Respiratory Distress Syndrome, Adult
Conditions
Keywords
ARDS, Acute Lung Injury, Acute Respiratory Failure
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: 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.
Interventions
DRUGTreprostinil Inhalation Solution
Treprostinil inhalation solution administered as blinded marketed product
DRUGPlacebo
Supplied by the manufacturer and similar to the active drug but containing no Treprostinil
Sponsors
United Therapeutics
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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 Arterial partial pressure of oxygen (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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Ratio of the Partial Pressure of Arterial Oxygen to the Fraction of Inspired Oxygen (PaO2/FiO2 Ratio) | Change in PaO2/FiO2 ratio from day 0 to day 2. | PaO2/FiO2 ratio |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Days Not on a Ventilator | 0-28 days post enrollment | Ventilator-free days |
| Number of Subjects Who Required Bi-level Positive Airway Pressure (BiPAP) or Continuous Positive Airway Pressure (CPAP) Via Face Mask | 0-28 days | BiPAP / CPAP |
| Acute Respiratory Distress Syndrome (ARDS) Associated Biomarkers | Change from day 0 on days 3 and 7 | Change in ARDS associated plasma biomarkers |
| Change in the Central Venous Oxygen Saturation (SCVO2). | Change in SCVO2 from Day 0 to 3 (if central venous catheter in place) | SCVO2 |
| Change in Central Venous Pressure (CVP). | Change in CVP from Day 0 to 3 (if central venous catheter in place) | CVP |
| Change in the Ratio of Peripheral Oxygen Saturation to Fraction of Inspired Oxygen (SaO2/FiO2) | 0-12 days | SaO2/FiO2 |
| All-cause Mortality | 0-28 days | All-cause mortality |
| Number of Subjects Requiring Intubation and Mechanical Ventilation | 0-28 days | Intubation / Mechanical Ventilation |
| Number of Deaths During Hospitalization | Deaths during hospitalization (up to 3 months) | Hospital Mortality |
| Peak Plasma Concentration Determined 15 Min After Inhalation and Trough Determined 4 Hours Following the Drug/Placebo Administration | Day 3 | Treprostinil Plasma Concentration |
| Number of Days From Study Enrollment Until Mechanical Ventilation is Required | Day 0 to day 28 | Time to intubation and mechanical ventilation |
| Change in Mean Arterial Pressure (MAP). | Change in MAP from Day 0 to day 7 | MAP |
Countries
United States
Participant flow
Pre-assignment details
One patient was consented, randomized (Placebo) and baseline data was collected. However, before receiving treatment the subject deteriorated, and a protocol defined stopping rule was met. The subject was defined as completed. Baseline data were used in the analyses, and the AEs recorded are presented in the AE section.
Participants by arm
| Arm | Count |
|---|---|
| Treprostinil Inhalation Solution 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.
Treprostinil Inhalation Solution: Treprostinil inhalation solution administered as blinded marketed product | 10 |
| Placebo Placebo administration will be administered as above for the active arm
Placebo: Supplied by the manufacturer and similar to the active drug but containing no Treprostinil | 4 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Treprostinil Inhalation Solution | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 49.2 years STANDARD_DEVIATION 13.1 | 51.8 years STANDARD_DEVIATION 7.6 | 50.0 years STANDARD_DEVIATION 11.6 |
| Race/Ethnicity, Customized African-American | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Caucasian | 8 Participants | 3 Participants | 11 Participants |
| Region of Enrollment United States | 10 Participants | 4 Participants | 14 Participants |
| Sex: Female, Male Female | 4 Participants | 2 Participants | 6 Participants |
| Sex: Female, Male Male | 6 Participants | 2 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 10 | 0 / 4 |
| other Total, other adverse events | 6 / 10 | 1 / 4 |
| serious Total, serious adverse events | 4 / 10 | 0 / 4 |
Outcome results
Primary
Change in the Ratio of the Partial Pressure of Arterial Oxygen to the Fraction of Inspired Oxygen (PaO2/FiO2 Ratio)
PaO2/FiO2 ratio
Time frame: Change in PaO2/FiO2 ratio from day 0 to day 2.
Population: Determination of this endpoint was dependent on subject consent for collection of an arterial blood sample. A baseline measure was obtained from thirteen subjects. Samples were obtained from seven subjects at day 2, and two subjects at day 7 and none at day 28. Analysis was limited to change from baseline to day 2.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treprostinil Inhalation Solution | Change in the Ratio of the Partial Pressure of Arterial Oxygen to the Fraction of Inspired Oxygen (PaO2/FiO2 Ratio) | 55.6 P/F ratio | Standard Error 31.2 |
| Placebo | Change in the Ratio of the Partial Pressure of Arterial Oxygen to the Fraction of Inspired Oxygen (PaO2/FiO2 Ratio) | 161.1 P/F ratio | Standard Error 0 |
Comparison: Only one placebo subject had data to allow for change from baseline to be calculatedp-value: 0.2416Wilcoxon (Mann-Whitney)
Secondary
Acute Respiratory Distress Syndrome (ARDS) Associated Biomarkers
Change in ARDS associated plasma biomarkers
Time frame: Change from day 0 on days 3 and 7
Population: Too few samples were collected at the designated days 3 and 7 to provide informative data. Plasma samples were not analyzed.
