Pulmonary Hypertension
Conditions
Keywords
Pulmonary Arterial Hypertension
Brief summary
This is a double-blind placebo-controlled clinical investigation into the efficacy and tolerability of inhaled treprostinil in patients with severe pulmonary arterial hypertension. The primary outcome is the change in 6-minute walk distance from baseline to week 12.
Detailed description
Patients who have been on a stable dose of 125 mg twice daily (bid) of bosentan or any stable dose of sildenafil for at least three months prior to study start were randomized to either treprostinil inhalation solution or matching placebo. Administration of study medication was performed by inhalation with the OPTINEB™ ultrasonic nebulizer. The proposed dosing regimen was four times daily-upon awakening, at midday, evening (dinner time) and bedtime. After a patient has completed the twelve-week study period, they were given the option of enrolling into an open-label extension study.
Interventions
Doses are titrated to 9 breaths four times daily. Each breath produces an 18 mcg dose of inhaled treprostinil.
Doses are titrated to 9 breaths four times daily.
Sponsors
United Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Clinically stable, pulmonary arterial hypertension diagnosed as either idiopathic or familial PAH, collagen vascular disease associated PAH, HIV PAH, or PAH induced by anorexigens, New York Heart Association (NYHA) Class III or Class IV. * Been on a stable dose of 125 mg twice daily (bid) of bosentan OR any stable dose of sildenafil for at least three months prior to study start * An unencouraged six minute walk test (6MWT) of between 200 and 450 meters at screening * Cardiac catheterization within the past 13 months consistent with PAH, specifically mean pulmonary artery pressure (PAPm) ≥25 mmHg (at rest), pulmonary capillary wedge pressure (PCWP) (or left ventricular end diastolic pressure) ≤15 mmHg, and pulmonary vascular resistance (PVR) \>3 mmHg/L/min * Within the past 12 months, patients must have had a chest radiograph consistent with the diagnosis of PAH * Willing and able to follow all study procedures
Exclusion criteria
* Considering pregnancy, are pregnant and/or lactating * PAH due to conditions other than noted in the above inclusion criteria. * Have had any change in or discontinued any PAH medication within the last three months, including but not limited to endothelin receptor antagonist (ERA), or calcium channel blockers (CCB) (with the exception of anticoagulants) * Have received any prostanoid within the 30 days before screening or are scheduled to receive any during the course of the study * Have received any investigational medication within 30 days prior to the start of this study or are scheduled to receive another investigational drug during the course of this study * Have a known intolerance to any drug, especially to treprostinil sodium or prostanoids * Have an increased risk of hemorrhage * Have a new type of chronic therapy (e.g., a different category of vasodilator, diuretic) for PAH added within the last month, except anticoagulants * Have any musculoskeletal disease or any other disease that would limit ambulation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Peak 6-minute Walk Distance | 12 weeks | Change in peak 6-minute walk distance from baseline to Week 12. Peak 6MWD was defined as a 6-minute walk test (6MWT) within 10 to 60 minutes after study drug inhalation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Borg Dyspnea Score | 12 weeks | The Borg dyspnea score is a patient reported number between 0 (no perceived shortness of breath) and 10 (maximum perceived shortness of breath), obtained at the completion of each 6MWT. |
| New York Heart Association (NYHA) Functional Classification | 12 weeks | Change in NYHA functional class at Week 12. NYHA classifications: Class I - Patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain or near syncope. Class II - Patients with pulmonary hypertension resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope. Class III - Patients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain or near syncope. Class IV - Patients with pulmonary hypertension in the inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity. |
| Trough 6MWD at Week 12 | 12 Weeks | Change in 6MWD from Baseline to trough 6MWD at Week 12. Trough was defined as a 6MWT conducted at least 4 hours following study drug inhalation. |
| Clinical Worsening Events | 12 weeks | Clinical worsening was defined as the first incidence of clinical worsening from randomization to the first occurrence of death, transplantation, hospitalization for PAH, or initiation of additional approved PAH therapy. |
| Quality of Life (Minnesota Living With Heart Failure) | 12 weeks | Quality of life as measured by the Minnesota Living With Heart Failure (MLWHF) questionnaire was evaluated at baseline and at Week 12. The MLWHF questionnaire consists of 21 questions assessing how the patient's heart failure has prevented them from living the way they wanted during the defined time period. Each question was graded by the patient with a numeric value between 0 (No/none) and 5 (very much). These scores were then summed across the 21 questions for a Global Score. Global scores ranged from 0 to 105. These questions were further grouped into Physical (8 of the questions) and Emotional (5 of the questions) dimensions to further characterize the effect of heart failure on the patient's life. Physical scores ranged from 0 to 40, and emotional scores ranged from 0 to 25. For all 3 categories, the lower the score, the better the outcome. Values presented as change from Baseline. |
