Clinical trial NCT02744339: Pharmacodynamic Effects of Riociguat in Pulmonary Hypertension and Heart Failure With Preserved Ejection Fraction
Official 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hypertension, Pulmonary
Heart Failure With Normal Ejection Fraction
Keywords: PH-HFpEF
Lead sponsor: Medical University of Vienna
Sponsor class: OTHER
First posted: 2016-04-20
Enrollment: 118
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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 \<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

Primary outcomes:
measure: Change from baseline of cardiac output at rest, measured by right heart catheterization
timeFrame: Baseline and 26 weeks after study drug treatment
Secondary outcomes:
measure: Change from baseline in cardiac magnetic resonance imaging parameters
timeFrame: Baseline and 26 weeks after study drug treatment
measure: Change from baseline in cardiac magnetic resonance imaging parameters
timeFrame: Baseline and 26 weeks after study drug treatment
measure: Change from baseline in cardiac magnetic resonance imaging parameters
timeFrame: Baseline and 26 weeks after study drug treatment
measure: Change from baseline in cardiac magnetic resonance imaging parameters
timeFrame: Baseline and 26 weeks after study drug treatment
measure: Change from baseline in hemodynamic parameters other than cardiac output
timeFrame: Baseline and 26 weeks after study drug treatment
measure: Change from baseline in hemodynamic parameters other than cardiac output
timeFrame: Baseline and 26 weeks after study drug treatment
measure: Change from baseline in hemodynamic parameters other than cardiac output
timeFrame: Baseline and 26 weeks after study drug treatment
measure: Change from baseline in hemodynamic parameters other than cardiac output
timeFrame: Baseline and 26 weeks after study drug treatment
measure: Change from baseline in WHO functional class
timeFrame: Baseline and 26 weeks after study drug treatment
measure: Change from baseline in biomarker levels
timeFrame: Baseline and 26 weeks after study drug treatment
Other outcomes:
measure: Change from baseline in T1-mapping parameters by CMR
timeFrame: Baseline and 26 weeks after study drug treatment
measure: Change from baseline in T1-mapping parameters by CMR
timeFrame: Baseline and 26 weeks after study drug treatment
measure: Change from baseline in echocardiography parameters
timeFrame: Baseline and 26 weeks after study drug treatment
measure: Change from baseline in echocardiography parameters
timeFrame: Baseline and 26 weeks after study drug treatment
measure: Change from baseline in echocardiography parameters
timeFrame: Baseline and 26 weeks after study drug treatment
measure: Change from baseline in echocardiography parameters
timeFrame: Baseline and 26 weeks after study drug treatment
measure: Change from baseline in echocardiography parameters
timeFrame: Baseline and 26 weeks after study drug treatment
measure: Change from baseline in echocardiography parameters
timeFrame: Baseline and 26 weeks after study drug treatment
measure: Change from baseline in echocardiography parameters
timeFrame: Baseline and 26 weeks after study drug treatment
measure: Change from baseline in echocardiography parameters
timeFrame: Baseline and 26 weeks after study drug treatment
measure: Change from baseline in echocardiography parameters
timeFrame: Baseline and 26 weeks after study drug treatment
measure: Change from baseline in echocardiography parameters
timeFrame: Baseline and 26 weeks after study drug treatment
measure: Change from baseline in echocardiography parameters
timeFrame: Baseline and 26 weeks after study drug treatment
measure: Change from baseline in echocardiography parameters
timeFrame: Baseline and 26 weeks after study drug treatment
measure: Change from baseline in echocardiography parameters
timeFrame: Baseline and 26 weeks after study drug treatment
measure: Change from baseline in exercise capacity: 6-minute walk distance
timeFrame: Baseline and 26 weeks after study drug treatment
measure: Change from baseline in exercise capacity: Borg CR 10 scale
timeFrame: Baseline and 26 weeks after study drug treatment
measure: Change from baseline in quality of life scores: EQ-5D
timeFrame: Baseline and 26 weeks after study drug treatment
measure: Change from baseline in quality of life scores: MLHF
timeFrame: Baseline and 26 weeks after study drug treatment
measure: Events of special interest
timeFrame: Baseline and 26 weeks after study drug treatment
measure: All-cause mortality
timeFrame: Baseline and 26 weeks after study drug treatment
measure: Composite endpoint
timeFrame: Baseline and 26 weeks after study drug treatment
Locations:
city: Vienna
country: Austria
facility: Medical University of Vienna
Study officials:
affiliation: Medical University of Vienna
name: Diana Bonderman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical University of Vienna
name: Johannes Kastner, MD
role: PRINCIPAL_INVESTIGATOR
References: