This is a Phase IIIb, multicentre, randomised, double-blind, placebo-controlled, parallel group study to evaluate the effect of baxdrostat 2mg versus placebo, administered QD orally, on the reduction of ambulatory 24-hour average SBP in participants with uHTN.

Consenting participants will be screened within 4 weeks and will subsequently enter a 4-week run-in period with placebo. Thereafter, participants will be randomised in a 1:1 ratio to receive one of the following 2 treatments QD, during a 12-week double-blind treatment period:

baxdrostat 2mg Placebo The randomisation will be stratified by mean ambulatory SBP at baseline (<140 mmHg, ≥140 mmHg) and the number of background antihypertensive medication classes (2, ≥3) at baseline.

During the 12-week double-blind treatment period, participants should remain on their background antihypertensive medication. Doses of background medications should not be changed during this period unless participants experience SBP < 100 mmHg with symptoms of hypotension. Rescue therapy is permitted if the SBP or DBP exceeds 170 or 105 mmHg, respectively. The choice of rescue therapy is based on the Investigator's best clinical judgement; however, the use of potassium-sparing diuretics and MRAs are prohibited.After completing the 12 weeks double-blind treatment period participants will complete a 2-week safety follow-up period. The total duration of study participation will be of approximately 22 weeks.

This is a Phase IIIb, multicentre, randomised, double-blind, placebo-controlled, parallel group study to evaluate the effect of baxdrostat 2mg versus placebo, administered QD orally, on the reduction of ambulatory 24-hour average SBP in participants with uHTN, defined as BP targets not being achieved in an individual despite a stable regimen of ≥2 antihypertensive agents from different therapeutic classes (at full doses per guidelines or maximum tolerated dose in the judgement of the Investigator), none of which is a diuretic.

Consenting participants will be screened within 4 weeks and will subsequently enter a 4-week run-in period with placebo. Thereafter, participants will be randomised in a 1:1 ratio to receive one of the following 2 treatments QD, during a 12-week double-blind treatment period:

baxdrostat 2mg Placebo The randomisation will be stratified by mean ambulatory SBP at baseline (<140 mmHg, ≥140 mmHg) and the number of background antihypertensive medication classes (2, ≥3) at baseline.

During the 12-week double-blind treatment period, participants should remain on their background antihypertensive medication. Doses of background medications should not be changed during this period unless participants experience SBP < 100 mmHg with symptoms of hypotension. Rescue therapy is permitted if the SBP or DBP exceeds 170 or 105 mmHg, respectively. The choice of rescue therapy is based on the Investigator's best clinical judgement; however, the use of potassium-sparing diuretics and MRAs are prohibited.

After completing the 12 weeks double-blind treatment period participants will complete a 2-week safety follow-up period. The total duration of study participation will be of approximately 22 weeks.

The study is planned to be conducted in approximately 50 study sites across China.

A Data Monitoring Committee will be appointed for this study to monitor the safety and scientific integrity of a human research intervention and to make recommendations to AstraZeneca regarding the stopping of a study due to any harm.

An Executive Committee will be formed to provide scientific oversight and confirmation of the overall study design, of CSP and any protocol amendments (If appliable).

Inclusion Criteria:

Participants are eligible to be included in the study only if all of the following criteria apply:

Age 1. Participant must be ≥18 years old, at the time of signing the informed consent.

Type of Participant and Disease Characteristics

1. Mean seated SBP on AOBPM ≥140 mmHg and <170 mmHg at screening. Seated BP will be measured using standardised automated BP machines and using standardised procedures.

2. Have a stable regimen (≥ 4 weeks before the screening visit) of ≥ 2 antihypertensive medications, from different therapeutic classes (should not be a diuretic), at full doses per guidelines or maximum tolerated doses in the judgement of the Investigator, for at least 4 weeks prior to screening (participants who do not meet this criterion may be rescreened at the Investigator's discretion. Beta blockers used to treat other conditions (i.e., migraine, heart failure [HF], coronary artery disease) should not be counted as an antihypertensive medication for the purpose of qualifying for this study.

3. Have eGFR ≥45 mL/min/1.73m2 at screening.

4. Serum potassium (K+) level ≥3.5 and <5.0 mmol/L at screening, determined as per central laboratory.

   Sex and Contraceptive/Barrier Requirements

5. Only female participants:

   Contraceptive use by females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

   a) Female participants: i. Females not of childbearing potential are defined as females who are either permanently sterilised (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are postmenopausal. Females will be considered postmenopausal if they have been amenorrhoeic for 12 months prior to the planned date of randomisation without an alternative medical cause. The following age specific requirements apply:

   • Women <50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment and follicle-stimulating hormone levels within the postmenopausal range.
   • Women ≥50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatment ii. Female participants of child-bearing potential must use one highly effective form of birth control. A highly effective method of contraception is defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly. Females of child-bearing potential who are sexually active with a non-sterilised male partner must agree to use one highly effective method of birth control, as defined below, from 30 days before enrolment and throughout the study, and until at least 30 days after last dose of study intervention. Cessation of contraception after this point should be discussed with a responsible physician.

