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| Name | Class |
|---|---|
| United Therapeutics | INDUSTRY |
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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.
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:
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Treprostinil inhalation solution | Active Comparator | 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. |
|
| Placebo | Placebo Comparator | Placebo administration will be administered as above for the active arm |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Treprostinil Inhalation Solution | Drug | Treprostinil inhalation solution administered as blinded marketed product |
|
| 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. |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| 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 | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of North Carolina Hospitals | Chapel Hill | North Carolina | 27599 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 8970353 | Background | 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. | |
| 8630585 | Background | 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. |
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only summary data via publication/abstract
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One patient was consented, randomized (Placebo) and baseline data was collected. However, before receiving treatment the subject deteriorated, and a protocol defined stopping rule was met. The subject was defined as completed. Baseline data were used in the analyses, and the AEs recorded are presented in the AE section.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. Treprostinil Inhalation Solution: Treprostinil inhalation solution administered as blinded marketed product |
| FG001 | Placebo | Placebo administration will be administered as above for the active arm Placebo: Supplied by the manufacturer and similar to the active drug but containing no Treprostinil |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
All subjects who signed a consent are included in baseline measurements
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. Treprostinil Inhalation Solution: Treprostinil inhalation solution administered as blinded marketed product |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in the Ratio of the Partial Pressure of Arterial Oxygen to the Fraction of Inspired Oxygen (PaO2/FiO2 Ratio) | PaO2/FiO2 ratio | Determination of this endpoint was dependent on subject consent for collection of an arterial blood sample. A baseline measure was obtained from thirteen subjects. Samples were obtained from seven subjects at day 2, and two subjects at day 7 and none at day 28. Analysis was limited to change from baseline to day 2. | Posted | Mean | Standard Error | P/F ratio | Change in PaO2/FiO2 ratio from day 0 to day 2. |
|
From time of enrollment until end of follow-up, approximately 28 days.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. Treprostinil Inhalation Solution: Treprostinil inhalation solution administered as blinded marketed product |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Death | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea/Emesis | Gastrointestinal disorders | Systematic Assessment |
The study was stopped because of low recruitment. The limited number of subjects make it difficult to draw conclusions regarding the efficacy of Treprostinil in subjects at high risk of developing ARDS.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Wayne H Anderson, PhD | University of North Carolina at Chapel Hill | 919-445-0351 | wayne_anderson@med.unc.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 9, 2018 | Jul 30, 2019 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D012128 | Respiratory Distress Syndrome |
| D055371 | Acute Lung Injury |
| ID | Term |
|---|---|
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D012120 | Respiration Disorders |
| D055370 | Lung Injury |
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| ID | Term |
|---|---|
| C427248 | treprostinil |
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| Placebo | Drug | Supplied by the manufacturer and similar to the active drug but containing no Treprostinil |
|
|
| 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 |
| 7881662 | Background | 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. |
| 11176161 | Background | 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. |
| 15071401 | Background | 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. |
| 22851816 | Background | 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. |
| 12082102 | Background | 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. |
| 33095030 | Derived | 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. |
| BG001 | Placebo | Placebo administration will be administered as above for the active arm Placebo: Supplied by the manufacturer and similar to the active drug but containing no Treprostinil |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| OG001 | Placebo | Placebo administration will be administered as above for the active arm Placebo: Supplied by the manufacturer and similar to the active drug but containing no Treprostinil |
|
|
|
| Secondary | Change in the Ratio of Peripheral Oxygen Saturation to Fraction of Inspired Oxygen (SaO2/FiO2) | SaO2/FiO2 | Intent to treat | Posted | Least Squares Mean | Standard Error | S/F ratio | 0-12 days |
