A Study to Test the Effects of Riociguat in Patients With Pulmonary Hypertension Associated With Left Ventricular Systolic Dysfunction

Study Overview
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Brief Summary
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The aim of this study is to assess whether increasing oral doses of Riociguat are safe and improve the well-being, symptoms and outcome in patients with pulmonary hypertension associated with left ventricular systolic dysfunction

Detailed Description
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Pharmacokinetics parameters were regarded as exploratory parameters. Adverse event data will be covered in Adverse events section.

Official Title
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Randomized, Double Blind, Placebo Controlled, Parallel Group, Multi-center Study to Evaluate the Hemodynamic Effects of Riociguat (BAY 63-2521) as Well as Safety and Kinetics in Patients With Pulmonary Hypertension Associated With Left Ventricular Systolic Dysfunction

Conditions
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Hypertension, Pulmonary, Ventricular Dysfunction, Left

Intervention / Treatment
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* Drug: Riociguat (Adempas, BAY63-2521)
* Drug: Riociguat (Adempas, BAY63-2521)
* Drug: Riociguat (Adempas, BAY63-2521)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients with symptomatic pulmonary hypertension due to left ventricular systolic dysfunction despite optimized heart failure therapy Exclusion Criteria: Types of pulmonary hypertension other than group 2.1 of Dana Point Classification

