Study to Investigate Efficacy, Safety, and Tolerability of Zibotentan/Dapagliflozin Compared to Dapagliflozin in Participants With Chronic Kidney Disease and High Proteinuria (ZENITH High Proteinuria)

Inclusion Criteria:

1. Participant must be ≥ 18 years of age and of legal age of consent in thejurisdiction in which the study is taking place, at the time of signing the informedconsent.

2. Diagnosis of CKD, defined as eGFR ≥ 20 and < 90 mL/min/1.73 m2 and UACR > 700 mg/g (> 79 mg/mmol) or UPCR > 1000 mg/g (> 113 mg/mmoL).

3. All female participants must have a negative serum pregnancy test result atscreening.

4. Female participants must be either

• not of child-bearing potential or

• women of child bearing potential (WOCBP) using at least one highly effectivebirth control method for at least 3 months prior to first dose of studyintervention

5. Capable of giving signed informed consent

6. Provision of signed informed consent prior to any study specific procedure.

7. Provision of electronic informed consent prior to completion of the optional StudyParticipant Feedback Questionnaire (SPFQ).

8. Provision of signed and dated written Optional Genomics Initiative ResearchInformation and Consent Form prior to collection of samples for optional genomicsimitative research that supports the Genomic Initiative.

9. Receiving RAASi therapy (ACEi or ARB), and for the patient maximum toleratedlabelled daily dose, that has been stable for at least 4 weeks.

Exclusion Criteria:

1. Participants with NYHA class III or class IV Congestive HF at the time of enrolment.

2. Participants hospitalised for HF during the last 6 month prior to screening.

3. Evidence of rales or jugular venous distention on physical examination.

4. Participants with type 1 diabetes mellitus.

5. History of any life-threatening ventricular dysrhythmia (continuous or paroxysmal).

6. Blood pressure above 160 mmHg systolic.

7. Blood pressure below 90 mmHg systolic.

8. Participants hospitalised for heart disease or cardiac procedures or for COVID-19during the last 3 months prior to screening.

9. History of solid organ transplantation or bone marrow transplant.

10. History or ongoing allergy/hypersensitivity, as judged by the Investigator, toSGLT2i therapy (eg, dapagliflozin, canagliflozin, empagliflozin or other SGLT2inhibitors) or Endothelin Receptor Antagonists (eg, ambrisentan, atrasentan,bosentan, or other).

11. Any condition with a life expectancy of less than 2 years based on investigator´sclinical judgment.

12. Malignancy within the past 5 years. Exceptions to this criterion includenon-melanoma skin cancer and curatively treated cervical carcinoma in situ.

13. Significant liver disease as judged by the investigator or severe hepatic impairmentwith AST or ALT > 3 × ULN; or total bilirubin > 2 × ULN at time of screening. Anisolated increase in bilirubin in participants with known Gilbert's syndrome is nota reason for exclusion.

14. Known blood-borne diseases.

15. Clinically significant, unstable, or uncontrolled medical condition as assessed bythe Investigator.

16. Participants on renal replacement therapy or previous kidney transplant.

17. Known history of drug or alcohol abuse within 12 months of screening.

18. Participants on treatment with strong or moderate CYP3A4 inducer.

19. Participants on systemic immunosuppression therapy other than stable maintenancetherapy defined as prednisone 10 mg/day (or equivalent) or less, aziothioprine 100mg/day or less; MMF 1000 mg/day or less for at least 3 months prior to Visit 1.Inhaled, nasal or dermatological steroids are also allowed.

20. Participants treated or expecting to be treated with tolvaptan, any other ERAs, orbudesonide (where used to treat IBD or IgAN).

21. Participation in another clinical study with a study intervention administered inthe last 3 months.