Inclusion Criteria - Screening:

• Signed and dated ICF prior to any study-mandated procedure.
• Male and female subjects; 18 years (or year of country specific majority) or older.
• Historical documentation in the subject’s medical records of uncontrolled BP despite at least 3 background antihypertensive medications within 1 year before screening visit.
• Treated with at least 3 antihypertensive therapies of different pharmacological
  classes for at least 4 weeks before the screening visit (Visit 1).
• Mean SiSBP ≥ 140 mmHg measured by AOBPM at screening visit.
• Documentation in the subject’s medical records of diagnosis of RHT according to
  the site’s medical practice:
  • Exclusion of secondary causes of hypertension (e.g., serum aldosterone,
    plasma renin activity, duplex/doppler ultrasonography, computer tomography
    angiography assessments are performed to exclude the secondary causes of
    hypertension [Rimoldi 2013]);
  • Adherence to medication (e.g., how the adherence was checked and/or monitored) to eliminate apparent RHT.
• A woman of childbearing potential is eligible only if the following applies:
  • Negative pregnancy test at Screening and at baseline (i.e., end of RI period);
  • Agreement to undertake pregnancy tests during the study and up to 30 days
    after randomized study treatment discontinuation;
  • Agreement to use methods of birth control from Screening up to at least 30 days after randomized study treatment discontinuation.
• Mean trough SiSBP ≥ 140 mmHg measured by AOBPM at the switch from background antihypertensive medications (i.e., at least 3 medications from different pharmacological classes]) to the standardized background antihypertensive therapy.

Inclusion Criteria - RI:

• Switched to the standardized background antihypertensive therapy at least 4 weeks before the first RI visit.
• Mean trough SiSBP ≥ 140 mmHg measured by AOBPM.

Inclusion Criteria - Randomization (end of RI):

• Stable dose of the standardized background antihypertensive therapy for at least 1 week before Day –1 (end of the RI period).
• Mean trough SiSBP ≥ 140 mmHg measured by AOBPM.
• Subjects demonstrating ≥ 80% compliance (pill counting) to study treatment (i.e., placebo) as well as ≥ 80% compliance (pill counting) to the standardized background antihypertensive therapy during the RI period.

Exclusion Criteria - Screening:

• Pregnant or lactating subjects.
• Apparent/pseudo RHT due to white coat effect, medical inertia, poor therapeutic
  adherence, or secondary causes of hypertension (not including obstructive sleep
  apnea).
• Confirmed severe hypertension (grade 3) defined as mean SiSBP ≥ 180 mmHg
  and/or SiDBP ≥ 110 mmHg measured by AOBPM at two different time points.
  The BP re-measurement can be during the screening visit (e.g., after at least 3 h),
  or at the next planned visit, or at an unscheduled visit. The time of re-measurement
  is at the investigator’s discretion, taking into consideration the subject’s medical
  history.
• Known and documented transient ischemic attack, stroke, unstable angina or MI
  within 6 months prior to Screening.
• Clinically significant unstable cardiac disease at screening or in the past in the
  opinion of the investigator; e.g., uncontrolled symptomatic arrhythmia, atrial
  fibrillation, congestive heart failure NYHA stage II with relevant mitral valve
  insufficiency and/or aortic stenosis, congestive heart failure NYHA stage III or IV.
• Severe renal insufficiency defined as an eGFR per the CKD Epidemiology (CKD-EPI) collaboration creatinine equation < 15 mL/min/1.73 m^2.
• Type 1 DM.
• Subjects working night shifts.  A maximum of 2 night shifts per week is permitted except within 3 days prior to a study visit. Night shifts are not allowed during visits at which ABPM is recorded.
• Any known factor, disease or clinically relevant medical or surgical conditions that,
  in the opinion of the investigator, might put the subject at risk, interfere with treatment compliance, study conduct or interpretation of the results.
• Known concomitant life-threatening disease with a life expectancy < 18 months of
  Screening.
• Treatment with any medication which may affect BP and/or treatment with high dose of loop diuretics (i.e., furosemide greater than 80 mg/day, or equivalent dosage of other loop diuretics).
• Treatment with any other ERAs.
• Contraindication and/or known hypersensitivity to any of the three components of the standardized background antihypertensive therapies (fixed combination of CCB [amlodipine], ARB [valsartan] and diuretic [HCTZ]) according to their labels or
  drugs of the same class, or to any of the excipients.
• Known hypersensitivity to aprocitentan or drugs of the same class, or any of the
  excipients.
• Treatment with another investigational treatment within 3 months prior to
  Screening.
• Laboratory assessments based on central laboratory:
  • ALT or AST > 3 times the upper limit of normal range, or severe hepatic impairment;
  • Hemoglobin < 100 g/L;
  • NT-proBNP ≥ 500 pg/mL.

If one of these criteria is not met based on central laboratory report, a re-test must
be performed before Visit 2 (e.g., at the next screening visit, or at an unscheduled
visit). If the value is confirmed, the subject must discontinue from screening.

Exclusion Criteria - RI:

• Laboratory assessments based on local laboratory:
  • ALT or AST > 3 times the upper limit of normal range;
  • Hemoglobin < 100 g/L;
  • eGFR per the CKD-EPI creatinine equation < 15 mL/min/1.73 m^2.

At any time between Screening and Randomization the investigator/delegate must verify that the subject does not fulfill the exclusion criteria checked at the screening visit (as applicable).

• A woman is considered to be of childbearing potential unless she meets at least one of the following criteria:
  • Previous bilateral salpingectomy, bilateral salpingo-oophorectomy or hysterectom;
  • Postmenopausal (defined as 12 consecutive months with no menses without an alternative medical cause [ICH M3 definition]);
  • Premature ovarian failure (confirmed by a specialist), XY genotype, Turner syndrome, uterine agenesis.
• Childbearing potential status will be assessed at each visit and recorded in the electronic
  case report form (eCRF).