|
|
|
|
| Secondary | Number of Days Not on a Ventilator | Ventilator-free days | Posted | Mean | Standard Deviation | 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 | Intent to treat | Posted | Count of Participants | Participants | 0-28 days |
|
|
|
| Secondary | Acute Respiratory Distress Syndrome (ARDS) Associated Biomarkers | Change in ARDS associated plasma biomarkers | Too few samples were collected at the designated days 3 and 7 to provide informative data. Plasma samples were not analyzed. | Posted | Change from day 0 on days 3 and 7 |
|
|
| Secondary | Change in the Central Venous Oxygen Saturation (SCVO2). | SCVO2 | None of the patients had a central venous line, so no samples were obtained for analysis. | Posted | Change in SCVO2 from Day 0 to 3 (if central venous catheter in place) |
|
|
| Secondary | Change in Central Venous Pressure (CVP). | CVP | A central venous line was not in place for the subjects so measurements could not be obtained | Posted | Change in CVP from Day 0 to 3 (if central venous catheter in place) |
|
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| Secondary | Change in Mean Arterial Pressure (MAP). | MAP | Intent to Treat | Posted | Mean | Standard Deviation | mm Hg | Change in MAP from Day 0 to day 7 |
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| Secondary | All-cause Mortality | All-cause mortality | Posted | Count of Participants | Participants | 0-28 days |
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| Secondary | Number of Subjects Requiring Intubation and Mechanical Ventilation | Intubation / Mechanical Ventilation | Intent to treat | Posted | Count of Participants | Participants | 0-28 days |
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| Secondary | Number of Deaths During Hospitalization | Hospital Mortality | Intent to Treat | Posted | Count of Participants | Participants | Deaths during hospitalization (up to 3 months) |
|
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| Secondary | Peak Plasma Concentration Determined 15 Min After Inhalation and Trough Determined 4 Hours Following the Drug/Placebo Administration | Treprostinil Plasma Concentration | Only 3 plasma pharmacokinetic samples were collected from subjects treated with Treprostinil and therefore no measurements of plasma Treprostinil were made. | Posted | Day 3 |
|
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| Secondary | Number of Days From Study Enrollment Until Mechanical Ventilation is Required | Time to intubation and mechanical ventilation | Intent to Treat | Posted | Mean | Standard Deviation | days | Day 0 to day 28 |
|
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| 4 |
| 10 |
| 4 |
| 10 |
| 6 |
| 10 |
| EG001 | Placebo | Placebo administration will be administered as above for the active arm Placebo: Supplied by the manufacturer and similar to the active drug but containing no Treprostinil | 0 | 4 | 0 | 4 | 1 | 4 |
| septic shock | Infections and infestations | Systematic Assessment |
|
| Transfusion Reaction | Immune system disorders | Systematic Assessment |
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| Cholelithiasis | Gastrointestinal disorders | Systematic Assessment |
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| Metapneumovirus | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Pneumomediatinum/Bilateral pneumothoraces | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Retro-peritoneal hematoma | Injury, poisoning and procedural complications | Systematic Assessment |
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| Hematemesis | Gastrointestinal disorders | Systematic Assessment |
|
| Hypertension | Vascular disorders | Systematic Assessment |
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| Ileus | Gastrointestinal disorders | Systematic Assessment |
|
| Renal Failure | Renal and urinary disorders | Systematic Assessment |
|
| Sleep Interference | General disorders | Systematic Assessment |
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| Hematuria | Renal and urinary disorders | Systematic Assessment |
|
| Wheezing | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Acute Kidney Injury | Renal and urinary disorders | Systematic Assessment |
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| Hypernatremia | Renal and urinary disorders | Systematic Assessment |
|
| Transfusion Reaction | Immune system disorders | Systematic Assessment |
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| GI Bleed | Gastrointestinal disorders | Systematic Assessment |
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| Hypoxemia | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Hypotension | Cardiac disorders | Systematic Assessment |
|
| Hyponatremia | Renal and urinary disorders | Systematic Assessment |
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| Elevated Transaminase | Gastrointestinal disorders | Systematic Assessment |
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| Parapneuomonic Effusion with decortication | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Anemia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Delirium | Nervous system disorders | Systematic Assessment |
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| Hyperbilirubinemia | Blood and lymphatic system disorders | Systematic Assessment |
|
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