Pulmonary Hypertension
Conditions
Keywords
Pulmonary Arterial Hypertension
Brief summary
This study was an international, multi-center, randomized, double-blind, placebo-controlled study in subjects with PAH who were currently receiving approved therapy for their PAH (i.e., endothelin receptor antagonist and/or phosphodiesterase-5 inhibitor). Study visits occurred at 4 week intervals for 16 weeks; the key measure of efficacy was the 6-minute walk test. Study procedures included routine blood tests, medical history, physical exams, disease evaluation, and exercise tests. One optional substudy was also a part of FREEDOM-C at select centers - a hemodynamic substudy with a right heart catheterization at Baseline and Week 16. Patients who completed all assessments for 16-weeks were also eligible to enter an open-label, extension phase study (FREEDOM - EXT).
Interventions
UT-15C 0.25, 0.5, 1, or 5 mg oral tablets by mouth every 12 hours
DRUGPlacebo
Placebo 0.25, 0.5, 1, or 5 mg oral tablets by mouth every 12 hours
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
12 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Between 12 and 70 years of age, inclusive. * Body weight at least 45 kg (approximately 100 pounds). * PAH that is either idiopathic/heritable (including PAH associated with appetite suppressant/toxin use); PAH associated with repaired congenital systemic-to-pulmonary shunts (repaired ≥ 5 years); PAH associated with collagen vascular disease; or PAH associated with HIV. * Baseline 6-minute walk distance between 150 and 450 meters, inclusive. * Currently receiving an approved endothelin receptor antagonist and/or an approved phosphodiesterase-5 inhibitor for at least 90 days and on a stable dose for at least the last 30 days. * Previous testing (e.g., right heart catheterization, echocardiography) consistent with the diagnosis of PAH. * Reliable and cooperative with protocol requirements.
Exclusion criteria
* Nursing or pregnant. * Received a prostacyclin within the past 30 days. * PAH due to conditions other than noted in the above inclusion criteria. * History of uncontrolled sleep apnea, renal insufficiency, anemia, left sided heart disease, uncontrolled systemic hypertension, or parenchymal lung disease. * Use of an investigational drug within 30 days of Baseline.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Six Minute Walk Distance (6MWD) | Baseline and 16 Weeks | Placebo corrected change in six minute walk distance (6MWD) from Baseline to Week 16, correlates with the historical clinical standard for assessing patient functional status in the treatment of PAH and is considered an objective measure of patient functional status by the American Thoracic Society (ATS). The six minute walk test was to be conducted 3 to 6 hours after the previous dose of study drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Worsening Assessment | Baseline and 16 Weeks | Definition of clinical worsening required one of the following: 1. Death (all causes excluding accident) 2. Transplantation or atrial septostomy 3. Clinical deterioration as defined by: 1. Hospitalization as a result of PAH, or 2. ≥ 20% decrease in 6-minute walk distance from Baseline (or too ill to walk) and a decrease in WHO functional class And 3. Initiation of new PAH specific therapy (i.e., ERA, PDE5I, prostacyclin). |
| Dyspnea-Fatigue Index | Baseline and 16 Weeks | The dyspnea-fatigue index has three components, each rated on a scale of 0 to 4, for the magnitude of the task that evokes dyspnea or fatigue, the magnitude of the pace (or effort) with which the task is performed and the associated functional impairment in general activities. The ratings for each component were added to form an aggregate score, which could range from 0, for the worst condition, to 12, for the best. |
| Borg Dyspnea Score | Baseline and 16 Weeks | The Borg dyspnea score is a 10-point scale rating the maximum level of dyspnea experienced during the 6-minute walk test. The Borg dyspnea score was assessed immediately following the 6-minute walk test. Scores ranged from 0 (for no shortness of breath) to 10 (for greatest shortness of breath ever experienced). |
| Six Minute Walk Distance (6MWD) | Baseline and 12 weeks | Placebo corrected change in six minute walk distance (6MWD) from Baseline to Week 12, correlates with the historical clinical standard for assessing patient functional status in the treatment of PAH and is considered an objective measure of patient functional status by the American Thoracic Society (ATS). The six minute walk test was to be conducted 3 to 6 hours after the previous dose of study drug. |
| Change in Symptoms of PAH From Baseline to Week 16 | Baseline and 16 weeks | Defined symptoms of PAH including fatigue, dyspnea, edema, dizziness, syncope, chest pain, and orthopnea were assessed at Baseline prior to starting study drug and during the Treatment Phase at Week 16. Severity grade values (i.e., 0, 1, 2, or 3 in increasing severity) were assigned for each symptom. The outcome data describes the change in severity values from Baseline to Week 16 for each defined symptom of PAH. |
