Portopulmonary Hypertension, Pulmonary Arterial Hypertension, Pulmonary Hypertension
Conditions
Keywords
PAH, Pulmonary Hypertension, Remodulin, Treprostinil, Quality of Life
Brief summary
This was a multicenter, prospective, observational, open-label study. Patients meeting inclusion/exclusion criteria received treatment with treprostinil as recommended by their treating physicians and were followed according to standard of care. This observational study collected clinical data and biologic specimens from patients who were treated for portopulmonary hypertension (PoPH), with a goal of achieving hemodynamic parameters appropriate for orthotopic liver transplantation candidacy, including mean pulmonary arterial pressure (mPAP) less than 35 mmHg and pulmonary vascular resistance (PVR) less than 3 Wood-units (WU) at Week 24 in patients with severe PoPH.
Detailed description
Treprostinil is approved as a continuous subcutaneous (SC) or intravenous (IV) infusion by the FDA for the treatment of WHO group I PAH with New York Heart Association (NYHA) Functional Class II, III or IV symptomatology. To date, treprostinil has not been studied in the setting of PoPH; however, it is commonly prescribed in this setting. This was an observational, open-label, multicenter study which documented the safety and efficacy profile of this agent in PoPH to facilitate orthotopic liver transplantation (OLT).
Interventions
DRUGTreprostinil
Remodulin is supplied in concentrations of 1, 2.5 , 5, and 10 mg/mL and can be administered as supplied or diluted for intravenous (IV) infusion prior to administration. Remodulin is indicated for subcutaneous (SC) or IV use only as a continuous infusion. Remodulin is preferably infused subcutaneously, but can be administered by a central IV line if the SC route is not tolerated. The infusion rate is initiated at 1.25 ng/kg/min. If this initial dose cannot be tolerated because of systemic effects, the infusion rate should be reduced to 0.625 ng/kg/min.
Sponsors
University of California, Los Angeles
Brigham and Women's Hospital
University of Texas
Emory University
United Therapeutics
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Patients must: 1. Had portal hypertension. 2. Be otherwise suitable candidates for OLT. 3. Had severe pulmonary arterial hypertension (PAH) defined as a resting mean pulmonary arterial pressure (mPAP) \>35 mmHg and pulmonary vascular resistance (PVR) ≥3 Wood Units (WU) by right heart catheterization (RHC) performed as part of standard of care evaluation within 90 days of enrollment. 4. Treprostinil therapy must be recommended by the treating physician per standard of care. 5. Be NYHA Functional Class II, III, or IV. 6. Had pulmonary capillary wedge (PCW) pressure ≤18 mmHg and transpulmonary gradient (TPG) ≥15 mmHg.
Exclusion criteria
* Patients must not: 1. Had received any any investigational therapy as part of a clinical trial for any indication within 30 days prior to enrollment. 2. Had a change in dose of treatment for PAH (bosentan \[Tracleer\], ambrisentan \[Letairis\], tadalafil \[Adcirca\], or sildenafil \[Revatio\]), within 30 days prior to enrollment. That is, subjects may have been treated with any of these agents provided the dose was stable for at least 30 days prior to enrollment. 3. Had renal failure requiring hemodialysis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Who Achieved Hemodynamic Parameters Appropriate for Orthotopic Liver Transplantation Candidacy at Week 24. | 24 Weeks | The primary efficacy endpoint was the number of subjects who achieved a mean pulmonary arterial pressure (mPAP) less than 35 mmHg and a pulmonary vascular resistance (PVR) less than 3 Wood units (WU) at Week 24 in patients with severe portopulmonary hypertension (PoPH). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Echocardiogram Parameters (Right Atrium and Right Ventricle Area) From Baseline to Weeks 12 and 24 | Baseline and Weeks 12 and 24 | Standard transthoracic echocardiogram with continuous wave Doppler and color flow imaging was completed at Screening. All patients who were enrolled in this study underwent an echocardiogram within 30 days of enrollment as well as repeat echocardiograms on Weeks 12 and 24. |
| Change in Hemodynamic Parameters (Via Right Heart Catheterization [RHC]) at Rest From Baseline to Week 24 | 24 weeks | The change in hemodynamic parameters (including systolic pulmonary arterial pressure \[PAPs\], diastolic pulmonary arterial pressure \[PAPd\], mean pulmonary arterial pressure \[mPAP\], and transpulmonary gradient \[TPG\]) was evaluated at rest from Baseline to Week 24. The median change in hemodynamic parameters from Baseline to Week 24 via right-heart catheterization (RHC) is presented. |
