Pharmacodynamic Effects of Riociguat in Pulmonary Hypertension and Heart Failure With Preserved Ejection Fraction

Inclusion criteria

• 18 to <80 years of age at the time of informed consent (The lower age limit may be higher if legally required in participating countries.)
• Male and female subjects with symptomatic PH and HF-PEF (group 2 / 2.2 of Dana Point classification(4) and WHO class II to IV) (Other groups of PH, especially HF-REF, PAH, CTEPH, must have been ruled out according to accepted diagnostic procedures and guidelines, see section 5.1.2 Exclusion criteria.)
• PH-HF-PEF defined as:

• LVEF ≥50%, diagnosed by echocardiography or left heart catheterization (LHC) within 30 days before randomization
• PAPmean ≥25 mmHg at rest, measured by RHC
• PAWP >15 mmHg at rest, measured by RHC
• Optimized therapy for hypertension
• The dose regimen of the background treatment must have been stable for >30 days before randomization. Diuretic therapy must have been stable for ≥1 week.
• RHC results for the definite diagnosis of PH not older than 12 weeks at Visit 1. RHC must have been performed in the participating center under standardized conditions
• CMRI must be performed at Visit 1 (baseline) or must not be older than 12 weeks with all parameters measured as listed in Section 7.3.3
• Women are eligible if not of childbearing potential, defined as:
• Postmenopausal women (i.e. last menstrual bleeding at least 2 years before randomization)
• Women with bilateral tubal ligation
• Women with bilateral ovariectomy
• Women with hysterectomy or, if of childbearing potential, women are eligible if
• A serum pregnancy test is negative at the pre-study visit, and The woman uses a combination of condoms and a safe and highly effective contraception method (hormonal contraception with implants or combined oral contraceptives, certain intrauterine devices) for the entire duration of the study.
• Able to understand and follow instructions and to participate in the study for its entire duration
• Written informed consent

Exclusion criteria

• PH in groups other than group 2.2 according to Dana Point classification.(4) In particular, PAH, CTEPH, and HF-REF must have been ruled out according to accepted diagnostic procedures and guidelines.
• Cardiac decompensation, with hospitalization or visit to the emergency department,

≤30 days before randomization

• Left heart disease because of to ischemic heart disease or dilated cardiomyopathy
• Resynchronization therapy at any time
• Need for intravenous (IV) diuretics ≤30 days before randomization
• Treatment with inotropes or IV vasodilators ≤30 days before randomization
• Pre-treatment with endothelin receptor antagonists (ERAs), phosphodiesterase type 5 (PDE5) inhibitors, or prostanoids ≤30 days before randomization, or with nitrates ≤7 days before randomization
• Subjects who medically require treatment with drugs that are not in line with the in- or exclusion criteria of this study or that are prohibited concomitant medications (see section 6.9) for this study
• Bronchial asthma or chronic obstructive pulmonary disease (COPD) with forced expiratory volume in 1 second (FEV1) <60% of predicted
• Restrictive lung disease with total lung capacity (TLC) <60% of predicted
• Subjects on oxygen therapy
• Severe congenital abnormalities of the lung, thorax, or diaphragm
• Clinically relevant hepatic dysfunction shown by:
• Aspartate aminotransferase (AST) ≥3 times the upper limit of normal (ULN) or
• Child Pugh stage B and C in cirrhotic subjects
• Severe renal impairment (glomerular filtration rate [GFR] <30mL/min/1.73 m2 calculated by the Modification of Diet in Renal Disease [MDRD] formula)
• Uncontrolled arterial hypertension (SBP >180 mmHg or diastolic blood pressure [DBP] >110 mmHg)
• SBP <110 mmHg at baseline
• Myocardial disease, such as ischemic or dilative infiltrative myocardial disease (i.e. amyloidosis, hypertrophic cardiomyopathy)
• Severe aortic or mitral stenosis, or any such stenosis with indication for surgery
• Coronary artery disease with angina of Canadian Cardiovascular Society (CCS) class III or IV or requiring nitrates, unstable angina, or acute myocardial infarction <90 days before randomization
• Reperfusion procedure (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG]) <90 days before randomization, or <21 days in case of a negative stress test effect after PCI
• Stroke with persistent neurological deficit
• Subjects positive for human immunodeficiency virus (HIV)
• Resting HR while awake of <50 beats per minute (BPM) or >105 BPM (in case of atrial fibrillation >110 BPM)
• Participation in another clinical study <90 days before randomization
• Subjects with a medical disorder, condition, or history thereof that in the opinion of the investigator would impair the subject's ability to participate or complete the 26-week study
• Subjects with underlying medical disorders with an anticipated life expectancy below 2 years because of a non-cardiac disease (e.g. active cancer disease with localized and / or metastasized tumor mass)
• Subjects with a history of multiple drug allergies
• Subjects with hypersensitivity to the investigational drug or any of the excipients
• Previous assignment to treatment during this study