| World Health Organization Functional Classification for PAH | Week 16 | 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. These patients are comfortable at rest, but 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. Ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope. Class IV: Patients with pulmonary hypertension with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may be present even at rest. Discomfort is increased by any physical activity. |
Countries
Australia, Austria, Belgium, Canada, France, Germany, Ireland, Israel, Italy, Netherlands, Poland, Spain, United Kingdom, United States
Participant flow
Recruitment details
354 subjects were randomized with 350 subjects receiving a dose of study drug and subsequently analyzed from 20 October 2006 to 17 September 2008 at 70 sites across the United States, Canada, Europe, Israel, and Australia.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Arm Subjects were randomly allocated to receive oral placebo twice daily. | 176 |
| Active Subjects in this arm were randomly allocated to receive oral treprostinil twice daily. | 174 |
| Total | 350 |
Baseline characteristics
| Characteristic | Placebo Arm | Active | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 5 Participants | 3 Participants | 8 Participants |
| Age, Categorical >=65 years | 22 Participants | 20 Participants | 42 Participants |
| Age, Categorical Between 18 and 65 years | 149 Participants | 151 Participants | 300 Participants |
| Age, Continuous | 49.5 years STANDARD_DEVIATION 13.3 | 51.1 years STANDARD_DEVIATION 12.3 | 50.3 years STANDARD_DEVIATION 12.8 |
| Background PAH Therapy ERA | 51 participants | 55 participants | 106 participants |
| Background PAH Therapy ERA and PDE5-I | 82 participants | 74 participants | 156 participants |
| Background PAH Therapy PDE5-I | 43 participants | 45 participants | 88 participants |
| Baseline WHO Functional Classification WHO Functional Class I | 1 participants | 2 participants | 3 participants |
| Baseline WHO Functional Classification WHO Functional Class II | 31 participants | 41 participants | 72 participants |
| Baseline WHO Functional Classification WHO Functional Class III | 139 participants | 127 participants | 266 participants |
| Baseline WHO Functional Classification WHO Functional Class IV | 5 participants | 4 participants | 9 participants |
| Distance Traversed (meters) During Six Minute Walk Test at Baseline | 345.4 meters STANDARD_DEVIATION 75.5 | 346.1 meters STANDARD_DEVIATION 71.4 | 345.7 meters STANDARD_DEVIATION 73.4 |
| PAH Etiology Idiopathic / familial PAH | 119 participants | 113 participants | 232 participants |
| PAH Etiology PAH associated with collagen vasular disease | 43 participants | 49 participants | 92 participants |
| PAH Etiology PAH associated with HIV infection | 3 participants | 1 participants | 4 participants |
| PAH Etiology PAH associated wtih congenital heart defect | 11 participants | 11 participants | 22 participants |
| Sex: Female, Male Female | 140 Participants | 148 Participants | 288 Participants |
| Sex: Female, Male Male | 36 Participants | 26 Participants | 62 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 157 / 176 | 173 / 174 |
| serious Total, serious adverse events | 33 / 176 | 32 / 174 |
Outcome results
Primary
Six Minute Walk Distance (6MWD)
Placebo corrected change in six minute walk distance (6MWD) from Baseline to Week 16, correlates with the historical clinical standard for assessing patient functional status in the treatment of PAH and is considered an objective measure of patient functional status by the American Thoracic Society (ATS). The six minute walk test was to be conducted 3 to 6 hours after the previous dose of study drug.
Time frame: Baseline and 16 Weeks
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo Arm | Six Minute Walk Distance (6MWD) | 6MWD at Week 16 | 367.0 meters |
| Placebo Arm | Six Minute Walk Distance (6MWD) | Change in 6MWD from Baseline to Week 16 | 4.8 meters |
| Placebo Arm | Six Minute Walk Distance (6MWD) | 6MWD at Baseline | 362.5 meters |
| Active | Six Minute Walk Distance (6MWD) | 6MWD at Week 16 | 381.0 meters |
| Active | Six Minute Walk Distance (6MWD) | Change in 6MWD from Baseline to Week 16 | 14.5 meters |
| Active | Six Minute Walk Distance (6MWD) | 6MWD at Baseline | 362.5 meters |
Comparison: Change in 6MWD from Baseline to Week 16p-value: 0.07295% CI: [0, 22]ANCOVA
Secondary
Borg Dyspnea Score
The Borg dyspnea score is a 10-point scale rating the maximum level of dyspnea experienced during the 6-minute walk test. The Borg dyspnea score was assessed immediately following the 6-minute walk test. Scores ranged from 0 (for no shortness of breath) to 10 (for greatest shortness of breath ever experienced).
