Treprostinil Sodium Inhalation for Patients At High Risk for ARDS

NCT ID: NCT02370095

Last Updated: 2019-10-01

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 14 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-02-28
• Study Completion Date: 2017-11-07

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.

Conditions

Respiratory Distress Syndrome, Adult

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: TRIPLE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Treprostinil Inhalation Solution

Intervention Type: DRUG

Treprostinil inhalation solution administered as blinded marketed product

Placebo

Placebo administration will be administered as above for the active arm

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Supplied by the manufacturer and similar to the active drug but containing no Treprostinil

Interventions

Treprostinil Inhalation Solution

Treprostinil inhalation solution administered as blinded marketed product

Intervention Type: DRUG

Placebo

Supplied by the manufacturer and similar to the active drug but containing no Treprostinil

Intervention Type: DRUG

Other Intervention Names

TYVASO; Sterile saline solution

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.

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

United Therapeutics

INDUSTRY

Sponsor Role: collaborator

University of North Carolina, Chapel Hill

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Hubert J Ford, MD

Role: PRINCIPAL_INVESTIGATOR

University of North Carolina, Chapel Hill

Shannon Carson, MD

Role: PRINCIPAL_INVESTIGATOR

University of North Carolina, Chapel Hill

Wayne H Anderson, PhD

Role: PRINCIPAL_INVESTIGATOR

University of North Carolina, Chapel Hill

Locations

University of North Carolina Hospitals

Chapel Hill, North Carolina, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 8970353 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 8630585 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 7881662 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 11176161 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15071401 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 22851816 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12082102 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33095030 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

14-0490

Identifier Type: -

Identifier Source: org_study_id