A Study to Evaluate the Effect of Sodium Zirconium Cyclosilicate on Chronic Kidney Disease (CKD) Progression in Participants With CKD and Hyperkalaemia or at Risk of Hyperkalaemia

Inclusion Criteria:

1. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and protocol
2. Must be ≥ 18 years of age at the time of signing the informed consent.
3. Must have eGFR ≥ 25 and ≤ 59 mL/min/1.73m2 as calculated by central laboratory (CKD-EPI formula) at screening (Visit 1)
4. Must have UACR ≥ 200 and ≤ 5000 mg/g as calculated by central laboratory at screening (Visit 1). If the first sample does not fulfil eligibility criteria, a second sample can be obtained during the screening period; if so, the UACR measurement from the second sample must be within the eligibility range.

Any of the following criteria, a or b, at screening (Visit 1):

1. Cohort A: Hyperkalaemia (S-K > 5.0 to ≤ 6.5 mmol/L) as measured by the central laboratory, and on adequate* or limited** RAASi therapy due to hyperkalaemia.
2. Cohort B: Normokalaemia (S-K ≥ 3.5 to ≤ 5.0 mmol/L) as measured by the central laboratory and on limited** RAASi therapy due to high risk of hyperkalaemia. High risk of hyperkalaemia is defined as:

(i) Participants with a previous medical history or record of hyperkalaemia within the prior 24 months, who are on limited** RAASi therapy despite indication in CKD.

(ii) Participants in whom RAASi therapy is indicated in CKD, who are on limited** RAASi therapy and have S-K ≥ 4.7 to ≤ 5.0 mmol/L.

(iii) Participants in whom RAASi therapy has been discontinued or reduced to suboptimal* doses because of hyperkalaemia.

*Adequate RAASi dose levels are defined in protocol; doses lower than these are considered as suboptimal.

**Limited RAASi therapy is defined as no or suboptimal RAASi therapy according to dosing guidance provided in protocol.

1. If on thiazide or loop diuretics, the dose must have been stable for 2 weeks prior to screening (Visit 1).
2. If on RAASi therapy, the dose must have been stable for one month prior to screening (Visit 1) and remain stable during screening.
3. If on an SGLT2i treatment (ie, dapagliflozin and canagliflozin), finerenone, or any other medications in these 2 classes that are approved for CKD, the dose must have been stable for 3 months prior to screening (Visit 1).
4. Participants must be one-year postmenopausal, surgically sterile, or using one highly effective form of birth control (defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly). They should have been stable on their chosen method of birth control for a minimum of one month prior to screening (Visit 1) and willing to remain on the birth control until one month after the last dose of study intervention.

Exclusion Criteria:

1. New York Heart Association class III to IV congestive heart failure at the time of screening (Visit 1) or previous history of severe or symptomatic heart failure.
2. Myocardial infarction, unstable angina, stroke, or transient ischaemic attack within 3 months prior to screening (Visit 1).
3. Participants with a known history of systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 95 mmHg within 2 weeks prior to screening (Visit 1) are excluded. In addition, any participant with systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 95 mmHg as measured at screening (Visit 1) and confirmed by repeated measurement is excluded. Participants may be rescreened once blood pressure is controlled.
4. QTcF > 550 msec at screening (Visit 1).
5. History of QT prolongation associated with other medications that required discontinuation of that medication.
6. Congenital long QT syndrome.
7. Symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation and heart rate controlled by medication are permitted.
8. Lupus nephritis or anti-neutrophil cytoplasmic antibody-associated vasculitis.
9. Change in renal function requiring hospitalisation or dialysis within 3 months prior to screening (Visit 1).
10. History of renal transplant (or anticipated need for renal transplant during the study).
11. Severe hepatic impairment, biliary cirrhosis, or cholestasis.
12. History of hereditary or idiopathic angioedema.
13. Any prior hypersensitivity to ACEi or ARB that in the investigator's judgment precludes use of lisinopril and valsartan/irbesartan. Prior hypersensitivity reactions to consider include, but are not limited to, development of angioedema, icterus, hepatitis, or neutropaenia or thrombocytopaenia requiring treatment modification.
14. Known hypersensitivity or previous anaphylaxis to SZC or to components thereof.
15. Any condition outside the CV and renal disease area such as, but not limited to, malignancy, with a life expectancy of less than 2 years based on investigator´s clinical judgment.
16. Active malignancy requiring treatment at the time of screening (Visit 1), except for successfully treated basal cell or treated squamous cell carcinoma.
17. S-K > 6.5 or < 3.5 mmol/L by local laboratory within 1 day prior to the scheduled first dose of SZC in the initiation phase.
18. Evidence of COVID-19 infection within 2 weeks prior to screening (Visit 1).
19. Treated with dual blockade of RAAS (combined use of an ACEi and ARB) within 3 months prior to screening (Visit 1).
20. Treated with an angiotensin receptor neprilysin inhibitor (ARNI; sacubitril/valsartan [Entresto®]) within 3 months prior to screening (Visit 1).
21. Treated with an MRA not approved for CKD within 3 months prior to screening (Visit 1).
22. Treated with aliskiren-containing products with 3 months prior to screening (Visit 1).
23. Treated with SPS (eg, Kayexalate, Resonium), CPS (Resonium Calcium), patiromer (Veltassa®), or SZC (Lokelma®) within 7 days prior to screening (Visit 1).
24. Participation in another clinical study with an investigational product administered within one month prior to screening (Visit 1).
25. Not willing or not able to change to lisinopril or valsartan/irbesartan, the protocol-mandated RAASi study intervention. Note: For participants taking a fixed combination of an ACEi or ARB with another agent (eg, calcium blockers or diuretics) as SoC, the investigator must make a judgment that it will be safe and efficacious for such participants to change to the study ACEi or ARB and to the other drug as separate agents.
26. Previous dosing with SZC in the present study.
27. Currently pregnant (confirmed with positive pregnancy test at screening [Visit 1]) or breastfeeding.
28. Judgment by the investigator that the participant is unlikely to comply with study procedures, restrictions, and requirements.
29. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).