pharmacodynamic effects of riociguat in pulmonary hypertension and heart failure with preserved ejection fraction

Conditions: Hypertension, Pulmonary; Heart Failure With Normal Ejection Fraction

Summary: 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


Eligibility criteria:
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 \ 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

Keywords: ph-hfpef