E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Heart failure with preserved ejection fraction and pulmonary vascular disease |
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E.1.1.1 | Medical condition in easily understood language |
Left heart failure (inability of the heart to pump enough blood) may lead to increased pressure in the lung blood vessels. This increases the right heart workload and may lead to right heart failure. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10076396 |
E.1.2 | Term | Heart failure with preserved ejection fraction |
E.1.2 | System Organ Class | 100000004849 |
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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 the study is to evaluate whether macitentan 10 mg reduces NT-pro-BNP versus placebo at Week 24 in subjects with HFpEF and pulmonary vascular disease |
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E.2.2 | Secondary objectives of the trial |
The secondary objective of the study is to evaluate the effect of macitentan 10 mg as compared to placebo on: – Quality of life – Daily physical activity – Worsening of heart failure |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Signs or symptoms of Heart Failure (HF) (NYHA FC II and III) requiring treatment with at least one oral diuretic (any type) • Left Ventricular ejection fraction (LVEF) ≥ 40% (by echocardiography at Screening) • Structural heart disease consistent with heart failure with preserved ejection fraction (HFpEF) established by echocardiography at Screening • Elevated NT-proBNP • Pulmonary vascular disease or right ventricular dysfunction |
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E.4 | Principal exclusion criteria |
• Any prior valid measurement of LVEF < 40%. • Cardiovascular co-morbidities (e.g., significant unrepaired structural valvular heart disease; acute coronary syndrome, coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI) within 3 months of Screening; uncontrolled heart rate from atrial fibrillation or atrial flutter, history of serious life-threatening or hemodynamically significant arrhythmia; history of or anticipated heart transplant or ventricular assist device implantation, etc) • Systolic blood pressure (SBP) ≥ 180 mmHg, or diastolic blood pressure (DBP) ≥ 110 mmHg during Screening • Hemoglobin < 100g/L (< 10 g/dl). • Significant parenchymal lung disease (e .g., severe COPD, moderate or severe restrictive lung disease , diffuse interstitial fibrosis or alveolitis, pulmonary thromboembolism) • Severe renal dysfunction with an estimated Glomerular Filtration Rate (eGFR ) < 30 m L/min per 1.73 m2 • Severe hepatic impairment, e .g., Child Pugh Class C.
Other protocol-defined inclusion/exclusion criteria may apply. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary efficacy endpoint(s) • Percent of baseline NT-proBNP assessed at Week 24 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints • Change from baseline to Week 24 in the clinical summary score (as assessed by the Kansas City Cardiomyopathy Questionnaire [KCCQ]) • Change from baseline to Week 24 in accelerometer-assessed proportion of time spent in light to vigorous physical activity based on a threshold of > 100 activity counts per minute • Time to worsening heart failure (WHF) event over 52 weeks |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
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 | No |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 31 |
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 |
Argentina |
Austria |
Brazil |
Bulgaria |
Czech Republic |
Denmark |
France |
Germany |
Hungary |
Israel |
Poland |
Romania |
Russian Federation |
Spain |
Sweden |
United Kingdom |
United States |
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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
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Safety follow-up period or, if applicable, Post-treatment observation period have been completed. |
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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 | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |