Pulmonary Arterial Hypertension
Conditions
Keywords
Ventavis, iloprost, inhaled treatment, pulmonary arterial hypertension
Brief summary
Patients with symptomatic idiopathic pulmonary arterial hypertension (IPAH), or familial pulmonary arterial hypertension (FPAH) or pulmonary hypertension associated with Human immunodeficiency virus (HIV) or drugs/toxins in New York Heart Association (NYHA) functional class II to IV at baseline, naive to PAH treatment or currently being treated with a stable dose of either bosentan, ambrisentan or sildenafil will be enrolled in the PROWESS 15 study. This randomized, double blind, placebo-controlled, crossover, and single-dose study will determine whether a single inhaled dose of iloprost using the power 15 disc improves exercise capacity compared to placebo in patients with pulmonary arterial hypertension (PAH).
Interventions
DRUGiloprost (5 µg)
Single dose of iloprost 5 µg using I-neb(R) Adaptive Aerosol Delivery (AAD(R)) System power setting 15 disc
DRUGplacebo
Single dose of matching placebo using I-neb(R) Adaptive Aerosol Delivery (AAD(R)) System power setting 15 disc
Sponsors
Actelion
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
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
* Signed informed consent prior to initiation of any study mandated procedure, * Patients with symptomatic idiopathic, or familial pulmonary arterial hypertension or pulmonary hypertension associated with human immunodeficiency virus (HIV) or drugs/toxins in NYHA functional class II to IV. * 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
* Pulmonary arterial hypertension related to any condition other than those specified in the inclusion criteria, * 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, * 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, * Moderate to severe restrictive lung disease: total lung capacity (TLC) \< 60% of predicted value, * Pregnant or breast-feeding women, * Systemic hypertension (systolic blood pressure \> 160 mmHg or diastolic blood pressure \> 100 mmHg on repeated measurement), * Systolic blood pressure \< 95 mmHg, * Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C, * Chronic renal insufficiency defined by serum creatinine \> 2.5 mg/dL (221 μmol/L) or ongoing dialysis, * Clinically relevant bleeding disorder or active bleeding, * For those patients on monotherapy, any contraindication to bosentan, ambrisentan, or sildenafil, according to product label, * Known hypersensitivity to iloprost or any of its excipients.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 6-minute-walk Distance (6MWD) | Study day 2 or study day 3 | The 6-minute walk test was performed 20-40 minutes after treatment. This was a non-encouraged test (the person conducting the test did not encourage the patient to walk farther or faster) that measured the distance covered over a 6-minute walk. It was conducted by a trained member of the site staff who was listed on the site's delegation of authority sheet. For patients who had never performed a 6-minute walk test previously, a training test was requested before the qualifying tests for randomization. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Borg Dyspnea Score | Study day 2 or study day 3 | The Borg scale is a category-ratio scale, commonly used to evaluate the effects of exercise on dyspnea. The original and modified scales have ratio properties ranging from 0 = nothing at all to 10 = very, very severe, with descriptors from 0 to 10. Descriptors have been modified by others so that 10 has been labeled extremely severe, or the worst possible dyspnea imaginable. Reliability and validity have been reported in a general population and in patients with PAH as well as other respiratory conditions. |
Participant flow
Recruitment details
On Day 1 all patients received a single inhalation dose of placebo. Patients who satisfied the selection criteria in the single-blind period of the study were entered into the double-blind period to receive iloprost 5 μg and matching placebo (Days 2 and 3) in a single dose, two-period crossover design.
Pre-assignment details
Of the 70 randomized patients, 64 patients entered the double-blind period, (placebo/iloprost P15, 33 patients and iloprost P15/placebo, 31 patients). 1 patient in the iloprost P15/placebo treatment sequence was excluded from the per-protocol analysis which was defined as the primary analysis.
Participants by arm
| Arm | Count |
|---|---|
| Iloprost (5µg) / Placebo Single dose double-blind active iloprost (5µg) on study day 2 followed by single dose double-blind placebo on study day 3 | 31 |
| Placebo / Iloprost (5 µg) Single dose double-blind placebo on study day 2 followed by single dose double-blind active iloprost (5µg) on study day 3 | 33 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Inclusion/exclusion criteria violation | 2 | 3 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Iloprost (5µg) / Placebo | Placebo / Iloprost (5 µg) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 9 Participants | 18 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants | 24 Participants | 46 Participants |
| Age, Continuous | 55.5 years STANDARD_DEVIATION 13.57 | 55.8 years STANDARD_DEVIATION 16.4 | 55.7 years STANDARD_DEVIATION 14.98 |
| Region of Enrollment Austria | 2 participants | 2 participants | 4 participants |
| Region of Enrollment Germany | 1 participants | 1 participants | 2 participants |
| Region of Enrollment United States | 28 participants | 30 participants | 58 participants |
| Sex: Female, Male Female | 23 Participants | 28 Participants | 51 Participants |
| Sex: Female, Male Male | 8 Participants | 5 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 31 | 20 / 33 |
| serious Total, serious adverse events | 0 / 31 | 1 / 33 |
Outcome results
Primary
6-minute-walk Distance (6MWD)
The 6-minute walk test was performed 20-40 minutes after treatment. This was a non-encouraged test (the person conducting the test did not encourage the patient to walk farther or faster) that measured the distance covered over a 6-minute walk. It was conducted by a trained member of the site staff who was listed on the site's delegation of authority sheet. For patients who had never performed a 6-minute walk test previously, a training test was requested before the qualifying tests for randomization.
Time frame: Study day 2 or study day 3
Population: The analysis was per protocol, 64 patients started double blind phase of study, 63 completed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 6MWD After Placebo Treatment | 6-minute-walk Distance (6MWD) | 330.0 meters | 95% Confidence Interval 22.84 |
| 6MWD After Iloprost (5 µg) Treatment | 6-minute-walk Distance (6MWD) | 328.6 meters | 95% Confidence Interval 55.28 |
Comparison: With a sample size of at least 63 patients and based on the assumptions on the primary endpoint (normal distribution, SD of the difference of 30 m) the study was designed to detect a significant treatment effect with 90% power, assuming a difference exceeding 12.5 m between the mean values of the 6MWD following the iloprost power 15 treatment and the one following the placebo treatment.p-value: 0.788395% CI: [-12.3, 9.4]Generalized linear model
Secondary
Borg Dyspnea Score
The Borg scale is a category-ratio scale, commonly used to evaluate the effects of exercise on dyspnea. The original and modified scales have ratio properties ranging from 0 = nothing at all to 10 = very, very severe, with descriptors from 0 to 10. Descriptors have been modified by others so that 10 has been labeled extremely severe, or the worst possible dyspnea imaginable. Reliability and validity have been reported in a general population and in patients with PAH as well as other respiratory conditions.
Time frame: Study day 2 or study day 3
Population: The analysis was per protocol, 64 patients started double blind phase of study, 63 completed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 6MWD After Placebo Treatment | Borg Dyspnea Score | 3.5 scores on a scale | Standard Deviation 2.23 |
| 6MWD After Iloprost (5 µg) Treatment | Borg Dyspnea Score | 3.4 scores on a scale | Standard Deviation 2.25 |