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Treprostinil Sodium Inhalation for Patients At High Risk for ARDS

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ClinicalTrials.gov Identifier: NCT02370095
Recruitment Status : Terminated
First Posted : February 24, 2015
Results First Posted : October 1, 2019
Last Update Posted : October 1, 2019
Sponsor:
Collaborator:
United Therapeutics
Information provided by (Responsible Party):
University of North Carolina, Chapel Hill

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.

Condition or disease Intervention/treatment Phase
Respiratory Distress Syndrome, Adult Drug: Treprostinil Inhalation Solution Drug: Placebo Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 14 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Prevention
Official Title: Treprostinil Sodium Inhalation for Patients At High Risk for ARDS: Effect on Oxygenation and Disease-related Biomarkers
Study Start Date : February 2015
Actual Primary Completion Date : October 11, 2017
Actual Study Completion Date : November 7, 2017


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 Name: 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 Name: Sterile saline solution




Primary Outcome Measures :
  1. Change in the Ratio of the Partial Pressure of Arterial Oxygen to the Fraction of Inspired Oxygen (PaO2/FiO2 Ratio) [ Time Frame: Change in PaO2/FiO2 ratio from day 0 to day 2. ]
    PaO2/FiO2 ratio


Secondary Outcome Measures :
  1. Change in the Ratio of Peripheral Oxygen Saturation to Fraction of Inspired Oxygen (SaO2/FiO2) [ Time Frame: 0-12 days ]
    SaO2/FiO2

  2. Number of Days Not on a Ventilator [ Time Frame: 0-28 days post enrollment ]
    Ventilator-free days

  3. Number of Subjects Who Required Bi-level Positive Airway Pressure (BiPAP) or Continuous Positive Airway Pressure (CPAP) Via Face Mask [ Time Frame: 0-28 days ]
    BiPAP / CPAP

  4. Acute Respiratory Distress Syndrome (ARDS) Associated Biomarkers [ Time Frame: Change from day 0 on days 3 and 7 ]
    Change in ARDS associated plasma biomarkers

  5. Change in the Central Venous Oxygen Saturation (SCVO2). [ Time Frame: Change in SCVO2 from Day 0 to 3 (if central venous catheter in place) ]
    SCVO2

  6. Change in Central Venous Pressure (CVP). [ Time Frame: Change in CVP from Day 0 to 3 (if central venous catheter in place) ]
    CVP

  7. Change in Mean Arterial Pressure (MAP). [ Time Frame: Change in MAP from Day 0 to day 7 ]
    MAP

  8. All-cause Mortality [ Time Frame: 0-28 days ]
    All-cause mortality

  9. Number of Subjects Requiring Intubation and Mechanical Ventilation [ Time Frame: 0-28 days ]
    Intubation / Mechanical Ventilation

  10. Number of Deaths During Hospitalization [ Time Frame: Deaths during hospitalization (up to 3 months) ]
    Hospital Mortality

  11. Peak Plasma Concentration Determined 15 Min After Inhalation and Trough Determined 4 Hours Following the Drug/Placebo Administration [ Time Frame: Day 3 ]
    Treprostinil Plasma Concentration

  12. Number of Days From Study Enrollment Until Mechanical Ventilation is Required [ Time Frame: Day 0 to day 28 ]
    Time to intubation and mechanical ventilation



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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02370095


Locations
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United States, North Carolina
University of North Carolina Hospitals
Chapel Hill, North Carolina, United States, 27599
Sponsors and Collaborators
University of North Carolina, Chapel Hill
United Therapeutics
Investigators
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Principal Investigator: Hubert J Ford, MD University of North Carolina, Chapel Hill
Principal Investigator: Shannon Carson, MD University of North Carolina, Chapel Hill
Principal Investigator: Wayne H Anderson, PhD University of North Carolina, Chapel Hill
  Study Documents (Full-Text)

Documents provided by University of North Carolina, Chapel Hill:

Publications:

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Responsible Party: University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT02370095     History of Changes
Other Study ID Numbers: 14-0490
First Posted: February 24, 2015    Key Record Dates
Results First Posted: October 1, 2019
Last Update Posted: October 1, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: only summary data via publication/abstract
Keywords provided by University of North Carolina, Chapel Hill:
ARDS
Acute Lung Injury
Acute Respiratory Failure
Additional relevant MeSH terms:
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Respiratory Distress Syndrome, Newborn
Respiratory Distress Syndrome, Adult
Acute Lung Injury
Respiration Disorders
Respiratory Tract Diseases
Lung Diseases
Infant, Premature, Diseases
Infant, Newborn, Diseases
Lung Injury
Treprostinil
Pharmaceutical Solutions
Antihypertensive Agents