Treprostinil Sodium Inhalation for Patients At High Risk for ARDS

Respiratory Distress Syndrome, Adult Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02370095
• Other study ID #: 14-0490
• Status: Terminated
• Phase: Phase 2
• Start date: February 2015
• Est. completion date: November 7, 2017

Study information

• Verified date: July 2019
• Source: University of North Carolina, Chapel Hill
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 14
• Est. completion date: November 7, 2017
• Est. primary completion date: October 11, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Lung Injury
• Respiratory Distress Syndrome, Adult
• Respiratory Distress Syndrome, Newborn

Intervention

Drug:
• Treprostinil Inhalation Solution
Treprostinil inhalation solution administered as blinded marketed product
• Placebo
Supplied by the manufacturer and similar to the active drug but containing no Treprostinil

Locations

Country	Name	City	State
United States	University of North Carolina Hospitals	Chapel Hill	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
University of North Carolina, Chapel Hill	United Therapeutics

Country where clinical trial is conducted

United States, 

References & Publications (7)

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. — View 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. — View 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. Review. — View 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. Epub 2002 Jun 24. — View 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. — View 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. — View 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. — View Citation

Outcome

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