REPO-HYPER II

Other illness

• The participant has one or more of the following conditions: stable or unstable angina within 3 months of enrolment, myocardial infarction within 3 months of enrolment, heart failure, stroke or transient ischemic attack, or atrial fibrillation.

Lab values

• The participant has an estimated glomerular filtration rate (eGFR) of <45 mL/min/1.73m2, using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation (GFR = 141 * min (Scr/κ,1) α * max (Scr/κ, 1)-1.209 * 0.993Age * 1.018 [if female] * 1.159 [if black]). Scr is serum creatinine (mg/dL), κ is 0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ or 1.
• The participant requires chronic oxygen support or mechanical ventilation other than nocturnal respiratory support for sleep apnea (e.g. CPAP, BiPAP). 5. The participant is being treated chronically (e.g. daily use) with non-steroidal anti-inflammatory drugs (NSAIDs). Low-dose aspirin therapy is allowed. 6. The participant is under treatment for pulmonary hypertension. 7. The participant has known form of secondary hypertension, such as pheochromocytoma, Cushing ’s syndrome (hypercortisolism), primary hyperaldosteronism, coarctation of the aorta, untreated hyper- or hypothyroidism, or primary hyperparathyroidism. (Note: treated and controlled patients with hyperthyroidism or hypothyroidism can be included). 8. The participant has a scheduled or planned surgery that, in the opinion of the investigator, may affect study endpoints. 9. The participant has a documented condition that would prohibit or interfere with the ability to obtain an accurate blood pressure measurement using the protocol-specified automatic blood pressure monitor and/or ABPM (e.g., upper arm circumference outside cuff size ranges available by geography or arrhythmia that interferes with automatic monitor’s pulse sensing and prohibits an accurate measurement). 10. The participant has severe cardiac valve stenosis for which, in the opinion of the investigator, a significant reduction of blood pressure is contraindicated. 11. The participant is pregnant, nursing or planning to become pregnant during the study follow-up. (Note: Pre-menopausal female participants must have a negative serum or urine human chorionic gonadotropin (hCG) pregnancy test). 12. The participant has a known unresolved history of drug use or alcohol dependency and lacks the ability to comprehend or follow instructions, or would be unlikely or unable, in the opinion of the investigator, to comply with study follow-up requirements. 13. The participant is currently enrolled in a concurrent investigational drug or device study, unless approved by the study sponsor. (Note: For the purpose of this protocol, participants involved in extended follow-up studies for products that were investigational but are currently commercially available are not considered enrolled in an investigational study). 14. The participant has polycystic kidney disease, unilateral kidney, or a history of renal transplant. 15. Contraindications to experimental drugs studied. 16. Liver cirrhosis stage Child-Pugh C. 17. Patients under treatment with moderate to strong CYP3A4 and/or P-gp inhibitors including ritonavir, saquinavir, ketoconazole, itraconazole, erythromycin and drugs listed in https://www.fda.gov/drugs/druginteractions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table3-2. Remark: Male patients taking PDE-5 inhibitors for erectile dysfunction can be included in this trial if they agree to discontinue their usual medication for erectile dysfunction permanently at least 4 weeks prior to baseline visit.

Other

• The participant has had ≥1 episode(s) of syncope in the last year.

• The participant is ≥ 18 and ≤ 80 years old at the time of consent.
• The participant agrees to have all study procedures performed and is competent and willing to provide written, informed consent to participate in this clinical study.
• The participant has an office sBP ≥ 140 mmHg and <180 mmHg and/or an office dBP ≥90 mmHg measured at Screening Visit 1, according to the 2024 ESC/ESH guidelines.
• The participant has a 24-hour mean ABPM value for sBP >130 mmHg and <170 mmHg and/or dBP >80 mmHg measured at Screening Visit 2 according to the 2024 ESC/ESH guidelines.
• The participant has a diagnosis of treatment-resistant hypertension according to the 2024 ESC/ESH guidelines: 1) despite optimal doses (or best-tolerated doses) of an appropriate therapeutic strategy, which should typically include an ACE inhibitor or an angiotensin receptor blocker (ACE-I or ARB), with a dihydropyridine calcium channel blocker (CCB) and a thiazide/thiazide-type diuretic, fails to lower clinic SBP and DBP values to < 140 mmHg and/or 90 mmHg, respectively; 2) the inadequate control of arterial blood pressure has been confirmed by ambulatory blood pressure monitoring (ABPM) or by home blood pressure monitoring (HBPM); and 3) after exclusion of various causes of pseudo-resistant hypertension (especially poor medication adherence) and secondary hypertension.
• Elevated plasma NOX5/ADMA levels (> 170 pg/ml), please refer to attached SoP for evaluation of NOX5 levels.