Time frame: Baseline and 16 Weeks
Population: One subject in the placebo arm did not have a Baseline Borg score value.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm | Borg Dyspnea Score | Borg dyspnea score at Week 16 | 4.64 units on a scale | Standard Deviation 2.62 |
| Placebo Arm | Borg Dyspnea Score | Change in Borg dyspnea score from BL to Wk 16 | 0.38 units on a scale | Standard Deviation 2.06 |
| Placebo Arm | Borg Dyspnea Score | Borg dyspnea score at Baseline | 4.26 units on a scale | Standard Deviation 2.25 |
| Active | Borg Dyspnea Score | Borg dyspnea score at Baseline | 4.22 units on a scale | Standard Deviation 2.24 |
| Active | Borg Dyspnea Score | Borg dyspnea score at Week 16 | 4.18 units on a scale | Standard Deviation 2.59 |
| Active | Borg Dyspnea Score | Change in Borg dyspnea score from BL to Wk 16 | -0.03 units on a scale | Standard Deviation 2.13 |
Comparison: Change in Borg dyspnea score from Baseline to Week 16p-value: 0.06295% CI: [-1, 0]Wilcoxon rank-sum test
Secondary
Change in Symptoms of PAH From Baseline to Week 16
Defined symptoms of PAH including fatigue, dyspnea, edema, dizziness, syncope, chest pain, and orthopnea were assessed at Baseline prior to starting study drug and during the Treatment Phase at Week 16. Severity grade values (i.e., 0, 1, 2, or 3 in increasing severity) were assigned for each symptom. The outcome data describes the change in severity values from Baseline to Week 16 for each defined symptom of PAH.
Time frame: Baseline and 16 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm | Change in Symptoms of PAH From Baseline to Week 16 | Change in dizziness symptoms | 0.00 units on a scale | Standard Error 0 |
| Placebo Arm | Change in Symptoms of PAH From Baseline to Week 16 | Change in fatigue symptoms | 0.0 units on a scale | Standard Error 0 |
| Placebo Arm | Change in Symptoms of PAH From Baseline to Week 16 | Change in edema symptoms | 0.00 units on a scale | Standard Error 0 |
| Placebo Arm | Change in Symptoms of PAH From Baseline to Week 16 | Change in chest pain symptoms | 0.00 units on a scale | Standard Error 0 |
| Placebo Arm | Change in Symptoms of PAH From Baseline to Week 16 | Change in dypsnea symptoms | 0.00 units on a scale | Standard Error 0 |
| Placebo Arm | Change in Symptoms of PAH From Baseline to Week 16 | Change in orthopnea symptoms | 0.00 units on a scale | Standard Error 0 |
| Placebo Arm | Change in Symptoms of PAH From Baseline to Week 16 | Change in syncope symptoms | 0.00 units on a scale | Standard Error 0 |
| Active | Change in Symptoms of PAH From Baseline to Week 16 | Change in orthopnea symptoms | -0.20 units on a scale | Standard Error 0.1 |
| Active | Change in Symptoms of PAH From Baseline to Week 16 | Change in fatigue symptoms | 0.01 units on a scale | Standard Error 0.1 |
| Active | Change in Symptoms of PAH From Baseline to Week 16 | Change in edema symptoms | -0.06 units on a scale | Standard Error 0.1 |
| Active | Change in Symptoms of PAH From Baseline to Week 16 | Change in dizziness symptoms | -0.16 units on a scale | Standard Error 0.11 |
| Active | Change in Symptoms of PAH From Baseline to Week 16 | Change in syncope symptoms | -0.10 units on a scale | Standard Error 0.09 |
| Active | Change in Symptoms of PAH From Baseline to Week 16 | Change in chest pain symptoms | -0.09 units on a scale | Standard Error 0.11 |
| Active | Change in Symptoms of PAH From Baseline to Week 16 | Change in dypsnea symptoms | -0.01 units on a scale | Standard Error 0.09 |
Secondary
Clinical Worsening Assessment
Definition of clinical worsening required one of the following: 1. Death (all causes excluding accident) 2. Transplantation or atrial septostomy 3. Clinical deterioration as defined by: 1. Hospitalization as a result of PAH, or 2. ≥ 20% decrease in 6-minute walk distance from Baseline (or too ill to walk) and a decrease in WHO functional class And 3. Initiation of new PAH specific therapy (i.e., ERA, PDE5I, prostacyclin).