| Change in Signs and Symptoms of PAH | 12 weeks | Signs and symptoms of PAH (Loud P2 sound, Ascites, Right ventricular S3 sound, Dyspnea, Right ventricular S4 sound, Orthopnea, Right ventricular heave, Dizziness, Murmur of tricuspid insufficiency, Syncope, Murmur of pulmonic insufficiency, Chest pain, Hepatomegaly, Palpitations, Jugular venous distension at 45 degrees, Fatigue, Edema) were assessed at Baseline and Week 12. The status of each sign and symptom (absent or present) was assessed at each visit. To assess overall change from baseline in signs and symptoms, a 1 was assigned for each sign and symptom that was present at the Week 12 but was absent at baseline, a -1 was assigned for each sign and symptom that was absent at Week 12 but was present at baseline, and a 0 was assigned for no change. An overall change score at each post-baseline assessment was then calculated by summing these values for all signs and symptoms. The overall change score had the potential to range from -17 to 17. |
| N-terminal Pro-B-Type Natriuretic Peptide (NT Pro-BNP) | 12 weeks | Change in NT pro-BNP from Baseline to Week 12. Plasma samples were collected from patients at Baseline and Week 12 in order to measure any change over time in circulating plasma levels of this biomarker. |
| Peak 6MWD at Week 6 | 6 weeks | Change in peak 6MWD between Baseline and Week 6. |
Countries
Austria, Belgium, France, Germany, Ireland, Israel, Italy, Spain, United Kingdom, United States
Participant flow
Recruitment details
The first subject was enrolled on 7 June 2005 and the last subject exited the study on 12 Oct 2007.
Participants by arm
| Arm | Count |
|---|---|
| Inhaled Treprostinil Initial dose: 3 breaths. Titrated to 9 breaths, four times daily. | 115 |
| Placebo Identical placebo inhalation solution | 120 |
| Total | 235 |
Baseline characteristics
| Characteristic | Inhaled Treprostinil | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 55 years FULL_RANGE 13.1 | 52 years | 54 years |
| Background PAH Therapy Bosentan | 77 participants | 88 participants | 165 participants |
| Background PAH Therapy Sildenafil | 38 participants | 32 participants | 70 participants |
| Baseline NYHA Class Class III | 112 participants | 118 participants | 230 participants |
| Baseline NYHA Class Class IV | 3 participants | 2 participants | 5 participants |
| Baseline Six-Minute Walk Distance (6MWD) | 346 meters STANDARD_DEVIATION 63 | 351 meters STANDARD_DEVIATION 69 | 348 meters STANDARD_DEVIATION 66 |
| Pulmonary Arterial Hypertension (PAH) Etiology Connective Tissue Disease (CTD) | 40 participants | 37 participants | 77 participants |
| Pulmonary Arterial Hypertension (PAH) Etiology Idiopathic PAH (IPAH) | 64 participants | 67 participants | 131 participants |
| Pulmonary Arterial Hypertension (PAH) Etiology Other | 11 participants | 16 participants | 27 participants |
| Sex: Female, Male Female | 93 Participants | 98 Participants | 191 Participants |
| Sex: Female, Male Male | 22 Participants | 22 Participants | 44 Participants |
| Time on Background Therapy Bosentan | 98 weeks STANDARD_DEVIATION 79 | 90 weeks STANDARD_DEVIATION 75 | 94 weeks STANDARD_DEVIATION 77 |
| Time on Background Therapy Sildenafil | 65 weeks STANDARD_DEVIATION 60 | 77 weeks STANDARD_DEVIATION 69 | 70 weeks STANDARD_DEVIATION 64 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 101 / 115 | 100 / 120 |
| serious Total, serious adverse events | 9 / 115 | 13 / 120 |
Outcome results
Primary
Peak 6-minute Walk Distance
Change in peak 6-minute walk distance from baseline to Week 12. Peak 6MWD was defined as a 6-minute walk test (6MWT) within 10 to 60 minutes after study drug inhalation
Time frame: 12 weeks
Population: Intention to treat analysis
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Inhaled Treprostinil | Peak 6-minute Walk Distance | Week 12 | 366.0 meters |
| Inhaled Treprostinil | Peak 6-minute Walk Distance | Change from Baseline | 21.6 meters |
| Placebo | Peak 6-minute Walk Distance | Week 12 | 360.0 meters |
| Placebo | Peak 6-minute Walk Distance | Change from Baseline | 3.0 meters |
Comparison: Sample size was calculated based on the primary endpoint; change in 6MWD at Week 12. Assuming a between-treatment difference of 35m, a standard deviation of 75m, and a type I (alpha) error of 0.05 (i.e., two-sided p-value of less than 0.05), in order to have 90% power to detect this difference, 100 subjects per treatment group were required for this trial (total n=200). This allowed for a dropout rate of 10% as 110 subjects per group was planned.p-value: 0.0004495% CI: [8, 32.8]ANCOVA
Secondary
Borg Dyspnea Score
The Borg dyspnea score is a patient reported number between 0 (no perceived shortness of breath) and 10 (maximum perceived shortness of breath), obtained at the completion of each 6MWT.
