Hypertension, Pulmonary Clinical Trial
— DYNAMICOfficial title:
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
Verified date | November 2020 |
Source | Medical University of Vienna |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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
Status | Completed |
Enrollment | 118 |
Est. completion date | September 2020 |
Est. primary completion date | August 2020 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years to 80 Years |
Eligibility | 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 |
Country | Name | City | State |
---|---|---|---|
Austria | Medical University of Vienna | Vienna |
Lead Sponsor | Collaborator |
---|---|
Medical University of Vienna |
Austria,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | Change from baseline in T1-mapping parameters by CMR | Change from baseline in native T1 times of the left ventricular myocardium | Baseline and 26 weeks after study drug treatment | |
Other | Change from baseline in T1-mapping parameters by CMR | Change from baseline in extracellular volume of the left ventricular myocardium | Baseline and 26 weeks after study drug treatment | |
Other | Change from baseline in echocardiography parameters | Change from baseline in left ventricular end-systolic volume by echocardiography | Baseline and 26 weeks after study drug treatment | |
Other | Change from baseline in echocardiography parameters | Change from baseline in left ventricular end-diastolic volume by echocardiography | Baseline and 26 weeks after study drug treatment | |
Other | Change from baseline in echocardiography parameters | Change from baseline in tricuspid annular plan systolic excursion by echocardiography | Baseline and 26 weeks after study drug treatment | |
Other | Change from baseline in echocardiography parameters | Change from baseline in pressure gradient of tricuspid valve by echocardiography | Baseline and 26 weeks after study drug treatment | |
Other | Change from baseline in echocardiography parameters | Change from baseline in diameter of inferior vena cava by echocardiography | Baseline and 26 weeks after study drug treatment | |
Other | Change from baseline in echocardiography parameters | Change from baseline in respiratory collapsibility of inferior vena cava by echocardiography | Baseline and 26 weeks after study drug treatment | |
Other | Change from baseline in echocardiography parameters | Change from baseline in mitral peak velocity of early (E) filling by echocardiography | Baseline and 26 weeks after study drug treatment | |
Other | Change from baseline in echocardiography parameters | Change from baseline in mitral peak velocity of late (A) filling by echocardiography | Baseline and 26 weeks after study drug treatment | |
Other | Change from baseline in echocardiography parameters | Change from baseline in E-wave deceleration time by echocardiography | Baseline and 26 weeks after study drug treatment | |
Other | Change from baseline in echocardiography parameters | Change from baseline in left ventricular ejection fraction by echocardiography | Baseline and 26 weeks after study drug treatment | |
Other | Change from baseline in echocardiography parameters | Change from baseline in estimate of mean right atrial pressure by echocardiography | Baseline and 26 weeks after study drug treatment | |
Other | Change from baseline in echocardiography parameters | Change from baseline in systolic pulmonary artery pressure by echocardiography | Baseline and 26 weeks after study drug treatment | |
Other | Change from baseline in echocardiography parameters | Change from baseline in E/A ratio by echocardiography | Baseline and 26 weeks after study drug treatment | |
Other | Change from baseline in exercise capacity: 6-minute walk distance | Baseline and 26 weeks after study drug treatment | ||
Other | Change from baseline in exercise capacity: Borg CR 10 scale | Baseline and 26 weeks after study drug treatment | ||
Other | Change from baseline in quality of life scores: EQ-5D | Baseline and 26 weeks after study drug treatment | ||
Other | Change from baseline in quality of life scores: MLHF | Baseline and 26 weeks after study drug treatment | ||
Other | Events of special interest | Events of special interest considered for calculation of the combined endpoint "time to clinical worsening" | Baseline and 26 weeks after study drug treatment | |
Other | All-cause mortality | Baseline and 26 weeks after study drug treatment | ||
Other | Composite endpoint | Composite endpoint as defined by: time to death from cardiovascular causes or first hospitalization for a cardiovascular event, including acute or worsening heart failure, acute myocardial infarction, stroke, or ventricular arrhythmia | Baseline and 26 weeks after study drug treatment | |
Primary | Change from baseline of cardiac output at rest, measured by right heart catheterization | Change from baseline of cardiac output at rest, measured by right heart catheterization after 26 weeks of study drug treatment | Baseline and 26 weeks after study drug treatment | |
Secondary | Change from baseline in cardiac magnetic resonance imaging parameters | Change from baseline in right ventricular ejection fraction by cardiac magnetic resonance imaging | Baseline and 26 weeks after study drug treatment | |
Secondary | Change from baseline in cardiac magnetic resonance imaging parameters | Change from baseline in right ventricular volume by cardiac magnetic resonance imaging | Baseline and 26 weeks after study drug treatment | |
Secondary | Change from baseline in cardiac magnetic resonance imaging parameters | Change from baseline in left atrial area by cardiac magnetic resonance imaging | Baseline and 26 weeks after study drug treatment | |
Secondary | Change from baseline in cardiac magnetic resonance imaging parameters | Change from baseline in right atrial area by cardiac magnetic resonance imaging | Baseline and 26 weeks after study drug treatment | |
Secondary | Change from baseline in hemodynamic parameters other than cardiac output | Change from baseline in pulmonary vascular resistance by right heart catheterization | Baseline and 26 weeks after study drug treatment | |
Secondary | Change from baseline in hemodynamic parameters other than cardiac output | Change from baseline in pulmonary arterial wedge pressure by right heart catheterization | Baseline and 26 weeks after study drug treatment | |
Secondary | Change from baseline in hemodynamic parameters other than cardiac output | Change from baseline in transpulmonary gradient by right heart catheterization | Baseline and 26 weeks after study drug treatment | |
Secondary | Change from baseline in hemodynamic parameters other than cardiac output | Change from baseline in systemic vascular resistance by right heart catheterization | Baseline and 26 weeks after study drug treatment | |
Secondary | Change from baseline in WHO functional class | Baseline and 26 weeks after study drug treatment | ||
Secondary | Change from baseline in biomarker levels | Change from baseline in serum N-terminal prohormone B-type natriuretic peptide (NTproBNP) | Baseline and 26 weeks after study drug treatment |
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