| Change in Heart Rate at Rest From Baseline to Week 24 | 24 weeks | The change in heart rate was evaluated at rest from Baseline to Week 24. |
| Change in Cardiac Output at Rest From Baseline to Week 24 | 24 weeks | The change in cardiac output was evaluated at rest from Baseline to Week 24. The median change in cardiac output from Baseline to Week 24 is presented. |
| Change in Arterial and Venous Oxygen Saturation at Rest From Baseline to Week 24 | 24 weeks | The change in arterial and venous oxygen saturation was evaluated at rest from Baseline to Week 24. |
| Change in 6-minute Walk Distance (6MWD) From Baseline to Weeks 12 and 24. | Baseline and Weeks 12 and 24 | The 6-Minute Walk Test was conducted at Screening, Baseline prior to starting study drug and at least 24 hours after the Screening test, and during the Treatment Phase at Weeks 12 and 24. |
| Change in Echocardiogram Parameters (Right Ventricle Diameter) From Baseline to Weeks 12 and 24 | Baseline and Weeks 12 and 24 | Standard transthoracic echocardiogram with continuous wave Doppler and color flow imaging was completed at Screening. All patients who were enrolled in this study underwent an echocardiogram within 30 days of enrollment as well as repeat echocardiograms on Weeks 12 and 24. |
| Change in Echocardiogram Parameters (Right Ventricular Systolic Pressure) From Baseline to Weeks 12 and 24 | Baseline and Weeks 12 and 24 | Standard transthoracic echocardiogram with continuous wave Doppler and color flow imaging was completed at Screening. All patients who were enrolled in this study underwent an echocardiogram within 30 days of enrollment as well as repeat echocardiograms on Weeks 12 and 24. |
| Change in Echocardiogram Parameters (Tricuspid Annular Plane Systolic Excursion) From Baseline to Weeks 12 and 24 | Baseline and Weeks 12 and 24 | Standard transthoracic echocardiogram with continuous wave Doppler and color flow imaging was completed at Screening. All patients who were enrolled in this study underwent an echocardiogram within 30 days of enrollment as well as repeat echocardiograms on Weeks 12 and 24. |
| Change in Quality of Life From Baseline to Weeks 12 and 24 | Baseline and Weeks 12 and 24 | The 36-item Short Form Survey (SF-36) is a health related quality of life instrument, which measures dimensions of physical and social roles and functioning, mental health, vitality, and pain. Items are scored on a 0 to 100 range so that the lowest scores represent the highest disability. The quality of life assessment was conducted at Baseline and Weeks 12 and 24 and the change from Baseline to Weeks 12 and 24 is presented. |
| Change in Plasma Brain N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to Weeks 12 and 24 | Baseline to Weeks 12 and 24 | NT-proBNP was assessed at Baseline, Weeks 12 and 24. |
| Change in Pulmonary Vascular Resistance (PVR) at Rest From Baseline to Week 24 | 24 weeks | The change in pulmonary vascular resistance (PVR) was evaluated at rest from Baseline to Week 24. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treprostinil Injection Subjects meeting inclusion/exclusion criteria with portopulmonary hypertension (PoPH) and severe pulmonary arterial hypertension (PAH). | 13 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Death | 2 |
Baseline characteristics
| Characteristic | Treprostinil Injection |
|---|---|
| Age, Continuous | 55.8 Years STANDARD_DEVIATION 8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Gender Female | 8 Participants |
| Gender Male | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 13 Participants |
| Region of Enrollment United States | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 13 / 13 |
| serious Total, serious adverse events | 8 / 13 |
Outcome results
Primary
Number of Subjects Who Achieved Hemodynamic Parameters Appropriate for Orthotopic Liver Transplantation Candidacy at Week 24.
The primary efficacy endpoint was the number of subjects who achieved a mean pulmonary arterial pressure (mPAP) less than 35 mmHg and a pulmonary vascular resistance (PVR) less than 3 Wood units (WU) at Week 24 in patients with severe portopulmonary hypertension (PoPH).
Time frame: 24 Weeks
Population: The total number of subjects enrolled and analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treprostinil Injection | Number of Subjects Who Achieved Hemodynamic Parameters Appropriate for Orthotopic Liver Transplantation Candidacy at Week 24. | Primary endpoint achieved | 1 participants |
| Treprostinil Injection | Number of Subjects Who Achieved Hemodynamic Parameters Appropriate for Orthotopic Liver Transplantation Candidacy at Week 24. | Primary endpoint not achieved | 12 participants |
Secondary
Change in 6-minute Walk Distance (6MWD) From Baseline to Weeks 12 and 24.
