venous Oxygen Saturation (SCVO2). | SCVO2 | Change in SCVO2 from Day 0 to 3 (if central venous catheter in place) | 
| Change in Central Venous Pressure (CVP). | CVP | Change in CVP from Day 0 to 3 (if central venous catheter in place) | 
| Change in Mean Arterial Pressure (MAP). | MAP | Change in MAP from Day 0 to day 7 | 
| All-cause Mortality | All-cause mortality | 0-28 days | 
| Number of Subjects Requiring Intubation and Mechanical Ventilation | Intubation / Mechanical Ventilation | 0-28 days | 
| Number of Deaths During Hospitalization | Hospital Mortality | Deaths during hospitalization (up to 3 months) | 
| Peak Plasma Concentration Determined 15 Min After Inhalation and Trough Determined 4 Hours Following the Drug/Placebo Administration | Treprostinil Plasma Concentration | Day 3 | 
| Number of Days From Study Enrollment Until Mechanical Ventilation is Required | Time to intubation and mechanical ventilation | Day 0 to day 28 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ARDS, Acute Lung Injury, Acute Respiratory Failure