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Riociguat (Adempas, BAY63-2521) up to 2 mg<br>Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg). | Drug: Riociguat (Adempas, BAY63-2521)<br>* up to 2 mg three times a day (increasing from 0.5 to 1 to 2 mg)<br>|
| Experimental: Riociguat (Adempas, BAY63-2521) up to 1 mg<br>Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg). | Drug: Riociguat (Adempas, BAY63-2521)<br>* up to 1 mg three times a day (increasing from 0.5 to 1 mg)<br>|
| Experimental: Riociguat (Adempas, BAY63-2521) fixed 0.5 mg<br>Participants received riociguat 0.5 mg tid (fixed dose). | Drug: Riociguat (Adempas, BAY63-2521)<br>* fixed 0.5 mg three times a day<br>|
| Placebo Comparator: Placebo<br>Participants received placebo tid. | Drug: Placebo<br>* Placebo three times a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pulmonary Artery Mean Pressure (PAPmean) at Rest - Change From Baseline to Week 16 | Mean pulmonary arterial pressure (PAPmean) is a directly measured hemodynamic parameter. PAPmean is recorded during a right heart catheterization. | Baseline and visit 6 (16 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Venous Oxygen Saturation (SvO2) - Change From Baseline to Week 16 | The mixed venous oxygen saturation rate (SvO2) is a directly measured hemodynamic parameter. SvO2 is recorded during a right heart catheterization. | Baseline and visit 6 (16 weeks) | 
| Pulmonary Vascular Resistance (PVR) - Change From Baseline to Week 16 | The pulmonary vascular resistance (PVR) is a calculated hemodynamic parameter. PVR is derived from the directly measured parameters mean pulmonary arterial pressure (PAPmean) and pulmonary capillary wedge pressure (PCWP), divided by the cardiac output (CO). PVR and PAPmean are acquired during a right heart catheterization. CO is a calculated hemodynamic parameter, too. Formula: PVR = 80*(PAPmean - PCWP)/CO | Baseline and visit 6 (16 weeks) | 
| Pulmonary Vascular Resistance Index (PVRi) - Change From Baseline to Week 16 | The pulmonary vascular resistance index (PVRi) is a calculated hemodynamic parameter. PVRi is derived from the pulmonary vascular resistance (PVR) normalized by the body surface area (BSA). Formula: PVRi = 80*(PAPmean - PCWP)*BSA/CO | Baseline and visit 6 (16 weeks) | 
| Systemic Vascular Resistance (SVR) - Change From Baseline to Week 16 | The systemic vascular resistance (SVR) is a calculated hemodynamic parameter. SVR is derived from the directly measured parameter mean right atrial pressure (RAPmean) and the calculated parameter mean systemic arterial pressure (SAPmean) divided by the cardiac output (CO). RAPmean is acquired during a right heart catheterization. CO is a calculated hemodynamic parameter, too. Formula: SVR = 80*(SAPmean - RAPmean)/CO | Baseline and visit 6 (16 weeks) | 
| Systemic Vascular Resistance Index (SVRi) - Change From Baseline to Week 16 | The systemic vascular resistance index (SVRi) is a calculated hemodynamic parameter. SVRi is derived from the systemic vascular resistance (SVR) normalized by the body surface area (BSA). Formula: SVRi = 80*(SAPmean - RAPmean)*BSA/CO | Baseline and visit 6 (16 weeks) | 
| Transpulmonary Pressure Gradient (TPG) - Change From Baseline to Week 16 | The transpulmonary pressure gradient (TPG) is a calculated hemodynamic parameter. TPG is calculated from the directly measured parameters mean pulmonary arterial pressure (PAPmean) and pulmonary capillary wedge pressure (PCWP). These 2 parameters are acquired during a right heart catheterization. Formula: TPG = PAPmean - PCWP | Baseline and visit 6 (16 weeks) | 
| Pulmonary Capillary Wedge Pressure (PCWP) - Change From Baseline to Week 16 | Pulmonary capillary wedge pressure (PCWP) is a directly measured hemodynamic parameter acquired during a right heart catheterization. | Baseline and visit 6 (16 weeks) | 
| Tricuspid Annular Plane Systolic Excursion (TAPSE) - Change From Baseline to Week 16 | The tricuspid annular plane systolic excursion (TAPSE) is a measured echocardiography parameter. It is acquired during a non-invasive echocardiography examination. | Baseline and visit 6 (16 weeks) | 
| Systolic Pulmonary Arterial Pressure (PAPsyst) - Change From Baseline to Week 16 | Systolic pulmonary arterial pressure (PAPsyst) is a directly measured hemodynamic parameter acquired during a right heart catheterization. | Baseline and visit 6 (16 weeks) | 
| Left Ventricular Ejection Fraction (LVEF) - Change From Baseline to Week 16 | The left ventricular ejection fraction work index (LVEF) is a calculated echocardiography parameter. LVEF is derived from the directly measured parameters left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV). These 2 parameters are acquired during a non-invasive echocardiography examination. Formula: LEVF = 100*(LVEDV - LVESV)/LVEDV | Baseline and visit 6 (16 weeks) | 
| Left Ventricular End-systolic Volume (LVESV) - Change From Baseline to Week 16 | Left ventricular end-systolic volume (LVESV) is a measured echocardiography parameter. It is acquired during a non-invasive echocardiography examination. | Baseline and visit 6 (16 weeks) | 
| Left Ventricular End-diastolic Volume (LVEDV) - Change From Baseline to Week 16 | Left ventricular end-diastolic volume (LVEDV) is a measured echocardiography parameter. It is acquired during a non-invasive echocardiography examination. | Baseline and visit 6 (16 weeks) | 
| E-wave Deceleration Time - Change From Baseline to Week 16 | E-wave deceleration time is a measured echocardiography parameter. It is acquired during a non-invasive echocardiography examination. | Baseline and visit 6 (16 weeks) | 
| Ratio of Mitral Peak Velocity of Early Filling to Mitral Peak Velocity of Late Filling (E/A) - Change From Baseline to Week 16 | E/A ratio is a measured echocardiography parameter and describes the ratio of mitral peak velocity of early filling to mitral peak velocity of late filling. It is acquired during a non-invasive echocardiography examination. | Baseline and visit 6 (16 weeks) | 
| 6-minute Walking Distance (6MWD) - Change From Baseline to Week 16 | 6-minute walking distance (6MWD) is a measure for the objective evaluation of a patient's functional exercise capacity. | Baseline and visit 6 (16 weeks) | 
| WHO (World Health Organization) Functional Class - Change From Baseline to Week 16 | The WHO functional assessment of pulmonary arterial hypertension ranged from functional class I (Patients with PH but without resulting limitation of physical activity) to class IV (Patients with PH with inability to carry out any physical activity without symptoms. These patients manifest signs of right-heart failure.). Changes to a lower WHO functional class resemble improvement, changes to a higher functional class resemble deterioration of PAH. | Baseline and visit 6 (16 weeks) | 
| Percentage of Participants With Clinical Worsening | The combined endpoint time to clinical worsening, made up of the following components, defined by the first occurrence: all cause mortality, including cardiovascular mortality; first hospitalization for a cardiovascular event, including heart failure, acute myocardial infarction, stroke or ventricular arrhythmia; upgrade of the HTx (heart transplantation) status to next higher level; need for IV diuretics; persistent worsening of WHO functional class due to deterioration of PH or cardiac function. | At visit 6 (16 weeks) | 
| Borg CR 10 Scale - Change From Baseline to Week 16 | The Borg CR10 Scale is a patient reported outcome measure used in clinical diagnosis of e.g. breathlessness and dyspnea. It documents the patient's exertion during a physical test. Low values indicate low levels of exertion, high values indicate more intense exertion reported by the patient. The score ranges from 0 (Nothing at all) to 10 (Extremely strong - Maximal). | Baseline and visit 6 (16 weeks) | 
| EQ-5D Utility Score - Change From Baseline to Week 16 | EQ-5D utility score is a Quality-of-Life patient reported outcome measure. An increase in the utility score represents an improvement in quality of life. The score ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). | Baseline and visit 6 (16 weeks) | 
| Minnesota Living With Heart Failure Questionnaire (MLHF) Score - Change From Baseline to Week 16 | The self-reported Minnesota Living with Heart Failure questionnaire (MLHF) is designed to measure the effects of PH and PH-specific treatments on an individual's quality of life. The MLHF total score can range from 0 (best) to 105 (worst). | Baseline and visit 6 (16 weeks) | 
| Cystatin C - Change From Baseline to Week 16 | Cystatin C is a biomarker for predicting new onset or deteriorating cardiovascular disease. | Baseline and visit 6 (16 weeks) | 
| N-terminal Pro-brain Natriuretic Peptide (NT-pro BNP) - Change From Baseline to Week 16 | N-terminal pro-brain natriuretic peptide (NT-pro BNP) levels in the blood are used for screening, diagnosis of acute congestive heart failure (CHF) and may be useful to establish prognosis in heart failure. | Baseline and visit 6 (16 weeks) | 
| Troponin T - Change From Baseline to Week 16 | Troponin T is a cardiac-specific protein which is released from damaged or injured heart muscle cells. | Baseline and visit 6 (16 weeks) | 
| Asymmetric Dimethylarginine (ADMA) - Change From Baseline to Week 16 | Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxides. Recent clinical studies have indicated that ADMA may have diagnostic relevance as a novel cardiovascular risk marker. | Baseline and visit 6 (16 weeks) | 
| Osteopontin - Change From Baseline to Week 16 | Osteopontin is a cytokine-like pro-fibrotic mediator, which is expressed in cardiovascular tissues. Its expression is induced by increased pressure and volume load in the myocardium, kidney and lung. Therefore, osteopontin may be used as a prognostic marker in patients with cardiovascular diseases. | Baseline and visit 6 (16 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary Hypertension, Left ventricular dysfunction