Pulmonary Arterial Hypertension
Conditions
Brief summary
This study enrolls patients with pulmonary arterial hypertension (PAH) treated with inhaled treprostinil. During the study, the treatment with inhaled treprostinil will be tapered off and simultaneously replaced with an oral treatment (selexipag) targeting the disease in a similar way. The purpose of the study is i) to investigate the safety and tolerability of oral selexipag in patients who transition from inhaled treprostinil, ii) to investigate the effects of oral selexipag on PAH severity and exercise ability before and after transition, and iii) to gain new information about the patients experience taking oral selexipag compared to inhaled treprostinil. Study participants may stay in the study until the FDA has granted marketing authorization.
Interventions
DRUGSelexipag
Tablets for oral administration containing 200 micrograms (mcg) of selexipag to be administered twice a day. The individual dose is to be established during the first 12 weeks of the study. Doses are in the range from 200 micrograms (1 tablet) to 1,600 micrograms (8 tablets).
Sponsors
Actelion
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Male and female patients aged from 18 to 75 years (inclusive) with pulmonary arterial hypertension (PAH). * Etiology of PAH belonging to one of the following subgroups: idiopathic PAH, Heritable PAH, drug or toxin induced, associated with connective tissue disease, associated with HIV infection, associated with congenital heart disease with simple systemic-to-pulmonary shunt at least 1 year after surgical repair. * Women of childbearing potential are eligible only if the following apply: Negative serum pregnancy test at Visit 1 and a negative urine pregnancy test at Visit on Day 1, agreement to undertake monthly urine pregnancy tests during the study and up to 30 days after study drug discontinuation, agreement to use efficient methods of birth control from Visit 1 up to at least 30 days after study treatment discontinuation. * Documented hemodynamic diagnosis of PAH by right heart catheterization (RHC). * Inhaled treprostinil treatment ongoing for at least 90 days and at stable dose for at least 30 days prior to Day 1. * WHO functional class (FC) II or III at Visit 1 and Visit 2. * 6-minute walk distance (6MWD) ≥ 300 m at Visit 1. * On background oral PAH therapy for at least 90 days and on a stable dose for 30 days prior to Visit 2. Acceptable concomitant PAH therapies are one or two of the following: a) Endothelin receptor antagonist (ERA), b) Phosphodiesterase type 5 (PDE-5) inhibitor or soluble guanylate cyclase (sGC) stimulator.
Exclusion criteria
* Treatment with any prostacyclin or prostacyclin analogs other than inhaled treprostinil within 90 days before Day 1, or patients scheduled to receive any of these treatments within the duration of the study. * Any hospitalization within 90 days before Day 1. * Worsening in WHO FC within 30 days prior to Day 1. * At any time prior to Day 1, documented moderate or severe obstructive or restrictive lung disease. * Known or suspicion of pulmonary veno-occlusive disease (PVOD). * Anemia: \< 80 g/L (5.0 mmol/L) hemoglobin. * Clinically relevant thyroid disease (hypo- or hyperthyroidism). * Known and documented severe hepatic impairment. * Uncontrolled hypertension. * Sitting systolic blood pressure \< 85 mmHg. * Acute myocardial infarction within the last 90 days prior to Visit 1. * History of left-sided heart disease. * Left ventricular disease/dysfunction risk factors. * Documented pericardial effusion within 90 days prior to Visit 1. * Documented severe renal insufficiency. * Receiving or having received any investigational drugs within 90 days before Day 1. * Having received selexipag at any time before Day 1. * Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements. * Recently conducted or planned cardio-pulmonary rehabilitation program based on exercise training during the study. * Psychotic, addictive or other disorder limiting the ability to provide informed consent or to comply with study requirements. * Known concomitant life-threatening disease with a life expectancy \< 12 months. * Females who are lactating or pregnant or plan to become pregnant during the study. * Known hypersensitivity to any of the excipients of the drug formulation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Adverse Events Leading to Premature Discontinuation of Selexipag | Up to 22 weeks on average | Number of subjects with adverse events leading to premature discontinuation of selexipag is determined from the first dose of selexipag up to the last dose of selexipag |
| Absolute Change From Baseline Over Time in Blood Pressure | Baseline, Week 4, Week 12, Week 16 | Both systolic(SBP) and diastolic (DBP) arterial blood pressure were measured in a sitting position after at least 5 minutes of rest at scheduled time points. Median change from baseline to pre-specified post-baseline visits are calculated |
