A 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).
- Conditions
- Pulmonary Arterial HypertensionMedDRA version: 20.0Level: PTClassification code 10064911Term: Pulmonary arterial hypertensionSystem Organ Class: 10038738 - Respiratory, thoracic and mediastinal disordersTherapeutic area: Diseases [C] - Cardiovascular Diseases [C14]
- Registration Number
- EUCTR2014-004786-25-ES
- Lead Sponsor
- Actelion Pharmaceuticals Ltd.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 170
1. Signed and dated ICF.
2. Male and female subjects = 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 an RHC = 1 year after surgical repair.
5. PAH diagnosis confirmed by hemodynamic evaluation 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
7. No history of PAH-specific treatment or 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:
- 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. Subject 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 128
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 42
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, telithromycin, nefazodone, ritonavir, and saquinavir) 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 left-sided 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 Child Pugh Score C or a 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) at Screening or Randomization.
23. Systemic hypertension (SBP > 160 or DBP > 100 mmHg) at Screening.
24. Acute myocardial infarction or cerebrovascular event (e.g., strok
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Secondary Objective: • To evaluate the effect of the M/T FDC compared to the respective monotherapies on:<br>- Exercise capacity<br>- PAH symptoms and their impacts on subject’s life.<br>- WHO FC.<br>• To evaluate the safety and tolerability of the M/T FDC in the subject population.;Main Objective: 1. To evaluate the effect of the macitentan/tadalafil fixed dose combination (M/T FDC) vs macitentan 10 mg alone on PVR at EDBT in subjects with symptomatic WHO Group 1 PAH who are PAH-specific treatment-naïve or are currently being treated with an ERA as monotherapy.<br>2. To evaluate the effect of the M/T FDC vs tadalafil 40 mg alone on PVR at EDBT in subjects with symptomatic WHO Group 1 PAH who are PAH-specific treatment-naïve or are currently being treated with a PDE-5i as monotherapy.;Primary end point(s): • Change in PVR expressed as the ratio of the geometric means of end of double blind treatment (EDBT) to baseline.;Timepoint(s) of evaluation of this end point: end of double blind treatment (EDBT)
- Secondary Outcome Measures
Name Time Method Secondary end point(s): • Change from baseline to EDBT in 6-minute walk distance.<br>• Change from baseline to EDBT in PAH-SYMPACT™ Cardiopulmonary symptom domain score.<br>• Change from baseline to EDBT in PAH-SYMPACT™ Cardiovascular symptom domain score.<br>• Change from baseline to EDBT in PAH-SYMPACT™ Physical impact domain score.<br>• Change from baseline to EDBT in PAH-SYMPACT™ Cognitive/emotional impact domain score.<br>• Proportion of subjects with absence of worsening in WHO FC from baseline to EDBT.;Timepoint(s) of evaluation of this end point: end of double blind treatment (EDBT)