Pulmonary Hypertension
Conditions
Brief summary
This study is an international, multi-center, randomized, double-blind, placebo-controlled study in subjects with PAH who are currently receiving approved therapy for their PAH (i.e., endothelin receptor antagonist and/or phosphodiesterase-5 inhibitor). Study visits will occur at 4 week intervals for 16 weeks with the key measure of efficacy being the 6-minute walk test. Study procedures include routine blood tests, medical history, physical exams, disease evaluation, and exercise tests. Patients who complete all assessments for 16-weeks will also be eligible to enter an open-label, extension phase study (FREEDOM - EXT).
Interventions
DRUGUT-15C SR
treprostinil diolamine sustained release tablets
DRUGPlacebo
Sponsors
United Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* A subject is eligible for inclusion in this study if all of the following criteria apply: * Between 18 and 75 years of age, inclusive. * Body weight at least 40 kg (approximately 90 lbs.) * PAH that is either idiopathic/heritable; associated with appetite suppressant or toxin use; associated with collagen vascular disease; associated with repaired congenital shunts; associated with HIV. * 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. * Baseline six-minute walk distance (6MWD) between 150-425 meters * Previous testing (e.g., right heart catheterization, echocardiography) consistent with the diagnosis of PAH. * Reliable and cooperative with protocol requirements.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 6-minute Walk Distance (6MWD) | Baseline and 16 weeks | Placebo-corrected change in 6MWD from Baseline to Week 16, correlates with the current 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 6MWD was to be assessed between 3 and 6 hours after the morning dose of study drug and background therapy(ies). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 six-minute walk test (6MWT). The Borg dyspnea score was assessed immediately following the 6MWT. Scores ranged from 0 (for no shortness of breath) to 10 (for the greatest shortness of breath ever experienced). |
| World Health Organization (WHO) Functional Class | Baseline and 16 Weeks | Class I: No limitation of physical activity. Class II: Slight limitation of physical activity. Class III: Marked limitation of physical activity. Class IV: Inability to carry out any physical activity without symptoms. |
| Symptoms of PAH | Baseline and 16 Weeks | Symptoms of PAH including fatigue, dyspnea, edema, dizziness, syncope, chest pain and orthopnea were assessed by the physician at Baseline and Week 16. Severity grade values (i.e., 0, 1, 2 or 3) for each symptom were provided each subject. A severity of 0 indicated no symptoms, the maximum severity was 3, indicating severe symptoms. Mean change in symptom severity from Baseline to Week 16 is described. |
| Clinical Worsening Assessment | Baseline and 16 Weeks | Definition of clinical worsening included patients who met at least one of the following criteria during the 16 weeks of study: 1. Death (all causes excluding accident) 2. Transplantation 3. Atrial septostomy 4. Hospitalization as a result of right heart failure 5. Greater than or equal to a 20% decrease in 6MWD from Baseline (or too ill to walk) AND addition of an inhaled prostacyclin analogue, ERA, or PDE-5i 6. Initiation of parenteral prostacyclin therapy (i.e., epoprostenol, iloprost, or treprostinil) for the treatment of PAH |
| N-terminal proBNP (NT-proBNP) | Baseline and 16 Weeks | Serum N-terminal pro-BNP concentration was assessed at Baseline and Week 16. |
| Quality of Life (QoL) Assessment: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) | Baseline and 16 Weeks | Change in CAMPHOR Scores from Baseline to Week 16. The CAMPHOR is a health related quality of life instrument validated for pulmonary hypertension that assesses impairment (symptoms), disability (activities) and quality of life. The questionnaire is divided into three sections; Symptoms (Scores 0-25; high scores indicate more symptoms), Activity (Score 0-30; low score indicates good functioning)and Quality of Life (0-25; high scores indicate poor QoL). The sum of these scores equates to the Total score (0-80). In the CAMPHOR scores, lower scores indicate improvements. |
| Dyspnea Fatigue Index | Baseline and 16 Weeks | The dyspnea-fatigue index was assessed at Baseline and Week 16. Each of the three components of the dyspnea-fatigue index were rated on a scale 0 to 4, with 0 being the worst condition and 4 being the best condition for each component. The dyspnea-fatigue index is computed by summing the three component scores. |
Countries
Belgium, Canada, France, Germany, Israel, Italy, Netherlands, Portugal, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
The recruitment period for this study was June 2009 to July 2011. Sites were located in North America, Europe and Asia.