The 6-Minute Walk Test was conducted at Screening, Baseline prior to starting study drug and at least 24 hours after the Screening test, and during the Treatment Phase at Weeks 12 and 24.
Time frame: Baseline and Weeks 12 and 24
Population: All subjects with data available at Baseline and Weeks 12 and 24
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treprostinil Injection | Change in 6-minute Walk Distance (6MWD) From Baseline to Weeks 12 and 24. | Change from Baseline to Week 12 | 54.5 Meters |
| Treprostinil Injection | Change in 6-minute Walk Distance (6MWD) From Baseline to Weeks 12 and 24. | Change from Baseline to Week 24 | 12.0 Meters |
Secondary
Change in Arterial and Venous Oxygen Saturation at Rest From Baseline to Week 24
The change in arterial and venous oxygen saturation was evaluated at rest from Baseline to Week 24.
Time frame: 24 weeks
Population: All subjects with data available at Baseline and Week 24
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treprostinil Injection | Change in Arterial and Venous Oxygen Saturation at Rest From Baseline to Week 24 | Mixed venous oxygen saturation (%) | -2.0 percentage bound to hemoglobin |
| Treprostinil Injection | Change in Arterial and Venous Oxygen Saturation at Rest From Baseline to Week 24 | Arterial oxygen saturation (%) | 0.5 percentage bound to hemoglobin |
Secondary
Change in Cardiac Output at Rest From Baseline to Week 24
The change in cardiac output was evaluated at rest from Baseline to Week 24. The median change in cardiac output from Baseline to Week 24 is presented.
Time frame: 24 weeks
Population: All subjects with data available at Baseline and Week 24
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treprostinil Injection | Change in Cardiac Output at Rest From Baseline to Week 24 | 0.3 L/min |
Secondary
Change in Echocardiogram Parameters (Right Atrium and Right Ventricle Area) From Baseline to Weeks 12 and 24
Standard transthoracic echocardiogram with continuous wave Doppler and color flow imaging was completed at Screening. All patients who were enrolled in this study underwent an echocardiogram within 30 days of enrollment as well as repeat echocardiograms on Weeks 12 and 24.
Time frame: Baseline and Weeks 12 and 24
Population: All subjects with data available at Baseline and Weeks 12 and 24.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treprostinil Injection | Change in Echocardiogram Parameters (Right Atrium and Right Ventricle Area) From Baseline to Weeks 12 and 24 | Right atrium area (cm2) | -0.1 cm2 |
| Treprostinil Injection | Change in Echocardiogram Parameters (Right Atrium and Right Ventricle Area) From Baseline to Weeks 12 and 24 | Right ventricle area (cm2) | -1.0 cm2 |
| Treprostinil Injection-Baseline to Week 24 | Change in Echocardiogram Parameters (Right Atrium and Right Ventricle Area) From Baseline to Weeks 12 and 24 | Right atrium area (cm2) | -1.7 cm2 |
| Treprostinil Injection-Baseline to Week 24 | Change in Echocardiogram Parameters (Right Atrium and Right Ventricle Area) From Baseline to Weeks 12 and 24 | Right ventricle area (cm2) | -7.4 cm2 |
Secondary
Change in Echocardiogram Parameters (Right Ventricle Diameter) From Baseline to Weeks 12 and 24
Standard transthoracic echocardiogram with continuous wave Doppler and color flow imaging was completed at Screening. All patients who were enrolled in this study underwent an echocardiogram within 30 days of enrollment as well as repeat echocardiograms on Weeks 12 and 24.
Time frame: Baseline and Weeks 12 and 24
Population: All subjects with data available at Baseline and Weeks 12 and 24.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treprostinil Injection | Change in Echocardiogram Parameters (Right Ventricle Diameter) From Baseline to Weeks 12 and 24 | -5.0 mm |
| Treprostinil Injection-Baseline to Week 24 | Change in Echocardiogram Parameters (Right Ventricle Diameter) From Baseline to Weeks 12 and 24 | 3.0 mm |
Secondary
Change in Echocardiogram Parameters (Right Ventricular Systolic Pressure) From Baseline to Weeks 12 and 24
Standard transthoracic echocardiogram with continuous wave Doppler and color flow imaging was completed at Screening. All patients who were enrolled in this study underwent an echocardiogram within 30 days of enrollment as well as repeat echocardiograms on Weeks 12 and 24.
