Clinical trial NCT02370095: Treprostinil Sodium Inhalation for Patients At High Risk for ARDS
Official title: Treprostinil Sodium Inhalation for Patients At High Risk for ARDS: Effect on Oxygenation and Disease-related Biomarkers
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Respiratory Distress Syndrome, Adult
Keywords: ARDS
Acute Lung Injury
Acute Respiratory Failure
Lead sponsor: University of North Carolina, Chapel Hill
Sponsor class: OTHER
Collaborators: name: United Therapeutics
First posted: 2015-02-24
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility criteria: 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.

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 mean arterial pressure (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 \[Epoprostenol (Flolan or Veletri), Iloprost (Ventavis), Treprostinil (Orenitram, oral) (Remodulin, IV or SC)\]
18. Patient has a language barrier

Primary outcomes:
measure: Change in the Ratio of the Partial Pressure of Arterial Oxygen to the Fraction of Inspired Oxygen (PaO2/FiO2 Ratio)
timeFrame: Change in PaO2/FiO2 ratio from day 0 to day 2.
Secondary outcomes:
measure: Change in the Ratio of Peripheral Oxygen Saturation to Fraction of Inspired Oxygen (SaO2/FiO2)
timeFrame: 0-12 days
measure: Number of Days Not on a Ventilator
timeFrame: 0-28 days post enrollment
measure: Number of Subjects Who Required Bi-level Positive Airway Pressure (BiPAP) or Continuous Positive Airway Pressure (CPAP) Via Face Mask
timeFrame: 0-28 days
measure: Acute Respiratory Distress Syndrome (ARDS) Associated Biomarkers
timeFrame: Change from day 0 on days 3 and 7
measure: Change in the Central Venous Oxygen Saturation (SCVO2).
timeFrame: Change in SCVO2 from Day 0 to 3 (if central venous catheter in place)
measure: Change in Central Venous Pressure (CVP).
timeFrame: Change in CVP from Day 0 to 3 (if central venous catheter in place)
measure: Change in Mean Arterial Pressure (MAP).
timeFrame: Change in MAP from Day 0 to day 7
measure: All-cause Mortality
timeFrame: 0-28 days
measure: Number of Subjects Requiring Intubation and Mechanical Ventilation
timeFrame: 0-28 days
measure: Number of Deaths During Hospitalization
timeFrame: Deaths during hospitalization (up to 3 months)
measure: Peak Plasma Concentration Determined 15 Min After Inhalation and Trough Determined 4 Hours Following the Drug/Placebo Administration
timeFrame: Day 3
measure: Number of Days From Study Enrollment Until Mechanical Ventilation is Required
timeFrame: Day 0 to day 28
Other outcomes:
Locations:
city: Chapel Hill
country: United States
facility: University of North Carolina Hospitals
state: North Carolina
Study officials:
affiliation: University of North Carolina, Chapel Hill
name: Hubert J Ford, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of North Carolina, Chapel Hill
name: Shannon Carson, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of North Carolina, Chapel Hill
name: Wayne H Anderson, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Zwissler B, Kemming G, Habler O, Kleen M, Merkel M, Haller M, Briegel J, Welte M, Peter K. Inhaled prostacyclin (PGI2) versus inhaled nitric oxide in adult respiratory distress syndrome. Am J Respir Crit Care Med. 1996 Dec;154(6 Pt 1):1671-7. doi: 10.1164/ajrccm.154.6.8970353.
citation: Walmrath D, Schneider T, Schermuly R, Olschewski H, Grimminger F, Seeger W. Direct comparison of inhaled nitric oxide and aerosolized prostacyclin in acute respiratory distress syndrome. Am J Respir Crit Care Med. 1996 Mar;153(3):991-6. doi: 10.1164/ajrccm.153.3.8630585.
citation: Walmrath D, Schneider T, Pilch J, Schermuly R, Grimminger F, Seeger W. Effects of aerosolized prostacyclin in severe pneumonia. Impact of fibrosis. Am J Respir Crit Care Med. 1995 Mar;151(3 Pt 1):724-30. doi: 10.1164/ajrccm.151.3.7881662.
citation: Domenighetti G, Stricker H, Waldispuehl B. Nebulized prostacyclin (PGI2) in acute respiratory distress syndrome: impact of primary (pulmonary injury) and secondary (extrapulmonary injury) disease on gas exchange response. Crit Care Med. 2001 Jan;29(1):57-62. doi: 10.1097/00003246-200101000-00015.
citation: Dahlem P, van Aalderen WM, de Neef M, Dijkgraaf MG, Bos AP. Randomized controlled trial of aerosolized prostacyclin therapy in children with acute lung injury. Crit Care Med. 2004 Apr;32(4):1055-60. doi: 10.1097/01.ccm.0000120055.52377.bf.
citation: Dorris SL, Peebles RS Jr. PGI2 as a regulator of inflammatory diseases. Mediators Inflamm. 2012;2012:926968. doi: 10.1155/2012/926968. Epub 2012 Jul 18.
citation: Raychaudhuri B, Malur A, Bonfield TL, Abraham S, Schilz RJ, Farver CF, Kavuru MS, Arroliga AC, Thomassen MJ. The prostacyclin analogue treprostinil blocks NFkappaB nuclear translocation in human alveolar macrophages. J Biol Chem. 2002 Sep 6;277(36):33344-8. doi: 10.1074/jbc.M203567200. Epub 2002 Jun 24.
citation: Ford HJ, Anderson WH, Wendlandt B, Bice T, Ceppe A, Lanier J, Carson SS. Randomized, Placebo-controlled Trial of Inhaled Treprostinil for Patients at Risk for Acute Respiratory Distress Syndrome. Ann Am Thorac Soc. 2021 Apr;18(4):641-647. doi: 10.1513/AnnalsATS.202004-374OC.