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

Phase 1

Conditions: Pulmonary hypertension and heart failure with preserved ejectionfraction
Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Registration Number: EUCTR2014-003055-60-DE

Lead Sponsor: Medical University of Vienna

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 114

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.
Between the first RHC and study enrollment there must be no changes in concomitant
medication which may affect hemodynamic parameters.
? 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.
? Men enrolled in this study must agree to use adequate barrier birth control measures
during the treatment period of the study and inform their sexual partners during the
study period and three months beyond their study participation about the possibility of
foetal impairment.
? Able to understand and follow instructions and to participate in the study for its entire
duration
? Written informed consent
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 24
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 90

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 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 6.8) 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

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The primary objective of this study is to<br>- Assess the pharmacodynamic profile of riociguat in subjects with<br>symptomatic pulmonary hypertension and heart failure with preserved<br>ejection fraction;Secondary Objective: The secondary objectives of this study are to<br>- Assess safety and tolerability of riociguat in this study population<br>- Assess changes in dimensions of left and right ventricles and cardiac<br>function parameters using cardiac magnetic resonance imaging;Primary end point(s): Change from baseline of cardiac output (CO) at rest, measured by right<br>heart catheter (RHC);Timepoint(s) of evaluation of this end point: Baseline and after 26 weeks of study drug treatment

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): right ejection fraction, measured by CMRI<br>- Change from baseline in PVR, SVR, TPG, and PAWP, measured by RHC<br>- Change from baseline in WHO class<br>- Change from baseline in cardiac biomarkers NT-pro BNP;Timepoint(s) of evaluation of this end point: Baseline and after 26 weeks of study drug treatment

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