Time frame: Baseline and Weeks 12 and 24
Population: All subjects with data available at Baseline and Weeks 12 and 24.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treprostinil Injection | Change in Echocardiogram Parameters (Right Ventricular Systolic Pressure) From Baseline to Weeks 12 and 24 | -12 mmHg |
| Treprostinil Injection-Baseline to Week 24 | Change in Echocardiogram Parameters (Right Ventricular Systolic Pressure) From Baseline to Weeks 12 and 24 | -5.0 mmHg |
Secondary
Change in Echocardiogram Parameters (Tricuspid Annular Plane Systolic Excursion) From Baseline to Weeks 12 and 24
Standard transthoracic echocardiogram with continuous wave Doppler and color flow imaging was completed at Screening. All patients who were enrolled in this study underwent an echocardiogram within 30 days of enrollment as well as repeat echocardiograms on Weeks 12 and 24.
Time frame: Baseline and Weeks 12 and 24
Population: All subjects with data available at Baseline and Weeks 12 and 24.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treprostinil Injection | Change in Echocardiogram Parameters (Tricuspid Annular Plane Systolic Excursion) From Baseline to Weeks 12 and 24 | 0.5 cm |
| Treprostinil Injection-Baseline to Week 24 | Change in Echocardiogram Parameters (Tricuspid Annular Plane Systolic Excursion) From Baseline to Weeks 12 and 24 | 0.1 cm |
Secondary
Change in Heart Rate at Rest From Baseline to Week 24
The change in heart rate was evaluated at rest from Baseline to Week 24.
Time frame: 24 weeks
Population: All subjects with data available at Baseline and Week 24
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treprostinil Injection | Change in Heart Rate at Rest From Baseline to Week 24 | 0.5 beats/min |
Secondary
Change in Hemodynamic Parameters (Via Right Heart Catheterization [RHC]) at Rest From Baseline to Week 24
The change in hemodynamic parameters (including systolic pulmonary arterial pressure \[PAPs\], diastolic pulmonary arterial pressure \[PAPd\], mean pulmonary arterial pressure \[mPAP\], and transpulmonary gradient \[TPG\]) was evaluated at rest from Baseline to Week 24. The median change in hemodynamic parameters from Baseline to Week 24 via right-heart catheterization (RHC) is presented.
Time frame: 24 weeks
Population: All subjects with data available at Baseline and Week 24
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treprostinil Injection | Change in Hemodynamic Parameters (Via Right Heart Catheterization [RHC]) at Rest From Baseline to Week 24 | Mean pulmonary arterial pressure (mmHg) | -3.8 mmHg |
| Treprostinil Injection | Change in Hemodynamic Parameters (Via Right Heart Catheterization [RHC]) at Rest From Baseline to Week 24 | Systolic pulmonary arterial pressure (mmHg) | -2.0 mmHg |
| Treprostinil Injection | Change in Hemodynamic Parameters (Via Right Heart Catheterization [RHC]) at Rest From Baseline to Week 24 | Diastolic pulmonary arterial pressure (mmHg) | -4.0 mmHg |
| Treprostinil Injection | Change in Hemodynamic Parameters (Via Right Heart Catheterization [RHC]) at Rest From Baseline to Week 24 | Mean right arterial pressure (mmHg) | -2.0 mmHg |
| Treprostinil Injection | Change in Hemodynamic Parameters (Via Right Heart Catheterization [RHC]) at Rest From Baseline to Week 24 | Mean systemic arterial pressure (mmHg) | -0.7 mmHg |
| Treprostinil Injection | Change in Hemodynamic Parameters (Via Right Heart Catheterization [RHC]) at Rest From Baseline to Week 24 | Systolic systemic arterial pressure (mmHg) | 7.0 mmHg |
| Treprostinil Injection | Change in Hemodynamic Parameters (Via Right Heart Catheterization [RHC]) at Rest From Baseline to Week 24 | Diastolic systemic arterial pressure | 0 mmHg |
| Treprostinil Injection | Change in Hemodynamic Parameters (Via Right Heart Catheterization [RHC]) at Rest From Baseline to Week 24 | Mean pulmonary capillary wedge pressure (mmHg) | 0 mmHg |
| Treprostinil Injection | Change in Hemodynamic Parameters (Via Right Heart Catheterization [RHC]) at Rest From Baseline to Week 24 | Transpulmonary gradient (mmHg) | -6.8 mmHg |
Secondary
Change in Plasma Brain N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to Weeks 12 and 24
NT-proBNP was assessed at Baseline, Weeks 12 and 24.