Pre-assignment details
The 310 subjects who received a dose of study drug are presented here.
Participants by arm
| Arm | Count |
|---|---|
| UT-15C SR Doses were initiated at 0.25 mg BID and increased by 0.25 mg BID every three days (as clinically indicated based on tolerability and symptoms of PAH), to a max dose of 16 mg BID. | 157 |
| Placebo Identical placebo tablets to UT-15C, doses were titrated in the same manner | 153 |
| Total | 310 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 18 | 5 |
| Overall Study | Clinical Worsening | 4 | 4 |
| Overall Study | Death | 2 | 3 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Placebo | UT-15C SR | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 31 Participants | 38 Participants | 69 Participants |
| Age, Categorical Between 18 and 65 years | 122 Participants | 119 Participants | 241 Participants |
| Age Continuous | 50.4 years FULL_RANGE 14.5 | 51.5 years FULL_RANGE 15 | 51.0 years |
| Background PAH therapy ERA | 28 participants | 25 participants | 53 participants |
| Background PAH therapy PDE-5i | 65 participants | 67 participants | 132 participants |
| Background PAH therapy PDE-5i + ERA | 60 participants | 65 participants | 125 participants |
| Baseline Six-minute walk distance | 336.8 meters STANDARD_DEVIATION 63.5 | 329.4 meters STANDARD_DEVIATION 69.2 | 333 meters STANDARD_DEVIATION 66.4 |
| PAH Etiology Collagen vascular disease | 49 participants | 48 participants | 97 participants |
| PAH Etiology HIV infection | 4 participants | 2 participants | 6 participants |
| PAH Etiology Idiopathic or familial | 99 participants | 104 participants | 203 participants |
| PAH Etiology Repaired congenital heart disease | 1 participants | 3 participants | 4 participants |
| Sex: Female, Male Female | 122 Participants | 119 Participants | 241 Participants |
| Sex: Female, Male Male | 31 Participants | 38 Participants | 69 Participants |
| Time since PAH diagnosis | 3.3 years STANDARD_DEVIATION 4.1 | 2.5 years STANDARD_DEVIATION 2.6 | 2.9 years STANDARD_DEVIATION 3.4 |
| World Health Organization (WHO) Functional Class Class II | 37 Participants | 43 Participants | 80 Participants |
| World Health Organization (WHO) Functional Class Class III | 115 Participants | 110 Participants | 225 Participants |
| World Health Organization (WHO) Functional Class Class IV | 0 Participants | 3 Participants | 3 Participants |
| World Health Organization (WHO) Functional Class Unknown | 1 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 157 / 157 | 136 / 153 |
| serious Total, serious adverse events | 23 / 157 | 23 / 153 |
Outcome results
Primary
6-minute Walk Distance (6MWD)
Placebo-corrected change in 6MWD from Baseline to Week 16, correlates with the current 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 6MWD was to be assessed between 3 and 6 hours after the morning dose of study drug and background therapy(ies).
Time frame: Baseline and 16 weeks
Population: Intention to treat analysis
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| UT-15C SR | 6-minute Walk Distance (6MWD) | Week 16 Values | 370 meters |
| UT-15C SR | 6-minute Walk Distance (6MWD) | Change from Baseline | 15 meters |
| Placebo | 6-minute Walk Distance (6MWD) | Week 16 Values | 365 meters |
| Placebo | 6-minute Walk Distance (6MWD) | Change from Baseline | 11 meters |
Comparison: Using an allocation ratio of 1:1 between UT-15C SR and placebo, a fixed sample size of approximately 266 subjects would provide at least 90% power at a significance level of 0.05 (two-sided hypothesis) to detect a 30 meter between-treatment difference in the change from Baseline in distance traversed during the 6-Minute Walk, assuming a standard deviation of 75 meters. A total sample size of approximately 300 subjects was determined to account for discontinuations during the enrollment period.p-value: 0.08995% CI: [-2, 22]non-parametric ANCOVA
Secondary
Borg Dyspnea Score
The Borg dyspnea score is a 10-point scale rating the maximum level of dyspnea experienced during the six-minute walk test (6MWT). The Borg dyspnea score was assessed immediately following the 6MWT. Scores ranged from 0 (for no shortness of breath) to 10 (for the greatest shortness of breath ever experienced).