Time frame: Baseline and 16 Weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Arm | Clinical Worsening Assessment | 12 participants |
| Active | Clinical Worsening Assessment | 8 participants |
p-value: 0.491Fisher Exact
Secondary
Dyspnea-Fatigue Index
The dyspnea-fatigue index has three components, each rated on a scale of 0 to 4, for the magnitude of the task that evokes dyspnea or fatigue, the magnitude of the pace (or effort) with which the task is performed and the associated functional impairment in general activities. The ratings for each component were added to form an aggregate score, which could range from 0, for the worst condition, to 12, for the best.
Time frame: Baseline and 16 Weeks
Population: Five subjects in the placebo arm and three subjects in the active arm did not have a Baseline dypsnea-fatigue index score.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Arm | Dyspnea-Fatigue Index | Dyspnea-fatigue index at Week 16 | 5.1 units on a scale | Standard Deviation 2.5 |
| Placebo Arm | Dyspnea-Fatigue Index | Change in dyspnea-fatigue index from BL to Wk 16 | -0.4 units on a scale | Standard Deviation 1.9 |
| Placebo Arm | Dyspnea-Fatigue Index | Dyspnea-fatigue index at Baseline | 5.5 units on a scale | Standard Deviation 2.2 |
| Active | Dyspnea-Fatigue Index | Dyspnea-fatigue index at Week 16 | 5.7 units on a scale | Standard Deviation 2.5 |
| Active | Dyspnea-Fatigue Index | Change in dyspnea-fatigue index from BL to Wk 16 | 0.0 units on a scale | Standard Deviation 1.9 |
| Active | Dyspnea-Fatigue Index | Dyspnea-fatigue index at Baseline | 5.7 units on a scale | Standard Deviation 2.1 |
Comparison: Change in dyspnea-fatigue index from Baseline to Week 16p-value: 0.01195% CI: [0, 1]Wilcoxon sum-rank test
Secondary
Six Minute Walk Distance (6MWD)
Placebo corrected change in six minute walk distance (6MWD) from Baseline to Week 12, correlates with the historical clinical standard for assessing patient functional status in the treatment of PAH and is considered an objective measure of patient functional status by the American Thoracic Society (ATS). The six minute walk test was to be conducted 3 to 6 hours after the previous dose of study drug.
Time frame: Baseline and 12 weeks
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo Arm | Six Minute Walk Distance (6MWD) | 6MWD at Baseline | 362.5 meters |
| Placebo Arm | Six Minute Walk Distance (6MWD) | 6MWD at Week 12 | 366.4 meters |
| Placebo Arm | Six Minute Walk Distance (6MWD) | Change in 6MWD from Baseline to Week 12 | 5.8 meters |
| Active | Six Minute Walk Distance (6MWD) | 6MWD at Baseline | 362.5 meters |
| Active | Six Minute Walk Distance (6MWD) | 6MWD at Week 12 | 378.0 meters |
| Active | Six Minute Walk Distance (6MWD) | Change in 6MWD from Baseline to Week 12 | 16.5 meters |
Comparison: Change in 6MWD from Baseline to Week 12p-value: 0.01595% CI: [3, 23]ANCOVA
Secondary
Six Minute Walk Distance (6MWD)
Placebo corrected change in six minute walk distance (6MWD) from Baseline to Week 8, correlates with the historical clinical standard for assessing patient functional status in the treatment of PAH and is considered an objective measure of patient functional status by the American Thoracic Society (ATS). The six minute walk test was to be conducted 3 to 6 hours after the previous dose of study drug.