| Maximal Tolerated Dose | At Week 12, in subjects still on selexipag at Week 16 | This is the individual maximal tolerated dose (MTD) observed at Week 12 in the subjects still on selexipag at Week 16. MTD is defined as the dose of selexipag reached with the last dose change up to Week 12 |
| Absolute Change From Baseline Over Time in Heart Rate (HR) | Baseline, Week 4, Week 12, Week 16 | Pulse rate is measured after at least 5 minutes of rest in a sitting position. Median change from baseline to pre-specified post-baseline visits are calculated. |
| Percentage of Subjects With Sustained Treatment Transition | At Week 16 | A sustained treatment transition is considered if the 3 following criteria are met a) being on study treatment (selexipag) at Week 16, and b) not having a study treatment interruption(s) of a total of 8 days or more prior to Week 16, and c) absence of inhaled treprostinil or any prostanoid treatment after Week 8 up to Week 16. The percentage of subjects with a sustained treatment transition is calculated with 95% confidence interval (CI) using the Clopper-Pearson method. |
| Percentage of Subjects With Treatment-emergent Adverse Events (AEs), | 26 weeks on average (from the first dose of selexipag up to 30 days after the last dose of selexipag) | Percentage of subjects with treatment-emergent AEs (serious and non serious), regardless of relationship to selexipag |
| Time to Discontinuation of Inhaled Treprostinil. | Baseline to Week 16 | Median time from baseline (Day1) to the end of down-titration of inhaled treprostinil is calculated |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With WHO Functional Class (FC) Change From Baseline | Baseline and Week 16 | The World Health Organization (WHO) defines 4 classes to classify the functional status of patients with pulmonary hypertension: Class I (FC I): No limitation of physical activity. Class II (FC II): Slight limitation of physical activity. Class III (FC III): Marked limitation of physical activity. Class IV (FC IV): Inability to carry out any physical activity without symptoms. Number of patients with improvement (shift from a higher to a lower class), worsening (shift from a lower to a higher class) or no change in WHO functional class at end of study compared to baseline are determined. |
| Absolute Change in 6-minute Walk Distance (6MWD) at Trough | Baseline and Week 16 | The 6MWT is a non-encouraged test, which measures the distance (in meters) covered by the subject during a 6-minute walk. It is performed in a 30-meters long flat corridor, where the patient is instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. Absolute change from baseline to Week 16 in 6MWD is measured at trough levels of inhaled treprostinil and/or selexipag. The trough level of inhaled treprostinil is defined as the last dose having been taken not less than 4 hours and not more than 48 hours prior to the 6MWT at Visit 1 (screening). The trough level of selexipag was defined as the last dose having been taken not less than 8 hours and not more than 7 days prior to the 6MWT at Visit 5 (Week 16). |
| Percentage of Patients With Change in 6-minute Walk Distance (6MWD) | Baseline and Week 16 | Percentage of patients with an increase (\> 8% of baseline), maintenance (+/- 8% of baseline), or decrease (\< -8% of baseline) in their 6MWD (at trough) from baseline to Week 16. The ± 8% boundaries for change in 6MWD reflect the approximately 8% coefficient of variation in the reproducibility of the 6MWD. The trough level of inhaled treprostinil is defined as the last dose having been taken not less than 4 hours and not more than 48 hours prior to the 6MWD test at Visit 1 (screening). The trough level of selexipag was defined as the last dose having been taken not less than 8 hours and not more than 7 days prior to the 6MWD test at Visit 5 (Week 16). |
| Geometric Mean of the Ratio in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) of Week 16 to Baseline | Baseline and Week 16 | Changes in NT-proBNP levels in plasma are expressed by the geometric mean of the ratio of Week 16 to baseline |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 16 in the Treatment Satisfaction Questionnaire for Medication Questionnaire (TSQM II) | Baseline and Week 16 | The Treatment Satisfaction Questionnaire for Medication, Version II (TSQM II) is a validated tool that evaluate the subject's satisfaction with the study treatment. It includes a total of 11 questions related to satisfaction with treatment effectiveness, side effects,convenience, and global satisfaction. TSQM scores range from 0 to 100 for each domain; a higher score indicates higher satisfaction with treatment. |
Countries
United States
Participant flow
Recruitment details
Thirty-seven patients were screened. Among them, thirty-four patients with pulmonary arterial hypertension (PAH) and treated with inhaled treprostinil for at least 90 days were enrolled at 12 sites in the USA.
