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

• Status: Completed
• Trial end date: 2020-09-01
• Target enrollment: 0
• Participant gender: All

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

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Medical University of Vienna
• Treatments: Riociguat

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 <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