A Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects With Pulmonary Arterial Hypertension (PAH)
Condition: Hypertension, Pulmonary
MeSH terms: Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Hypertension
Intervention: ambrisentan; tadalafil
Intervention description: ambrisentan (target dose: 10mg); tadalafil (target dose: 40mg)
Intervention MeSH terms: Ambrisentan; Tadalafil
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 610.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Pulmonary Arterial Hypertension; Ambrisentan; Sponsor Rest of World: GSK; Tadalafil; PAH; Sponsor US: Gilead

Summary:

      The purpose of this study is to compare the two treatment strategies; first-line combination
      therapy (ambrisentan and tadalafil) versus first-line monotherapy (ambrisentan or tadalafil)
      in subjects with Pulmonary Arterial Hypertension. This will be assessed by time to the first
      clinical failure event.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subjects must have a diagnosis of Pulmonary Arterial Hypertension (PAH) due to the
             following:

             a. idiopathic or heritable PAH b. PAH associated with: i. connective tissue disease
             (e.g., limited scleroderma, diffuse scleroderma, mixed connective tissue disease,
             systemic lupus erythematosus, or overlap syndrome) ii. drugs or toxins iii. Human
             Immunodeficiency Virus (HIV) infection iv. congenital heart defects repaired greater
             than 1 year prior to screening (i.e., atrial septal defects, ventricular septal
             defects, and patent ductus arteriosus) NB: subjects with portopulmonary hypertension
             and pulmonary veno-occlusive disease are NOT eligible for the study

          -  Subject must have a current diagnosis of being in World Health Organisation (WHO)
             Functional Class II or III.

          -  Subject must meet all of the following haemodynamic criteria by means of a right heart
             catheterization prior to screening:

             i. mPAP of ≥25 mmHg ii. PVR ≥ 300 dynes/sec/cm5 iii. PCWP or LVEDP of ≤12 mmHg if PVR
             ≥300 to <500 dyne/sec/cm5 , or PCWP/LVEDP ≤ 15 mmHg if PVR ≥500 dynes/sec/cm5

          -  Subject must walk a distance of ≥125m and ≤500m at the screening visit

        Exclusion Criteria:

          -  Subject received previous PAH therapy (phosphodiesterase type 5 inhibitor (PDE5i),
             endothelin receptor antagonist (ERA), chronic prostanoid*) within 4 weeks prior to the
             screening visit (*Chronic prostanoid use is considered >7 days of treatment)

          -  Subject received ERA treatment (e.g., bosentan or sitaxentan) or PDE5i treatment (e.g.
             Sildenafil) at any time AND discontinued due to tolerance issues other than those
             associated with liver function abnormalities

          -  Subjects who have previously discontinued ambrisentan or tadalafil in either another
             clinical study or commercial product (Volibris/Letairis or Adcirca) for safety or
             tolerability reasons.