Time frame: Baseline and 16 Weeks
Population: All subjects with a Baseline Borg Score were included in the analysis. One subject in the placebo group did not have a Baseline Borg Score recorded.
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| UT-15C SR | Borg Dyspnea Score | Week 16 Value | 3.0 score | Inter-Quartile Range 2.47 |
| UT-15C SR | Borg Dyspnea Score | Change from Baseline | 0 score | — |
| Placebo | Borg Dyspnea Score | Week 16 Value | 4.0 score | Inter-Quartile Range 2.05 |
| Placebo | Borg Dyspnea Score | Change from Baseline | 0 score | — |
p-value: 0.2295% CI: [-1, 0]Wilcoxon rank sum test
Secondary
Clinical Worsening Assessment
Definition of clinical worsening included patients who met at least one of the following criteria during the 16 weeks of study: 1. Death (all causes excluding accident) 2. Transplantation 3. Atrial septostomy 4. Hospitalization as a result of right heart failure 5. Greater than or equal to a 20% decrease in 6MWD from Baseline (or too ill to walk) AND addition of an inhaled prostacyclin analogue, ERA, or PDE-5i 6. Initiation of parenteral prostacyclin therapy (i.e., epoprostenol, iloprost, or treprostinil) for the treatment of PAH
Time frame: Baseline and 16 Weeks
Population: Intention to treat analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| UT-15C SR | Clinical Worsening Assessment | 11 number of clinical worsening events |
| Placebo | Clinical Worsening Assessment | 10 number of clinical worsening events |
p-value: 1Fisher Exact
Secondary
Dyspnea Fatigue Index
The dyspnea-fatigue index was assessed at Baseline and Week 16. Each of the three components of the dyspnea-fatigue index were rated on a scale 0 to 4, with 0 being the worst condition and 4 being the best condition for each component. The dyspnea-fatigue index is computed by summing the three component scores.
Time frame: Baseline and 16 Weeks
Population: Subjects without a Dyspnea Fatigue Index score at Baseline were not included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| UT-15C SR | Dyspnea Fatigue Index | 5.7 units on a scale | Standard Deviation 2.6 |
| Placebo | Dyspnea Fatigue Index | 6.0 units on a scale | Standard Deviation 2.5 |
p-value: 0.395% CI: [0, 1]Wilcoxon rank sum test
Secondary
N-terminal proBNP (NT-proBNP)
Serum N-terminal pro-BNP concentration was assessed at Baseline and Week 16.
Time frame: Baseline and 16 Weeks
Population: Subjects who were missing Week 16 samples were not included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| UT-15C SR | N-terminal proBNP (NT-proBNP) | Change from Baseline | 135 pg/mL | Standard Deviation 913 |
| UT-15C SR | N-terminal proBNP (NT-proBNP) | Week 16 Value | 1310 pg/mL | Standard Deviation 1663 |
| Placebo | N-terminal proBNP (NT-proBNP) | Week 16 Value | 1627 pg/mL | Standard Deviation 2401 |
| Placebo | N-terminal proBNP (NT-proBNP) | Change from Baseline | 136 pg/mL | Standard Deviation 1242 |
Secondary
Quality of Life (QoL) Assessment: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR)
Change in CAMPHOR Scores from Baseline to Week 16. The CAMPHOR is a health related quality of life instrument validated for pulmonary hypertension that assesses impairment (symptoms), disability (activities) and quality of life. The questionnaire is divided into three sections; Symptoms (Scores 0-25; high scores indicate more symptoms), Activity (Score 0-30; low score indicates good functioning)and Quality of Life (0-25; high scores indicate poor QoL). The sum of these scores equates to the Total score (0-80). In the CAMPHOR scores, lower scores indicate improvements.
