Epoprostenol for Injection in Pulmonary Arterial Hypertension

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)

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.

Inclusion Criteria:

1. Male or female subjects aged 18-65 years

2. 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

3. Patients with PAH in modified NYHA functional class III or IV at the time of enrollment in need of injectable epoprostenol.

4. 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

5. Women of childbearing potential must use a reliable method of contraception.

Exclusion Criteria:

1. Patients with respiratory and/or cardiovascular distress in need of emergency care including i.v. epoprostenol administration or any vasopressive i.v. drugs

2. Known pulmonary veno-occlusive disease (PVOD)

3. Current use of i.v. inotropic agents

4. Tachycardia with heart rate > 120 beats/min

5. Pulmonary arterial hypertension related to any condition other than those specified in the inclusion criteria

6. Known hypersensitivity to the formulations of ACT-385781A or any of its excipients, and Flolan or any of its excipients

7. Use of inhaled iloprost or treprostinil during the week prior to screening

8. Cerebrovascular events (e.g., transient ischemic attack or stroke) within 6 months of screening

9. History of myocardial infarction

10. 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

11. Chronic bleeding disorder

12. Infection(s) within the past month that in the mind of the investigator would contraindicate the use of epoprostenol

13. Pregnancy or breast-feeding

14. Participation in another clinical trial, except observational (noninterventional), or receipt of an investigational product within 30 days prior to randomization

15. 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

16. Known concomitant life-threatening disease other than PAH with a life expectancy < 12 months