Time frame: 12 weeks
Population: Intention to treat population. A Week 12 observation was not present for one subject and that data point is not included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Inhaled Treprostinil | Borg Dyspnea Score | Week 12 | 3.68 score | Standard Deviation 2.26 |
| Inhaled Treprostinil | Borg Dyspnea Score | Change from Baseline | 0.0 score | Standard Deviation 2.07 |
| Placebo | Borg Dyspnea Score | Week 12 | 3.91 score | Standard Deviation 2.33 |
| Placebo | Borg Dyspnea Score | Change from Baseline | 0.0 score | Standard Deviation 1.72 |
p-value: 0.62395% CI: [-0.5, 0]Wilcoxon rank sum test
Secondary
Change in Signs and Symptoms of PAH
Signs and symptoms of PAH (Loud P2 sound, Ascites, Right ventricular S3 sound, Dyspnea, Right ventricular S4 sound, Orthopnea, Right ventricular heave, Dizziness, Murmur of tricuspid insufficiency, Syncope, Murmur of pulmonic insufficiency, Chest pain, Hepatomegaly, Palpitations, Jugular venous distension at 45 degrees, Fatigue, Edema) were assessed at Baseline and Week 12. The status of each sign and symptom (absent or present) was assessed at each visit. To assess overall change from baseline in signs and symptoms, a 1 was assigned for each sign and symptom that was present at the Week 12 but was absent at baseline, a -1 was assigned for each sign and symptom that was absent at Week 12 but was present at baseline, and a 0 was assigned for no change. An overall change score at each post-baseline assessment was then calculated by summing these values for all signs and symptoms. The overall change score had the potential to range from -17 to 17.
Time frame: 12 weeks
Population: Intention to treat population.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Inhaled Treprostinil | Change in Signs and Symptoms of PAH | 0 units on a scale | Full Range 3.5 |
| Placebo | Change in Signs and Symptoms of PAH | 0 units on a scale | Full Range 2.5 |
Secondary
Clinical Worsening Events
Clinical worsening was defined as the first incidence of clinical worsening from randomization to the first occurrence of death, transplantation, hospitalization for PAH, or initiation of additional approved PAH therapy.
Time frame: 12 weeks
Population: Intention to treat population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Inhaled Treprostinil | Clinical Worsening Events | 4 clinical worsening events |
| Placebo | Clinical Worsening Events | 6 clinical worsening events |
Secondary
New York Heart Association (NYHA) Functional Classification
Change in NYHA functional class at Week 12. NYHA classifications: Class I - Patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain or near syncope. Class II - Patients with pulmonary hypertension resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope. Class III - Patients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain or near syncope. Class IV - Patients with pulmonary hypertension in the inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity.
Time frame: 12 weeks
Population: Intention to treat population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Inhaled Treprostinil | New York Heart Association (NYHA) Functional Classification | NYHA Class III | 88 participants |
| Inhaled Treprostinil | New York Heart Association (NYHA) Functional Classification | NYHA Class IV | 5 participants |
| Inhaled Treprostinil | New York Heart Association (NYHA) Functional Classification | NYHA Class II | 22 participants |
| Placebo | New York Heart Association (NYHA) Functional Classification | NYHA Class III | 93 participants |
| Placebo | New York Heart Association (NYHA) Functional Classification | NYHA Class II | 22 participants |
| Placebo | New York Heart Association (NYHA) Functional Classification | NYHA Class IV | 5 participants |
p-value: 0.80795% CI: [0, 0]Wilcoxon rank sum test
Secondary
N-terminal Pro-B-Type Natriuretic Peptide (NT Pro-BNP)
Change in NT pro-BNP from Baseline to Week 12. Plasma samples were collected from patients at Baseline and Week 12 in order to measure any change over time in circulating plasma levels of this biomarker.