Time frame: Baseline and 8 weeks
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo Arm | Six Minute Walk Distance (6MWD) | 6MWD at Baseline | 362.5 meters |
| Placebo Arm | Six Minute Walk Distance (6MWD) | 6MWD at Week 8 | 368.5 meters |
| Placebo Arm | Six Minute Walk Distance (6MWD) | Change in 6MWD from Baseline to Week 8 | 7.0 meters |
| Active | Six Minute Walk Distance (6MWD) | 6MWD at Baseline | 362.5 meters |
| Active | Six Minute Walk Distance (6MWD) | 6MWD at Week 8 | 379.0 meters |
| Active | Six Minute Walk Distance (6MWD) | Change in 6MWD from Baseline to Week 8 | 15.0 meters |
Comparison: Change in 6MWD from Baseline to Week 8p-value: 0.05195% CI: [0, 18]ANCOVA
Secondary
Six Minute Walk Distance (6MWD)
Placebo corrected change in six minute walk distance (6MWD) from Baseline to Week 4, correlates with the historical clinical standard for assessing patient functional status in the treatment of PAH and is considered an objective measure of patient functional status by the American Thoracic Society (ATS). The six minute walk test was to be conducted 3 to 6 hours after the previous dose of study drug.
Time frame: Baseline and 4 weeks
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo Arm | Six Minute Walk Distance (6MWD) | 6MWD at Baseline | 362.5 meters |
| Placebo Arm | Six Minute Walk Distance (6MWD) | 6MWD at Week 4 | 363.0 meters |
| Placebo Arm | Six Minute Walk Distance (6MWD) | Change in 6MWD from Baseline to Week 4 | 2.1 meters |
| Active | Six Minute Walk Distance (6MWD) | 6MWD at Week 4 | 370.5 meters |
| Active | Six Minute Walk Distance (6MWD) | 6MWD at Baseline | 362.5 meters |
| Active | Six Minute Walk Distance (6MWD) | Change in 6MWD from Baseline to Week 4 | 5.5 meters |
Comparison: Change in 6MWD from Baseline to Week 4p-value: 0.23895% CI: [-2.4, 12]ANCOVA
Secondary
World Health Organization Functional Classification for PAH
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. These patients are comfortable at rest, but 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. Ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope. Class IV: Patients with pulmonary hypertension with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may be present even at rest. Discomfort is increased by any physical activity.
Time frame: Week 16
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo Arm | World Health Organization Functional Classification for PAH | WHO Class I | 1 participants |
| Placebo Arm | World Health Organization Functional Classification for PAH | WHO Class II | 48 participants |
| Placebo Arm | World Health Organization Functional Classification for PAH | WHO Class III | 114 participants |
| Placebo Arm | World Health Organization Functional Classification for PAH | WHO Class IV | 13 participants |
| Active | World Health Organization Functional Classification for PAH | WHO Class IV | 11 participants |
| Active | World Health Organization Functional Classification for PAH | WHO Class I | 2 participants |
| Active | World Health Organization Functional Classification for PAH | WHO Class III | 103 participants |
| Active | World Health Organization Functional Classification for PAH | WHO Class II | 58 participants |
Post Hoc
Change in Six Minute Walk Distance (6MWD) From Baseline in Subjects Who Received Oral Treprostinil by Last Study Drug Dose and Reason for Discontinuation
In general, the dose of study drug was increased in 0.5 mg increments every 3 days, in the absence of dose-limiting drug-related AEs, to ensure the subject received the optimal clinical dose throughout the study.
