A study to evaluate whether macitentan is an effective and safe treatment for patients with heart failure with preserved ejection fraction and pulmonary vascular disease
- Conditions
- Heart failure with preserved ejection fraction and pulmonary vascular diseaseMedDRA version: 19.1Level: LLTClassification code 10076396Term: Heart failure with preserved ejection fractionSystem Organ Class: 100000004849Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]
- Registration Number
- EUCTR2016-003653-15-ES
- Lead Sponsor
- ACTELION Pharmaceuticals Ltd
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 142
1. Signs or symptoms of heart failure requiring treatment with at least one oral diuretic (any type)
2. LVEF = 40% (by echocardiography at screening)
3. NYHA FC II to III
4. Subjects with at least one of the following:
a. HF hospitalization (defined as HF as the major reason for hospitalization or treatment for HF lasting > 12 hours and/or including i.v. diuretics at a healthcare facility) within 12 months prior to Screening
b. Cardiac catheterization performed within 6 months prior to Screening showing end-expiratory PAWP or LVEDP > 15 mmHg
c. Patients with structural heart disease defined as either one of the following by echocardiography at Screening:
i. Left atrial (LA) enlargement:
• Left atrial volume (LAV) > 58 ml (male) / > 52 ml (female) or
• Left atrial volume index (LAVI) = 28 ml/m2, or
• LA area > 20 cm2, or
• LA diameter > 4.0 cm (male) / > 3.8 cm (female)
ii. Left ventricular septal thickness or posterior wall thickness >= 1.1 cm
5. Elevated NT-proBNP / BNP: = 250 / 75 pg/mL for subjects in sinus rhythm or = 1000 / 300 pg/mL for subjects with atrial fibrillation (AF) at any time within 3 months prior to Screening
6. Pulmonary vascular disease or RV dysfunction meeting at least one of the following echocardiographic (at screening) and/or right heart catheterization (RHC) parameters (within 6 months prior to Screening):
a. Echocardiographic peak TR velocity > 2.8 m/s or invasive mPAP = 25 mmHg or invasive PASP > 40 mmHg (RHC) and evidence of RV dysfunction (TAPSE < 17 mm or RV fractional area change < 35% or RV tissue Doppler s’ velocity < 9.5 cm/s)
b. Diastolic Pulmonary Vascular Pressure Gradient (DPG) > 5 mmHg (RHC)
c. PVR > 3 Wood Units (RHC)
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 60
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 240
1. Any prior measurement of LVEF < 40%.
Cardiovascular comorbidities:
2. Significant unrepaired structural valvular heart disease (i.e., greater than mild aortic or mitral stenosis, and greater than moderate aortic or mitral regurgitation).
3. Hypertrophic, restrictive, and infiltrative cardiomyopathies.
4. Pericardial disease.
5. Acute coronary syndrome, including ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI) or unstable coronary artery disease or has undergone coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI) within 3 months of Screening.
6. Known indication for PCI or CABG.
7. Uncontrolled heart rate (HR) from atrial fibrillation or atrial flutter (> 110 beats per minute) as assessed by ECG.
8. History of serious life-threatening or hemodynamically significant arrhythmias, including symptomatic or sustained ventricular tachycardia or defibrillator shock within 12 month(s) of Screening.
9. History of or anticipated heart transplant or anticipated/implanted ventricular assist device.
10. Transient ischemic attack (TIA) or stroke within 3 months of Screening.
11. Systolic blood pressure (SBP) = 180 mmHg1 or diastolic blood pressure (DBP) = 110 mmHg.
Other causes of right heart failure not associated with left ventricular dysfunction:
12. Significant parenchymal lung disease fulfilling any of the following:
a. Forced expiratory volume in 1 second / forced vital capacity (FEV1/FVC ratio) < 0.7 associated with FEV1 < 50% of predicted value after bronchodilator administration
b. Known moderate or severe restrictive lung disease, e.g., total lung capacity (TLC) < 60% (predicted)
c. Clinical suspicion of diffuse interstitial fibrosis or alveolitis, unless excluded by high resolution computed tomography (CT)
d. Clinical suspicion of pulmonary thromboembolism within 12 months prior to Screening, unless excluded by ventilation/perfusion (V/Q) scan or computed tomography angiography (CTA)
13. Severe renal dysfunction with an estimated Glomerular Filtration Rate (eGFR) < 30 mL/min per 1.73 m2 using the Modification of Diet in Renal Disease (MDRD) formula.
14. Known and documented severe hepatic impairment, e.g., Child Pugh Class C.
15. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) = 3 × the upper limit of normal (ULN) at Screening.
16. Hemoglobin < 100g/L (< 10 g/dl) at Screening.
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: 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;Secondary Objective: The secondary objective of the study is to evaluate the effect of macitentan 10 mg as compared to placebo on:<br>– Daily physical activity<br>– Quality of life<br>– Worsening of heart failure;Primary end point(s): Primary efficacy endpoint(s)<br>• Percent of baseline NT-proBNP assessed at Week 24;Timepoint(s) of evaluation of this end point: Week 24
- Secondary Outcome Measures
Name Time Method Secondary end point(s): Secondary efficacy endpoints<br>• 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<br>• Change from baseline to Week 24 in the clinical summary score (as assessed by the Kansas City Cardiomyopathy Questionnaire [KCCQ])<br>• Time to worsening heart failure (WHF) event over 52 weeks;Timepoint(s) of evaluation of this end point: Week 24, Week 52