IV Epoprostenol in Pulmonary Arterial Hypertension
IV Epoprostenol in Pulmonary Arterial Hypertension
This prospective, multicenter, single-arm, open-label, phase IIIb study was conducted at 8 centers in 6 countries (Belgium, Canada, France, Italy, the Netherlands, and Spain) to assess the effects of transitioning patients on stable epoprostenol GM therapy to epoprostenol AS on: dose adjustment, efficacy, safety and tolerability, and quality of life, for 3 months after the transition. The study was conducted in accordance with the Declaration of Helsinki and its amendments and the laws and regulations of the countries conducting the study, as well as following the International Conference on Harmonization Good Clinical Practice guidelines. The protocol received approval from the ethics committees at each institution, and each patient provided signed informed consent before study entry. The trial was registered at http://www.clinicaltrials.gov (EPITOME-2 registration number: NCT01431716) and was sponsored by Actelion Pharmaceuticals Ltd, which was responsible for designing the protocol and data collection under the leadership of the independent study investigators. Medical writing assistance was provided by a professional medical writer paid by the sponsor. All authors received the original study data, reviewed and interpreted the data, agreed on manuscript content, and reviewed and revised all drafts. All authors approved the final version and agreed to submission.
Patients 18 years or older with idiopathic or heritable PAH, or PAH associated with connective tissue disease or induced by drugs and toxins, were enrolled. Eligibility criteria were defined to enroll stable patients whose disease was reasonably well controlled. All patients must have been receiving epoprostenol GM treatment for at least 12 months before study entry and have been on a stable dose for at least the past 3 months. Concomitant PAH-specific therapies including bosentan, ambrisentan, sitaxentan, sildenafil, and tadalafil were permitted if patients were already receiving these therapies for 90 days and on a stable dose for 30 days before enrollment. Calcium-channel blockers, diuretics, oxygen (if on a stable dose 30 days before enrollment), and oral anticoagulants were permitted. Women of childbearing potential were included if they were using a reliable method of contraception. Exclusion criteria included the following: need for emergency care, known or suspected pulmonary veno-occlusive disease, use of IV inotropic agents, prostacyclin treatment other than epoprostenol GM, tachycardia with a heart rate >120 beats/min at rest, a history of myocardial infarction, left-sided heart disease or a chronic bleeding disorder, a central venous line infection within 90 days of screening and/or a history of recurring line infections, any factor that might interfere with treatment compliance, or any known concomitant life-threatening disease with a life expectancy of <12 months. Patients were screened for eligibility up to 14 days before study entry.
Reconstituted solutions of epoprostenol AS were immediately diluted and administered within 24 hours.
Patients were hospitalized for the transition, which was done by directly replacing the medication cassette containing epoprostenol GM with a cassette containing epoprostenol AS at the infusion pump. The dose of epoprostenol AS at the time of transition was requested to be similar (±10%) to the last dose of epoprostenol GM. The concentration of epoprostenol AS in the IV solution and the infusion rate were eventually adjusted to allow for administration from one cassette over a period of 24 hours (without cooling). Cassette volumes were either 50 or 100 mL. Patients were monitored in the hospital for any changes to vital signs and symptoms of PAH, before and after transition. They were discharged when their treating physician determined them to be clinically stable and trained on epoprostenol AS preparation and administration. Length of hospital stay was determined by the investigator but was expected to be between 1 and 3 days. Dose adjustments were permitted throughout the study, as per the investigator's judgment, to balance maximum tolerability and clinical benefit. Treatment could be temporarily or permanently discontinued if assessed necessary by the investigator.
Efficacy assessments were conducted at baseline and month 3 and included 6-minute walk distance (6MWD), Borg dyspnea score, NYHA FC, and N-terminal pro–brain natriuretic peptide (NT-proBNP) levels, and hemodynamics. The hemodynamic parameters of right atrial pressure, cardiac output, mean pulmonary artery pressure, and mean pulmonary capillary wedge pressure were measured by right heart catheterization. Epoprostenol AS safety and tolerability were assessed by recording adverse events (AEs) throughout the study and at 24 hours (all AEs) and 30 days (serious AEs only) after study end and vital signs (heart rate, blood pressure, body weight). Epoprostenol AS dose adjustments were allowed throughout treatment. Patients' quality of life was evaluated using the abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9) at baseline and month 3, to obtain the patients' perception of treatment effectiveness, treatment convenience, and global satisfaction. The TSQM-9 scores range from 0 to 100, where higher scores reflect improved perception of these parameters. At the end of the 3-month study, patients had the opportunity to continue treatment with epoprostenol AS as part of an open-label extension.
A small sample size was anticipated, and so no formal statistical hypothesis was set for this exploratory study. The all-treated set, which included all enrolled patients who received the study drug, was used for all analyses. Patient demographics and clinical characteristics, dosing, efficacy, and treatment satisfaction end point assessments were summarized descriptively by arithmetic means with SDs and medians with ranges for continuous variables. Categorical variables were described using proportions. The geometric mean of the percentage ratio (month 3/baseline) and its 95% confidence limits (CLs) were used to estimate the level of change from baseline to month 3 for efficacy end points and vital signs. The mean of the difference (month 3 minus baseline) and its 95% CL were used to estimate the level of change from baseline to month 3 for the treatment satisfaction end points.
