Pulmonary arterial hypertension MedDRA version: 21.1 Level: PT Classification code 10064911 Term: Pulmonary arterial hypertension System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders
Conditions
Interventions
Trade Name: Opsumit®
Product Name: macitentan tablets
Product Code: JNJ-67896062 / ACT-064992
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: MACITENTAN
CAS Number: 441798-33-0
Concentrat
Sponsors
ACTELION Pharmacteuticals Ltd.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 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 populationa: 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 high
Exclusion criteria
Exclusion criteria: 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 run-in period, 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] 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 MRI-incompatible 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To demonstrate superiority of macitentan 75 mg in prolonging the time to the first CEC-adjudicated morbidity or mortality (M/M) event in participants with symptomatic pulmonary arterial hypertension (PAH) compared to macitentan 10 mg.;Secondary Objective: - To demonstrate that macitentan 75 mg improves exercise capacity compared to macitentan 10 mg - To demonstrate that macitentan 75 mg prolongs the time to death or hospitalization due to PAH (adjudicated by an independent CEC) compared to macitentan 10 mg - To assess the effect of macitentan 75 mg compared to macitentan 10 mg on PAH symptoms on participants' life - To assess the effect on prolongation of the CEC-adjudicated time to death of macitentan 75 mg compared to macitentan 10 mg;Primary end point(s): - Time to first CEC-adjudicated M/M event on-treatment (ie, up to 7 days after the last dose of double-blind (DB) study intervention), defined as time from randomization to the first of the following events: - All-cause death, including deaths caused by an on-treatment AE, that occur within 4 weeks of study DB treatment discontinuation - Non-planned PAH-related hospitalization (including for worsening of PAH, atrial septostomy, lung transplantation with or without heart transplantation, or initiation of parenteral prostacyclins) - PAH-related disease progression, defined as (both criteria must be satisfied): o Deterioration by at least 15% in exercise capacity, as measured by the 6-minute walk distance (6MWD) from baseline, confirmed by second 6MWD test performed on a different days within 2 weeks of the initial test o Initiation of additional PAH therapy or Worsening of WHO FC;Timepoint(s) of evaluation of this end point: At each study visits, monthly and at any time in case of event occurrence, until 217 M/M events are reached | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Change from baseline to Week 24 in 6MWD - Time to first occurence of either death due to PAH or hospitalization for PAH, CEC adjudicated event on-treatment (ie, up to 7 days after the last dose of DB studyintervention), as defined hereafter: - Death due to PAH, including deaths caused by on-treatment AE that occur 4 weeks of study DB treatment discontinuation OR - Non-planned PAH-related hospitalization - Change from baseline to Week 24 in PAH-SYMPACT: - Cardiopulmonary symptom domain score - Cardiovascular symptom domain score - Time to death occurring between randomization and end of double-blind treatment (EDBT) period as defined hereafter: - All-cause death, including all deaths occurring during the DB period regardless of potential discontinuation of study intervention or initiation or change in PAH medication;Timepoint(s) of evaluation of this end point: Screening, Day 1, Month 3, and all scheduled visits thereafter until EDBT or anytime in case of event, with the exception of PAH-SYMPACT | — |
Countries
Argentina, Australia, Austria, Belarus, Belgium, Bulgaria, Canada, China, Colombia, Czechia, Czech Republic, Denmark, France, Germany, Hungary, Israel, Italy, Japan, Korea, Republic of, Malaysia, Mexico, Netherlands, Norway, Poland, Portugal, Russian Federation, Serbia, Singapore, Slovakia, Spain, Sweden, Taiwan, Thailand, Turkey, Ukraine, United Kingdom, United States, Viet Nam
Contacts
Public ContactClinical Registry group
Janssen-Cilag International NV
Outcome results
None listed