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

• ClinicalTrials.gov Identifier: NCT02744339
• Recruitment Status: Completed
• First Posted: April 20, 2016
• Last Update Posted: November 4, 2020
• Sponsor: Medical University of Vienna
• Information provided by (Responsible Party): DBonderman, Medical University of Vienna

Study Description

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

Condition or disease	Intervention/treatment	Phase
Hypertension, Pulmonary; Heart Failure With Normal Ejection Fraction	Drug: Riociguat; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 118 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: March 2016
• Actual Primary Completion Date: August 2020
• Actual Study Completion Date: September 2020

Arms and Interventions

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 Name: Adempas
Placebo Comparator: Placebo; Placebo sham-titrated TID	Drug: Placebo; Placebo sham-titrated TID

Outcome Measures

Primary Outcome Measures :

1. Change from baseline of cardiac output at rest, measured by right heart catheterization [ Time Frame: Baseline and 26 weeks after study drug treatment ]
   Change from baseline of cardiac output at rest, measured by right heart catheterization after 26 weeks of study drug treatment

Secondary Outcome Measures :

1. Change from baseline in cardiac magnetic resonance imaging parameters [ Time Frame: Baseline and 26 weeks after study drug treatment ]
   Change from baseline in right ventricular ejection fraction by cardiac magnetic resonance imaging
2. Change from baseline in cardiac magnetic resonance imaging parameters [ Time Frame: Baseline and 26 weeks after study drug treatment ]
   Change from baseline in right ventricular volume by cardiac magnetic resonance imaging
3. Change from baseline in cardiac magnetic resonance imaging parameters [ Time Frame: Baseline and 26 weeks after study drug treatment ]
   Change from baseline in left atrial area by cardiac magnetic resonance imaging
4. Change from baseline in cardiac magnetic resonance imaging parameters [ Time Frame: Baseline and 26 weeks after study drug treatment ]
   Change from baseline in right atrial area by cardiac magnetic resonance imaging
5. Change from baseline in hemodynamic parameters other than cardiac output [ Time Frame: Baseline and 26 weeks after study drug treatment ]
   Change from baseline in pulmonary vascular resistance by right heart catheterization
6. Change from baseline in hemodynamic parameters other than cardiac output [ Time Frame: Baseline and 26 weeks after study drug treatment ]
   Change from baseline in pulmonary arterial wedge pressure by right heart catheterization
7. Change from baseline in hemodynamic parameters other than cardiac output [ Time Frame: Baseline and 26 weeks after study drug treatment ]
   Change from baseline in transpulmonary gradient by right heart catheterization
8. Change from baseline in hemodynamic parameters other than cardiac output [ Time Frame: Baseline and 26 weeks after study drug treatment ]
   Change from baseline in systemic vascular resistance by right heart catheterization
9. Change from baseline in WHO functional class [ Time Frame: Baseline and 26 weeks after study drug treatment ]
10. Change from baseline in biomarker levels [ Time Frame: Baseline and 26 weeks after study drug treatment ]
    Change from baseline in serum N-terminal prohormone B-type natriuretic peptide (NTproBNP)

Other Outcome Measures:

