Evaluation of Hemodynamic Effects and Safety of Riociguat in Patients with Pulmonary Hypertension Due to Left Ventricular Systolic Dysfunction
- Trial ID
- 2023-507001-34-00
- Protocol
- 14308
- Sponsor
- Bayer AG
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **hemodynamic** profile of **Riociguat** in patients with symptomatic pulmonary hypertension associated with left ventricular systolic dysfunction (PH-sLVD). This is clinically relevant as it aims to evaluate the potential of Riociguat to improve cardiovascular function in a population with compromised heart function due to PH-sLVD.
The secondary objectives of this study are to assess the safety, tolerability, and pharmacokinetic profile of Riociguat in the same patient population. Additionally, the study seeks to explore appropriate doses and potential endpoints for a subsequent phase III trial. These objectives are crucial for determining the overall therapeutic potential and safety of Riociguat, guiding future clinical development and ensuring patient safety.
Participants
The clinical trial involves a total of **139 participants** who are symptomatic with **pulmonary hypertension** associated with left ventricular systolic dysfunction (PH-sLVD). The study population includes both male and female subjects, aged between **18 to 80 years**. Participants were selected based on their diagnosis of PH-sLVD, which is characterized by a left ventricular ejection fraction (LVEF) of 40% or less and a mean pulmonary arterial pressure (PAPmean) of 25 mmHg or more at rest. The trial includes individuals with ischemic heart disease or dilated cardiomyopathy, and transplant candidates are also eligible. Participants must have been pre-treated and maximally titrated with optimized chronic heart failure (CHF) therapy according to established guidelines, with stable medication regimens prior to randomization. The study population is considered vulnerable, and all participants provided written informed consent. Lifestyle considerations such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, placebo-controlled, parallel-group, multi-center study** to evaluate the hemodynamic effects of **Riociguat** in patients with **pulmonary hypertension** associated with left ventricular systolic dysfunction (PH-sLVD). The primary objective is to assess the hemodynamic profile of Riociguat in this patient population. The trial is expected to run until December 31, 2025, with recruitment having started on April 14, 2010. Participants will be involved in the study for a maximum treatment period of 815 days, during which they will receive either Riociguat or a placebo in the form of film-coated tablets administered orally.
The study includes several key visits: an initial screening visit, multiple follow-up visits, and an end-of-study visit. During the **screening visit**, eligibility criteria are assessed, including age, symptomatic status, and previous treatment regimens. Participants must be between 18 and 80 years old and have a confirmed diagnosis of PH-sLVD, with specific hemodynamic parameters measured by right heart catheterization. Follow-up visits are scheduled to monitor changes in pulmonary artery mean pressure, venous oxygen saturation, and other hemodynamic and clinical parameters. The **end-of-study visit** will evaluate the overall safety and efficacy of the treatment.
Participants are expected to adhere to the study protocol, including stable dosing of concomitant medications and regular attendance at study visits. Conditions that may lead to early termination from the study include non-compliance with the study protocol, adverse events, or withdrawal of consent. The trial aims to provide comprehensive data on the safety and efficacy of Riociguat in improving hemodynamic parameters and quality of life in patients with PH-sLVD.
Treatment
The clinical trial involves the administration of **Riociguat Bayer**, a **film-coated tablet** containing the active substance **riociguat**. This medication is a small molecule developed by Bayer AG, with the sponsor product code BAY 632521. The pharmaceutical form is a film-coated tablet, and the route of administration is oral. The maximum daily dose is 6 mg, with a total maximum dose of 34.45 mg over a treatment period of up to 815 days. The medication is not a paediatric formulation and is not classified as an orphan drug. The chemical origin of the active substance is confirmed, and the product is authorized for use in the trial.
In addition to the experimental medication, a **placebo** is used as a comparator in this study. The placebo is designed to match the experimental treatment in appearance but does not contain the active substance **riociguat**. The placebo is administered in the same manner as the active treatment, ensuring the study remains double-blind and placebo-controlled. The placebo's pharmaceutical form and route of administration are not specified, but it is implied to be consistent with the active treatment to maintain the study's integrity.
Efficacy
The efficacy of Riociguat in patients with symptomatic **pulmonary hypertension** associated with left ventricular systolic dysfunction (PH-sLVD) will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline to week 16 in pulmonary artery mean pressure (PAPmean) at rest. This will be measured using right heart catheterization (RHC), a standard procedure for evaluating hemodynamic parameters in patients with pulmonary hypertension.
Secondary endpoints include changes from baseline in several hemodynamic and functional parameters. These include venous oxygen saturation (SvO2), pulmonary vascular resistance (PVR), systemic vascular resistance (SVR), transpulmonary pressure gradient (TPG), and pulmonary capillary wedge pressure (PCWP), all measured by RHC. Additionally, echocardiography will be used to assess changes in tricuspid annular plane systolic excursion (TAPSE), systolic pulmonary arterial pressure (PAPsyst), left ventricular ejection fraction (LVEF), and other related metrics.
Functional capacity and quality of life will be evaluated through changes in the 6-minute walking distance (6MWD), Borg CR 10 scale, EQ-5D questionnaire, and the Minnesota Living with Heart Failure Questionnaire (MLHF). Biomarkers such as N-terminal pro-brain natriuretic peptide (NT-pro BNP), troponin T, asymmetric dimethyl arginine (ADMA), and osteopontin will also be monitored. The study will consider events of special interest for the calculation of the combined endpoint "time to clinical worsening," as well as all-cause mortality and a composite endpoint of time to death from cardiovascular causes or first hospitalization for a cardiovascular event.