Time frame: Baseline and 16 weeks
Population: Of 174 subjects randomized to receive oral treprostinil, 153 subjects who completed the study and 6 additional subjects who did not complete the study but discontinued the study due to adverse events were included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo Arm | Change in Six Minute Walk Distance (6MWD) From Baseline in Subjects Who Received Oral Treprostinil by Last Study Drug Dose and Reason for Discontinuation | 3.8 meters |
| Active | Change in Six Minute Walk Distance (6MWD) From Baseline in Subjects Who Received Oral Treprostinil by Last Study Drug Dose and Reason for Discontinuation | 18.0 meters |
| 3.5 - 16 mg | Change in Six Minute Walk Distance (6MWD) From Baseline in Subjects Who Received Oral Treprostinil by Last Study Drug Dose and Reason for Discontinuation | 34.0 meters |
Post Hoc
Six Minute Walk Distance (6MWD) by Background PAH Therapy: ERA
Time frame: Baseline and 16 weeks
Population: The subjects in this subgroup were receiving treatment with an ERA for 90 days or greater at the time of randomization.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo Arm | Six Minute Walk Distance (6MWD) by Background PAH Therapy: ERA | 6MWD at Week 16 | 377.0 meters |
| Placebo Arm | Six Minute Walk Distance (6MWD) by Background PAH Therapy: ERA | Change in 6MWD from Baseline to Week 16 | -3.0 meters |
| Placebo Arm | Six Minute Walk Distance (6MWD) by Background PAH Therapy: ERA | 6MWD at Baseline | 382.0 meters |
| Active | Six Minute Walk Distance (6MWD) by Background PAH Therapy: ERA | 6MWD at Week 16 | 385.0 meters |
| Active | Six Minute Walk Distance (6MWD) by Background PAH Therapy: ERA | 6MWD at Baseline | 372.0 meters |
| Active | Six Minute Walk Distance (6MWD) by Background PAH Therapy: ERA | Change in 6MWD from Baseline to Week 16 | 4.0 meters |
Comparison: Change in 6MWD from Baseline to Week 16p-value: 0.61595% CI: [-12, 24]ANCOVA
Post Hoc
Six Minute Walk Distance (6MWD) by Background PAH Therapy: ERA and PDE5-I
Time frame: Baseline and 16 weeks
Population: The subjects in this subgroup were receiving treatment with an ERA and PDE5-I for 90 days or greater at the time of randomization.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo Arm | Six Minute Walk Distance (6MWD) by Background PAH Therapy: ERA and PDE5-I | 6MWD at Baseline | 351.5 meters |
| Placebo Arm | Six Minute Walk Distance (6MWD) by Background PAH Therapy: ERA and PDE5-I | 6MWD at Week 16 | 359.2 meters |
| Placebo Arm | Six Minute Walk Distance (6MWD) by Background PAH Therapy: ERA and PDE5-I | Change in 6MWD from Baseline to Week 16 | 8.0 meters |
| Active | Six Minute Walk Distance (6MWD) by Background PAH Therapy: ERA and PDE5-I | 6MWD at Baseline | 358.5 meters |
| Active | Six Minute Walk Distance (6MWD) by Background PAH Therapy: ERA and PDE5-I | 6MWD at Week 16 | 381.0 meters |
| Active | Six Minute Walk Distance (6MWD) by Background PAH Therapy: ERA and PDE5-I | Change in 6MWD from Baseline to Week 16 | 14.5 meters |
Comparison: Change in 6MWD from Baseline to Week 16p-value: 0.20995% CI: [-6, 28]ANCOVA
Post Hoc
Six Minute Walk Distance (6MWD) by Background PAH Therapy: PDE5-I
Time frame: Baseline and 16 weeks
Population: The subjects in this subgroup were receiving treatment with a PDE5-I for 90 days or greater at the time of randomization.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo Arm | Six Minute Walk Distance (6MWD) by Background PAH Therapy: PDE5-I | 6MWD at Baseline | 360.0 meters |
| Placebo Arm | Six Minute Walk Distance (6MWD) by Background PAH Therapy: PDE5-I | 6MWD at Week 16 | 357.0 meters |
| Placebo Arm | Six Minute Walk Distance (6MWD) by Background PAH Therapy: PDE5-I | Change in 6MWD from Baseline to Week 16 | 8.0 meters |
| Active | Six Minute Walk Distance (6MWD) by Background PAH Therapy: PDE5-I | 6MWD at Baseline | 348.0 meters |
| Active | Six Minute Walk Distance (6MWD) by Background PAH Therapy: PDE5-I | 6MWD at Week 16 | 373.0 meters |
| Active | Six Minute Walk Distance (6MWD) by Background PAH Therapy: PDE5-I | Change in 6MWD from Baseline to Week 16 | 23.0 meters |
Comparison: Change in 6MWD from Baseline to Week 16p-value: 0.2395% CI: [-6, 40]ANCOVA
Post Hoc
Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 2 (303 - 362 Meters)
Time frame: Baseline and 16 weeks
