A Research Study To Assess The Effectiveness And Safety Of Different Doses Of Oral PF-00489791 In The Treatment Of Adult Patients With Pulmonary Arterial Hypertension

• Hourly changes from baseline in cardiac index, mean PAP and other hemodynamic parameters [ Time Frame: Day 1, up to 4 hours post dose ] [ Designated as safety issue: No ]
• Changes from baseline in PaO2 and PaCO2 [ Time Frame: Day 1, up to 4 hours post dose ] [ Designated as safety issue: Yes ]
• Plasma concentrations of PF-00489791 and sildenafil [ Time Frame: up to Day 3 - 5 ] [ Designated as safety issue: No ]
• Safety and tolerability of PF-00489791 after a single dose administration as assessed by incidence of treatment-emergent adverse events, changes from baseline in clinical laboratory tests, and ECG [ Time Frame: up to Day 3 - 5 ] [ Designated as safety issue: Yes ]
• Greatest reduction and hourly changes from baseline in PVRI [ Time Frame: Day 1, up to 4 hours post dose ] [ Designated as safety issue: No ]
• Mean change, greatest reduction and hourly changes from baseline in SVRI [ Time Frame: Day 1, up to 4 hours post dose ] [ Designated as safety issue: No ]
• Safety and tolerability of PF-00489791 after a single dose administration as assessed by incidence of treatment-emergent adverse events [ Time Frame: up to Day 10 - 14 ] [ Designated as safety issue: Yes ]

• Hourly changes from baseline in cardiac index, mean PAP and other hemodynamic parameters [ Time Frame: Day 1, up to 4 hours post dose ] [ Designated as safety issue: No ]
• Changes from baseline in PaO2 and PaCO2 [ Time Frame: Day 1, up to 4 hours post dose ] [ Designated as safety issue: Yes ]
• Plasma concentrations of PF-00489791 and sildenafil [ Time Frame: up to Day 4 ] [ Designated as safety issue: No ]
• Safety and tolerability of PF-00489791 after a single dose administration as assessed by incidence of treatment-emergent adverse events, changes from baseline in clinical laboratory tests, and ECG [ Time Frame: up to Day 4 ] [ Designated as safety issue: Yes ]
• Greatest reduction and hourly changes from baseline in PVRI [ Time Frame: Day 1, up to 4 hours post dose ] [ Designated as safety issue: No ]
• Mean change, greatest reduction and hourly changes from baseline in SVRI [ Time Frame: Day 1, up to 4 hours post dose ] [ Designated as safety issue: No ]
• Safety and tolerability of PF-00489791 after a single dose administration as assessed by incidence of treatment-emergent adverse events [ Time Frame: up to Day 10 - 14 ] [ Designated as safety issue: Yes ]

Study will assess PF-00489791 efficacy and safety in Pulmonary Arterial Hypertension (PAH)

Pfizer decided to stop this trial early upon Stage 1 completion due to change in PF-00489791 development and not as a result of safety concerns for PF-00489791. Date of termination (LSLV) occurred on July 28, 2010.

• Drug: PF-00489791
  tablet form, 1 mg, single dose (Day 1)
• Drug: PF-00489791
  tablet form, 2 mg, single dose (Day 1)
• Drug: PF-00489791
  tablet form, 4 mg, single dose (Day 1)
• Drug: PF-00489791
  tablet form, 10 mg, single dose (Day 1)
• Drug: PF-00489791
  tablet form, 20 mg, single dose (Day 1)
• Drug: placebo
  tablet form, single dose (Day 1)
• Drug: sildenafil
  tablet form, 20 mg, single dose (Day 1)
  Other Name: Revatio

• Experimental: PF-00489791 1 mg
  Intervention: Drug: PF-00489791
• Experimental: PF-00489791 2 mg
  Intervention: Drug: PF-00489791
• Experimental: PF-00489791 4 mg
  Intervention: Drug: PF-00489791
• Experimental: PF-00489791 10 mg
  Intervention: Drug: PF-00489791
• Experimental: PF-00489791 20 mg
  Intervention: Drug: PF-00489791
• Placebo Comparator: Placebo
  Intervention: Drug: placebo
• Active Comparator: Sildenafil
  Observational comparator arm
  Intervention: Drug: sildenafil

Inclusion Criteria:

• Idiopathic or familial pulmonary arterial hypertension (PAH)
• Mean PAP at least 25 mm Hg, PCWP < 15 mm Hg at rest
• For females of child-bearing potential negative pregnancy test at screening and use of contraception during the study and 4 weeks after its completion
• Signed and dated informed consent
• Willingness to comply with the study plan and procedures

Exclusion Criteria:

• pulmonary arterial hypertension (PAH)other than idiopathic or familial
• For females, pregnancy or lactation
• Use of specific PAH treatments, potent CYP3A4 inhibitors, protease inhibitors, alpha blockers or arginine 30 days prior tio randomization and during the study
• Change of dose or class of standard background PAH therapy, i.e. oxygen, calcium channel blockers, digoxin, diuretics 30 days prior tio randomization and during the study
• Large shift in altitude (defined as >5000 feet or 1524 meters) during 90 days prior to baseline visit and/or during the study visit
• Subjects with intracardiac shunts and/or serious heart, lung or other health conditions
• HIV positive subjects
• Subjects participating in another clinical trial with an investigational drug or device
• Subjects with degenerative retinal disorders, history of non-arteritic anterior ischemic optic neuropathy or untreated proliferative diabetic retinopathy
• Allergies and previous intolerance of PDE5 inhibitors
• Alcohol or drug abuse
• Blood donation during the study, or 1 month before or after the study