Participants by arm
| Arm | Count |
|---|---|
| Selexipag The subjects participated in a 16-week main treatment period including down-titration of treprostinil to end of Week 8 and parallel up-titration of selexipag to the maximum tolerated dose (MTD) up to Week 12, for each individual patient but not above 1600 mcg twice daily.
From Week 12 up to Week 16, patients continued selexipag at their individual MTD. Patients could continue the study drug selexipag during the extended treatment period from Week 16 until commercial availability of selexipag. | 34 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Extended Treatment Period | Lack of Efficacy | 1 |
| Main Treatment Period | Adverse Event | 1 |
| Main Treatment Period | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Selexipag |
|---|---|
| Age, Customized Age categories as per protocol <= 65 years | 28 Participants |
| Age, Customized Age categories as per protocol >65 years and <75 years | 5 Participants |
| Age, Customized Age categories as per protocol >= 75 years | 1 Participants |
| Etiology of pulmonary arterial hypertension (PAH) Associated PAH | 10 Participants |
| Etiology of pulmonary arterial hypertension (PAH) Drug or toxin induced | 5 Participants |
| Etiology of pulmonary arterial hypertension (PAH) Heritable | 0 Participants |
| Etiology of pulmonary arterial hypertension (PAH) Idiopathic | 19 Participants |
| PAH-specific therapy at baseline ERAs alone | 4 Participants |
| PAH-specific therapy at baseline ERAs and PDE-5 | 19 Participants |
| PAH-specific therapy at baseline ERAs and sCG stimulator | 4 Participants |
| PAH-specific therapy at baseline PDE5-inhibitors alone | 7 Participants |
| Race/Ethnicity, Customized Race categories as per protocol Asian | 3 Participants |
| Race/Ethnicity, Customized Race categories as per protocol Black or African American | 2 Participants |
| Race/Ethnicity, Customized Race categories as per protocol Other | 1 Participants |
| Race/Ethnicity, Customized Race categories as per protocol White | 28 Participants |
| Sex: Female, Male Female | 28 Participants |
| Sex: Female, Male Male | 6 Participants |
| Time since initial inhaled treprostinil | 37.8 Months |
| Treprostinil stable dose < 54 mcg q.i.d. | 2 Participants |
| Treprostinil stable dose > 54 mcg q.i.d. | 12 Participants |
| Treprostinil stable dose 54 mcg q.i.d. | 20 Participants |
| World Health Organization Functional class (WHO FC) FC I | 0 Participants |
| World Health Organization Functional class (WHO FC) FC II | 25 Participants |
| World Health Organization Functional class (WHO FC) FC III | 9 Participants |
| World Health Organization Functional class (WHO FC) FC IV | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 34 |
| other Total, other adverse events | 33 / 34 |
| serious Total, serious adverse events | 2 / 34 |
Outcome results
Primary
Absolute Change From Baseline Over Time in Blood Pressure
Both systolic(SBP) and diastolic (DBP) arterial blood pressure were measured in a sitting position after at least 5 minutes of rest at scheduled time points. Median change from baseline to pre-specified post-baseline visits are calculated
Time frame: Baseline, Week 4, Week 12, Week 16
Population: All subjects who took at least one dose of selexipag were included in the safety analyses
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Selexipag | Absolute Change From Baseline Over Time in Blood Pressure | DBP change from baseline at week 4 | -3.00 mmHg |
| Selexipag | Absolute Change From Baseline Over Time in Blood Pressure | SBP change from baseline at week 4 | 1.00 mmHg |
| Selexipag | Absolute Change From Baseline Over Time in Blood Pressure | SBP change from baseline at week 12 | -3.00 mmHg |
| Selexipag | Absolute Change From Baseline Over Time in Blood Pressure | SBP change from baseline at week 16 | -4.00 mmHg |
| Selexipag | Absolute Change From Baseline Over Time in Blood Pressure | DBP change from baseline at week 12 | -4.00 mmHg |
| Selexipag | Absolute Change From Baseline Over Time in Blood Pressure | DBP change from baseline at week 16 | -6.00 mmHg |
Primary
Absolute Change From Baseline Over Time in Heart Rate (HR)
Pulse rate is measured after at least 5 minutes of rest in a sitting position. Median change from baseline to pre-specified post-baseline visits are calculated.
