Phase III Study Investigating Heart Failure and Cardiovascular Death With Baxdrostat in Combination With Dapagliflozin

Participants include men and women ≥ 40 years of age with T2DM, established CV disease, a history of HTN with an SBP of at least 130 mmHg at screening, who meet the predefined serum potassium level, and with at least one additional risk factor for HF.

The study will include an optional pre-screening period to facilitate sites' identification of potentially eligible participants to enter the full screening assessments. Participants will not be required to visit the site and no informed consent is required for the optional pre-screening period. The pre-screening assessments do not replace the full screening tests at Visit 1.

Upon entering the screening period, all consented participants (after signature of screening ICF) will be screened during an up to 14-day screening period. Participants who meet all screening inclusion/exclusion criteria but are not treated with SGLT2i or are treated for less than 4 weeks will enter a run-in period with dapagliflozin 10 mg once daily for at least 4 weeks (and not more than 6 weeks) before randomisation.

Site visits will take place at approximately 2-, 4-, 8-, 16-, and 34-weeks following randomisation. Thereafter visits will occur approximately every 4 months.

The study closure procedures will be initiated when the predetermined number of the first secondary endpoint events (ie, the composite of hospitalisation for HF or CV death) is predicted to have occurred i.e., the PACD.

In case of premature discontinuation of the blinded study intervention, participants will remain in the study. Unless a participant meets the dapagliflozin specific discontinuation criteria, they will continue to receive open label dapagliflozin 10 mg. It is important that the scheduled study visits and data collection continue according to the study protocol.


Eligibility Criteria:
Inclusion Criteria:

1. Participants of any sex and gender must be ≥ 40 years old at the time of signing the informed consent.
2. Diagnosed with T2DM and requiring treatment
3. Established CV disease (ischaemic heart disease, cerebrovascular disease, peripheral arterial disease)
4. History of HTN and an SBP ≥ 130 mmHg at screening and ≥ 120 mmHg at the Randomisation Visit.
5. Central laboratory serum potassium must meet the following criteria at the Screening

   Visit, based on screening eGFR:
   * for participants with screening eGFR ≥ 45 mL/min/1.73 m2, potassium must be

     ≥ 3.0 and ≤ 4.8 mmol/L at the Screening Visit
   * for participants with screening eGFR \< 45 mL/min/1.73 m2, potassium must be ≥ 3.0 and ≤ 4.5 mmol/L at the Screening Visit
6. At least one additional risk factor for HF:

   * Age ≥ 70 years
   * UACR \> 20 mg/g
   * eGFR \< 60 mL/min/1.73 m2
   * History of polyvascular disease (at least two of: ischaemic heart disease, cerebrovascular disease, and peripheral arterial disease)
   * History of atrial fibrillation or atrial flutter
   * NT-proBNP \> 125 ng/L

Exclusion Criteria:

1. Previously confirmed diagnosis and treatment of heart failure
2. An eGFR \< 30 mL/min/1.73 m2 at screening
3. Known hyperkalaemia, defined as potassium ≥ 5.5 mmol/L within 3 months prior to screening
4. Type 1 diabetes mellitus or uncontrolled T2DM with HbA1c \> 10.5% (\> 91 mmol/mol) at screening
5. Serum sodium \< 135 mmol/L at screening, determined as per central laboratory assessment
6. Stroke, transient ischaemic cerebral attack, valve implantation or valve replacement, carotid surgery, carotid angioplasty, or cardiac surgery, within 3 months prior to randomisation
7. Myocardial infarction within 3 months prior to randomisation, or within 1 month prior to randomisation when there is no further planned revascularisation
8. Percutaneous coronary intervention within 1 month prior to randomisation
9. Known severe hepatic impairment, defined as Child-Pugh Class C, based on records that confirm documented medical history
10. Documented history of adrenal insufficiency
11. Any dialysis (including for acute kidney injury) within 3 months prior to screening
12. Any acute kidney injury within 3 months prior to screening
13. History or known allergy/hypersensitivity to the study treatment, as judged by the Investigator (eg, SGLT2i or active substance or excipients)
14. History of organ transplant or bone marrow transplant, or planned organ transplant within 6 months following randomisation (including kidney transplant)
15. Any clinical condition requiring systemic immunosuppression therapy other than maintenance therapy (stable for at least 3 months prior to screening)
16. Drug or alcohol abuse that in the Investigator's judgement makes the participant a poor candidate for the study
17. Any use of mineralocorticoid receptor antagonists (such as spironolactone, eplerenone, or finerenone) or aldosterone synthase inhibitor within 4 weeks prior to screening and/or during the study
18. Concomitant therapy with strong inducers of cytochrome P450
19. Use of potassium-sparing diuretics (such as triamterene or amiloride) and direct renin inhibitor (eg, aliskiren) at the time of screening
20. Use of potassium binders (such as sodium zirconium cyclosilicate, patiromer, or sodium polystyrene sulfonate) within 4 weeks prior to screening