Time frame: Baseline and 16 Weeks
Population: Subjects in countries where the CAMPHOR has not been validated in the local language were not included in these analyses. Additionally, only subjects with completed questionnaires at Baseline and Week 16 were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| UT-15C SR | Quality of Life (QoL) Assessment: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) | Symptom Score | 10.0 units on a scale |
| UT-15C SR | Quality of Life (QoL) Assessment: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) | Quality of Life Score | 9.0 units on a scale |
| UT-15C SR | Quality of Life (QoL) Assessment: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) | Activity Score | 10.0 units on a scale |
| UT-15C SR | Quality of Life (QoL) Assessment: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) | Total Score | 28.0 units on a scale |
| Placebo | Quality of Life (QoL) Assessment: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) | Total Score | 24.5 units on a scale |
| Placebo | Quality of Life (QoL) Assessment: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) | Symptom Score | 9.0 units on a scale |
| Placebo | Quality of Life (QoL) Assessment: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) | Activity Score | 10.0 units on a scale |
| Placebo | Quality of Life (QoL) Assessment: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) | Quality of Life Score | 5.0 units on a scale |
Secondary
Symptoms of PAH
Symptoms of PAH including fatigue, dyspnea, edema, dizziness, syncope, chest pain and orthopnea were assessed by the physician at Baseline and Week 16. Severity grade values (i.e., 0, 1, 2 or 3) for each symptom were provided each subject. A severity of 0 indicated no symptoms, the maximum severity was 3, indicating severe symptoms. Mean change in symptom severity from Baseline to Week 16 is described.
Time frame: Baseline and 16 Weeks
Population: Subjects without Baseline assessments of PAH symptoms were not included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| UT-15C SR | Symptoms of PAH | Change in Edema Symptoms | 0.0 units on a scale | Standard Deviation 1 |
| UT-15C SR | Symptoms of PAH | Change in Syncope Symptoms | 0.2 units on a scale | Standard Deviation 0.8 |
| UT-15C SR | Symptoms of PAH | Change in Dyspnea Symptoms | -0.1 units on a scale | Standard Deviation 0.9 |
| UT-15C SR | Symptoms of PAH | Change in Chest Pain Symptoms | 0.1 units on a scale | Standard Deviation 1 |
| UT-15C SR | Symptoms of PAH | Change in Dizziness Symptoms | 0.1 units on a scale | Standard Deviation 1 |
| UT-15C SR | Symptoms of PAH | Change in Orthopnea Symptoms | 0.2 units on a scale | Standard Deviation 1 |
| UT-15C SR | Symptoms of PAH | Change in Fatigue Symptoms | 0.0 units on a scale | Standard Deviation 0.9 |
| Placebo | Symptoms of PAH | Change in Orthopnea Symptoms | 0.1 units on a scale | Standard Deviation 0.9 |
| Placebo | Symptoms of PAH | Change in Fatigue Symptoms | 0.0 units on a scale | Standard Deviation 1 |
| Placebo | Symptoms of PAH | Change in Dyspnea Symptoms | -0.2 units on a scale | Standard Deviation 0.9 |
| Placebo | Symptoms of PAH | Change in Edema Symptoms | 0.0 units on a scale | Standard Deviation 0.9 |
| Placebo | Symptoms of PAH | Change in Dizziness Symptoms | 0.0 units on a scale | Standard Deviation 1 |
| Placebo | Symptoms of PAH | Change in Syncope Symptoms | 0.2 units on a scale | Standard Deviation 0.7 |
| Placebo | Symptoms of PAH | Change in Chest Pain Symptoms | 0.1 units on a scale | Standard Deviation 1 |
Secondary
World Health Organization (WHO) Functional Class
Class I: No limitation of physical activity. Class II: Slight limitation of physical activity. Class III: Marked limitation of physical activity. Class IV: Inability to carry out any physical activity without symptoms.
