Efficacy Study of Ambrisentan in Chinese Patients With Pulmonary Arterial Hypertension (PAH)
Condition: Vascular Disease
MeSH terms: Pulmonary Arterial Hypertension; Hypertension; Vascular Diseases
Intervention: ambrisentan
Intervention description: Ambrisentan 5 mg will be administered to eligible subjects for 12 weeks
Intervention MeSH terms: Ambrisentan
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 134.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No

Summary:

      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).
    

Eligibility criteria:

        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.