| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pulmonary hypertension and heart failure with preserved ejection fraction |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pulmonary hypertension and heart failure with preserved ejection fraction |
| Lungenhochdruck in Verbindung mit einer Herzinsuffizienz und erhaltener Linksventrikelfunktion |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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 |
|
| E.2.2 | Secondary objectives of the trial |
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 |
|
| 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 and HF-PEF (group 2 / 2.2 of Dana Point classification 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 of the protocol)
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 (refer to the study-specific Swan-Ganz catheterization manual).
- 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 of the protocol
- 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
- Men enrolled in this study must agree to use adequate barrier birth control measures during the treatment period of the study and inform their sexual partners during the study period and three months beyond their study participation about the possibility of foetal impairment.
- Able to understand and follow instructions and to participate in the study for its entire duration
- Written informed consent
|
|
| E.4 | Principal exclusion criteria |
- PH in groups other than group 2.2 according to Dana Point classification
- 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 of study protocol) 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
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline of cardiac output (CO) at rest, measured by right heart catheter (RHC) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Baseline and after 26 weeks of study drug treatment |
|
| E.5.2 | Secondary end point(s) |
- Change from baseline in left atrial area, right ventricular volume, and right ejection fraction, measured by CMRI
- Change from baseline in PVR, SVR, TPG, and PAWP, measured by RHC
- Change from baseline in WHO class
- Change from baseline in cardiac biomarkers NT-pro BNP |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Baseline and after 26 weeks of study drug treatment |
|
| 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 | Yes |
| 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 | No |
| 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 | 2 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| 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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