1. Change from baseline in T1-mapping parameters by CMR [ Time Frame: Baseline and 26 weeks after study drug treatment ]
   Change from baseline in native T1 times of the left ventricular myocardium
2. Change from baseline in T1-mapping parameters by CMR [ Time Frame: Baseline and 26 weeks after study drug treatment ]
   Change from baseline in extracellular volume of the left ventricular myocardium
3. Change from baseline in echocardiography parameters [ Time Frame: Baseline and 26 weeks after study drug treatment ]
   Change from baseline in left ventricular end-systolic volume by echocardiography
4. Change from baseline in echocardiography parameters [ Time Frame: Baseline and 26 weeks after study drug treatment ]
   Change from baseline in left ventricular end-diastolic volume by echocardiography
5. Change from baseline in echocardiography parameters [ Time Frame: Baseline and 26 weeks after study drug treatment ]
   Change from baseline in tricuspid annular plan systolic excursion by echocardiography
6. Change from baseline in echocardiography parameters [ Time Frame: Baseline and 26 weeks after study drug treatment ]
   Change from baseline in pressure gradient of tricuspid valve by echocardiography
7. Change from baseline in echocardiography parameters [ Time Frame: Baseline and 26 weeks after study drug treatment ]
   Change from baseline in diameter of inferior vena cava by echocardiography
8. Change from baseline in echocardiography parameters [ Time Frame: Baseline and 26 weeks after study drug treatment ]
   Change from baseline in respiratory collapsibility of inferior vena cava by echocardiography
9. Change from baseline in echocardiography parameters [ Time Frame: Baseline and 26 weeks after study drug treatment ]
   Change from baseline in mitral peak velocity of early (E) filling by echocardiography
10. Change from baseline in echocardiography parameters [ Time Frame: Baseline and 26 weeks after study drug treatment ]
    Change from baseline in mitral peak velocity of late (A) filling by echocardiography
11. Change from baseline in echocardiography parameters [ Time Frame: Baseline and 26 weeks after study drug treatment ]
    Change from baseline in E-wave deceleration time by echocardiography
12. Change from baseline in echocardiography parameters [ Time Frame: Baseline and 26 weeks after study drug treatment ]
    Change from baseline in left ventricular ejection fraction by echocardiography
13. Change from baseline in echocardiography parameters [ Time Frame: Baseline and 26 weeks after study drug treatment ]
    Change from baseline in estimate of mean right atrial pressure by echocardiography
14. Change from baseline in echocardiography parameters [ Time Frame: Baseline and 26 weeks after study drug treatment ]
    Change from baseline in systolic pulmonary artery pressure by echocardiography
15. Change from baseline in echocardiography parameters [ Time Frame: Baseline and 26 weeks after study drug treatment ]
    Change from baseline in E/A ratio by echocardiography
16. Change from baseline in exercise capacity: 6-minute walk distance [ Time Frame: Baseline and 26 weeks after study drug treatment ]
17. Change from baseline in exercise capacity: Borg CR 10 scale [ Time Frame: Baseline and 26 weeks after study drug treatment ]
18. Change from baseline in quality of life scores: EQ-5D [ Time Frame: Baseline and 26 weeks after study drug treatment ]
19. Change from baseline in quality of life scores: MLHF [ Time Frame: Baseline and 26 weeks after study drug treatment ]
20. Events of special interest [ Time Frame: Baseline and 26 weeks after study drug treatment ]
    Events of special interest considered for calculation of the combined endpoint "time to clinical worsening"
21. All-cause mortality [ Time Frame: Baseline and 26 weeks after study drug treatment ]
22. Composite endpoint [ Time Frame: Baseline and 26 weeks after study drug treatment ]
    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

Eligibility Criteria

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

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

Contacts and Locations

Locations

Austria

Medical University of Vienna

Vienna, Austria, 1090

Sponsors and Collaborators

Medical University of Vienna

Investigators

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

More Information

• Responsible Party: DBonderman, Assoc.Prof.Priv.Doz.Dr., Medical University of Vienna
• ClinicalTrials.gov Identifier: NCT02744339
• Other Study ID Numbers: RIO-40400; 2014-003055-60 ( EudraCT Number )
• First Posted: April 20, 2016
• Last Update Posted: November 4, 2020
• Last Verified: November 2020

Keywords provided by DBonderman, Medical University of Vienna:

PH-HFpEF

Additional relevant MeSH terms:

Hypertension, Pulmonary; Hypertension; Heart Failure; Vascular Diseases; Cardiovascular Diseases; Heart Diseases; Lung Diseases; Respiratory Tract Diseases; Riociguat; Enzyme Activators; Molecular Mechanisms of Pharmacological Action