Pulmonary Arterial Hypertension
Conditions
Keywords
pulmonary arterial hypertension, PAH, treprostinil sodium, inhalation, ventavis, iloprost
Brief summary
This is a 24-month, multi-center, prospective, open-label, safety evaluation in PAH subjects following transition from a stable dose of inhaled iloprost (Ventavis). Subjects are to be evaluated for safety throughout the course of the study while secondary assessments will be conducted at Baseline, Week 6, Week 12, and Months 6, 12, 18 and 24 following initiation of treprostinil sodium.
Interventions
Sponsors
United Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Between 18 and 75 years of age * PAH diagnosis defined by following WHO Group I categories: idiopathic/familial, associated with unrepaired or repaired congenital systemic-to-pulmonary shunts (repaired \>/= 5 years), associated with collagen vascular disease, associated with HIV, associated with appetite suppressant/toxin use * Baseline six-minute walk distance (6MWD) \>/= 250 meters * Currently receiving Ventavis and be stable at current dose for 30 days prior to Baseline * If currently receiving other approved background therapy (i.e. endothelin receptor antagonist or phosphodiesterase-5-inhibitor or both) must be on stable dose for 30 days prior to Baseline * Previous testing (e.g. right heart catheterization, echocardiography) consistent with diagnosis of PAH
Exclusion criteria
* Nursing or pregnant * Has acute concomitant disease (e.g. portal hypertension, chronic thromboembolic disease, pulmonary veno-occlusive disease, etc) other than those accepted as part of the inclusion criteria or has had atrial septostomy * History of uncontrolled sleep apnea, left-sided heart disease, or parenchymal lung disease * Use of investigational drug within 30 days of Baseline
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Adverse Events | up to 24 months | Overall safety of transitioning from inhaled iloprost to inhaled treprostinil was assessed by type and frequency of adverse events. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Quality of Life (QoL) Assessment: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) | Baseline and 12 weeks | Change in CAMPHOR Scores from Baseline to Week 12. 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. |
| Treatment Satisfaction Questionnaire of Medication (TSQM) | Baseline and 12 weeks | Change in TSQM score from Baseline to Week 12. The TSQM is a validated instrument (Health and Quality of Life Outcomes 2004, 2:12) that measures major dimensions of patient satisfaction with medications. The questionnaire is comprised of 15 questions which fall into one of four categories; Effectiveness, Side-Effects, Convenience, and Global Satisfaction. Responses are scaled on a seven point bipolar scale from 'Extremely Satisfied' to 'Extremely Dissatisfied' where higher scores indicate improvements (total scores from 0-100). The questionnaire was completed at Baseline and Week 12. The Baseline questionnaire focused on the subject's satisfaction with inhaled iloprost treatment, while the questionnaire completed at Week 12 focused on the subject's satisfaction with inhaled treprostinil. |
| Patient Impression of Change | Baseline and 12 weeks | The patient impression of change (PIC) was three single therapy-related questions related to the subjects overall impression of the transition from inhaled iloprost to inhaled treprostinil. Subjects were surveyed related to their overall impression of the transition from inhaled iloprost to inhaled treprostinil at Week 12. |
| Six-minute Walk Distance (6MWD) | Baseline and 12 weeks | Change in 6MWD from Baseline to Week 12. The 6-minute walk test (6MWT) was conducted at Baseline (10-30 minutes following the last dose of inhaled iloprost) and at Week 12 (10-60 minutes following the dose of inhaled treprostinil). The change in distance (meters) between Baseline and Week 12 is reported below. |
| World Health Organization (WHO) Functional Class | Baseline and 12 Weeks | Change in WHO Functional Class (FC) from Baseline to Week 12. Data presented as percent of subjects who either improved FC, worsened FC, or had no change in FC from Baseline to Week 12. |
| Drug Administration Activities Questionnaire | Baseline and 12 weeks | Change in tasks from Baseline to Week 12. At Baseline and Week 12, subjects provided information related to the daily administration and time requirements of inhaled iloprost (Baseline) and inhaled treprostinil (Week 12). |
| N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) | Baseline and Week 12 | Change in NTpro-BNP from Baseline to Week 12. Blood samples were collected for plasma NTpro-BNP analysis during the study. |
Countries
United States
Participant flow
Recruitment details
Recruitment began 09-Dec-2008 and ended 09-Mar-2010. All recruitment took place in medical clinic settings.
Pre-assignment details
Not applicable given this was an open-label study.