Secondary
All-cause Mortality
All-cause mortality
Time frame: 0-28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treprostinil Inhalation Solution | All-cause Mortality | 4 Participants |
| Placebo | All-cause Mortality | 0 Participants |
p-value: 0.2507Fisher Exact
Secondary
Change in Central Venous Pressure (CVP).
CVP
Time frame: Change in CVP from Day 0 to 3 (if central venous catheter in place)
Population: A central venous line was not in place for the subjects so measurements could not be obtained
Secondary
Change in Mean Arterial Pressure (MAP).
MAP
Time frame: Change in MAP from Day 0 to day 7
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treprostinil Inhalation Solution | Change in Mean Arterial Pressure (MAP). | -9.96 mm Hg | Standard Deviation 15.5 |
| Placebo | Change in Mean Arterial Pressure (MAP). | 8.18 mm Hg | Standard Deviation 13.1 |
p-value: 0.567Mixed Models Analysis
Secondary
Change in the Central Venous Oxygen Saturation (SCVO2).
SCVO2
Time frame: Change in SCVO2 from Day 0 to 3 (if central venous catheter in place)
Population: None of the patients had a central venous line, so no samples were obtained for analysis.
Secondary
Change in the Ratio of Peripheral Oxygen Saturation to Fraction of Inspired Oxygen (SaO2/FiO2)
SaO2/FiO2
Time frame: 0-12 days
Population: Intent to treat
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Treprostinil Inhalation Solution | Change in the Ratio of Peripheral Oxygen Saturation to Fraction of Inspired Oxygen (SaO2/FiO2) | 303.7 S/F ratio | Standard Error 22 |
| Placebo | Change in the Ratio of Peripheral Oxygen Saturation to Fraction of Inspired Oxygen (SaO2/FiO2) | 382.3 S/F ratio | Standard Error 36.9 |
p-value: 0.06Mixed Models Analysis
Secondary
Number of Days From Study Enrollment Until Mechanical Ventilation is Required
Time to intubation and mechanical ventilation
Time frame: Day 0 to day 28
Population: Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treprostinil Inhalation Solution | Number of Days From Study Enrollment Until Mechanical Ventilation is Required | 2.8 days | Standard Deviation 2.2 |
| Placebo | Number of Days From Study Enrollment Until Mechanical Ventilation is Required | 0 days | Standard Deviation 0 |
Secondary
Number of Days Not on a Ventilator
Ventilator-free days
Time frame: 0-28 days post enrollment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treprostinil Inhalation Solution | Number of Days Not on a Ventilator | 16.4 days | Standard Deviation 14.1 |
| Placebo | Number of Days Not on a Ventilator | 28 days | Standard Deviation 0 |
p-value: 0.0679Wilcoxon (Mann-Whitney)
Secondary
Number of Deaths During Hospitalization
Hospital Mortality
Time frame: Deaths during hospitalization (up to 3 months)
Population: Intent to Treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treprostinil Inhalation Solution | Number of Deaths During Hospitalization | 3 Participants |
| Placebo | Number of Deaths During Hospitalization | 0 Participants |
p-value: 0.5055Fisher Exact
Secondary
Number of Subjects Requiring Intubation and Mechanical Ventilation
Intubation / Mechanical Ventilation
Time frame: 0-28 days
Population: Intent to treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treprostinil Inhalation Solution | Number of Subjects Requiring Intubation and Mechanical Ventilation | 4 Participants |
| Placebo | Number of Subjects Requiring Intubation and Mechanical Ventilation | 0 Participants |
Secondary
Number of Subjects Who Required Bi-level Positive Airway Pressure (BiPAP) or Continuous Positive Airway Pressure (CPAP) Via Face Mask
BiPAP / CPAP
Time frame: 0-28 days
Population: Intent to treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treprostinil Inhalation Solution | Number of Subjects Who Required Bi-level Positive Airway Pressure (BiPAP) or Continuous Positive Airway Pressure (CPAP) Via Face Mask | 2 Participants |
| Placebo | Number of Subjects Who Required Bi-level Positive Airway Pressure (BiPAP) or Continuous Positive Airway Pressure (CPAP) Via Face Mask | 1 Participants |
Secondary
Peak Plasma Concentration Determined 15 Min After Inhalation and Trough Determined 4 Hours Following the Drug/Placebo Administration
Treprostinil Plasma Concentration
Time frame: Day 3
Population: Only 3 plasma pharmacokinetic samples were collected from subjects treated with Treprostinil and therefore no measurements of plasma Treprostinil were made.