EUCTR2014-004786-25-DE进行中（未招募）1 期
Prospective, multi-center, double-blind, randomized, active-controlled, triple-dummy, parallel-group, group-sequential, adaptive Phase 3 clinical study to compare the efficacy and safety of macitentan and tadalafil monotherapies with the corresponding fixed dose combination in subjects with pulmonary arterial hypertension (PAH), followed by an open-label treatment period with macitentan and tadalafil fixed dose combination therapy
适应症
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 250
研究概览
简要总结
暂无简介。
研究设计
- 研究类型
- Interventional clinical trial of medicinal product
入排标准
- 性别
- All
入选标准
- •1. Signed and dated ICF.
- •2. Male and female participants = 18 years old and = 75 years old.
- •3. Confirmed diagnosis of symptomatic PAH in WHO FC II or III.
- •4. Symptomatic PAH belonging to one of the following subgroups of WHO Group 1 pulmonary hypertension [Simonneau 2013]:
- •- Idiopathic.
- •- Heritable.
- •- Drug- or toxin-induced.
- •- Associated with one of the following:
- •o Connective tissue disease.
- •o HIV infection.
- •o Portal hypertension.
- •o Congenital heart disease with simple systemic-to-pulmonary shunt (atrial septal defect, ventricular septal defect, patent ductus arteriosus) with persistent pulmonary hypertension documented by a right heart catheterization (RHC) = 1 year after surgical repair.
- •5. PAH diagnosis confirmed by hemodynamic evaluation (based on central reading) at rest, evaluated within 5 weeks prior to randomization:
- •- Mean pulmonary artery pressure (mPAP) = 25 mmHg, AND
- •- Pulmonary artery wedge pressure (PAWP) or left ventricular end diastolic pressure (LVEDP) = 15 mmHg, AND
- •- Pulmonary vascular resistance (PVR) = 3 WU (i.e., = 240 dyn·sec·cm-5)
- •6. Negative vasoreactivity test in idiopathic, heritable, and drug/toxin-induced PAH (Patients for whom no vasoreactivity test was performed at diagnosis can be eligible if currently treated with PAH therapy for more than 3 months and PAH diagnosis confirmed by hemodynamic evaluation at least 3 months after introduction of their PAH therapy).
- •7. Currently receiving a stable dose of ERA or PDE-5i monotherapy for at least 3 months prior to baseline RHC, within the following prespecified doses below or no history of PAH-specific treatment:
- •- Bosentan: 250 mg total daily dose
- •- Macitentan: 10 mg total daily dose
- •- Ambrisentan: 10 mg total daily dose
- •- Sildenafil: 60–120 mg total daily dose
- •- Tadalafil: 40 mg total daily dose
- •- Vardenafil: 10 mg total daily dose
- •8. Participant able to perform the 6MWT with a minimum distance of 100 m and maximum distance of 450 m at Screening.
- •9. A woman of childbearing potential is eligible only if the following applies:
- •- Negative serum pregnancy test at Screening and a negative urine pregnancy test at Randomization.
- •- Agreement to undertake monthly urine pregnancy tests during the study and up to at least 30 days after study treatment discontinuation.
- •- Agreement to follow the contraception scheme from Screening up to at least 30 days after study treatment discontinuation.
- •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 187
- •F.1.3 Elderly (>=65 years) yes
- •F.1.3.1 Number of subjects for this age range 63
排除标准
- •PAH treatments:
- •1. Treatment with a soluble guanylate cyclase stimulator, L-arginine, any form of prostanoids or prostacyclin-receptor agonists (including oral, inhaled, or infused routes) in the 3-month period prior to start of treatment.
- •2. Treatment with combination therapy of ERA and PDE-5i in the 3-month period prior to start of treatment or history of intolerance to ERA and PDE-5i combination therapy.
- •3. Hypersensitivity to any of the study treatments or any excipient of their formulations.
- •Other therapies:
- •4. Treatment with a strong cytochrome P450 3A4 (CYP3A4) inducer (e.g., rifabutin, rifampin, rifampicin, rifapentin, carbamazepine, phenobarbital, phenytoin, St. John’s Wort) in the 1-month period prior to start of treatment.
- •5. Treatment with a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, elithromycin, nefazodone, ritonavir, or saquinavir) or a moderate dual CYP3A4/CYP2C9 inhibitor (e.g., fluconazole, amiodarone) or coadministration of a combination of moderate CYP3A4 and moderate CYP2C9 inhibitors in the 1-month period prior to start of treatment.
- •6. Treatment with doxazosin.
- •7. Treatment with any form of organic nitrate, either regularly or intermittently
- •8. Diuretic treatment initiated or dose changed within 1 week prior to the RHC or start of treatment.
- •9. Treatment with another investigational drug in the 3-month period prior to start of treatment.
- •Medical history/current medical conditions:
- •10. Body mass index (BMI) > 40 kg/m2 at Screening.
- •11. Known presence of three or more of the following risk factors for heart failure with preserved ejection fraction at Screening:
- •- BMI > 30 kg/m2.
- •- Diabetes mellitus of any type.
- •- Essential hypertension (even if well controlled).
- •- Coronary artery disease, i.e., any of the following:
- •o History of stable angina, or
- •o Known more than 50% stenosis in a coronary artery, or
- •o History of myocardial infarction, or
- •o History of or planned coronary artery bypass grafting and/or coronary artery stenting.
- •12. Known presence of moderate or severe obstructive lung disease (forced expiratory volume in 1 second [FEV1] / forced vital capacity [FVC] < 70%; and FEV1 < 65% of predicted after bronchodilator administration) any time prior to Screening.
- •13. Known presence of moderate or severe restrictive lung disease (total lung capacity or FVC < 60% of normal predicted value) any time prior to Screening.
- •14. Clinically significant aortic or mitral valve disease; pericardial constriction; restrictive or congestive leftsided cardiomyopathy; life-threatening cardiac arrhythmias; significant left ventricular dysfunction; or left ventricular outflow obstruction.
- •15. Known permanent atrial fibrillation.
- •16. Known or suspected uncontrolled thyroid disease (hypo- or hyperthyroidism).
- •17. Documented pulmonary veno-occlusive disease.
- •Criteria linked to macitentan/tadalafil use:
- •18. Hemoglobin < 100 g/L (<10 g/dL) at Screening.
- •19. Known severe hepatic impairment defined as Model for End-Stage Liver Disease (MELD) score = 19.
- •20. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 × upper limit of normal (ULN) at Screening.
- •21. Severe renal impairment (Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 equation [Levey 2009] calculated creatinine clearance < 30 mL/min) at Screening.
- •22. Systemic hypotension (systolic blood pressure [SBP] < 90 or diastolic blood pressure [DBP] < 50 mmHg)
研究者
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