A multi-center, double-blind, placebo-controlled Phase 2b study to evaluate the efficacy and safety of macitentan in subjects with heart failure with preserved ejection fraction and pulmonary vascular disease
- Conditions
- I27.8Other specified pulmonary heart diseases
- Registration Number
- DRKS00013360
- Lead Sponsor
- Actelion Pharmaceuticals Ltd.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Recruiting stopped after recruiting started
- Sex
- All
- Target Recruitment
- 143
1. Signed informed consent prior to any study-mandated procedure 2. Male or female subjects = 18 years of age 3. Signs or symptoms of heart failure (HF) requiring treatment with at least one oral diuretic (any type) 4. Left ventricular ejection fraction (LVEF) = 40% (by echocardiography at Screening) 5. New York Heart Association (NYHA) functional class (FC) II to III 6. 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 intravenous (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 7. Patients with HFpEF defined as either one of the following by echocardiography at Screening: a. Left atrial (LA) enlargement: i. Left atrial volume > 58 mL (male) / > 52 mL (female) or ii. Left atrial volume index = 28 mL/m2, or iii. LA area > 20 cm2, or iv. LA diameter > 4.0 cm (male) / > 3.8 cm (female)
b. Left ventricular septal thickness or posterior wall thickness = 1.1 cm 8. 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 or at Screening 9. Pulmonary vascular disease or right ventricular (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 (RHC) or PASP > 40 mmHg 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. Pulmonary vascular resistance (PVR) > 3 Wood Units (RHC) 10. A woman of childbearing potential must have a negative pre-treatment serum pregnancy test, agree to use reliable contraception from at least 30 days prior to Visit 2 up to at least 30 days after study treatment discontinuation, and agree to undertake monthly pregnancy tests from Screening up to at least 30 days after study treatment discontinuation.
Disease-related 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-STsegment 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 mmHg 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. Body mass index = 45 kg/m2 at Screening 14. Clinically significant congenital heart disease that could be the cause of the patient’s symptoms and signs of HF. Criteria related to macitentan use: 15. Administration of pulmonary arterial hypertension specific therapy (i.e., endothelin receptor antagonists, prostanoids, phosphodiesterase-5 [PDE-5] inhibitors, guanylate cyclase stimulators) within 1 month prior to Screening 16. Hypotension, i.e., SBP < 90 mmHg or DBP < 50 mmHg 17. 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 18. Known and documented severe hepatic impairment, e.g., Child-Pugh Class C 19. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) = 3 the upper limit of normal at Screening 20. Hemoglobin 100 g/L (< 10 g/dl) at Screening 21. Plan to become pregnant or lactating 22. Treatment with strong cytochrome P-450 3A4 (CYP3A4) inducers such as rifabutin, rifampin, rifampicin, rifapentin, carbamazepine, phenobarbital, phenytoin, or St. John’s wort within 1 month prior to Screening 23. Treatment with strong CYP3A4 inhibitors such as ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir within 1 month prior to Screening 24. Treatment with the following breast-cancer resistant protein (BCRP) substrates within 1 month prior to Screening: methotrexate,
Study & Design
- Study Type
- interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method To evaluate whether macitentan 10 mg reduces n-terminal pro-brain natriuretic peptide (NT-pro_BNP) versus placebo at Week 24 in subjects with heart failure with preserved ejection fraction (HFpEF) and pulmonary vascular disease.
- Secondary Outcome Measures
Name Time Method To evaluate the effect of macitentan 10mg as compared to placebo on: <br>* daily physical activity<br>* Quality of life<br>* Worsening of heart failure<br>