Participants by arm
| Arm | Count |
|---|---|
| Inhaled Treprostinil Inhaled treprostinil was titrated up to 12 breaths four times daily. | 73 |
| Total | 73 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Death | 1 |
| Overall Study | Disease progression | 1 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Inhaled Treprostinil |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 10 Participants |
| Age, Categorical Between 18 and 65 years | 63 Participants |
| Age Continuous | 49.4 years STANDARD_DEVIATION 12.6 |
| Background PAH therapy Endothelin receptor antagonist (ERA) | 19 participants |
| Background PAH therapy ERA and PDE-5i | 43 participants |
| Background PAH therapy None | 3 participants |
| Background PAH therapy Phosphodiesterase-5 inhibitor (PDE-5i) | 8 participants |
| N-terminal prohormone brain natriuretic peptide (NT-proBNP) | 626 pg/mL |
| Pulmonary Arterial Hypertension (PAH) etiology CHD-unrepaired shunt | 15 participants |
| Pulmonary Arterial Hypertension (PAH) etiology Congenital heart disease (CHD)-repaired shunt | 4 participants |
| Pulmonary Arterial Hypertension (PAH) etiology Connective Tissue Diseases (CTD) | 16 participants |
| Pulmonary Arterial Hypertension (PAH) etiology HIV | 3 participants |
| Pulmonary Arterial Hypertension (PAH) etiology Idiopathic PAH or familial PAH | 35 participants |
| Region of Enrollment United States | 73 participants |
| Sex: Female, Male Female | 57 Participants |
| Sex: Female, Male Male | 16 Participants |
| Six-minute walk distance (6MWD) | 378 meters FULL_RANGE 78 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 71 / 73 |
| serious Total, serious adverse events | 10 / 73 |
Outcome results
Primary
Number of Adverse Events
Overall safety of transitioning from inhaled iloprost to inhaled treprostinil was assessed by type and frequency of adverse events.
Time frame: up to 24 months
Population: All subjects who received at least one dose of inhaled treprostinil were included in the safety analysis population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Inhaled Treprostinil | Number of Adverse Events | Possibly or Probably related events | 266 number of events |
| Inhaled Treprostinil | Number of Adverse Events | Overall events | 440 number of events |
| Inhaled Treprostinil | Number of Adverse Events | Severe events | 41 number of events |
| Inhaled Treprostinil | Number of Adverse Events | Serious events | 15 number of events |
Secondary
Drug Administration Activities Questionnaire
Change in tasks from Baseline to Week 12. At Baseline and Week 12, subjects provided information related to the daily administration and time requirements of inhaled iloprost (Baseline) and inhaled treprostinil (Week 12).
Time frame: Baseline and 12 weeks
Population: Subjects who completed the questionnaire at Baseline and Week 12.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Inhaled Treprostinil | Drug Administration Activities Questionnaire | Week 12 Total Daily Dosing Time | 39.1 minutes | Standard Deviation 25.1 |
| Inhaled Treprostinil | Drug Administration Activities Questionnaire | Change in Time Total Daily Dosing Time | -79.3 minutes | Standard Deviation 80.5 |
Secondary
N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP)
Change in NTpro-BNP from Baseline to Week 12. Blood samples were collected for plasma NTpro-BNP analysis during the study.
Time frame: Baseline and Week 12
Population: Subjects with a NTproBNP sample drawn at Baseline and Week 12
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Inhaled Treprostinil | N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) | -74 pg/mL |
p-value: 0.001Wilcoxon signed-rank test
Secondary
Patient Impression of Change
The patient impression of change (PIC) was three single therapy-related questions related to the subjects overall impression of the transition from inhaled iloprost to inhaled treprostinil. Subjects were surveyed related to their overall impression of the transition from inhaled iloprost to inhaled treprostinil at Week 12.
Time frame: Baseline and 12 weeks
Population: Subjects who completed questionnaire at Baseline and Week 12
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Inhaled Treprostinil | Patient Impression of Change | Improvement of Symptoms | 73 percentage of patients | 80.5 |
| Inhaled Treprostinil | Patient Impression of Change | Improvment in Time Spent | 91 percentage of patients | — |
| Inhaled Treprostinil | Patient Impression of Change | Overall Satisfaction | 94 percentage of patients | — |
Secondary
Quality of Life (QoL) Assessment: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR)
Change in CAMPHOR Scores from Baseline to Week 12. 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 12 weeks
Population: Subjects who were still enrolled and completed the questionnaire at Baseline and Week 12. Total analysis population was less for the activity score and total score (N = 67).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Inhaled Treprostinil | Quality of Life (QoL) Assessment: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) | Change in Total Score | -6.4 units on a scale | Full Range 7.7 |
| Inhaled Treprostinil | Quality of Life (QoL) Assessment: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) | Symptom Score at Week 12 | 5.3 units on a scale | — |
| Inhaled Treprostinil | Quality of Life (QoL) Assessment: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) | Change in Symptom Score | -2.9 units on a scale | Full Range 3.9 |
| Inhaled Treprostinil | Quality of Life (QoL) Assessment: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) | Activity Score at Week 12 | 6.6 units on a scale | — |
| Inhaled Treprostinil | Quality of Life (QoL) Assessment: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) | Change in Activity Score | -1.2 units on a scale | Full Range 2.5 |
| Inhaled Treprostinil | Quality of Life (QoL) Assessment: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) | Quality of Life Score at Week 12 | 4.9 units on a scale | — |
| Inhaled Treprostinil | Quality of Life (QoL) Assessment: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) | Change in Quality of Life Score | -2.4 units on a scale | Full Range 3.9 |
| Inhaled Treprostinil | Quality of Life (QoL) Assessment: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) | Total Score at Week 12 | 16.8 units on a scale | — |
p-value: <0.001Wilcoxon signed rank test
Secondary
Six-minute Walk Distance (6MWD)
Change in 6MWD from Baseline to Week 12. The 6-minute walk test (6MWT) was conducted at Baseline (10-30 minutes following the last dose of inhaled iloprost) and at Week 12 (10-60 minutes following the dose of inhaled treprostinil). The change in distance (meters) between Baseline and Week 12 is reported below.
