Please select the eligibility criteria that correspond to the clinical trial below.
Title: An Interaction Study to Evaluate Changes in Blood Pressure Following 1, 1.5, 2, and 2.5 mg Riociguat Tid (Dose Titration) Compared to Placebo Treatment on the Background of Stable Sildenafil Pretreatment in Subjects With Symptomatic Pulmonary Arterial Hypertension
Brief Summary: Pulmonary Arterial Hypertension (PAH) is a severe progressive disease with a high mortality. Although several drugs are available for the treatment of PAH none offer a cure, therefore there is still a high medical need for new treatments.

Soluble guanylate cyclase (sGC) is one of the chemicals involved in the pathways controlling vascular tone, which is impaired in patients with PAH. This causes constriction and thickening of the blood vessels wall in the lungs and increase of blood pressure in the lungs. This can lead to the very debilitating symptoms of PAH such as tiredness, shortness of breath on exertion, collapse and often the inability of the patient to perform their daily life activities.

Inhalation of Nitric Oxide, which activates sGC is used to treat PAH, but its effect wears off as soon as inhalation stops. Direct stimulation of sGC using this new compound Riociguat may be a new approach for the treatment of PAH.

The phosphodiesterase 5 (PDE5)-inhibitor Sildenafil is one of licensed treatments for PAH. The Patent Plus is a double-blind, placebo-controlled safety study, designed to investigate the effect of Riociguat on blood pressure in patients with PAH when given in combination with Sildenafil.


Options:
A: Inclusion Criteria:

* Male and female patients with symptomatic PAH (Idiopathic, Familial, Associated PAH due to connective tissue disease, congenital heart disease, portal hypertension with liver cirrhosis, or due to anorexigen or amphetamine use)
* Treatment naive patients and patients pre-treated with an Endothelin Antagonist or a Prostacyclinanalogue (except I.V.).

Exclusion Criteria:

* All types of pulmonary hypertension except subtypes of Venice Group I specified in the inclusion criteria, severe COPD (chronic obstructive pulmonary disease), uncontrolled arterial hypertension, left heart failure.
B: Inclusion Criteria:

* Patients who have completed 12 weeks of treatment in the double blind trial PATENT 1

Exclusion Criteria:

* Patients who have an ongoing serious adverse event from PATENT 1 that is assessed as related to BAY63-2521 are not allowed to participate in the extension trial.
C: Inclusion Criteria:

* Diagnosis of an interstitial lung disease (usual interstitial pneumonia \[UIP\], nonspecific interstitial pneumonia \[NSIP\] or sarcoidosis) with high resolution CT and a total lung capacity (TLC) ≤ 90% or scleroderma associated pulmonary arterial hypertension (PAH) with total lung capacity (TLC) ≤ 80%.
* Interstitial lung disease (ILD) must have been stable for at least 3 months (decrease in forced vital capacity (FVC)\< 10% and diffusing capacity of lung for carbon monoxide (DLco) \< 15 % in 3 months), i.e. no significant changes in pulmonary function testing and stable medication in terms of ILD (e.g., corticosteroids, immunosuppressants)
* Mean pulmonary vascular resistance (PVR) \> 400 dyne sec cm-5 or mean pulmonary arterial pressure (PAP mean) \> 30 mmHg
* Pulmonary capillary wedge pressure (PCWP) \< 15 mmHg
* Hemodynamic parameters at baseline (PAP, PCWP, cardiac output \[CO\], systemic mean arterial pressure \[SAP\])
* High resolution computer tomography (HRCT) (should not be older than 12 months prior start of the study)
* Heart rate \> 55 beats per minute (BPM) and \< 105 BPM at rest
* Systolic blood pressure (SBP) \> 90 mmHg
* World Health Organisation (WHO) functional class II, III and IV
* 6 Minute Walking Test (6MWT) \> 100m and \< 450 m
* Stable controlled arterial hypertension according to current guidelines
* Women of childbearing potential will be included in the study if the pregnancy test is negative and combination of condoms with a safe and highly effective contraception method (hormonal contraception with implants or combined oral contraceptives, certain intra-uterine devices \[IUDs\]) is granted.

Exclusion Criteria:

* Co-medication:

  * Patients pretreated with specific medication for pulmonary arterial hypertension (PAH) like endothelin receptor antagonists, prostaglandins or phosphodiesterase type 5 (PDE 5) blockers are excluded from the trial.
  * Requirement for concomitant use of nitrates are contraindicated.
* Pre-existing clinically relevant lung disease other than ILD including.

  * Bronchial asthma and Chronic Obstructive Pulmonary Disease (COPD) with a forced expiratory volume in one second (FEV1)/FVC \<60% pred., active tuberculosis
  * Pulmonary hypertension of another WHO group (I, II, IV and V)
  * Severe congenital abnormalities of the lungs, thorax and diaphragm
  * Clinical or radiological evidence of a pulmovenoocclusive disease (PVOD)
* Systemic hemodynamics

  * Acute or severe chronic left heart failure (ejection fraction (EF) \< 50%)
  * Severe coronary artery disease (CAD; EF \< 50%); CAD patients must be asymptomatic and stable
  * Congenital or acquired valvular or myocardial disease if clinically significant apart from tricuspid valvular insufficiency due to pulmonary hypertension
* Pulmonary function

  * TLC predicted \< 30%
  * FEV1 (related to FVC) \< 60% predicted
* Blood gases at room air

  * Arterial partial carbon dioxide pressure (Pa CO2) \> 45 mmHg
  * Arterial partial oxygen pressure (Pa O2) \< 50 mmHg at O2 supply \>/= 4 L/min
* Peripheral organ function

  * Moderate or severe hepatic insufficiency (Child-Pugh Class Band C and/or total bilirubin \> 2.5 mg/dl (0.043 mmol/L); and/or hepatic transaminases \>3 upper limit normal \[ULN\])
  * Moderate or severe renal insufficiency (creatinine \> 2 mg/dl) or creatinine clearance according to Cockroft-Gault formula \< 35 mL/ min
D: 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

Answer: D