Population: The study population was divided into quartiles by Baseline 6MWD. The subjects in this subgroup were in quartile 2 (303 - 362 meters).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo Arm | Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 2 (303 - 362 Meters) | 6MWD at Baseline | 332.0 meters |
| Placebo Arm | Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 2 (303 - 362 Meters) | 6MWD at Week 16 | 348.0 meters |
| Placebo Arm | Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 2 (303 - 362 Meters) | Change in 6MWD from Baseline to Week 16 | 12.0 meters |
| Active | Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 2 (303 - 362 Meters) | 6MWD at Baseline | 339.0 meters |
| Active | Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 2 (303 - 362 Meters) | 6MWD at Week 16 | 359.0 meters |
| Active | Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 2 (303 - 362 Meters) | Change in 6MWD from Baseline to Week 16 | 17.0 meters |
Comparison: Change in 6MWD from Baseline to Week 16p-value: 0.06995% CI: [-7, 41]ANCOVA
Post Hoc
Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 3 (363 - 397 Meters)
Time frame: Baseline and 16 weeks
Population: The study population was divided into quartiles by Baseline 6MWD. The subjects in this subgroup were in quartile 3 (363 - 397 meters).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo Arm | Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 3 (363 - 397 Meters) | 6MWD at Baseline | 385.0 meters |
| Placebo Arm | Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 3 (363 - 397 Meters) | 6MWD at Week 16 | 388.0 meters |
| Placebo Arm | Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 3 (363 - 397 Meters) | Change in 6MWD from Baseline to Week 16 | 6.5 meters |
| Active | Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 3 (363 - 397 Meters) | 6MWD at Baseline | 383.0 meters |
| Active | Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 3 (363 - 397 Meters) | 6MWD at Week 16 | 396.0 meters |
| Active | Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 3 (363 - 397 Meters) | Change in 6MWD from Baseline to Week 16 | 13.0 meters |
Comparison: Change in 6MWD from Baseline to Week 16p-value: 0.88995% CI: [-15, 24]ANCOVA
Post Hoc
Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 4 (398 - 450 Meters)
Time frame: Baseline and 16 weeks
Population: The study population was divided into quartiles by Baseline 6MWD. The subjects in this subgroup were in quartile 4 (398 - 450 meters).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo Arm | Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 4 (398 - 450 Meters) | 6MWD at Baseline | 425.5 meters |
| Placebo Arm | Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 4 (398 - 450 Meters) | 6MWD at Week 16 | 442.0 meters |
| Placebo Arm | Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 4 (398 - 450 Meters) | Change in 6MWD from Baseline to Week 16 | 15.0 meters |
| Active | Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 4 (398 - 450 Meters) | 6MWD at Baseline | 425.0 meters |
| Active | Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 4 (398 - 450 Meters) | 6MWD at Week 16 | 438.5 meters |
| Active | Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 4 (398 - 450 Meters) | Change in 6MWD from Baseline to Week 16 | 15.0 meters |
Comparison: Change in 6MWD from Baseline to Week 16p-value: 0.96695% CI: [-23, 24]ANCOVA
Post Hoc
Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartiles: Quartile 1 (126-302 Meters)
Time frame: Baseline and 16 weeks
Population: The study population was divided into quartiles by Baseline 6MWD. The subjects in this subgroup were in quartile 1 (126 - 302 meters).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo Arm | Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartiles: Quartile 1 (126-302 Meters) | 6MWD at Baseline | 247.0 meters |
| Placebo Arm | Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartiles: Quartile 1 (126-302 Meters) | 6MWD at Week 16 | 241.0 meters |
| Placebo Arm | Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartiles: Quartile 1 (126-302 Meters) | Change in 6MWD from Baseline to Week 16 | -5.6 meters |
| Active | Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartiles: Quartile 1 (126-302 Meters) | 6MWD at Baseline | 255.0 meters |
| Active | Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartiles: Quartile 1 (126-302 Meters) | 6MWD at Week 16 | 265.0 meters |
| Active | Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartiles: Quartile 1 (126-302 Meters) | Change in 6MWD from Baseline to Week 16 | 17.0 meters |
