Pulmonary Arterial Hypertension
Conditions
Keywords
pulmonary arterial hypertension, inhaled treatment, inhalation solution, iloprost, Ventavis
Brief summary
Patients with symptomatic idiopathic (IPAH) or familial (FPAH) pulmonary arterial hypertension in New York Heart Association (NYHA) class II to IV , naive to PAH treatment or currently being treated with a stable dose of either bosentan or sildenafil and who complete PROWESS 15 will be enrolled in the PROWESS 15 Extension study. This is a double-blind (12 week), randomized study to compare the safety and tolerability of inhaled iloprost power disc-15 and power disc-6 in patients with symptomatic pulmonary arterial hypertension (PAH). After completion of the double blind period, patients will be entered in the open label period using iloprost power disc-15.
Interventions
DRUGiloprost
Iloprost 5 mcg delivered by I-neb(R) adaptive aerosol delivery (AAD)(R) System power disc-6 administered 6 to 9 times per day for 12 weeks. If patient enters open label follow-up period, iloprost 5 mcg delivered by I-neb(R)AAD(R) System power disc-15 administered 6 to 9 times per day until the end of study.
Sponsors
Actelion
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Signed informed consent prior to initiation of any study mandated procedure, 2. Patients with symptomatic idiopathic or familial pulmonary arterial hypertension in NYHA functional class II to IV who have completed study AC-063A301, 3. Women of childbearing potential must have a negative urine pregnancy test and must use an adequate method of contraception during the study and for 28 days after discontinuation of the study drug.
Exclusion criteria
1. Pulmonary arterial hypertension related to any condition other than those specified in the inclusion criteria, 2. Pulmonary arterial hypertension associated with significant venous or capillary involvement (Pulmonary capillary wedge pressure (PCWP) \> 15 mmHg), known pulmonary veno-occlusive disease, or pulmonary capillary hemangiomatosis, 3. Moderate to severe obstructive lung disease: forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) \< 70% and FEV1 \< 65% of predicted value after bronchodilator administration, 4. Moderate to severe restrictive lung disease: total lung capacity (TLC) \< 60% of predicted value, 5. Pregnant or breast-feeding women, 6. Systemic hypertension (systolic blood pressure \> 160 mmHg or diastolic blood pressure \> 100 mmHg on repeated measurement), 7. Systolic blood pressure \< 95 mmHg, 8. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C, 9. Chronic renal insufficiency defined by serum creatinine \> 2.5 mg/dL (221 μmol/L) or ongoing dialysis, 10. Clinically relevant bleeding disorder or active bleeding, 11. Known hypersensitivity to iloprost or any of its excipients.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment-emergent Adverse Events | Double-blind period: from first inhalation of study drug to end of 12-week treatment period. Open-label period: from the start to end of open-label medication, mean duration of exposure was 284.5 days. | Number of adverse events |
| Treatment-emergent Serious Adverse Events | Double-blind period: from first inhalation of study drug to end of 12-week treatment period. Open-label period: from the start to end of open-label medication, mean duration of exposure was 284.5 days. | Number of serious adverse events |
| Adverse Events Leading to Premature Discontinuation of Study Drug | Double-blind period: from the first inhalation of study drug to discontinuation. Open-label period: from the start of open-label medication to discontinuation, mean duration of exposure was 284.5 days. | Number of adverse events leading to discontinuation of study treatment |
| Patients With Adverse Events Leading to Premature Discontinuation of Study Drug | Double-blind period: from the first inhalation of study drug to discontinuation. Open-label period: from the start of open-label medication to discontinuation, mean duration of exposure was 284.5 days. | Number of patients with adverse events leading to discontinuation of study treatment |
Other
| Measure | Time frame | Description |
|---|---|---|
| Average Inhalation Time | 12 weeks | Average inhalation time of iloprost during the double-blind period (i.e., the sum of the duration of each inhalation divided by the number of inhalations during the double-blind period) |
Countries
Austria, Germany, United States
Participant flow
Recruitment details
The double-blind period of the study was conducted at 20 centers in the US and Germany, and the following open-label period of the study was conducted at 17 centers in the US only. First patient, first visit was 4 September 2008 and the last patient, last visit was 17 June 2010.
Pre-assignment details
Out of the 63 patients who completed the core study of AC-063A301, 49 gave informed consent and enrolled into this extension study.
