Pulmonary hypertension

Inclusion Criteria

- 18 to 75 years of age at Visit 1
- Male and female subjects with symptomatic PAH (Group I Dana Point Updated Clinical Classification 2008), a 6-min walking distance (6MWD) of more than 150 m, a pulmonary vascular resistance (PVR) >300 dyn*s*cm-5, and a mean pulmonary artery pressure (PAPmean) ≥ 25 mmHg
 - For Study Part 1: subjects on stable pretreatment with sildenafil at a dose of 20 mg tid
 - Unspecific treatments which may also be used for the treatment of PAH such as oral anticoagulants, diuretics, digitalis, calcium channel blockers or oxygen supplementation are permitted. However, treatment with anticoagulants (if indicated) must have been started at least 30 days before Visit 1 and treatment with diuretics needs to be stable for at least 30 days before Visit 1
 - Subjects with supplemental long-term oxygen therapy may be included, if the amount of supplemental oxygen and the delivery method was stable on average for at least 90 days before Visit 1
 - SBP >/=95 mmHg and heart rate (HR) </=105 beats per minute (BPM) in the first 2 h after intake of sildenafil (measured at Visits 0 and 1)
 - Women without child-bearing potential
 - Subjects who are able to understand and follow instructions and who are able to participate in the study for the entire period
 - Subjects must have given their written informed consent to participate in the study after having received adequate previous information and prior to any study-specific procedures

Exclusion Criteria

- Subject’s participating in another clinical trial or who have done so within 30 days before Visit 1
 - Previous assignment to treatment during this study
 - Pregnant women
 - Subjects with a medical disorder, condition, or history of such that would impair the subject’s ability to participate or complete this study in the opinion of the investigator
 - Subjects with substance abuse (eg alcohol or drug abuse) within the previous 180 days before Visit 1
 - Subjects with underlying medical disorders with an anticipated life expectancy below 2 years (eg active cancer disease with localized and/or metastasized tumor mass)
 - Subjects with a history of severe allergies or multiple drug allergies
 - Subjects with hypersensitivity to the investigational drug or any of the excipients
 - Subjects unable to perform a valid 6MWD test, eg subjects with a severe peripheral artery occlusive disease
 - Subjects with a relative difference (ie absolute difference/mean) of more than 15% between the eligibility- and the baseline 6MWD test
 - All types of pulmonary hypertension except subtypes of Updated Clinical Classification of pulmonary hypertension (PH) (Dana Point 2008) Group I specified in the inclusion criteria
 - Moderate to severe obstructive lung disease (forced expiratory volume <60% predicted). The predicted forced expiratory volume in 1 second (FEV1) is a calculated value
 - Severe restrictive lung disease (total lung capacity <70% predicted). The predicted total lung capacity (TLC) is a calculated value
 - Severe congenital abnormalities of the lungs, thorax, and diaphragm
 - Oxygen saturation (SaO2) <88% despite supplemental oxygen therapy
 - Arterial partial oxygen pressure (PaO2) <55 mmHg despite supplemental oxygen therapy
 - Arterial partial pressure of carbon dioxide (PaCO2) >45 mmHg
 - Uncontrolled arterial hypertension (SBP >180 mmHg and /or diastolic blood pressure >110 mmHg
 - Atrial fibrillation within the last 90 days before Visit 1
 - Pulmonary venous hypertension with pulmonary capillary wedge pressure 15 mmHg
 - Hypertrophic obstructive cardiomyopathy
 - Severe proven or suspected coronary artery disease
 - Clinical evidence of symptomatic atherosclerotic disease
 - Congenital or acquired valvular or myocardial disease if clinically significant apart from tricuspid valvular insufficiency due to pulmonary hypertension
 - Clinical relevant hepatic dysfunction indicated by:
 -- Bilirubin >2 times upper limit normal (ULN)
 -- and/or ALT (alanine aminotransferase) or AST (aspartate aminotransferase) >3 times ULN
 -- and/or signs of severe hepatic insufficiency (eg impaired albumin synthesis with an albumin <32 g/L, hepatic encephalopathy > grade 1
 - Renal insufficiency (glomerular filtration rate <30 mL/min, eg calculated based on the Cockcroft-Gault or Modification of Diet in Renal Disease (MDRD) formulas