Efficacy Study of Ambrisentan in Chinese Patients With Pulmonary Arterial Hypertension (PAH)

Inclusion Criteria

• Signed written informed consent prior to beginning study-related procedures.
• Subject must be between 18-75 years of age, inclusive, at the Screening Visit.
• Subjects must weight ≥40 kg at the Screening Visit.
• Subjects must have symptomatic or severe PAH (WHO functional class II or III) and be categorised as class 1 PAH (defined by the Updated Clinical Classification of Pulmonary Hypertension 2009), due to iPAH, congenital heart disease-congenital heart defects repaired greater than 1 year prior to screening (i.e., atrial septal defects, ventricular septal defects or patent ductus arteriosus) or CTD-related PAH (e.g., limited scleroderma, diffuse scleroderma, mixed CTD, systemic lupus erythematosus or overlap syndrome).

NOTE: subjects with portopulmonary hypertension and pulmonary venoocclusive disease are NOT eligible for the study.

• Subjects must have had a right heart catheterisation within 6 months prior to screening and meet all of the following haemodynamic criteria:
• Mean PAP ≥ 25 mmHg.
• A PVR ≥ 240 dyn/sec/cm5.
• A PCWP or left ventricular (LV) end-diastolic pressure of ≤ 15 mmHg.
• Subjects must be able to walk a distance of at least 150 m but no more than 450 m. In addition, the screening and baseline 6MWT test values must not vary by greater than 10% (calculated using (baseline - screening)/screening with the result to be between -0.1 and 0.1).
• Subjects must meet both of the following pulmonary function criteria. The tests should have been completed no more than 24 weeks prior to the Screening Visit, if not performed within the previous 24 weeks, the test must be completed at Day 0:
• Total lung capacity (TLC) ≥ 60% of predicted normal.
• Forced expiratory volume in one second (FEV1) ≥ 55% of predicted normal.
• Subjects receiving CCBs must be on stable therapy (i.e., the dose level does not need to change to maintain disease control) for at least 1 month prior to the Screening Visit.
• Subjects receiving 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (i.e., statins) must be on stable therapy (i.e., the dose level does not need to change to maintain disease control) for at least 12 weeks prior to the Screening Visit.
• Female subjects of childbearing potential must have a negative pregnancy test at the Screening Visit and Day 0.
• Female subjects of childbearing potential who are sexually active must agree to use two reliable methods of contraception (as described in Appendix 3 ) from the Screening Visit until study completion and for at least 30 days following the last dose of IP. Subjects who have had a Copper T 380A intrauterine device (IUD) or LNg 20 IUD inserted are not required to use an additional method of contraception.
• Subject must agree not to participate in a clinical study involving another IP or device throughout this study.

Exclusion Criteria

• The subject has received PAH therapy (PDE-5 inhibitors, ERA, chronic prostanoid*) within 4 weeks prior to the Screening Visit.

*Prostanoid use is classed as chronic when treatment continues for more than 7 days.

• The subject has received intravenous inotropes (e.g., dopamine, dobutamine) within 2 weeks prior to the Screening Visit.
• The subject has previously been discontinued from ERA treatment (e.g., bosentan) due to safety or tolerance issues other than those associated with liver function abnormalities.
• The subject has a serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value that is >2 x the upper limit of normal (ULN) at the Screening Visit.
• The subject has serum bilirubin value that is >1.5 x ULN at the Screening Visit.
• The subject has severe hepatic impairment (Child-Pugh class C with or without cirrhosis) at the Screening Visit.
• The subject has severe renal impairment (creatinine clearance <30 mL/min) at the Screening Visit.
• The subject has clinically significant anaemia, defined as haemoglobin concentration <10 g/dL or haematocrit <30% at the Screen