Time frame: Baseline, Week 4, Week 12, Week 16
Population: All subjects who took at least one dose of selexipag were included in the safety analyses
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Selexipag | Absolute Change From Baseline Over Time in Heart Rate (HR) | HR change from baseline at week 4 | 4.00 beats per minute (bpm) |
| Selexipag | Absolute Change From Baseline Over Time in Heart Rate (HR) | HR change from baseline at week 12 | 6.00 beats per minute (bpm) |
| Selexipag | Absolute Change From Baseline Over Time in Heart Rate (HR) | HR change from baseline at week 16 | 3.00 beats per minute (bpm) |
Primary
Maximal Tolerated Dose
This is the individual maximal tolerated dose (MTD) observed at Week 12 in the subjects still on selexipag at Week 16. MTD is defined as the dose of selexipag reached with the last dose change up to Week 12
Time frame: At Week 12, in subjects still on selexipag at Week 16
Population: Sensitivity analysis: only patients being on selexipag at week 16 are considered.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Selexipag | Maximal Tolerated Dose | 1200 mcg |
Primary
Number of Subjects With Adverse Events Leading to Premature Discontinuation of Selexipag
Number of subjects with adverse events leading to premature discontinuation of selexipag is determined from the first dose of selexipag up to the last dose of selexipag
Time frame: Up to 22 weeks on average
Population: All subjects who took at least one dose of selexipag were included in the safety analyses
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Selexipag | Number of Subjects With Adverse Events Leading to Premature Discontinuation of Selexipag | 3 Participants |
Primary
Percentage of Subjects With Sustained Treatment Transition
A sustained treatment transition is considered if the 3 following criteria are met a) being on study treatment (selexipag) at Week 16, and b) not having a study treatment interruption(s) of a total of 8 days or more prior to Week 16, and c) absence of inhaled treprostinil or any prostanoid treatment after Week 8 up to Week 16. The percentage of subjects with a sustained treatment transition is calculated with 95% confidence interval (CI) using the Clopper-Pearson method.
Time frame: At Week 16
Population: All subjects who took at least one dose of selexipag were included in the safety analyses
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Selexipag | Percentage of Subjects With Sustained Treatment Transition | 82.4 Percentage of participants |
Primary
Percentage of Subjects With Treatment-emergent Adverse Events (AEs),
Percentage of subjects with treatment-emergent AEs (serious and non serious), regardless of relationship to selexipag
Time frame: 26 weeks on average (from the first dose of selexipag up to 30 days after the last dose of selexipag)
Population: All subjects who took at least one dose of selexipag were included in the safety analyses
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Selexipag | Percentage of Subjects With Treatment-emergent Adverse Events (AEs), | 97.1 Percentage of participants |
Primary
Time to Discontinuation of Inhaled Treprostinil.
Median time from baseline (Day1) to the end of down-titration of inhaled treprostinil is calculated
Time frame: Baseline to Week 16
Population: All subjects who took at least one dose of selexipag were included in the safety analyses
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Selexipag | Time to Discontinuation of Inhaled Treprostinil. | 6.21 weeks |
Secondary
Absolute Change in 6-minute Walk Distance (6MWD) at Trough
The 6MWT is a non-encouraged test, which measures the distance (in meters) covered by the subject during a 6-minute walk. It is performed in a 30-meters long flat corridor, where the patient is instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. Absolute change from baseline to Week 16 in 6MWD is measured at trough levels of inhaled treprostinil and/or selexipag. The trough level of inhaled treprostinil is defined as the last dose having been taken not less than 4 hours and not more than 48 hours prior to the 6MWT at Visit 1 (screening). The trough level of selexipag was defined as the last dose having been taken not less than 8 hours and not more than 7 days prior to the 6MWT at Visit 5 (Week 16).