Time frame: Baseline to Weeks 12 and 24
Population: All subjects with data available at Baseline and Weeks 12 and 24.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treprostinil Injection | Change in Plasma Brain N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to Weeks 12 and 24 | Change from Baseline to Week 12 | -628 pg/mL |
| Treprostinil Injection | Change in Plasma Brain N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to Weeks 12 and 24 | Change from Baseline to Week 24 | -478 pg/mL |
Secondary
Change in Pulmonary Vascular Resistance (PVR) at Rest From Baseline to Week 24
The change in pulmonary vascular resistance (PVR) was evaluated at rest from Baseline to Week 24.
Time frame: 24 weeks
Population: All subjects with data available at Baseline and Week 24
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treprostinil Injection | Change in Pulmonary Vascular Resistance (PVR) at Rest From Baseline to Week 24 | -0.3 Wood Units |
Secondary
Change in Quality of Life From Baseline to Weeks 12 and 24
The 36-item Short Form Survey (SF-36) is a health related quality of life instrument, which measures dimensions of physical and social roles and functioning, mental health, vitality, and pain. Items are scored on a 0 to 100 range so that the lowest scores represent the highest disability. The quality of life assessment was conducted at Baseline and Weeks 12 and 24 and the change from Baseline to Weeks 12 and 24 is presented.
Time frame: Baseline and Weeks 12 and 24
Population: All subjects with data available at Baseline and Weeks 12 and 24.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treprostinil Injection | Change in Quality of Life From Baseline to Weeks 12 and 24 | Physical functioning | 5.7 units on a scale |
| Treprostinil Injection | Change in Quality of Life From Baseline to Weeks 12 and 24 | Role-Physical | 7.9 units on a scale |
| Treprostinil Injection | Change in Quality of Life From Baseline to Weeks 12 and 24 | Bodily pain | 3.6 units on a scale |
| Treprostinil Injection | Change in Quality of Life From Baseline to Weeks 12 and 24 | General health | 4.5 units on a scale |
| Treprostinil Injection | Change in Quality of Life From Baseline to Weeks 12 and 24 | Vitality | 5.9 units on a scale |
| Treprostinil Injection | Change in Quality of Life From Baseline to Weeks 12 and 24 | Social functioning | 7.5 units on a scale |
| Treprostinil Injection | Change in Quality of Life From Baseline to Weeks 12 and 24 | Role-Emotional | 13.9 units on a scale |
| Treprostinil Injection | Change in Quality of Life From Baseline to Weeks 12 and 24 | Mental health | 2.6 units on a scale |
| Treprostinil Injection | Change in Quality of Life From Baseline to Weeks 12 and 24 | Physical component summary | 9.8 units on a scale |
| Treprostinil Injection | Change in Quality of Life From Baseline to Weeks 12 and 24 | Mental component summary | 7.0 units on a scale |
| Treprostinil Injection-Baseline to Week 24 | Change in Quality of Life From Baseline to Weeks 12 and 24 | Mental health | 0 units on a scale |
| Treprostinil Injection-Baseline to Week 24 | Change in Quality of Life From Baseline to Weeks 12 and 24 | Physical functioning | 10.5 units on a scale |
| Treprostinil Injection-Baseline to Week 24 | Change in Quality of Life From Baseline to Weeks 12 and 24 | Social functioning | 0 units on a scale |
| Treprostinil Injection-Baseline to Week 24 | Change in Quality of Life From Baseline to Weeks 12 and 24 | Role-Physical | 9.0 units on a scale |
| Treprostinil Injection-Baseline to Week 24 | Change in Quality of Life From Baseline to Weeks 12 and 24 | Mental component summary | 2.6 units on a scale |
| Treprostinil Injection-Baseline to Week 24 | Change in Quality of Life From Baseline to Weeks 12 and 24 | Bodily pain | 6.0 units on a scale |
| Treprostinil Injection-Baseline to Week 24 | Change in Quality of Life From Baseline to Weeks 12 and 24 | Role-Emotional | 10.4 units on a scale |
| Treprostinil Injection-Baseline to Week 24 | Change in Quality of Life From Baseline to Weeks 12 and 24 | General health | 3.6 units on a scale |
| Treprostinil Injection-Baseline to Week 24 | Change in Quality of Life From Baseline to Weeks 12 and 24 | Physical component summary | 8.2 units on a scale |
| Treprostinil Injection-Baseline to Week 24 | Change in Quality of Life From Baseline to Weeks 12 and 24 | Vitality | 7.4 units on a scale |