Phase IV study on right ventricular remodeling in Pulmonary arterial hypertensio
- Conditions
- Pulmonary Arterial HypertensionMedDRA version: 18.0Level: SOCClassification code 10038738Term: Respiratory, thoracic and mediastinal disordersSystem Organ Class: 10038738 - Respiratory, thoracic and mediastinal disordersTherapeutic area: Diseases [C] - Cardiovascular Diseases [C14]
- Registration Number
- EUCTR2014-004066-20-IT
- Lead Sponsor
- ACTELION PHARMACEUTICALS LTD
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 100
1.Signed informed consent prior to any study-mandated procedure.
2.Symptomatic PAH.
3.World Health Organization (WHO) Functional Class (FC) I to III.
4.PAH etiology belonging to one of the following groups according to Nice classification:
1.1 Idiopathic PAH
1.2 Heritable PAH
1.3 Drug- and toxin-induced PAH
1.4.4 PAH associated with congenital heart diseases: only simple (atrial septal defect, ventricular septal defect, patent ductus arteriosus) congenital systemic to pulmonary shunts at least 2 year post surgical repair.
5.Hemodynamic diagnosis of PAH confirmed by right heart catheterization (RHC) during screening showing:
•Mean pulmonary arterial pressure (mPAP) = 25 mmHg and
oPulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) = 12 mmHg and pulmonary vascular resistance (PVR) = 4 Woods Units (WU) (320 dyn.sec.cm-5) or
o12 mmHg = PCWP or LVEDP = 15 mmHg and PVR = 6 WU (480 dyn.sec.cm-5).
6.6-minute walk distance (6MWD) = 150 m during screening.
7.For patients treated with oral diuretics, treatment dose must have been stable at least 1 month prior to RHC during the screening period.
8.For patients treated with phosphodiesterase type-5 (PDE-5) inhibitors, treatment dose must have been stable at least 3 months prior to RHC during the screening period.
9.For patients treated with beta blockers, treatment dose must have been stable at least 1 month prior to the RHC during the screening period.
10.Men or women = 18 and < 65 years.
11.Women of childbearing potential [see Section 4.5.1] must:
a.Have a negative serum pregnancy test during screening and a negative urine pregnancy test on Day 1, and
b.Agree to use reliable methods of contraception [see Section 4.5] from screening up to 30 days after study treatment discontinuation, and
Agree to perform monthly pregnancy tests up to 30 days after study treatment discontinuation.
b.Agree to use reliable methods of contraception [see Section 4.5] from screening up to 30 days after study treatment discontinuation, and
c.Agree to perform monthly pregnancy tests up to 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 100
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range
1.Body weight < 40 kg.
2.Body mass index (BMI) > 35kg/m2. For patients with 30kg/m2 < BMI < 35kg/m2, an eligibility form will be submitted to a Steering Committee member who will reserve the right to exclude the patient.
3.Pregnancy, breastfeeding, or intention to become pregnant during the study.
4.Recently started (< 8 weeks prior to informed consent signature) or planned cardio-pulmonary rehabilitation program.
5.Known concomitant life-threatening disease with a life expectancy < 12 months.
6.Any condition likely to affect protocol or treatment compliance.
7.Hospitalization for PAH within 3 months prior to informed consent signature.
8.Left atrial volume indexed for body surface area = 43mL/m2 by echocardiography or cardiac MRI.
9.Valvular disease grade 2 or higher.
10.History of pulmonary embolism or deep vein thrombosis.
11.Documented moderate to severe chronic obstructive pulmonary disease.
12.Documented moderate to severe restrictive lung disease.
13.Historical evidence of significant coronary artery disease established by:
oHistory of myocardial infarction or
oMore than 50% stenosis in a coronary artery (by percutaneous coronary intervention or angiography) or
oElevation of the ST segment on electrocardiogram or
oHistory of coronary artery bypass grafting or
oStable angina.
14.Diabetes mellitus.
15.Moderate to severe renal insufficiency (calculated creatinine clearance < 60 mL/min/1.73 m2).
16.Cancer.
17.Systolic blood pressure < 90 mmHg.
18.Severe hepatic impairment (with or without cirrhosis) according to National Cancer Institute organ dysfunction working group criteria, defined as total bilirubin > 3 × upper limit of the normal range (ULN) accompanied by an aspartate aminotransferase (AST) elevation > ULN at screening.
19.Hemoglobin < 100g/L.
20.Serum AST and/or alanine aminotransferase (ALT) > 3 × ULN.
21.Need for dialysis.
22.Responders to acute vasoreactivity test based on medical history.
23.Prior use of endothelin receptor antagonists (ERAs), stimulators of soluble guanylate cyclase or prostacyclin or prostacyclin analogues.
24.Treatment with strong inducers of cytochrome P450 isozyme 3A4 (CYP3A4) within 4 weeks prior to study treatment initiation (e.g., carbamazepine, rifampicin, rifabutin, phenytoin and St. John’s Wort).
25.Treatment with strong inhibitors of CYP3A4 within 4 weeks prior to study treatment initiation (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir).
26.Treatment with another investigational drug (planned, or taken within the 3 months prior to study treatment initiation).
27.Hypersensitivity to any ERA or any excipients of the formulation of macitentan (lactose, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, polyvinyl alcohol, polysorbate, titanium dioxide, talc, xanthan gum, and lecithin soya).
28.Claustrophobia.
29.Permanent cardiac pacemaker, automatic internal cardioverter.
30.Metallic implant (e.g., defibrillator, neurostimulator, hearing aid, permanent use of infusion device).
31.Atrial fibrillation, multiple premature ventricular or atrial contractions, or any other condition that would interfere with proper cardiac gating during MRI.
32.For patients enrolling in the metabolism sub-study only: glucose intolerance.
33.For patients enrolling in the biopsy sub-study only: PAH etiology belonging to Nice classification 1.4.4: PAH associated with congenital he
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: To evaluate the effect of macitentan on right ventricular and hemodynamic properties in patients with symptomatic pulmonary arterial hypertension (PAH).;Secondary Objective: To investigate the effect of macitentan on ventriculo-arterial coupling in patients with symptomatic PAH.<br>To evaluate the safety and tolerability of macitentan in patients with symptomatic PAH.<br>;Primary end point(s): Primary efficacy endpoints The study has two primary efficacy endpoints: -Change from baseline to Week 26 in Right Ventricular (RV) Stroke Volume (RVSV) assessed by cardiac MRI from pulmonary artery flow. -Ratio of Week 26 to baseline PVR assessed by RHC.;Timepoint(s) of evaluation of this end point: week 26
- Secondary Outcome Measures
Name Time Method Secondary end point(s): Change from baseline to Week 26 in: -RV End Diastolic Volume (RVEDV) - RV End Systolic Volume (RVESV) -RV Ejection Fraction (RVEF) -RV mass - Arterial elastance -RV end-systolic elastance -RV maximum isovolumic pressure -6MWD -WHO FC;Timepoint(s) of evaluation of this end point: week 26