Participants by arm
| Arm | Count |
|---|---|
| Iloprost Power 6 (Double-blind Period) The study medication was 5 μg iloprost delivered as an aerosol using the I-neb® adaptive aerosol delivery (AAD®) System utilizing a power setting 6 disc | 25 |
| Iloprost Power 15 (Double-blind Period) The study medication was 5 μg iloprost delivered as an aerosol using the I-neb®AAD® System utilizing a power setting 15 disc | 24 |
| Iloprost Power 15 (Open-label Period) The study medication was 5 μg iloprost delivered as an aerosol using the I-neb®AAD® System utilizing a power setting 15 disc | 0 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double-blind Period | Administrative reason | 1 | 3 | 0 |
| Double-blind Period | Death | 1 | 1 | 0 |
| Double-blind Period | Lost to Follow-up | 1 | 1 | 0 |
| Double-blind Period | Withdrawal of consent | 3 | 3 | 0 |
| Open-label Period | Administrative reason | 0 | 0 | 5 |
| Open-label Period | Death | 0 | 0 | 1 |
| Open-label Period | Lost to Follow-up | 0 | 0 | 1 |
| Open-label Period | Withdrawal of consent | 0 | 0 | 7 |
Baseline characteristics
| Characteristic | Iloprost Power 15 (Double-blind Period) | Iloprost Power 6 (Double-blind Period) | Total |
|---|---|---|---|
| Age, Continuous | 55.4 years FULL_RANGE 13.96 | 58.3 years FULL_RANGE 16.49 | 56.9 years FULL_RANGE 15.21 |
| Gender Female | 19 participants | 19 participants | 38 participants |
| Gender Male | 5 participants | 6 participants | 11 participants |
| Region of Enrollment Germany | 2 participants | 2 participants | 4 participants |
| Region of Enrollment United States | 22 participants | 23 participants | 45 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 23 / 25 | 23 / 24 | 25 / 32 |
| serious Total, serious adverse events | 6 / 25 | 5 / 24 | 8 / 32 |
Outcome results
Primary
Adverse Events Leading to Premature Discontinuation of Study Drug
Number of adverse events leading to discontinuation of study treatment
Time frame: Double-blind period: from the first inhalation of study drug to discontinuation. Open-label period: from the start of open-label medication to discontinuation, mean duration of exposure was 284.5 days.
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Iloprost Power 6 (Double-blind Period) | Adverse Events Leading to Premature Discontinuation of Study Drug | 3 adverse events |
| Iloprost Power 15 (Double-blind Period) | Adverse Events Leading to Premature Discontinuation of Study Drug | 10 adverse events |
| Iloprost Power 15 (Open-label Period) | Adverse Events Leading to Premature Discontinuation of Study Drug | 7 adverse events |
Primary
Patients With Adverse Events Leading to Premature Discontinuation of Study Drug
Number of patients with adverse events leading to discontinuation of study treatment
Time frame: Double-blind period: from the first inhalation of study drug to discontinuation. Open-label period: from the start of open-label medication to discontinuation, mean duration of exposure was 284.5 days.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Iloprost Power 6 (Double-blind Period) | Patients With Adverse Events Leading to Premature Discontinuation of Study Drug | 2 participants |
| Iloprost Power 15 (Double-blind Period) | Patients With Adverse Events Leading to Premature Discontinuation of Study Drug | 6 participants |
| Iloprost Power 15 (Open-label Period) | Patients With Adverse Events Leading to Premature Discontinuation of Study Drug | 7 participants |
Primary
Treatment-emergent Adverse Events
Number of adverse events
Time frame: Double-blind period: from first inhalation of study drug to end of 12-week treatment period. Open-label period: from the start to end of open-label medication, mean duration of exposure was 284.5 days.
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Iloprost Power 6 (Double-blind Period) | Treatment-emergent Adverse Events | 148 adverse events |
| Iloprost Power 15 (Double-blind Period) | Treatment-emergent Adverse Events | 139 adverse events |
| Iloprost Power 15 (Open-label Period) | Treatment-emergent Adverse Events | 126 adverse events |
Primary
Treatment-emergent Serious Adverse Events
Number of serious adverse events
Time frame: Double-blind period: from first inhalation of study drug to end of 12-week treatment period. Open-label period: from the start to end of open-label medication, mean duration of exposure was 284.5 days.
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Iloprost Power 6 (Double-blind Period) | Treatment-emergent Serious Adverse Events | 11 serious adverse events |
| Iloprost Power 15 (Double-blind Period) | Treatment-emergent Serious Adverse Events | 11 serious adverse events |
| Iloprost Power 15 (Open-label Period) | Treatment-emergent Serious Adverse Events | 10 serious adverse events |
Other Pre-specified
Average Inhalation Time
Average inhalation time of iloprost during the double-blind period (i.e., the sum of the duration of each inhalation divided by the number of inhalations during the double-blind period)
Time frame: 12 weeks
Population: All treated population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Iloprost Power 6 (Double-blind Period) | Average Inhalation Time | 10.9 minutes | Standard Deviation 4.5 |
| Iloprost Power 15 (Double-blind Period) | Average Inhalation Time | 5.8 minutes | Standard Deviation 1.14 |
p-value: <0.000195% CI: [-7, -3.1]t-test, 2 sided