A prospective, multicenter, single-arm, open-label, phase 4 study to evaluate the effects of macitentan on Right vEntricular remodeling in Pulmonary ArterIal hypeRtension assessed by cardiac magnetic resonance imaging
- Conditions
- Pulmonary Arterial HypertensionElevated blood pressure in blood vessels in the lungs.10037454
- Registration Number
- NL-OMON45109
- Lead Sponsor
- Actelion Pharmaceuticals
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 15
1.Signed informed consent prior to any study-mandated procedure
2.Symptomatic pulmonary arterial hypertension (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
1.4.1 PAH associated with connective tissue disease
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) performed between Day -28 and Day 1 (inclusion RHC; RHC data obtained at study site within this time frame, prior to obtaining signed informed consent, are acceptable) showing:
• mPAP >= 25 mmHg and
o PCWP or LVEDP <= 12 mmHg and PVR >= 4 Wood Units (WU) (320 dyn.sec.cm-5) or
o 12 mmHg <= PCWP or LVEDP <= 15 mmHg and PVR >= 6WU (480 dyn.sec.cm-5)
6.6-minute walk distance (6MWD) >= 150 m during screening
7.For patients treated with oral loop diuretics, treatment dose must be stable since at least 1 month prior to the inclusion RHC.
8.For patients treated with PDE-5 inhibitors, treatment dose must be stable since at least 3 months prior to the inclusion RHC (initiation of PDE-5 inhibitors during screening is allowed after all screening assessments have been performed).
9.For patients treated with beta blockers, treatment dose must be stable since at least 1 month prior to the inclusion RHC.
10.Men or women >=18 and < 75 years. For patients aged >= 65 and < 75 years, an eligibility form will be submitted to a Steering Committee member who will reserve the right to exclude the patient.
11.Women of childbearing potential 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 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
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 (except for diagnosis of PAH) within 3 months prior to informed consent signature
8.Left atrial volume indexed for body surface area (BSA) >= 43mL/m2 by echocardiography or cardiac MRI
9.Moderate to severe left-heart valvular disease
10.History of pulmonary embolism or deep vein thrombosis
11.Presence of one or more of the following signs of relevant lung disease at any time up to screening:
o Diffusing capacity of the lung for carbon monoxide (DLCO) < 40% of predicted (eligible only if no or mild interstitial lung disease on computed tomography).
o FVC < 60% of predicted.
o Forced expiratory volume in one second (FEV1) < 60% of predicted.
12. Moderate to severe restrictive lung disease (i.e., total lung capacity < 60% of predicted value) at any time prior to enrollment.
13.Historical evidence of significant coronary artery disease established by:
o History of myocardial infarction or
o More than 50% stenosis in a coronary artery (by percutaneous coronary intervention or angiography) or
o Elevation of the ST segment on electrocardiogram or
o History of coronary artery bypass grafting or
o Stable angina
14. Known uncontrolled diabetes mellitus (in the opinion of the investigator)
15. Severe renal insufficiency (calculated creatinine clearance < 30 mL/min)
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 × ULN accompanied by an AST elevation > ULN at Screening.
19.Hemoglobin < 100g/L
20.Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 times the upper limit of the normal range
21.Need for dialysis
22.Responders to acute vasoreactivity test based on medical history
23.Prior use of endothelin receptor antagonists, stimulators of soluble guanylate cyclase or prostacyclin or prostacyclin analogs
24.Treatment with strong inducers of 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 endothelin receptor antagonist 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.MRI-incompatible permanent c
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>The study has two primary efficacy endpoints:<br /><br>• Change from baseline to Week 26 in Right Ventricular (RV) Stroke Volume<br /><br>(RVSV) assessed by cardiac MRI from pulmonary artery flow.<br /><br>• Ratio of Week 26 to baseline PVR assessed by RHC.<br /><br>RVSV is determined by the IAC. Assessors are blinded to the patient identity<br /><br>and to the date of image acquisition.</p><br>
- Secondary Outcome Measures
Name Time Method <p>In the same way as the primary endpoints, secondary endpoints are assessed at<br /><br>26 weeks. They consist in characteristics of the right ventricle and pulmonary<br /><br>vasculature, and in widely accepted tools to assess PAH progression:<br /><br>Change from baseline to Week 26 in:<br /><br>• RV End Diastolic Volume (RVEDV)<br /><br>• RV End Systolic Volume (RVESV)<br /><br>• RV Ejection Fraction (RVEF)<br /><br>• RV mass<br /><br>• 6MWD<br /><br>• WHO FC<br /><br>MRI variables and variables determined from pressure-volume relationship will<br /><br>be assessed by the IAC.</p><br>