Prospective, multicenter, open-label study evaluating the effects of first-line oral combination therapy of macitentan and tadalafil in patients with newly diagnosed pulmonary arterial hypertensio
- Conditions
- Therapeutic area: Diseases [C] - Respiratory Tract Diseases [C08]Pulmonary arterial hypertensionMedDRA version: 18.0 Level: PT Classification code 10064911 Term: Pulmonary arterial hypertension System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders
- Registration Number
- EUCTR2015-002078-19-FR
- Lead Sponsor
- ACTELION Pharmaceuticals France
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- Not specified
- Target Recruitment
- 46
1.Signed informed consent prior to any study-mandated procedure.
2.Male or female = 18 and = 75 years of age at screening.
3.Initial PAH diagnosis < 6 months prior to Day 1.
4.Right heart catheterization (RHC) performed between Day -28 and Day 1 (RHC data obtained at the study site within this time frame, but before the study, i.e., before signed informed consent, are acceptable), meeting all the following criteria:
•Resting mean pulmonary arterial pressure (mPAP) = 25 mmHg.
•Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) = 15 mmHg.
•PVR = 400 dyn·sec/cm5 (= 5 Wood units) if PCWP < 12 mmHg OR PVR = 500 dyn·sec/cm5 (= 6.25 Wood units) if PCWP in [12-15] mmHg.
•Negative vasoreactivity test mandatory in idiopathic PAH (at this or a previous RHC).
5.World Health Organization (WHO) Functional Class (FC) II to III.
6.PAH etiology belonging to one of the following groups:
•Idiopathic.
•Heritable.
•Anorexigens induced.
•Associated with one of the following:
o Connective tissue disease
o Congenital heart disease with simple systemic-to-pulmonary shunt (atrial septal defect, ventricular septal defect, patent ductus arteriosus) = 1 year after surgical repair
o HIV infection
7.6MWD = 50 m at screening.
8.Women of childbearing potential [defined in Section 4.5.1] must:
• Have a negative serum pregnancy test at the screening visit and a negative urine pregnancy test at the Day 1 visit, and
• Agree to perform monthly pregnancy tests up to 30 days after EOT2, and
• Agree to use reliable contraception [defined in Section 4.5.2] from screening up to 30 days after EOT2. Reliable contraception must be started at least 11 days prior to Day 1.
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 50
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 10
1.Any PAH-specific drug therapy [e. g. any endothelin receptor antagonist, phosphodiesterase-5 inhibitors (PDE-5i), soluble guanylate cyclase stimulator, prostacyclin, prostacyclin analog, or prostacyclin receptor agonist] at any time prior to Day 1 (single-dose administration for vasoreactivity testing is permitted; previous iloprost used intermittently for the treatment of digital ulcers or Raynaud’s phenomenon is permitted if stopped > 6 months prior to Day 1).
2.Subjects who changed the dose or discontinued calcium channel blockers within 3 months prior to Day 1.
3.Initiation of diuretics within 1 week prior to RHC.
4.Subjects on oral diuretics in whom the dose has not been stable for at least 1 week prior to RHC.
5.Treatment with other PDE-5i for erectile dysfunction.
6.Treatment with strong inducers of CYP3A4 (e.g., carbamazepine, rifampin, rifampicin, rifabutin, rifapentin, phenobarbital, phenytoin, and St. John’s wort) = 28 days prior to Day 1.
7.Treatment with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, boceprevir, telaprevir, saquinavir, lopinavir, fosamprenavir, darunavir, tipranavir, atazanavir, nelfinavir, amprenavir, indinavir) = 28 days prior to Day 1.
8.History of priapism.
9.Significant aortic and mitral valve disease.
10.Pericardial constriction.
11.Significant left ventricular dysfunction in the opinion of the investigator.
12.Life-threatening arrhythmia.
13.Uncontrolled hypertension.
14.Symptomatic coronary artery disease.
15.Cardio-pulmonary rehabilitation program based on exercise (planned, or started = 12 weeks prior to Day 1).
16.Body mass index (BMI) > 40 kg/m2 at screening.
17.Acute myocardial infarction = 12 weeks prior to Day 1.
18.Known permanent atrial fibrillation.
19.Low blood pressure < 90/50 mmHg at screening or Day 1.
20.Ongoing or planned treatment with nitrates and/or doxazosin.
21.Presence of = 1 of the following signs of relevant lung disease at any time prior to Day 1:
•DLCO < 40% of predicted value;
•FEV1/FVC < 70% and FEV1 < 65% of predicted after bronchodilator administration;
•Total Lung Capacity (TLC) < 60% of predicted.
22.Known or suspicion of pulmonary veno-occlusive disease (PVOD).
23.Severe renal insufficiency (estimated creatinine clearance = 30 mL/min/1.73m²) assessed by central laboratory at screening
24.Ongoing or planned dialysis.
25.Documented severe hepatic impairment (with or without cirrhosis) according to National Cancer Institute organ dysfunction working group criteria, defined as total bilirubin > 3 x ULN accompanied by AST > ULN (assessed by central laboratory at screening); and/or Child Pugh Class C.
26.Serum AST and/or ALT > 3 x ULN (assessed by central laboratory at screening).
27.Porto-pulmonary hypertension.
28.Hemoglobin < 100 g/L assessed by central laboratory at screening.
29.Hypersensitivity to any active substance or excipient of macitentan or tad
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: To document the effect of first line dual oral combination therapy with macitentan 10mg and tadalafil 40mg on pulmonary vascular resistance (PVR) in treatment-naïve patients with newly diagnosed pulmonary arterial hypertension (PAH).;Secondary Objective: To document the effect of a first line dual oral combination therapy with macitentan 10mg and tadalafil 40mg on cardio-pulmonary hemodynamic parameters other than PVR, on exercise capacity and disease severity, on NT-proBNP and on safety and tolerability in treatment-naïve patients with newly diagnosed PAH.;Primary end point(s): The primary endpoint is the ratio of Week 16 to baseline PVR.;Timepoint(s) of evaluation of this end point: Baseline and Week 16
- Secondary Outcome Measures
Name Time Method <br> Secondary end point(s): •Percentage of patients with clinically meaningful improvement of PVR (decrease = 30% from baseline to Week 16).<br> •Change from baseline to Week 16 in mean right atrial pressure (mRAP), mean pulmonary arterial pressure (mPAP), cardiac index (CI), total pulmonary resistance (TPR), and mixed venous oxygen saturation (SvO2), all measured at rest.<br> •Change from baseline to Week 16 in 6-minute walk distance (6MWD).<br> •Change from baseline to Week 16 in WHO functional class.<br> •Percentage of patients with improvement/worsening of WHO functional class from baseline to Week 16.<br> •Change in NT-proBNP from Baseline to Week 16.<br> ;Timepoint(s) of evaluation of this end point: Baseline and Week 16