Treprostinil Sodium Inhalation for Patients At High Risk for ARDS

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

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.

Study Overview

• Status: Terminated
• Conditions: Respiratory Distress Syndrome, Adult
• Intervention / Treatment: Drug: Treprostinil Inhalation Solution; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina Hospitals

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: 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.	Drug: Treprostinil Inhalation Solution; Treprostinil inhalation solution administered as blinded marketed product; Other Names: TYVASO
PLACEBO_COMPARATOR: Placebo; Placebo administration will be administered as above for the active arm	Drug: Placebo; Supplied by the manufacturer and similar to the active drug but containing no Treprostinil; 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

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: United Therapeutics
• Investigators: Principal Investigator: Hubert J Ford, MD, University of North Carolina, Chapel Hill; Principal Investigator: Wayne H Anderson, PhD, University of North Carolina, Chapel Hill

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: February 1, 2015
• Primary Completion (ACTUAL): October 11, 2017
• Study Completion (ACTUAL): November 7, 2017

Study Registration Dates

• First Submitted: January 30, 2015
• First Submitted That Met QC Criteria: February 17, 2015
• First Posted (ESTIMATE): February 24, 2015

Study Record Updates

• Last Update Posted (ACTUAL): October 1, 2019
• Last Update Submitted That Met QC Criteria: September 12, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: ARDS; Acute Lung Injury; Acute Respiratory Failure
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Antihypertensive Agents; Pharmaceutical Solutions; Treprostinil
• Other Study ID Numbers: 14-0490

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: only summary data via publication/abstract