A Phase 3 study to compare long-term efficacy and safety of macitentan 75 mg versus 10 mg in Pulmonary Arterial Hypertension.
- Conditions
- Pulmonary arterial hypertensionMedDRA version: 21.1Level: PTClassification code 10064911Term: Pulmonary arterial hypertensionSystem Organ Class: 10038738 - Respiratory, thoracic and mediastinal disordersTherapeutic area: Diseases [C] - Cardiovascular Diseases [C14]
- Registration Number
- EUCTR2019-002533-11-BG
- Lead Sponsor
- ACTELION Pharmacteuticals Ltd.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 900
1. Target population: = 18 (or the legal age of consent in the jurisdiction
in which the study is taking place) years of age.
2. Target population: Symptomatic PAH in WHO FC II, III, or IV.
3. Must sign an ICF (or their legally acceptable representative must sign)
indicating that he or she understands the purpose of, and procedures
required for, the study and is willing to participate in the study.
4. Target population: PAH subtype falling in one of the below
classifications:
- Idiopathic
- Heritable
- Drug- or toxin-induced
- Related to:
*Connective tissue disease,
*HIV infection,
*Portal hypertension
*Congenital heart disease with
o small/coincidental cardiac defect with systemic-to-pulmonary shunt
(eg, atrial septal defect, ventricular septal defect, patent ductus
arteriosus, atrioventricular septal defect) which does not account for the
elevated PVR or
o persistent PAH documented by an RHC = 1 year after simple systemicto
pulmonary shunt repair.
5. PAH diagnosis confirmed by hemodynamic evaluation at rest at any
time prior to Screening:
- Mean pulmonary artery pressure (mPAP) > 20 mm Hg, AND
- Pulmonary artery wedge pressure (PAWP) or left ventricular end
diastolic pressure (LVEDP) = 15 mm Hg, AND
- PVR = 3 Wood Units (ie, = 240 dyn·sec·cm-5).
6. Negative vasoreactivity test in idiopathic, heritable, and drug/toxininduced
PAH.
Patients for whom no vasoreactivity test was performed at diagnosis and
currently treated with PAH therapy for more than 3 months, must have a
confirmatory PAH diagnosis documented by hemodynamic evaluation at
least 3 months after introduction of their PAH therapy.
7. Able to perform the 6MWT with a minimum distance of 50 m and
maximum distance of 440 m at Screening. Patients able to walk more
than 440 m at screening are eligible if they are in WHO FC III or IV and
NT-proBNP level is = 300 ng/L at screening, based on central laboratory
results.
8. Patients already receiving PAH therapies (mono or combination
therapies) must be on a stable regimen b for at least 3 months prior to
screening visit and planned to be:
- If on ERA therapy: discontinued at randomization or start of run-in (ie,
last dose of ERA taken the day before initiating study intervention),
- If on PAH therapy other than ERA: maintained on top of the study
intervention.
9. Must sign a separate informed consent form (or their legally-acceptable representative must sign) if he or she agrees to provide optional samples for biomarker research (where local regulations permit). Refusal to give consent for the optional biomarker research samples does not exclude a participant from participation in the study.
10. A female participant of childbearing potential must have a negative highly sensitive serum (ß-human chorionic gonadotropin [ß-hCG]) test at Screening and a negative urine pregnancy test prior to receiving their first dose of study intervention (i.e. either at beginning of the run-in period or prior to randomization [see Section 4.1]).
11. A female participant must be (as defined in Appendix 6 (Contraceptive and Barrier Guidance and Collection )
a) Not of childbearing potential,
b) Of childbearing potential and
- Practicing a highly effective, preferably user-independent method of contraception (failure rate of < 1% per year when used consistently and correctly) and agrees to remain on a highly effective method while
receiving study intervention and until 30 days after last dose - the end of relevant systemic exposure.
Examples of highly effect
2. Treatment with a strong CYP3A4 inducer (eg, rifabutin, rifampin,
rifampicin, rifapentin, carbamazepine, phenobarbital, phenytoin, St.
John's Wort) within 1 month prior to randomization or start of run-in, if
applicable.
3. Treatment with a strong CYP3A4 inhibitor or a moderate dual
CYP3A4/CYP2C9 inhibitor, or co-administration of a combination of
moderate CYP3A4 and moderate CYP2C9 inhibitors in the 1-month
period prior to randomization, or start of run-in, if applicable. External
use (cream, shampoo, etc) per approved label is permitted.
4. For participants involved in the cardiac remodeling and/or
hemodynamic substudies only: Diuretic treatment initiated or dose
changed within 1 week prior to the MRI or RHC assessment.
5. Known presence of three or more of the following risk factors for
heart failure with preserved ejection fraction at Screening, based on
records that confirm documented medical history:
- Body mass index (BMI) > 30 kg/m2,
- Diabetes mellitus of any type,
- Essential hypertension (even if well controlled),
- Coronary artery disease, ie, any of the following:
*History of stable angina, or
*Known more than 50% stenosis in a coronary artery, or
*History of myocardial infarction, or
*History of or planned coronary artery bypass grafting and/or coronary
artery stenting.
6. Presence of moderate or severe obstructive lung disease (forced
expiratory volume in 1 second [FEV1] / forced vital capacity [FVC] <
70%; and FEV1 < 60% of predicted after bronchodilator administration)
in participants with a known or suspected history of significant lung
disease, as documented by a spirometry test performed within 1 year
prior to Screening.
7. Presence of moderate or severe restrictive lung disease (eg, total lung
capacity [TLC] or FVC < 60% of normal predicted value) in participants
with a known or suspected history of significant lung disease, as
documented by a spirometry test performed within 1 year prior to
Screening.
8. Significant unrepaired structural left heart valvular disease (ie,
moderate or severe aortic or mitral stenosis or regurgitation);
pericardial constriction; restrictive or congestive left-sided
cardiomyopathy; life-threatening cardiac arrhythmias; significant left
ventricular dysfunction; or left ventricular outflow obstruction.
9. Permanent atrial fibrillation or atrial flutter, in the opinion of the
investigator.
10. Known or suspected pulmonary veno-occlusive disease (PVOD).
11. Known moderate to severe hepatic impairment, defined as Child-
Pugh Class B or C (see Appendix 5), based on records that confirm
documented medical history.
12. Serum aspartate aminotransferase (AST) and/or alanine
aminotransferase (ALT)> 1.5 X upper limit of normal (ULN) at Screening.
13. Hemoglobin < 100 g/L (< 10 g/dL) at Screening.
14. Severe renal impairment as defined with an estimated glomerular
filtration rate (eGFR) < 30 mL/min/1.73m2 (Chronic Kidney Disease
Epidemiology Collaboration [CKD EPI] 2009 equation) at screening
15. Systemic hypotension (systolic blood pressure [SBP] < 90 or
diastolic blood pressure [DBP] < 50 mm Hg) at Screening.
16. For selected sites taking part to the cardiac MRI sub-study only:
participants must not be considered for this sub-study in case of MRIincompatible
permanent cardiac pacemaker, automatic internal
cardioverter, metallic implant (eg, defibrillator, neurostimulator, hearing
aid, permanent use of infusion device), multiple premature ventricular or
atrial contractions, or any other conditio
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method