Inclusion and Exclusion 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-sLVD (group 2 / 2.1 of Dana Point Classification and World Health Organization [WHO] class II-IV) due to ischemic heart disease or dilated cardiomyopathy (DCM). Transplant candidates can be included. (Other groups of pulmonary hypertension, especially CTEPH, must have been ruled out according to accepted diagnostic procedures and guidelines, see section 5.1.2 Exclusion criteria.) PH-sLVD is defined as: - LVEF ≤ 40%, diagnosed by echocardiography, radionuclide ventriculography or left heart catheter (LHC) exam within 30 days before randomization, or in the baseline echocardiography (Note: the definition of PH-sLVD was changed in amendment 3 see section 13.2.1.2) - PAPmean ≥ 25 mmHg at rest, measured by right heart catheter (RHC)
- Subjects must be pre treated and individually maximally titrated with optimized CHF therapy according to European Society of Cardiology (ESC) (9), American College of Cardiology/American Heart Association (ACC/AHA) (10) or Japanese Circulation Society (11) guidelines with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), beta blockers and mineralocorticoid receptor (MR) antagonists as clinically indicated. The dose regimen must have been stable for > 30 days prior to randomization. Diuretic therapy must have been stable for ≥ 1 week before performing baseline RHC.
- RHC results for the definite diagnosis of PH not older than 1 week at Visit 1. RHC must have been performed in the participating centre under standardized conditions (refer to the study specific right heart catheterization manual).
- Left heart catheter results available any time prior to randomization to judge if left-heart disease is caused by ischemic heart disease or dilated cardiomyopathy
- A negative stress test must have been performed < 1 year prior to randomization according to guidelines (stress electrocardiography [ECG], stress echocardiography, stress scintigraphy) to exclude overt or silent ischemia.
- 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 serological 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 duration of the study.
- Subject is able to understand and follow instructions and is able to participate in the study for the entire period
- Written informed consent.
Exclusion Criteria
- PH in groups other than group 2.1 according to Dana Point classification (2). In particular, CTEPH must have been ruled out according to accepted diagnostic procedures and guidelines.
- Cardiac decompensation, either with hospitalization or visit to the emergency department, ≤ 30 days prior to randomization
- Resynchronization therapy initiated ≤ 90 days prior to randomization
- Need of intravenous (IV) diuretics ≤ 30 days prior to randomization
- Treatment with IV inotropes or IV vasodilators ≤ 30 days prior to randomization
- Chronic treatment with endothelin receptor antagonists (ERAs), phosphodiesterase type 5 (PDE5) inhibitors or prostanoids ≤ 30 days prior to randomization, or with nitrates ≤ 7 days prior to randomization (PDE5 inhibitors ≤ 7 days prior to randomization if indicated for erectile dysfunction)
- 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 one second (FEV1) < 60% of predicted
- Restrictive lung disease with total lung capacity (TLC) < 60% of predicted
- Subjects on O2 therapy
- Severe congenital abnormalities of the lungs, thorax or diaphragm
- Clinically relevant hepatic dysfunction indicated by either: - aspartate aminotransferase (AST) ≥ 3 times the upper limit of normal (ULN) - Child Pugh stage B and C in cirrhotic patients.
- Severe renal impairment (glomerular filtration rate [GFR] < 30 mL/min calculated by Modification of Diet in Renal Disease [MDRD] formula)
- Uncontrolled arterial hypertension (systolic blood pressure [SBP] > 180 mmHg or diastolic blood pressure [DBP] > 110 mmHg)
- SBP < 100 mmHg at baseline or clinical signs or symptoms of hypotension (Note: limit changed and additional text added in amendment 3 see section 13.2.1.3)
- Myocardial disease other than ischemic or dilatative, such as 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 less than 90 days prior to randomization
- Reperfusion procedure (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG]) less than 90 days prior to randomization, or less than 3 weeks in case of a negative stress test after PCI
- Stroke with persistent neurological deficit or known hemodynamically relevant symptomatic carotid artery stenosis
- Subjects positive for human immunodeficiency virus (HIV)
- Resting heart rate (HR) while awake of < 50 beats per minute (BPM) or > 105 BPM (in case of atrial fibrillation > 110 BPM)
- Investigational treatment in another clinical trial during the preceding 30 days
- 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 4 month main study
- Subjects with underlying medical disorders with an anticipated life expectancy below 2 years not due to cardiac conditions (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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Not Recruiting | 14 Apr 2010 | 25 |
 Germany | Not Recruiting | 14 Apr 2010 | 28 |
 Italy | Not Recruiting | 14 Apr 2010 | 15 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Riociguat Bayer | Test | FILM-COATED TABLET | ORAL | 6 | 815 | PRD10153664 |
Riociguat Bayer | Test | FILM-COATED TABLET | ORAL | 6 | 815 | PRD10153667 |
Placebo for riociguat | Placebo | N/A | — | — | — | N/A |
Riociguat Bayer | Test | FILM-COATED TABLET | ORAL | 6 | 815 | PRD10153666 |