   iii. The following are not acceptable methods of contraception: periodic abstinence (calendar, symptom-thermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only and lactational amenorrhoea. Female condom and male condom should not be used together.

   iv. All females of child-bearing potential must have a negative pregnancy test result at screening and not be at stage of breastfeeding v. Highly effective birth control methods include: Total sexual abstinence is an acceptable method provided it is the usual lifestyle of the participant (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments) ([periodic abstinence - e.g., calendar, ovulation, sympto-thermal, post-ovulation methods - declaration of abstinence for the duration of exposure to study intervention and withdrawal are not acceptable methods of contraception]); a vasectomised partner; subdermal contraceptive implants; bilateral tubal occlusion; intrauterine device/levonorgestrel intrauterine system; injectable contraceptive; oral contraceptive associated with inhibition of ovulation; and contraceptive transdermal patch, or vaginal ring.

   Informed Consent

6. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

   5.1.1 Randomisation Criteria

   Participants are eligible to be randomised to a treatment group only if all the following criteria apply:

7. Ambulatory 24-hour average SBP ≥130 mmHg.

8. Have an 80% to 120% adherence to placebo during the Run-in period, based on pill counts on the morning of randomization. Adherence will be derived for each patient based on pill counts as the number of pills taken (dispensed - returned), divided by the expected number of pills taken.

9. Have no change in background therapy regimen and dose consisting of ≥ 2 antihypertensive medications (none of which is a diuretic), for at least 4 weeks prior to randomisation. Beta-blockers used to treat other conditions (i.e., migraine, HF, coronary artery disease) should not be counted as an antihypertensive medication for the purpose of qualifying for this study.

10. Demonstrated good adherence to the prescribed antihypertensive medications by performing DOT.

Exclusion Criteria:

Participants are excluded from the study if any of the following criteria apply:

Medical Conditions

1. As judged by the investigator, any evidence of which in the investigator's opinion makes it undesirable for the participant to participate in the study.

2. Mean seated SBP on AOBPM ≥170 mmHg (participants who do not meet this criterion may be rescreened at the Investigator's discretion, see Section 5.4.2 for rescreening criteria and Section 8.2.1 for BP measurement procedures).

3. Mean seated DBP on AOBPM ≥110 mmHg (participants who do not meet this criterion may be rescreened at the Investigator's discretion).

4. Serum sodium level (Na+) <135 mmol/L at screening, determined as per central laboratory.

5. Has the following known secondary causes of hypertension: renal artery stenosis, uncontrolled or untreated hyperthyroidism, uncontrolled or untreated hypothyroidism, pheochromocytoma, Cushing's syndrome, aortic coarctation.

6. New York Heart Association functional HF class IV at Screening.

7. Medical history of stroke, acute coronary syndrome, hypertensive encephalopathy, or hospitalization for HF within 6 months prior to Screening.

8. Planned percutaneous coronary intervention/coronary artery bypass grafting or percutaneous coronary intervention/coronary artery bypass grafting done within 6 months prior to screening.

9. Known current severe left ventricular outflow obstruction, such as obstructive hypertrophic cardiomyopathy and/or severe aortic valvular disease.

10. Known severe hepatic impairment, defined as Child-Pugh Class C, based on records that confirm documented medical history.

11. Uncontrolled diabetes with HbA1c >10.0% (86 mmol/mol) at Screening.

12. Participants suspected to have severe cardiac hypertrophy.

13. Participants who are pregnant or breastfeeding. Prior/Concomitant Therapy

14. Simultaneous use of angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) or angiotensin receptor-neprilysin inhibitor (ARNI) in current or prior treatment within the 4 weeks before screening

15. Prior medical treatment with any MRAs, antiarrhythmic medications (beta blockers and calcium channel blockers classified as Class II/IV antiarrhythmics used to treat hypertension, and digoxin are permitted), direct renin inhibitor, thiazide diuretic, loop diuretic, potassium-sparing diuretic, or other diuretics use within 4 weeks prior to screening.

16. Is expected to receive or is receiving any herbal anti-hypertensive medicine or antihypertensive medication of unknown ingredients.

17. Treatment with potassium binders within 1 month prior to screening.

18. Is expected to receive or is receiving any of the exclusionary drugs such as strong inducers of cytochrome P450 (CYP) 3A, chronic (taken more than 3 times a week for more than 3 months) use of NSAIDs (use of low-dose aspirin is permitted, as per medical judgement), and/or chronic use of systemic steroids within 8 weeks prior to screening.

19. Current or prior treatment within 6 months prior to screening with cytotoxic therapy.

20. Treatment with K+ supplements are not prohibited but should be continuously assessed and monitored throughout the trial.

    Prior/Concurrent Clinical Study Experience

21. Known hypersensitivity to baxdrostat or drugs of the same class, or any of its excipients.

22. Participation in another clinical study with an IMP administered in the 3 months prior to randomisation in this study Other Exclusions

23. Participants working shifts (i.e., shifts that comprise working hours at different times on different days) or working night shifts.

24. Participants who cannot complete the 24-hour ABPM assessment at randomization (as judged by the Principal Investigator).