Time frame: 12 weeks
Population: Per protocol
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Inhaled Treprostinil | N-terminal Pro-B-Type Natriuretic Peptide (NT Pro-BNP) | Week 12 | 377 pg/mL |
| Inhaled Treprostinil | N-terminal Pro-B-Type Natriuretic Peptide (NT Pro-BNP) | Change from Baseline | -57 pg/mL |
| Placebo | N-terminal Pro-B-Type Natriuretic Peptide (NT Pro-BNP) | Change from Baseline | 40 pg/mL |
| Placebo | N-terminal Pro-B-Type Natriuretic Peptide (NT Pro-BNP) | Week 12 | 756 pg/mL |
p-value: 0.00195% CI: [-333, -64]Wilcoxon rank sum test
Secondary
Peak 6MWD at Week 6
Change in peak 6MWD between Baseline and Week 6.
Time frame: 6 weeks
Population: Intention to treat
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Inhaled Treprostinil | Peak 6MWD at Week 6 | Week 6 Values | 375 meters |
| Inhaled Treprostinil | Peak 6MWD at Week 6 | Change from Baseline | 21.6 meters |
| Placebo | Peak 6MWD at Week 6 | Week 6 Values | 367 meters |
| Placebo | Peak 6MWD at Week 6 | Change from Baseline | 3.0 meters |
p-value: 0.000395% CI: [8.5, 28.3]Wilcoxon rank sum test
Secondary
Quality of Life (Minnesota Living With Heart Failure)
Quality of life as measured by the Minnesota Living With Heart Failure (MLWHF) questionnaire was evaluated at baseline and at Week 12. The MLWHF questionnaire consists of 21 questions assessing how the patient's heart failure has prevented them from living the way they wanted during the defined time period. Each question was graded by the patient with a numeric value between 0 (No/none) and 5 (very much). These scores were then summed across the 21 questions for a Global Score. Global scores ranged from 0 to 105. These questions were further grouped into Physical (8 of the questions) and Emotional (5 of the questions) dimensions to further characterize the effect of heart failure on the patient's life. Physical scores ranged from 0 to 40, and emotional scores ranged from 0 to 25. For all 3 categories, the lower the score, the better the outcome. Values presented as change from Baseline.
Time frame: 12 weeks
Population: Intention to treat population.
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Inhaled Treprostinil | Quality of Life (Minnesota Living With Heart Failure) | Emotional Dimension | 0.0 units on a scale | Inter-Quartile Range 5.7 |
| Inhaled Treprostinil | Quality of Life (Minnesota Living With Heart Failure) | Global Score | -3.0 units on a scale | Inter-Quartile Range 18.7 |
| Inhaled Treprostinil | Quality of Life (Minnesota Living With Heart Failure) | Physical Dimension | -1.4 units on a scale | Inter-Quartile Range 8.9 |
| Placebo | Quality of Life (Minnesota Living With Heart Failure) | Global Score | 0.0 units on a scale | Inter-Quartile Range 16.2 |
| Placebo | Quality of Life (Minnesota Living With Heart Failure) | Physical Dimension | 0.0 units on a scale | Inter-Quartile Range 7.1 |
| Placebo | Quality of Life (Minnesota Living With Heart Failure) | Emotional Dimension | 0.0 units on a scale | Inter-Quartile Range 5.7 |
Comparison: Global Scorep-value: 0.02795% CI: [-8, 0]Wilcoxon rank sum test
Comparison: Physical Dimensionp-value: 0.03795% CI: [-3, 0]Wilcoxon rank sum test
Comparison: Emotional Dimension Scorep-value: 0.17395% CI: [-2, 0]Wilcoxon rank sum test
Secondary
Trough 6MWD at Week 12
Change in 6MWD from Baseline to trough 6MWD at Week 12. Trough was defined as a 6MWT conducted at least 4 hours following study drug inhalation.
Time frame: 12 Weeks
Population: Intention to treat population
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Inhaled Treprostinil | Trough 6MWD at Week 12 | Week 12 trough | 364.0 meters |
| Inhaled Treprostinil | Trough 6MWD at Week 12 | Change from Baseline | 12.4 meters |
| Placebo | Trough 6MWD at Week 12 | Week 12 trough | 365.0 meters |
| Placebo | Trough 6MWD at Week 12 | Change from Baseline | 0.8 meters |
p-value: 0.00795% CI: [4, 24.8]ANCOVA