| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients symptomatic with pulmonary hypertension associated with left ventricular systolic dysfunction (PH-sLVD) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10037406 |
| E.1.2 | Term | Pulmonary hypertension secondary |
| E.1.2 | System Organ Class | 100000004855 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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).
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to assess safety, tolerability and pharmacokinetic profile of Riociguat in patients with symptomatic pulmonary hypertension associated with left ventricular systolic dysfunction (PH-sLVD), and to explore doses and potential endpoints for phase III
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must fulfill the following criteria to be eligible for this study:
•• 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.
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| E.4 | Principal 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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint will be the change from baseline to week 16 in PAPmean at rest. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| the double blind phase of the trial will be followed by an open label extension phase |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 34 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Austria |
| Canada |
| China |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Italy |
| Japan |
| Netherlands |
| Poland |
| Singapore |
| Spain |
| Switzerland |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| Last patient completed the study |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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