Time frame: Baseline and Week 16
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Selexipag | Absolute Change in 6-minute Walk Distance (6MWD) at Trough | -10.25 meters |
Secondary
Geometric Mean of the Ratio in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) of Week 16 to Baseline
Changes in NT-proBNP levels in plasma are expressed by the geometric mean of the ratio of Week 16 to baseline
Time frame: Baseline and Week 16
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Selexipag | Geometric Mean of the Ratio in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) of Week 16 to Baseline | 1.1 Geometric mean of the ratio |
Secondary
Percentage of Patients With Change in 6-minute Walk Distance (6MWD)
Percentage of patients with an increase (\> 8% of baseline), maintenance (+/- 8% of baseline), or decrease (\< -8% of baseline) in their 6MWD (at trough) from baseline to Week 16. The ± 8% boundaries for change in 6MWD reflect the approximately 8% coefficient of variation in the reproducibility of the 6MWD. The trough level of inhaled treprostinil is defined as the last dose having been taken not less than 4 hours and not more than 48 hours prior to the 6MWD test at Visit 1 (screening). The trough level of selexipag was defined as the last dose having been taken not less than 8 hours and not more than 7 days prior to the 6MWD test at Visit 5 (Week 16).
Time frame: Baseline and Week 16
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Selexipag | Percentage of Patients With Change in 6-minute Walk Distance (6MWD) | 6MWD decreased | 26.5 Percentage of participants |
| Selexipag | Percentage of Patients With Change in 6-minute Walk Distance (6MWD) | 6MWD maintained | 55.9 Percentage of participants |
| Selexipag | Percentage of Patients With Change in 6-minute Walk Distance (6MWD) | 6MWD increased | 17.6 Percentage of participants |
Secondary
Percentage of Subjects With WHO Functional Class (FC) Change From Baseline
The World Health Organization (WHO) defines 4 classes to classify the functional status of patients with pulmonary hypertension: Class I (FC I): No limitation of physical activity. Class II (FC II): Slight limitation of physical activity. Class III (FC III): Marked limitation of physical activity. Class IV (FC IV): Inability to carry out any physical activity without symptoms. Number of patients with improvement (shift from a higher to a lower class), worsening (shift from a lower to a higher class) or no change in WHO functional class at end of study compared to baseline are determined.
Time frame: Baseline and Week 16
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Selexipag | Percentage of Subjects With WHO Functional Class (FC) Change From Baseline | % subjects with WHO FC improvement | 26.5 percentage of participants |
| Selexipag | Percentage of Subjects With WHO Functional Class (FC) Change From Baseline | % subjects with WHO FC worsening | 5.9 percentage of participants |
| Selexipag | Percentage of Subjects With WHO Functional Class (FC) Change From Baseline | % subjects with WHO FC unchanged | 67.6 percentage of participants |
Other Pre-specified
Change From Baseline to Week 16 in the Treatment Satisfaction Questionnaire for Medication Questionnaire (TSQM II)
The Treatment Satisfaction Questionnaire for Medication, Version II (TSQM II) is a validated tool that evaluate the subject's satisfaction with the study treatment. It includes a total of 11 questions related to satisfaction with treatment effectiveness, side effects,convenience, and global satisfaction. TSQM scores range from 0 to 100 for each domain; a higher score indicates higher satisfaction with treatment.
Time frame: Baseline and Week 16
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Selexipag | Change From Baseline to Week 16 in the Treatment Satisfaction Questionnaire for Medication Questionnaire (TSQM II) | Effectiveness (change from baseline) | 0.00 Units on a scale |
| Selexipag | Change From Baseline to Week 16 in the Treatment Satisfaction Questionnaire for Medication Questionnaire (TSQM II) | Side effects (change from baseline) | 0.00 Units on a scale |
| Selexipag | Change From Baseline to Week 16 in the Treatment Satisfaction Questionnaire for Medication Questionnaire (TSQM II) | Convenience (change from baseline) | 44.44 Units on a scale |
| Selexipag | Change From Baseline to Week 16 in the Treatment Satisfaction Questionnaire for Medication Questionnaire (TSQM II) | Global satisfaction (change from baseline) | 8.33 Units on a scale |