Comparison: Change in 6MWD from Baseline to Week 16p-value: 0.12195% CI: [0, 45]ANCOVA
Post Hoc
Six Minute Walk Distance (6MWD) by Lowest Dose Strength Available at Randomization: Smallest Dose Available 1 mg
Time frame: Baseline and 16 weeks
Population: The subjects in this subgroup had a minimum tablet strength of 1 mg for initiation of study drug dosing and dose titration.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo Arm | Six Minute Walk Distance (6MWD) by Lowest Dose Strength Available at Randomization: Smallest Dose Available 1 mg | 6MWD at Baseline | 348.0 meters |
| Placebo Arm | Six Minute Walk Distance (6MWD) by Lowest Dose Strength Available at Randomization: Smallest Dose Available 1 mg | 6MWD at Week 16 | 350.0 meters |
| Placebo Arm | Six Minute Walk Distance (6MWD) by Lowest Dose Strength Available at Randomization: Smallest Dose Available 1 mg | Change in 6MWD from Baseline to Week 16 | 15.0 meters |
| Active | Six Minute Walk Distance (6MWD) by Lowest Dose Strength Available at Randomization: Smallest Dose Available 1 mg | 6MWD at Baseline | 349.0 meters |
| Active | Six Minute Walk Distance (6MWD) by Lowest Dose Strength Available at Randomization: Smallest Dose Available 1 mg | 6MWD at Week 16 | 379.0 meters |
| Active | Six Minute Walk Distance (6MWD) by Lowest Dose Strength Available at Randomization: Smallest Dose Available 1 mg | Change in 6MWD from Baseline to Week 16 | 22.0 meters |
Comparison: Change in 6MWD from Baseline to Week 16p-value: 0.85395% CI: [-16, 28]ANCOVA
Post Hoc
Six Minute Walk Distance (6MWD) by Lowest Study Drug Dose Strength Available at Randomizaiton: Dose Strength 0.5 mg
Time frame: Baseline and 16 weeks
Population: The subjects in this subgroup had a minimum tablet strength of 0.5 mg for initiation of study drug dosing and dose titration.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo Arm | Six Minute Walk Distance (6MWD) by Lowest Study Drug Dose Strength Available at Randomizaiton: Dose Strength 0.5 mg | 6MWD at Baseline | 366.0 meters |
| Placebo Arm | Six Minute Walk Distance (6MWD) by Lowest Study Drug Dose Strength Available at Randomizaiton: Dose Strength 0.5 mg | 6MWD at Week 16 | 370.0 meters |
| Placebo Arm | Six Minute Walk Distance (6MWD) by Lowest Study Drug Dose Strength Available at Randomizaiton: Dose Strength 0.5 mg | Change in 6MWD from Baseline to Week 16 | 7.0 meters |
| Active | Six Minute Walk Distance (6MWD) by Lowest Study Drug Dose Strength Available at Randomizaiton: Dose Strength 0.5 mg | 6MWD at Baseline | 370.0 meters |
| Active | Six Minute Walk Distance (6MWD) by Lowest Study Drug Dose Strength Available at Randomizaiton: Dose Strength 0.5 mg | 6MWD at Week 16 | 375.5 meters |
| Active | Six Minute Walk Distance (6MWD) by Lowest Study Drug Dose Strength Available at Randomizaiton: Dose Strength 0.5 mg | Change in 6MWD from Baseline to Week 16 | 7.0 meters |
Comparison: Change in 6MWD from Baseline to Week 16p-value: 0.32795% CI: [-7, 21]ANCOVA
Post Hoc
Six Minute Walk Distance (6MWD) by Lowest Study Drug Dose Strength Available at Randomization: Study Drug Dose 0.25 mg
Time frame: Baseline and 16 weeks
Population: The subjects in this subgroup had a minimum tablet strength of 0.25 mg for initiation of study drug dosing and dose titration.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo Arm | Six Minute Walk Distance (6MWD) by Lowest Study Drug Dose Strength Available at Randomization: Study Drug Dose 0.25 mg | 6MWD at Baseline | 374.0 meters |
| Placebo Arm | Six Minute Walk Distance (6MWD) by Lowest Study Drug Dose Strength Available at Randomization: Study Drug Dose 0.25 mg | 6MWD at Week 16 | 374.0 meters |
| Placebo Arm | Six Minute Walk Distance (6MWD) by Lowest Study Drug Dose Strength Available at Randomization: Study Drug Dose 0.25 mg | Change in 6MWD from Baseline to Week 16 | -1.0 meters |
| Active | Six Minute Walk Distance (6MWD) by Lowest Study Drug Dose Strength Available at Randomization: Study Drug Dose 0.25 mg | 6MWD at Baseline | 384.0 meters |
| Active | Six Minute Walk Distance (6MWD) by Lowest Study Drug Dose Strength Available at Randomization: Study Drug Dose 0.25 mg | 6MWD at Week 16 | 398.0 meters |
| Active | Six Minute Walk Distance (6MWD) by Lowest Study Drug Dose Strength Available at Randomization: Study Drug Dose 0.25 mg | Change in 6MWD from Baseline to Week 16 | 21.0 meters |
Comparison: Change in 6MWD from Baseline to Week 16p-value: 0.08595% CI: [1, 73]ANCOVA