Ensayos clínicos

Inclusion Criteria:

• Target population: ≥ 18 (or the legal age of consent in the jurisdiction in which the study is taking place) years of age.
• Target population:
  • Symptomatic Pulmonary Arterial Hypertension (PAH) in World Health Organization Functional Class (WHO FC) II, III, or IV.
• 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; o
    • persistent PAH documented by an RHC ≥ 1 year after simple systemic-to pulmonary shunt repair.
• PAH diagnosis confirmed by hemodynamic evaluation at rest at any time prior to screening:
  • Mean pulmonary artery pressure (mPAP) > 20 millimeters of mercury (mmHg), and;
  • Pulmonary artery wedge pressure (PAWP) or left ventricular end diastolic pressure (LVEDP) ≤ 15 mmHg, and PVR ≥ 3 Wood Units (that is, ≥ 240 dyn*sec/cm^5).
• Able to perform the 6-minute walking test (6MWT) with a minimum distance of 50 meters and maximum distance of 440 meters at screening.

Exclusion Criteria:

Meets 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 runin period;
• The investigator considers that for safety reasons or tolerability reasons (e.g., 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.
• 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.
• Treatment with a strong CYP3A4 inhibitor (eg, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir) or a moderate dual CYP3A4/CYP2C9 inhibitor (eg, fluconazole, amiodarone) or coadministration of a combination of moderate CYP3A4 (eg, ciprofloxacin, cyclosporine, diltiazem, erythromycin, verapamil) and moderate CYP2C9 inhibitors (e.g., miconazole, piperine), 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.
• For participants involved in the cardiac remodeling and/or hemodynamic sub-studies only: Diuretic treatment initiated or dose changed within 1 week prior to the MRI or RHC assessment.
• Treatment with another investigational drug* in the 3-month period prior to randomization, or start of run-in, if applicable.
• *The following PH therapies used as investigational drug in a continued access setting (e.g., OL study, post-trial access program) are allowed: sildenafil, tadalafil, riociguat, beraprost, and treprostinil.
• 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/m^2;
  • 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.
• 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.
• Presence of moderate or severe restrictive lung disease (e.g., total lung capacity 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.
• Significant unrepaired structural left heart valvular disease (i.e., 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.
• Permanent atrial fibrillation or atrial flutter, in the opinion of the investigator.
• Known or suspected pulmonary veno-occlusive disease (PVOD).
• Known moderate to severe hepatic impairment, defined as Child-Pugh Class B or C, based on records that confirm documented medical history.
• Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 x upper limit of normal (ULN) at screening.
• Hemoglobin < 100 g/L (< 10 g/dL) at screening.
• Severe renal impairment as defined with an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m^2 (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] 2009 equation) (Levey 2009) at screening.
• Systemic hypotension (systolic blood pressure [SBP] < 90 or diastolic blood pressure [DBP] < 50 mm Hg) at screening.
• Known allergies, hypersensitivity, or intolerance to macitentan or drugs of the same class, or any of the excipients (e.g., soy lecithin, lactose).
• Patients included on a lung transplant list or planned to be included.
• Exercise training program for cardiopulmonary rehabilitation in the 12-week period prior to screening or planned to be started during the study.
• Plan to become pregnant or lactating.
• Any known factor or disease that might interfere with treatment adherence, study assessments, study conduct, or interpretation of the results as judged by the investigator (e.g., drug or alcohol dependence, psychiatric disease, use of walking aids, etc).
• Known concomitant life-threatening disease with a life expectancy < 12 months.

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 (e.g., defibrillator, neurostimulator, hearing aid, permanent use of infusion device), multiple premature ventricular or atrial contractions; or
• any other condition that may confound cardiac MRI assessment or for which, in the opinion of the investigator, participation would not be in the best interests of the participant (e.g., compromise well-being).

Eligibility last updated 5/9/22. Questions regarding updates should be directed to the study team contact.