Study of Add-on Ambrisentan Therapy to Background Phosphodiesterase Type-5 Inhibitor (PDE5i) Therapy in Pulmonary Arterial Hypertension (ATHENA-1)
Condition: Pulmonary Arterial Hypertension
MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension
Intervention: Ambrisentan; Placebo; Sildenafil; Tadalafil
Intervention description: Ambrisentan was administered orally once daily; dose level was 5 mg for the first 4 weeks, followed by 10 mg for the remainder of the study; ambrisentan was supplied as 5-mg and 10-mg tablets.; Placebo to match ambrisentan was administered orally once daily.; Sildenafil was administered at the dose previously established for each subject (20-100 mg) orally three times daily. Sildenafil was supplied as 20-mg tablets, or formulated as sildenafil citrate in 25-, 50-, or 100-mg tablets.; Tadalafil was administered at the dose previously established for each subject (not to exceed 40 mg per day) orally once daily. Tadalafil was supplied as 20-mg tablets.
Intervention MeSH terms: Ambrisentan; Sildenafil Citrate; Tadalafil
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 38.0
Sex: All
Minimum age: 16 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: ambrisentan; PAH; combination therapy; phosphodiesterase type-5 inhibitor (PDE-5i); cardiovascular; endothelin receptor antagonist; ERA

Summary:

      To evaluate the change from baseline in pulmonary vascular resistance (PVR), and other
      hemodynamic parameters, following the addition of ambrisentan to background phosphodiesterase
      type-5 inhibitor (PDE-5i) therapy in subjects with pulmonary arterial hypertension (PAH) who
      have demonstrated a sub-optimal response to PDE-5i monotherapy.

      The study was originally designed as a 2-arm, double-blind, randomized study in which
      patients received ambrisentan or placebo for 24 weeks, and then received ambrisentan blinded
      to dose for 24 weeks. With Protocol Amendment 2 (12 June, 2009), the study was switched to
      single-arm, open-label treatment, and all patients remaining in the placebo arm were switched
      to open-label ambrisentan treatment. Patients who enrolled after Amendment 2 all received
      open-label ambrisentan.
    

Eligibility criteria:

        Selected Inclusion Criteria

          -  Must be between 16 and 75 years of age;

          -  Must weigh at least 40 kg;

          -  Have a current diagnosis of idiopathic PAH, familial PAH, or PAH that is primarily due
             to connective tissue disease, congenital heart defects, drug or toxin use, or human
             immunodeficiency virus (HIV);

          -  Have WHO functional class III symptoms;

          -  Be receiving sildenafil or tadalafil monotherapy for the treatment of PAH for at least
             the past 12 weeks and at a stable dose for at least 8 consecutive weeks;

          -  Meet all of the following hemodynamic criteria by means of a right heart
             catheterization: mPAP of at least 25 mmHg; PVR of at least 400 dyne*sec/cm5; pulmonary
             capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) of
             not more than 15 mmHg;

          -  Meet all of the following pulmonary function test criteria no more than 12 weeks
             before the screening visit: total lung capacity at least 60% of predicted normal and
             forced expiratory volume in 1 second of at least 65% of predicted normal;

          -  Able to walk at least 150 meters during the screening 6-minute walk test (6MWT);

          -  If receiving calcium channel blockers or 5-hydroxy-3-methylglutaryl-coenzyme A
             reductase inhibitors (i.e., statins) must be on stable therapy for at least 4 weeks;

          -  If diagnosed with HIV, must have stable disease status.

        Selected Exclusion Criteria:

          -  Have a current pulmonary hypertension diagnosis other than idiopathic PAH, familial
             PAH, or PAH that is primarily due to connective tissue disease, congenital heart
             defects, drug or toxin use, or HIV;

          -  Have left ventricular ejection fraction (LVEF) ≤40% or clinically significant
             ischemic, valvular, or constrictive heart disease;

          -  Have received chronic prostanoid or endothelin receptor antagonist (ERA) therapy (eg,
             bosentan, sitaxsentan) within the past 12 weeks;

          -  Have discontinued ERA treatment for any adverse reaction other than those associated
             with liver function test abnormalities;

          -  Have received IV inotropes within 2 weeks;

          -  Have a serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value
             that is greater than 2.0x the upper limit of normal.