Study of ACT-293987 (NS-304) in Pulmonary Arterial Hypertension (PAH)
Study of ACT-293987 (NS-304) in Pulmonary Arterial Hypertension (PAH)
This is a multi-centre, multinational, open-label, single-dose acute hemodynamic study
 followed by randomized, double-blind, parallel-group, placebo controlled study. Eligible
 subjects will undergo an open-label, single-dose acute hemodynamic study with
 ACT-293987(NS-304) and 21 weeks of double-blind treatment during which subjects will receive
 either ACT-293987 (NS-304) or placebo b.i.d. Subjects who have completed the double-blind
 study can enter the open extension study (separate protocol) and receive administration of
 ACT-293987 (NS-304) if the subject wishes and the Investigator considers it appropriate.
This is a multi-centre, multinational, open-label, single-dose acute hemodynamic study
 followed by a randomized, double-blind, parallel-group, placebo controlled study. Eligible
 subjects will undergo screening followed by randomized allocation to treatment group for the
 double-blind study, followed in turn by immediate enrollment in an open-label, single-dose
 acute hemodynamic study with ACT-293987 (NS-304) and 21 weeks of double-blind treatment
 during which subjects will receive either ACT-293987 (NS-304)or placebo twice daily (b.i.d.).
 Subjects who have completed the double-blind study can enter the open extension study and
 receive administration of ACT-293987 (NS-304) (separate protocol)if the subject wishes and
 the investigator considers it appropriate.

 Unblinding will occur on a subject-by-subject basis when the Week 17 data for the subject
 have been fixed.

 Approximately 44 subjects are to be randomized in a ratio of 3:1 to the two treatment groups,
 ACT-293987 (NS-304) and placebo (33 subjects to ACT-293987 (NS-304) and 11 subjects to
 placebo).

 Subjects will be randomized to the study following screening.
Inclusion Criteria:

 1. Male and female subjects 18 years of age or older with symptomatic PAH despite
 treatment with anticoagulants, calcium channel blockers, diuretics, cardiac
 glycosides, supplemental oxygen, endothelin-receptor antagonists and/or
 phosphodiesterase inhibitors. Endothelin receptor antagonists and phosphodiesterase
 inhibitors must have been used at a stable dose for more than 12 weeks before
 screening.

 2. Subjects with idiopathic PAH, familial pulmonary arterial hypertension and PAH
 associated with collagen vascular disease, corrected congenital vitium (congenital
 systemic to pulmonary shunts surgically repaired at least five years before) or
 anorexigen use.

 3. Diagnosis of PAH established according to the standard criteria:

 1. Resting mean pulmonary arterial pressure > 25 mmHg.

 2. PVR > 240 dynes s/cm5.

 3. Pulmonary capillary wedge pressure or left ventricular end diastolic pressure <
 15 mmHg.

 4. PVR > 400 dynes s/cm5.

 5. Two 6MWTs between 150 and 500 m (inclusive) with the variation in 6MWT within ± 15%
 between the two tests despite other treatments for PAH.

 - Two 6MWT values are needed. Only one 6MWT should be performed at screening for
 confirmation of eligibility if 6MWT has been previously conducted within six weeks of
 the screening visit unless the subject was taking another investigational drug or
 participating in a specific training and exercise programme at the time of the
 previous test.

 6. Subjects who are able and willing to refrain from sunbathing, prolonged sun exposure,
 and solarium use, and to limit skin and eye exposure to sunlight using appropriate
 precautions (protective clothing, sunscreen and sunglasses) from the first dose until
 14 days after study drug discontinuation.

 Exclusion Criteria:

 Subjects will not be entered in the study for any of the following reasons:

 1. Subjects with clinically unstable right heart failure within the last three months
 (NYHA Class IV).

 2. Subjects who have received or have been scheduled to receive long-term treatment with
 epoprostenol within three months before screening.

 3. Hypotensive subjects (systemic systolic blood pressure < 85 mmHg).

 4. Subjects with PAH associated with portal hypertension, Human Immunodeficiency Virus
 infection or unrepaired congenital systemic to pulmonary shunts.

 5. Subjects with ventilation-perfusion lung scan or pulmonary angiography indicative of
 thromboembolic disease.

 6. Subjects with significant obstructive (forced expiratory volume in one second
 [FEV1]/forced vital capacity [FVC] < 70% predicted) or restrictive (total lung
 capacity < 70% predicted) lung disease.

 7. In collagen vascular diseases, subjects with significant interstitial disease (FVC <
 70% predicted).

 8. Subjects with evidence of left sided heart disease.

 9. Subjects with moderate or severe hepatic impairment (Child-Pugh B and C).

 10. Subjects with clinically significant chronic renal insufficiency (estimated creatinine
 clearance < 30 mL/minute, or serum creatinine > 2.5 mg/dL).

 11. Subjects who are receiving or have been receiving any investigational drugs within 30
 days before screening.

 12. Subjects with musculoskeletal disorder limiting ambulation.

 13. Females who are breast-feeding, pregnant or plan to become pregnant during the study
 and females who are not using a highly effective method of birth control (failure rate
 less than 1% per year) such as implants, injectables, combined oral contraceptives,
 some intrauterine devices, sexual abstinence or vasectomised partner.