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

Evaluation of the Pharmacodynamic Effects of Riociguat in Subjects With Pulmonary Hypertension and Heart Failure With Preserved Ejection Fraction in a Randomized, Double Blind, Placebo Controlled, Parallel Group, Multicenter Study

The primary objective of this study is to

• Assess the pharmacodynamic profile of riociguat in subjects with symptomatic pulmonary hypertension and heart failure with preserved ejection fraction

The secondary objectives of this study are to

• Assess safety and tolerability of riociguat in this study population
• Assess changes in dimensions of left and right ventricles and cardiac function parameters using cardiac magnetic resonance imaging

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