Time frame: Baseline and 16 Weeks
Population: Subjects with a WHO functional class assessment at Week 16
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| UT-15C SR | World Health Organization (WHO) Functional Class | WHO Class I | 1 participants |
| UT-15C SR | World Health Organization (WHO) Functional Class | WHO Class II | 58 participants |
| UT-15C SR | World Health Organization (WHO) Functional Class | WHO Class III | 70 participants |
| UT-15C SR | World Health Organization (WHO) Functional Class | WHO Class IV | 2 participants |
| Placebo | World Health Organization (WHO) Functional Class | WHO Class IV | 3 participants |
| Placebo | World Health Organization (WHO) Functional Class | WHO Class I | 3 participants |
| Placebo | World Health Organization (WHO) Functional Class | WHO Class III | 83 participants |
| Placebo | World Health Organization (WHO) Functional Class | WHO Class II | 47 participants |
p-value: 0.4395% CI: [0, 0]Wilcoxon rank sum test
Post Hoc
6-minute Walk Distance by Background PAH Therapy: PDE-5i Only
Time frame: 16 weeks
Population: Subjects receiving only a PDE-5i at Baseline
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| UT-15C SR | 6-minute Walk Distance by Background PAH Therapy: PDE-5i Only | 30 meters |
| Placebo | 6-minute Walk Distance by Background PAH Therapy: PDE-5i Only | 14 meters |
p-value: 0.05495% CI: [-1, 29]ANCOVA
Post Hoc
6-minute Walk Distance by PAH Etiology: Idiopathic PAH (IPAH) / Heritable PAH(HPAH)
Covariate analysis of change in 6MWD by PAH etiology, specifically idiopathic or heritable PAH
Time frame: Baseline and 16 Weeks
Population: Subjects with IPAH/HPAH
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| UT-15C SR | 6-minute Walk Distance by PAH Etiology: Idiopathic PAH (IPAH) / Heritable PAH(HPAH) | 21.5 meters |
| Placebo | 6-minute Walk Distance by PAH Etiology: Idiopathic PAH (IPAH) / Heritable PAH(HPAH) | 13 meters |
p-value: 0.05895% CI: [0, 28]ANCOVA
Post Hoc
6-minute Walk Distance by Time Since PAH Diagnosis: 0.9 - 1.74 Years
Time frame: 16 Weeks
Population: Subjects who had been diagnosed with PAH between 0.9 and 1.74 years prior to Baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| UT-15C SR | 6-minute Walk Distance by Time Since PAH Diagnosis: 0.9 - 1.74 Years | 20.1 meters |
| Placebo | 6-minute Walk Distance by Time Since PAH Diagnosis: 0.9 - 1.74 Years | 13.0 meters |
p-value: 0.2295% CI: [-10, 31]ANCOVA
Post Hoc
6-minute Walk Distance by Time Since PAH Diagnosis: 3.6 - 26.4 Years
Time frame: Baseline and 16 weeks
Population: Subjects who had been diagnosed with PAH for 3.6 to 26.4 years prior to Baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| UT-15C SR | 6-minute Walk Distance by Time Since PAH Diagnosis: 3.6 - 26.4 Years | 14.0 meters |
| Placebo | 6-minute Walk Distance by Time Since PAH Diagnosis: 3.6 - 26.4 Years | 16.0 meters |
p-value: 0.8495% CI: [-25, 22]ANCOVA
Post Hoc
6-minute Walk Distance by Time to PAH Diagnosis: 0 - 0.9 Years
Time frame: Baseline and 16 weeks
Population: Subjects who have been diagnosed with PAH between 0 to 0.9 years prior to Baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| UT-15C SR | 6-minute Walk Distance by Time to PAH Diagnosis: 0 - 0.9 Years | 21.5 meters |
| Placebo | 6-minute Walk Distance by Time to PAH Diagnosis: 0 - 0.9 Years | -6.0 meters |
p-value: 0.05995% CI: [1, 59]ANCOVA
Post Hoc
6-minute Walk Distance by Years Since PAH Diagnosis: 1.8 - 3.5 Years
Time frame: Baseline and 16 weeks
Population: Subjects who were diagnosed with PAH between 1.8 and 3.5 years prior to Baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| UT-15C SR | 6-minute Walk Distance by Years Since PAH Diagnosis: 1.8 - 3.5 Years | 15.5 meter |
| Placebo | 6-minute Walk Distance by Years Since PAH Diagnosis: 1.8 - 3.5 Years | 4.0 meter |
p-value: 0.9995% CI: [-23, 28]ANCOVA
Post Hoc
6-minute Walk Test by Background PAH Therapy: ERA Only
Time frame: Baseline and 16 weeks
Population: Subjects who were only receiving an ERA at Baseline
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| UT-15C SR | 6-minute Walk Test by Background PAH Therapy: ERA Only | -5 meters |
| Placebo | 6-minute Walk Test by Background PAH Therapy: ERA Only | -2.5 meters |
Post Hoc
6-minute Walk Test by Background PAH Therapy: ERA + PDE-5i
Time frame: 16 weeks
Population: Subjects receiving both an ERA and a PDE-5i at Baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| UT-15C SR | 6-minute Walk Test by Background PAH Therapy: ERA + PDE-5i | 14.0 meters |
| Placebo | 6-minute Walk Test by Background PAH Therapy: ERA + PDE-5i | 15.5 meters |
p-value: 0.67495% CI: [-16, 24]ANCOVA