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-DK
- 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 systemic to 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/toxin-induced 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 hig
1. Does meet any of the following run-in failure criteria (applies only to participants who are required to have a run-in period):
- Study intervention compliance < 80%,
- Laboratory results showing a decrease in hemoglobin by > 50 g/L from Screening or hemoglobin < 100 g/L or need for transfusion not explained by other confounding factors (if central laboratory results are not available at time of randomization local laboratory results will be used to confirm participants eligibility),
- Significant fluid retention as evidenced by one of the following:
*Administration of iv diuretics due to fluid retention,
*Addition of high potency thiazide diuretic (metolazone, indapamide), = 100% increase in loop diuretic to a total oral dose = 120 mg of furosemide equivalents/day,
*Increase in body weight by = 5% or = 5 kg from the value at the start of the run-in period.
- The investigator considers that for safety reasons or tolerability reasons (eg, AE) it is in the best interests of the participant to discontinue the study.
Subjects who are run-in failures per the criteria described above will be considered screen failures (see Section 5.4).
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 a
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