Ethics
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study.
Subjects
Patients aged ≥20 years at the time of informed consent and who had pulmonary hypertension classified as Group 1 using the Dana Point classification [16,17] for pulmonary hypertension were eligible if they had any of the following: idiopathic pulmonary arterial hypertension (IPAH), heritable pulmonary arterial hypertension (HPAH), PAH associated with drugs and toxins, or PAH associated with connective tissue disease. Only patients who had been treated with epoprostenol GM for ≥3 months before enrollment and at a stable dose for ≥30 days before the start of study treatment were included in the study. Females of childbearing potential had to have a negative serum pregnancy test at screening. They were also required to agree to take monthly urine/serum pregnancy tests and to use reliable contraceptives to avoid pregnancy from the time of the screening visit until 30 days after the end of the study.
Eligible patients were excluded if they met any of the exclusion criteria, such as diagnosis of respiratory or cardiovascular disorder requiring immediate surgery, presence of confirmed or suspected pulmonary vein occlusion, history of myocardial infarction, and resting pulse rate of ≥120 beats/min.
Trial Drug
Epoprostenol AS (Actelion Pharmaceuticals Japan Ltd.) was provided in 10-mL glass vials containing 0.5 mg or 1.5 mg epoprostenol sodium. Epoprostenol AS was dissolved and diluted by adding isotonic sodium chloride solution. At the start of the 12-week treatment period, epoprostenol GM was switched to an equal dose of epoprostenol AS in the hospital. For home therapy, epoprostenol was administered via a central venous catheter by continuous drip infusion using a portable infusion pump.
Study Design
This was a two-site, open-label, single-arm, Phase 3b study. The study consisted of a 2-week pretreatment screening period, a 12-week open-label treatment period (visiting at baseline, week 1, 2, 4, 8, and 12), and a continuous treatment period until marketing of the study drug (visiting every 4 weeks). Pulmonary hemodynamic measurements and variables of clinical laboratory tests were collected at baseline and week 12. Medical interviews and checks for vital signs were performed at each visit. Females of childbearing potential received a pregnancy test every month.
Outcome Measures
Safety/Tolerability
The safety/tolerability endpoints were adverse events occurring during the 12-week treatment phase, together with changes from baseline to week 12 for vital signs (blood pressure and heart rate on the same arm in sitting or supine position), body weight, and abnormal changes from baseline to week 12 for clinical laboratory tests (general biochemistry tests, including thyroid function test and hematology test). Vital signs and body weight were assessed at each visit and clinical laboratory tests were performed at baseline and week 12 (only thyroid function was assessed every month). Adverse events reported during the 12-week evaluation period were coded according to system organ class and terms using the Medical Dictionary for Regulatory Activities/Japanese version. The causality of adverse events in relation to the trial drug was judged by the investigators.
Efficacy Endpoints
The efficacy endpoints were changes in pulmonary hemodynamic factors, WHO functional class, and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) concentrations from baseline (within 60 min before the first dose of epoprostenol AS) to immediately after switching (within 60 min after the first dose of epoprostenol AS) or week 12. Pulmonary hemodynamic factors included systolic pulmonary artery pressure, diastolic pulmonary artery pressure, mean pulmonary artery pressure, pulmonary capillary wedge pressure, cardiac output, mean right atrial pressure, mixed venous oxygen saturation, cardiac index, pulmonary vascular resistance, and pulmonary vascular resistance index. Pulmonary hemodynamics were measured by right heart catheterization, which was performed according to standard local procedures through the internal jugular, subclavian, or femoral vein by a balloon catheter placed into either the right or left pulmonary artery in a sterilized cardiac catheterization laboratory. Cardiac Output (CO) was measured using Fick’s method [18].
Treatment Satisfaction
The abbreviated nine-item Treatment Satisfaction Questionnaire for Medication (TSQM-9), employed for the quality of life assessment, is a validated questionnaire that permits comparisons of patients’ treatment satisfaction across medication types and patient conditions [19]. The changes from baseline to week 12 in treatment satisfaction were assessed using the TSQM-9. This questionnaire includes three items for each of three domains: effectiveness, convenience, and global satisfaction. The scores for each domain range from 0 to 100, where higher scores indicate higher satisfaction on that domain.
Statistical Analysis
This study was an exploratory study. No hypothesis was set and no power considerations were made for this study. Patients who received at least one dose of the study drug were included in the all-treated set for analyses. Patients who had assessable data at baseline and week 12 were included in the analysis of pulmonary hemodynamics. All statistical analyses were considered to be exploratory and the significance level was set at 5% (two-sided). The efficacy variables were summarized descriptively by calculating the mean, standard deviation, standard error, median, 25th and 75th percentiles, minimum and maximum. Changes from baseline were examined using the Wilcoxon signed rank sum test. All analyses were performed using SAS (Version 9.2; SAS Inc., Cary, North Carolina, USA).