Pulmonary Hypertension
Conditions
Keywords
PAH, Pulmonary Arterial Hypertension
Brief summary
The purpose of this multi-center international trial is to evaluate the safety and effectiveness of adding iloprost or placebo (an inactive substance that contains no active study drug) to sildenafil therapy for pulmonary arterial hypertension (PAH). The study will also examine whether patients on sildenafil can reduce the number of iloprost inhalations from the approved 6 doses per day to 4 doses per day.
Interventions
DRUGInhaled Iloprost (5 μg)
iloprost inhalation solution (Ventavis) (5 μg)
DRUGInhaled Placebo
inhaled placebo
DRUGSildenafil
oral sildenafil (dosage between 60 and 300 mg/day)
DRUGBosentan
oral bosentan (dosage between 62.5 and 125 mg BID)
Sponsors
Actelion
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Aged 12-85 years; of either gender. * Confirmed PAH due to idiopathic pulmonary arterial hypertension (IPAH) or familial pulmonary arterial hypertension (FPAH). * 6-minute walk distance (6-MWD) between 100-450 meters at screening. * On a stable dose of sildenafil, with or without bosentan.
Exclusion criteria
* Any treatment for PAH with prostacyclins, prostacyclin analogues, endothelin-1 antagonists, or phosphodiesterase-5 (PDE-5) inhibitors other than sildenafil within the past 12 weeks. * Pulmonary hypertension due to conditions other than those stated in inclusion criteria. * Additional PAH medications added within the past 12 weeks.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline to Week 16 in 6-Minute Walk Distance (6MWD) During the Double-blind Treatment Period | Day 1 and Week 16 | The 6MWD test is a non-encouraged test, performed in a 30-meter long flat corridor, where the patient is instructed to walk as far as possible, back and forth around two cones during 6 minutes. They can slow down, rest, or stop if needed. This test is used to assess exercise capacity. The test was performed about 30 minutes after study drug administration. Any increase in the walk distance was considered improvement from baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With WHO Functional Class (WHO FC) Improvement at Week 16 | Day 1 and Week 16 | This test is used to assess disease severity. Four fucntional classes (FC) are defined from FC I (no limitation of physical activity) to FC IV (inability to carry out any physical activity without symptoms). Improvement is considered when a participant changes from a higher class to a lower class. |
| Time to Clinical Worsening | Week 16 and Week 48 | Clinical worsening is defined as one of the following: death due to worsening PAH, receipt of lung or heart-lung transplantation, or atrial septostomy, hospitalization for worsening PAH, any early discontinuation from study during the blinded or open-label phase due to worsening PAH, initiation of additional PAH-specific treatment. Due to insufficient data, time could not be assessed accurately and only number of patients with clinical worsening could be reported. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Any Adverse Events | From Day 1 to Week 16 and Week 48 | This is the overall number of participants in each group who reported at least one adverse event (i.e., any untoward medical occurrence or unfavorable and unintended sign whether or not considered related to the study drug) with an onset from the first administration of study drug up to the last study visit. |
Participant flow
Recruitment details
Due to slow participant enrollment, the study was prematurely terminated, and recruitment was stopped after 67 subjects had been recruited instead of 180 initially planned (37% of the originally-planned sample size)
Participants by arm
| Arm | Count |
|---|---|
| DB Iloprost 6×/Day Inhaled iloprost (5 μg) 6×/day plus sildenafil with or without bosentan | 26 |
| DB Iloprost 4×/Day Inhaled iloprost (5 μg) 4×/day plus inhaled placebo 2x/day plus sildenafil with or without bosentan | 27 |
| DB Placebo 6×/Day Inhaled placebo 6×/day plus sildenafil with or without bosentan | 14 |
| Total | 67 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Double Blind Period (New Patients) | Adverse Event | 0 | 0 | 3 | 0 | 0 |
| Double Blind Period (New Patients) | Disease progression | 0 | 1 | 1 | 0 | 0 |
| Double Blind Period (New Patients) | Investigator's judgement | 1 | 0 | 0 | 0 | 0 |
| Double Blind Period (New Patients) | Withdrawal by Subject | 2 | 1 | 0 | 0 | 0 |
| Open Label-Patients From Double-Blind | Adverse Event | 0 | 0 | 0 | 1 | 0 |
| Open Label-Patients From Double-Blind | Death | 0 | 0 | 0 | 1 | 1 |
| Open Label-Patients From Double-Blind | Disease progression | 0 | 0 | 0 | 1 | 2 |
| Open Label-Patients From Double-Blind | Investigator's judgement | 0 | 0 | 0 | 1 | 0 |
| Open Label-Patients From Double-Blind | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 |
