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

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ClinicalTrials.gov Identifier: NCT02744339
Recruitment Status : Unknown
Verified April 2016 by DBonderman, Medical University of Vienna.
Recruitment status was:  Recruiting
First Posted : April 20, 2016
Last Update Posted : April 20, 2016
Sponsor:
Information provided by (Responsible Party):
DBonderman, Medical University of Vienna

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 114 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
Study Start Date : March 2016
Estimated Primary Completion Date : February 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Riociguat

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




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



Information from the National Library of Medicine

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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02744339


Contacts
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Contact: Andreas Kammerlander, MD +4314040046140 andreas.kammerlander@meduniwien.ac.at

Locations
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Austria
Medical University of Vienna Recruiting
Vienna, Austria, 1090
Contact: Diana Bonderman, MD    014040046140    diana.bonderman@meduniwien.ac.at   
Contact: Julia Mascherbauer, MD    01 40400 46140    julia.mascherbauer@meduniwien.ac.at   
Sponsors and Collaborators
Medical University of Vienna
Investigators
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Principal Investigator: Diana Bonderman, MD Medical University of Vienna

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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    Key Record Dates
Last Update Posted: April 20, 2016
Last Verified: April 2016
Keywords provided by DBonderman, Medical University of Vienna:
PH-HFpEF
Additional relevant MeSH terms:
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Hypertension, Pulmonary
Hypertension
Heart Failure
Vascular Diseases
Cardiovascular Diseases
Heart Diseases
Lung Diseases
Respiratory Tract Diseases
Riociguat
Enzyme Activators
Molecular Mechanisms of Pharmacological Action