Aprocitentan tablets are currently the only endothelin dual receptor antagonist approved internationally for the treatment of resistant hypertension.This is a multicenter, randomized, double-blind, placebo-controlled Phase 3 study to evaluate the efficacy and safety of aprocitentan tablets(SYH9108) in patients with treatment-resistant hypertension (rHTN)

The study consists of a screening period (up to 2 weeks), a run-in period (4 weeks), a treatment period (8 weeks), and a follow-up period. During the study, all participants should continue their background antihypertensive medications (at the same agents and dosages as used within 4 weeks prior to screening) and maintain lifestyle interventions such as a low-salt diet.

Inclusion Criteria:

1. Male or female participants must be ≥18 years of age.
2. Participants must have received stable doses of ≥3 antihypertensive agents from distinct pharmacological classes for at least 4 weeks prior to signing the ICF, with such therapy maintained until randomization.
3. During the screening period and prior to randomization, SiSBP ≥140 mmHg with or without SiDBP ≥90 mmHg, and SiSBP <180 mmHg and SiDBP <110 mmHg.
4. Participants are able to understand and cooperate in completing this trial, voluntarily participate in the trial, and sign the Informed Consent Form (ICF).

Exclusion Criteria:

1. Presence of secondary hypertension.
2. Have had transient ischemic attack, stroke, unstable angina pectoris, or acute myocardial infarction occurring within the period from 12 months prior to signing the ICF up to randomization.
3. From screening to prior to randomization, have presence of uncontrolled severe disease or life-threatening disease, or failure to recover from major surgery, or prior thyroid surgery, or presence of malignant tumor, or meeting the criteria for severe hepatic insufficiency at screening.
4. Have had unstable cardiac disease occurring within the period from 6 months prior to signing the ICF up to randomization.
5. Have received dialysis at any time prior to signing the ICF or prior to randomization.
6. Type 1 diabetes.
7. Compliance with any background antihypertensive drug or placebo is <80% or >120% during the run-in period.
8. Use of endothelin receptor antagonists, antihypertensive drugs other than background medications, or other blood pressure-affecting drugs, or high-dose loop diuretics from 4 weeks prior to signing the ICF until randomization; or use of oligonucleotide antihypertensive agents within 1 year prior to signing the ICF.
9. Hypersensitivity or suspected hypersensitivity to the excipients of the investigational product, endothelin receptor antagonists, or background antihypertensive drugs, or potential hypersensitivity to the investigational product.
10. Participated in other clinical trials and received at least one dose of study treatment within 12 weeks prior to signing the ICF.
11. Average night shifts are ≥ 2 times per week during the 4 weeks prior to signing the ICF, the screening period, the run-in period, or the anticipated study period.
12. History of drug abuse or alcohol abuse within 5 years prior to signing the ICF.
13. Any of the following test results during the screening period or prior to randomization:

1) BMI≥37.5 kg/m2. 2) Hemoglobin < 100 g/L; 3) NT-proBNP ≥ 500 pg/mL; 4) QTcF: > 450 ms in males, > 470 ms in females; 5) eGFR < 15 mL/min/1.73 m²; 6) ALT or AST > 3 × ULN, or total bilirubin > 1.5 × ULN; 7) HbA1c > 8.0%; 8) TSH outside the normal range and FT3 and/or FT4 outside the normal range; 9) Positive HBsAg and positive HBV-DNA, or positive for any of anti-HCV antibody, anti-HIV antibody, anti-Treponema pallidum antibody.

14. Female participants of childbearing potential who are pregnant, breastfeeding, or have a positive pregnancy test from signing the ICF until randomization; or female participants of childbearing potential and male participants who plan to conceive (including sperm or egg donation) and/or are unable to use effective contraceptive methods during the study period and within 30 days after the end of treatment.