Time frame: Baseline and 12 weeks
Population: Subjects enrolled at Week 12 visit.
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Inhaled Treprostinil | Six-minute Walk Distance (6MWD) | Week 12 | 392.5 meters | — |
| Inhaled Treprostinil | Six-minute Walk Distance (6MWD) | Change from Baseline | 16 meters | Full Range 78 |
Comparison: Analysis of endpoints was descriptive in nature. Numeric endpoints for post-baseline assessments were compared to Baseline using Wilcoxon signed rank test, and p-values were calculated for descriptive purposes; no formal hypothesis testing was planned.p-value: <0.001Wilcoxon signed rank test]
Secondary
Treatment Satisfaction Questionnaire of Medication (TSQM)
Change in TSQM score from Baseline to Week 12. The TSQM is a validated instrument (Health and Quality of Life Outcomes 2004, 2:12) that measures major dimensions of patient satisfaction with medications. The questionnaire is comprised of 15 questions which fall into one of four categories; Effectiveness, Side-Effects, Convenience, and Global Satisfaction. Responses are scaled on a seven point bipolar scale from 'Extremely Satisfied' to 'Extremely Dissatisfied' where higher scores indicate improvements (total scores from 0-100). The questionnaire was completed at Baseline and Week 12. The Baseline questionnaire focused on the subject's satisfaction with inhaled iloprost treatment, while the questionnaire completed at Week 12 focused on the subject's satisfaction with inhaled treprostinil.
Time frame: Baseline and 12 weeks
Population: Subjects who completed the TSQM at Baseline and Week 12. Total analysis population was less for the Convenience Score (N=67) and Global Satisfaction Score (N=66).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Inhaled Treprostinil | Treatment Satisfaction Questionnaire of Medication (TSQM) | Effectiveness Score at Week 12 | 81.9 units on a scale | — |
| Inhaled Treprostinil | Treatment Satisfaction Questionnaire of Medication (TSQM) | Change in Effectiveness Score | 19.9 units on a scale | Full Range 21.5 |
| Inhaled Treprostinil | Treatment Satisfaction Questionnaire of Medication (TSQM) | Side-effects Score at Week 12 | 84.4 units on a scale | — |
| Inhaled Treprostinil | Treatment Satisfaction Questionnaire of Medication (TSQM) | Change in Side-Effects Score | -0.5 units on a scale | Full Range 21.3 |
| Inhaled Treprostinil | Treatment Satisfaction Questionnaire of Medication (TSQM) | Convenience Score at Week 12 | 83.3 units on a scale | — |
| Inhaled Treprostinil | Treatment Satisfaction Questionnaire of Medication (TSQM) | Change in Convenience Score | 38.3 units on a scale | Full Range 25.9 |
| Inhaled Treprostinil | Treatment Satisfaction Questionnaire of Medication (TSQM) | Global Satisfaction Score at Week 12 | 81.9 units on a scale | — |
| Inhaled Treprostinil | Treatment Satisfaction Questionnaire of Medication (TSQM) | Change in Global Satisfaction | 20.0 units on a scale | Full Range 23.7 |
p-value: 0.895Wilcoxon signed-rank test
p-value: <0.001Wilcoxon signed-rank test
p-value: <0.001Wilcoxon signed-rank test
p-value: <0.001Wilcoxon signed rank test
Secondary
World Health Organization (WHO) Functional Class
Change in WHO Functional Class (FC) from Baseline to Week 12. Data presented as percent of subjects who either improved FC, worsened FC, or had no change in FC from Baseline to Week 12.
Time frame: Baseline and 12 Weeks
Population: Subjects still enrolled at Week 12 with a WHO Functional Class at Baseline and Week 12.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Inhaled Treprostinil | World Health Organization (WHO) Functional Class | Improvement | 6 percentage of subjects |
| Inhaled Treprostinil | World Health Organization (WHO) Functional Class | No Change | 87 percentage of subjects |
| Inhaled Treprostinil | World Health Organization (WHO) Functional Class | Worsened | 7 percentage of subjects |