Methods
Trial Design
This prospective, multicenter, single-arm, open-label, phase IIIb study was conducted at 8 centers in 6 countries (Belgium, Canada, France, Italy, the Netherlands, and Spain) to assess the effects of transitioning patients on stable epoprostenol GM therapy to epoprostenol AS on: dose adjustment, efficacy, safety and tolerability, and quality of life, for 3 months after the transition. The study was conducted in accordance with the Declaration of Helsinki and its amendments and the laws and regulations of the countries conducting the study, as well as following the International Conference on Harmonization Good Clinical Practice guidelines. The protocol received approval from the ethics committees at each institution, and each patient provided signed informed consent before study entry. The trial was registered at http://www.clinicaltrials.gov (EPITOME-2 registration number: NCT01431716) and was sponsored by Actelion Pharmaceuticals Ltd, which was responsible for designing the protocol and data collection under the leadership of the independent study investigators. Medical writing assistance was provided by a professional medical writer paid by the sponsor. All authors received the original study data, reviewed and interpreted the data, agreed on manuscript content, and reviewed and revised all drafts. All authors approved the final version and agreed to submission.
Participants
Patients 18 years or older with idiopathic or heritable PAH, or PAH associated with connective tissue disease or induced by drugs and toxins, were enrolled. Eligibility criteria were defined to enroll stable patients whose disease was reasonably well controlled. All patients must have been receiving epoprostenol GM treatment for at least 12 months before study entry and have been on a stable dose for at least the past 3 months. Concomitant PAH-specific therapies including bosentan, ambrisentan, sitaxentan, sildenafil, and tadalafil were permitted if patients were already receiving these therapies for 90 days and on a stable dose for 30 days before enrollment. Calcium-channel blockers, diuretics, oxygen (if on a stable dose 30 days before enrollment), and oral anticoagulants were permitted. Women of childbearing potential were included if they were using a reliable method of contraception. Exclusion criteria included the following: need for emergency care, known or suspected pulmonary veno-occlusive disease, use of IV inotropic agents, prostacyclin treatment other than epoprostenol GM, tachycardia with a heart rate >120 beats/min at rest, a history of myocardial infarction, left-sided heart disease or a chronic bleeding disorder, a central venous line infection within 90 days of screening and/or a history of recurring line infections, any factor that might interfere with treatment compliance, or any known concomitant life-threatening disease with a life expectancy of <12 months. Patients were screened for eligibility up to 14 days before study entry.
Intervention, Transition, and Dosing Procedure
Reconstituted solutions of epoprostenol AS were immediately diluted and administered within 24 hours.
Patients were hospitalized for the transition, which was done by directly replacing the medication cassette containing epoprostenol GM with a cassette containing epoprostenol AS at the infusion pump. The dose of epoprostenol AS at the time of transition was requested to be similar (±10%) to the last dose of epoprostenol GM. The concentration of epoprostenol AS in the IV solution and the infusion rate were eventually adjusted to allow for administration from one cassette over a period of 24 hours (without cooling). Cassette volumes were either 50 or 100 mL. Patients were monitored in the hospital for any changes to vital signs and symptoms of PAH, before and after transition. They were discharged when their treating physician determined them to be clinically stable and trained on epoprostenol AS preparation and administration. Length of hospital stay was determined by the investigator but was expected to be between 1 and 3 days. Dose adjustments were permitted throughout the study, as per the investigator's judgment, to balance maximum tolerability and clinical benefit. Treatment could be temporarily or permanently discontinued if assessed necessary by the investigator.
Outcomes
Efficacy assessments were conducted at baseline and month 3 and included 6-minute walk distance (6MWD), Borg dyspnea score, NYHA FC, and N-terminal pro–brain natriuretic peptide (NT-proBNP) levels, and hemodynamics. The hemodynamic parameters of right atrial pressure, cardiac output, mean pulmonary artery pressure, and mean pulmonary capillary wedge pressure were measured by right heart catheterization. Epoprostenol AS safety and tolerability were assessed by recording adverse events (AEs) throughout the study and at 24 hours (all AEs) and 30 days (serious AEs only) after study end and vital signs (heart rate, blood pressure, body weight). Epoprostenol AS dose adjustments were allowed throughout treatment. Patients' quality of life was evaluated using the abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9) at baseline and month 3, to obtain the patients' perception of treatment effectiveness, treatment convenience, and global satisfaction. The TSQM-9 scores range from 0 to 100, where higher scores reflect improved perception of these parameters. At the end of the 3-month study, patients had the opportunity to continue treatment with epoprostenol AS as part of an open-label extension.
Statistical Methods
A small sample size was anticipated, and so no formal statistical hypothesis was set for this exploratory study. The all-treated set, which included all enrolled patients who received the study drug, was used for all analyses. Patient demographics and clinical characteristics, dosing, efficacy, and treatment satisfaction end point assessments were summarized descriptively by arithmetic means with SDs and medians with ranges for continuous variables. Categorical variables were described using proportions. The geometric mean of the percentage ratio (month 3/baseline) and its 95% confidence limits (CLs) were used to estimate the level of change from baseline to month 3 for efficacy end points and vital signs. The mean of the difference (month 3 minus baseline) and its 95% CL were used to estimate the level of change from baseline to month 3 for the treatment satisfaction end points.
Source...