Epoprostenol for Injection in Pulmonary Arterial Hypertension

Study Overview
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Brief Summary
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This is a prospective, multi-center, open-label, randomized, Phase IV exploratory study comparing safety, tolerability, pharmacokinetics, and effectiveness of ACT-385781A and Flolan (epoprostenol sodium) in patients with pulmonary arterial hypertension who are naïve to injectable prostanoid treatment and in need of such treatment. Approximately 30 patients from 8 U.S. clinical sites will be randomized to receive either ACT-385781A or Flolan (2:1 respectively) for 28 days of treatment.

Official Title
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A Phase IV, Open-label, Randomized, Multicenter Study of the Safety, Tolerability,and Pharmacokinetics of ACT- 385781A Compared to Flolan® in Injectable Prostanoid Treatment-naïve Patients With Pulmonary Arterial Hypertension (PAH)

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: ACT-385781A (Actelion Epoprostenol)
* Drug: Flolan®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects aged 18-65 years Patients with the following types of pulmonary arterial hypertension (PAH) belonging to WHO Group I: Idiopathic (IPAH) Heritable (HPAH) Associated (APAH) with Connective tissue diseases Drugs and toxins Patients with PAH in modified NYHA functional class III or IV at the time of enrollment in need of injectable epoprostenol. Patients must be injectable prostanoid treatment-naïve and either newly diagnosed and not yet treated with specific PAH therapies or currently treated with existing background PAH therapy with one or more of the following medications for 90 days prior to enrollment and on a stable dose for 30 days prior to enrollment: Bosentan Ambrisentan Sildenafil Tadalafil Women of childbearing potential must use a reliable method of contraception. Exclusion Criteria: Patients with respiratory and/or cardiovascular distress in need of emergency care including i.v. epoprostenol administration or any vasopressive i.v. drugs Known pulmonary veno-occlusive disease (PVOD) Current use of i.v. inotropic agents Tachycardia with heart rate > 120 beats/min Pulmonary arterial hypertension related to any condition other than those specified in the inclusion criteria Known hypersensitivity to the formulations of ACT-385781A or any of its excipients, and Flolan or any of its excipients Use of inhaled iloprost or treprostinil during the week prior to screening Cerebrovascular events (e.g., transient ischemic attack or stroke) within 6 months of screening History of myocardial infarction History of left-sided heart disease, including any of the following: hemodynamically significant aortic or mitral valve disease restrictive or congestive cardiomyopathy left ventricular ejection fraction < 40% by multigated radionucleotide angiogram(MUGA),angiography, or echocardiography unstable angina pectoris life-threatening cardiac arrhythmias Chronic bleeding disorder Infection(s) within the past month that in the mind of the investigator would contraindicate the use of epoprostenol Pregnancy or breast-feeding Participation in another clinical trial, except observational (noninterventional), or receipt of an investigational product within 30 days prior to randomization Any known factor or disease that might interfere with treatment compliance, study conduct or interpretation of the results such as drug or alcohol dependence or psychiatric disease Known concomitant life-threatening disease other than PAH with a life expectancy < 12 months

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>ACT-385781A (Actelion Epoprostenol) | Drug: ACT-385781A (Actelion Epoprostenol)<br>* per Prescribing Information<br>|
| Active Comparator: 2<br>Flolan® | Drug: Flolan®<br>* Per Prescribing Information<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Normalized Pharmacokinetics of 6,15-diketo-13,14-dihydro-Prostacyclin F1alpha at 2 ng/kg/Min | The plasma concentration for the epoprostenol metabolite 6,15-diketo-13,14-dihydro-Prostacyclin F1alpha was measured at 2 ng/kg/min just prior to the next up-titration. Dose-normalized concentrations are used to summarize the results. | Day 1 | 
| Dose Normalized Pharmacokinetics of 6,15-diketo-13,14-dihydro-Prostacyclin F1alpha at 4 ng/kg/Min | The plasma concentration for the epoprostenol metabolite 6,15-diketo-13,14-dihydro-Prostacyclin F1alpha was measured at 4 ng/kg/min just prior to the next up-titration. Dose-normalized concentrations are used to summarize the results. | Day 1 | 
| Dose Normalized Pharmacokinetics of 6-keto-Prostacyclin F1alpha at 2 ng/kg/Min | The plasma concentration for the epoprostenol metabolite 6-keto-Prostacyclin F1alpha was measured at 2 ng/kg/min just prior to the next up-titration. Dose-normalized concentrations are used to summarize the results. | Day 1 | 
| Dose Normalized Pharmacokinetics of 6-keto-Prostacyclin F1alpha at 4 ng/kg/Min | The plasma concentration for the epoprostenol metabolite 6-keto-Prostacyclin F1alpha was measured at 4 ng/kg/min just prior to the next up-titration. Dose-normalized concentrations are used to summarize the results. | Day 1 | 
| Six-minute Walk Distance (6MWD) - Baseline and Day 28 | The 6-minute walk test (6MWT) was to be performed prior to initiating study treatment either during the screening visit or on Day 1 prior to drug initiation, and Day 28 (End of treatment (EOT)). This assessment is a non-encouraged test that measures the distance walked for a duration of 6 minutes. The 6MWD was recorded in the Case Report Form (CRF). | Baseline and 28 days (+3 days) | 
| Patients With New York Heart Association (NYHA) Functional Class Change (Improved or Worsened) From Baseline to Day 28 | Disease severity was assessed by NYHA classification of PAH criteria: Class I: no limitation of physical activity (PA). Ordinary PA: no undue dyspnea/fatigue, chest pain, near syncope. Class II: slight limitation of PA. Comfortable at rest. Ordinary PA: undue dyspnea/fatigue, chest pain, near syncope. Class III: marked limitation of PA. Comfortable at rest. Less than ordinary PA: undue dyspnea/fatigue, chest pain, near syncope. Class IV: inability to carry out PA without symptoms. Right heart failure. Dyspnea/fatigue may even have been present at rest. Discomfort increased by any PA. | From baseline to 28 days (+3 days) | 
| Percentage Central Venous Blood Oxygen Saturation (ScVO2) - Baseline and Day 28 | Central venous blood oxygen saturation assessment was performed only in specific centers. Measurements for ScVO2 were performed during the inpatient hospitalization period on Day 1 (prior to drug initiation) and on Day 28 (EOT). Samples for ScVO2 were obtained by aspirating blood from the indwelling central venous catheter. After the sample had been drawn, the catheter was primed with study drug in order to refill the lumen to avoid interruption in treatment and sudden decompensation. | Baseline and 28 days | 
| Blood Pressure - Baseline and Day 28 | Blood pressure (systolic and diastolic) were measured indirectly using an automatic oscillometric device, on the same arm for each measurement. The Blood Pressure was assessed at baseline and at Day 28 (End of Study Treatment visit). | Baseline and 28 days | 
| Heart Rate - Baseline and Day 28 | Heart rate was measured indirectly using an automatic oscillometric device, on the same arm for each measurement. The Heart Rate was assessed at Baseline and at Day 28 (End of Study Treatment visit). | Baseline and 28 days | 
| Body Weight - Baseline and Day 28 | Body weight was measured both at baseline and day 28. | Baseline and 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary Arterial Hypertension, PAH, EPITOME-1