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

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

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

Study Overview

• Status: Completed
• Conditions: Hypertension, Pulmonary; Heart Failure With Normal Ejection Fraction
• Intervention / Treatment: Drug: Riociguat; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 118
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Medical University of Vienna

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Riociguat; Riociguat up-titrated to a maximum of 1.5mg TID	Drug: Riociguat; Adempas up-titrated to max. 1.5mg TID; Other Names: Adempas
Placebo Comparator: Placebo; Placebo sham-titrated TID	Drug: Placebo; Placebo sham-titrated TID

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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
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
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
Change from baseline in WHO functional class		Baseline and 26 weeks after study drug treatment
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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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
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
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
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
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
Change from baseline in echocardiography parameters	Change from baseline in E-wave deceleration time by echocardiography	Baseline and 26 weeks after study drug treatment
Change from baseline in echocardiography parameters	Change from baseline in left ventricular ejection fraction by echocardiography	Baseline and 26 weeks after study drug treatment
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
Change from baseline in echocardiography parameters	Change from baseline in systolic pulmonary artery pressure by echocardiography	Baseline and 26 weeks after study drug treatment
Change from baseline in echocardiography parameters	Change from baseline in E/A ratio by echocardiography	Baseline and 26 weeks after study drug treatment
Change from baseline in exercise capacity: 6-minute walk distance		Baseline and 26 weeks after study drug treatment
Change from baseline in exercise capacity: Borg CR 10 scale		Baseline and 26 weeks after study drug treatment
Change from baseline in quality of life scores: EQ-5D		Baseline and 26 weeks after study drug treatment
Change from baseline in quality of life scores: MLHF		Baseline and 26 weeks after study drug treatment
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
All-cause mortality		Baseline and 26 weeks after study drug treatment
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

Collaborators and Investigators

• Sponsor: Medical University of Vienna
• Investigators: Principal Investigator: Diana Bonderman, MD, Medical University of Vienna; Principal Investigator: Johannes Kastner, MD, Medical University of Vienna

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2016
• Primary Completion (Actual): August 1, 2020
• Study Completion (Actual): September 1, 2020

Study Registration Dates

• First Submitted: March 18, 2016
• First Submitted That Met QC Criteria: April 15, 2016
• First Posted (Estimate): April 20, 2016

Study Record Updates

• Last Update Posted (Actual): November 4, 2020
• Last Update Submitted That Met QC Criteria: November 2, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: PH-HFpEF
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Heart Failure; Hypertension; Hypertension, Pulmonary; Molecular Mechanisms of Pharmacological Action; Enzyme Activators; Riociguat
• Other Study ID Numbers: RIO-40400; 2014-003055-60 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No