| Open Label-Patients From Double-Blind | PH requiring lung transplant | 0 | 0 | 0 | 0 | 1 |
| Open Label-Patients From Double-Blind | Termination of the study by the sponsor | 0 | 0 | 0 | 1 | 0 |
| Open Label-Patients From Double-Blind | Withdrawal by Subject | 0 | 0 | 0 | 3 | 3 |
Baseline characteristics
| Characteristic | DB Iloprost 6×/Day | DB Iloprost 4×/Day | DB Placebo 6×/Day | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 10 Participants | 5 Participants | 18 Participants |
| Age, Categorical Between 18 and 65 years | 23 Participants | 17 Participants | 9 Participants | 49 Participants |
| Age, Continuous | 51.9 years STANDARD_DEVIATION 11.95 | 56.6 years STANDARD_DEVIATION 16.27 | 56.9 years STANDARD_DEVIATION 11.9 | 54.8 years STANDARD_DEVIATION 13.85 |
| Region of Enrollment Austria | 1 Participants | 2 Participants | 0 Participants | 3 Participants |
| Region of Enrollment Germany | 7 Participants | 6 Participants | 3 Participants | 16 Participants |
| Region of Enrollment Italy | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Spain | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Region of Enrollment United Kingdom | 4 Participants | 2 Participants | 1 Participants | 7 Participants |
| Region of Enrollment United States | 14 Participants | 15 Participants | 9 Participants | 38 Participants |
| Sex: Female, Male Female | 20 Participants | 19 Participants | 13 Participants | 52 Participants |
| Sex: Female, Male Male | 6 Participants | 8 Participants | 1 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 24 / 26 | 22 / 27 | 14 / 14 | 23 / 26 | 30 / 32 |
| serious Total, serious adverse events | 3 / 26 | 5 / 27 | 3 / 14 | 4 / 26 | 13 / 32 |
Outcome results
Primary
Absolute Change From Baseline to Week 16 in 6-Minute Walk Distance (6MWD) During the Double-blind Treatment Period
The 6MWD test is a non-encouraged test, performed in a 30-meter long flat corridor, where the patient is instructed to walk as far as possible, back and forth around two cones during 6 minutes. They can slow down, rest, or stop if needed. This test is used to assess exercise capacity. The test was performed about 30 minutes after study drug administration. Any increase in the walk distance was considered improvement from baseline.
Time frame: Day 1 and Week 16
Population: Only Participants in the double-blind treatment period were included if they received at least one dose of study drug and had at least one post-baseline efficacy measure at Week 16. Due to early study termination (about 30% of the enrollment goal) the study was severely under-powered and no accurate statistical analyses could be performed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DB Iloprost 6×/Day | Absolute Change From Baseline to Week 16 in 6-Minute Walk Distance (6MWD) During the Double-blind Treatment Period | 10.1 Meters | Standard Deviation 62.15 |
| DB Iloprost 4×/Day | Absolute Change From Baseline to Week 16 in 6-Minute Walk Distance (6MWD) During the Double-blind Treatment Period | 29.6 Meters | Standard Deviation 55.17 |
| DB Placebo 6×/Day | Absolute Change From Baseline to Week 16 in 6-Minute Walk Distance (6MWD) During the Double-blind Treatment Period | -22.0 Meters | Standard Deviation 124.7 |
Secondary
Number of Subjects With WHO Functional Class (WHO FC) Improvement at Week 16
This test is used to assess disease severity. Four fucntional classes (FC) are defined from FC I (no limitation of physical activity) to FC IV (inability to carry out any physical activity without symptoms). Improvement is considered when a participant changes from a higher class to a lower class.
Time frame: Day 1 and Week 16
Population: Only Participants in the double-blind treatment period were included if they received at least one dose of study drug and had at least one post-baseline efficacy measure at Week 16. Due to early study termination (about 30% of the enrollment goal) the study was severely under-powered and no accurate statistical analyses could be performed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| DB Iloprost 6×/Day | Number of Subjects With WHO Functional Class (WHO FC) Improvement at Week 16 | 4 Participants |
| DB Iloprost 4×/Day | Number of Subjects With WHO Functional Class (WHO FC) Improvement at Week 16 | 6 Participants |
| DB Placebo 6×/Day | Number of Subjects With WHO Functional Class (WHO FC) Improvement at Week 16 | 0 Participants |
Secondary
Time to Clinical Worsening
Clinical worsening is defined as one of the following: death due to worsening PAH, receipt of lung or heart-lung transplantation, or atrial septostomy, hospitalization for worsening PAH, any early discontinuation from study during the blinded or open-label phase due to worsening PAH, initiation of additional PAH-specific treatment. Due to insufficient data, time could not be assessed accurately and only number of patients with clinical worsening could be reported.
Time frame: Week 16 and Week 48
Population: Only participants who received at least one dose of study drug and with available data at Week 16 (for the double-blind period) and at Week 48 (for the open-label period) were included in the analysis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| DB Iloprost 6×/Day | Time to Clinical Worsening | 0 Participants |
| DB Iloprost 4×/Day | Time to Clinical Worsening | 1 Participants |
| DB Placebo 6×/Day | Time to Clinical Worsening | 1 Participants |
| OL Iloprost 6x/Day | Time to Clinical Worsening | 2 Participants |
| OL Iloprost 4x/Day | Time to Clinical Worsening | 3 Participants |
Other Pre-specified
Number of Participants With Any Adverse Events
This is the overall number of participants in each group who reported at least one adverse event (i.e., any untoward medical occurrence or unfavorable and unintended sign whether or not considered related to the study drug) with an onset from the first administration of study drug up to the last study visit.
Time frame: From Day 1 to Week 16 and Week 48
Population: Safety population: All randomiized subjects who received at least one dose of the study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| DB Iloprost 6×/Day | Number of Participants With Any Adverse Events | 24 Participants |
| DB Iloprost 4×/Day | Number of Participants With Any Adverse Events | 22 Participants |
| DB Placebo 6×/Day | Number of Participants With Any Adverse Events | 14 Participants |
| OL Iloprost 6x/Day | Number of Participants With Any Adverse Events | 23 Participants |
| OL Iloprost 4x/Day | Number of Participants With Any Adverse Events | 30 Participants |
Post Hoc
Number of Participants With Change From Baseline to Week 16 in 6-Minute Walk Test (MWT) During the Double-blind Period
The number of participants in the double-blind treatment period who showed improvement or worsening in the 6-MWT - from baseline distance between 100-450 meters - was assessed for each treatment group. The 6-minute walks were measured in meters. Any increase in walk distance at Week 16 was considered improvement from baseline, any decrease was considered as deterioration from baseline.
Time frame: Week 16
Population: Only Participants in the double-blind treatment period were included if they received at least one dose of study drug and had a post-baseline efficacy measure at Week 16.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| DB Iloprost 6×/Day | Number of Participants With Change From Baseline to Week 16 in 6-Minute Walk Test (MWT) During the Double-blind Period | No change | 1 Participants |
| DB Iloprost 6×/Day | Number of Participants With Change From Baseline to Week 16 in 6-Minute Walk Test (MWT) During the Double-blind Period | 6-MWT deterioration | 12 Participants |
| DB Iloprost 6×/Day | Number of Participants With Change From Baseline to Week 16 in 6-Minute Walk Test (MWT) During the Double-blind Period | 6-MWT improvement | 13 Participants |
| DB Iloprost 4×/Day | Number of Participants With Change From Baseline to Week 16 in 6-Minute Walk Test (MWT) During the Double-blind Period | 6-MWT deterioration | 8 Participants |
| DB Iloprost 4×/Day | Number of Participants With Change From Baseline to Week 16 in 6-Minute Walk Test (MWT) During the Double-blind Period | 6-MWT improvement | 18 Participants |
| DB Iloprost 4×/Day | Number of Participants With Change From Baseline to Week 16 in 6-Minute Walk Test (MWT) During the Double-blind Period | No change | 1 Participants |
| DB Placebo 6×/Day | Number of Participants With Change From Baseline to Week 16 in 6-Minute Walk Test (MWT) During the Double-blind Period | 6-MWT improvement | 9 Participants |
| DB Placebo 6×/Day | Number of Participants With Change From Baseline to Week 16 in 6-Minute Walk Test (MWT) During the Double-blind Period | No change | 0 Participants |
| DB Placebo 6×/Day | Number of Participants With Change From Baseline to Week 16 in 6-Minute Walk Test (MWT) During the Double-blind Period | 6-MWT deterioration | 4 Participants |