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

An Open Label Phase IIIb Study to Evaluate Efficacy and Safety of Ambrisentan in Chinese Patients With Pulmonary Arterial Hypertension (PAH)

This open label, single-arm, non-controlled, multicentre study will determine the effect of ambrisentan on exercise capacity (6MWT) in Chinese subjects with PAH. The study consists of a screening period of 4 weeks, a 12-week primary evaluation period (PEP) and a 12-week dose-adjustment period (DAP). Ambrisentan 5 mg will be administered to eligible subjects for 12 weeks (PEP).

Pulmonary arterial hypertension (PAH) consists of a group of progressive and incurable diseases of the pulmonary vasculature. These are characterised by profound vasoconstriction and abnormal proliferation of smooth muscle cells in the walls of the pulmonary arteries, which leads to a progressive increase in pulmonary vascular resistance (PVR) and sustained elevations in pulmonary artery pressure (PAP). A variety of drug classes have been used to treat PAH but no single compound has yet been shown to be effective in treating all patients with the disease. Three widely used treatment options are calcium channel blockers (CCBs), diuretics and anticoagulants but all have varying responses.There is a lack of clinical data on ambrisentan among the Chinese population,Ambrisentan is conditionally approved for the treatment of PAH in China.A clinical trial with a minimum of 100 patients in the ambrisentan arm was requested by SFDA.Several PAH medications have been approved in China, so a placebo-controlled study is not ethically appropriate while an active control non-inferiority design is unfeasible due to sample size requirements and inconsistency in indications.

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:

  1. Mean PAP ≥ 25 mmHg.
  2. A PVR ≥ 240 dyn/sec/cm5.
  3. 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:

  1. Total lung capacity (TLC) ≥ 60% of predicted normal.
  2. 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 Screening Visit.

• The subject has a laboratory result, physical examination finding, medical history incident or other finding, which is a contraindication for treatment with an ERA. Contraindications for treatment include, but are not limited to, evidence of elevated liver functions test or previously experiencing an event that would be defined as a serious AE (SAE) in a clinical trial (see Section 6.3.3.2), which was attributed to treatment with an ERA.

• The subject has severe hypotension (either diastolic blood pressure <50 mmHg or systolic blood pressure <90 mmHg).

• The subject has, in the opinion of the Investigator, clinically significant aortic or mitral valve disease, pericardial constriction, restrictive or congestive cardiomyopathy, life-threatening cardiac arrhythmias, significant LV dysfunction (defined as LV ejection fraction <45%), LV outflow obstruction, symptomatic coronary artery disease, autonomic hypotension or fluid depletion.

• The subject has a history of malignancies within the past 5 years, with the exception of basal cell carcinoma of the skin or in situ carcinoma of the cervix.

• The subject has cardiovascular, liver, renal, haematological, gastrointestinal, immunological, endocrine, metabolic or central nervous system disease that, in the opinion of the Investigator, may adversely affect the safety of the subject and/or efficacy of the study drug or severely limit the lifespan of the subject.

• A female subject who is pregnant or breastfeeding.

• The subject has demonstrated non-compliance with previous medical regimens or is unable to comply with the procedures described in this protocol.

• The subject has a history of abusing alcohol or drugs of abuse (including amphetamines, methamphetamines, opiates, cannabinoids, cocaine, benzodiazepines or barbiturates) within 12 months prior to the Screening Visit. Use of such drugs if prescribed by a Doctor and used according to the prescription would not exclude a subject.

• The subject has participated in a clinical study involving another IP or device within 4 weeks or five half-lives of an IP, whichever is longer, before the Screening Visit.