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:

• Capable of giving signed informed consent which includes compliance with therequirements and restrictions listed in the ICF and protocol

• Must be ≥ 18 years of age at the time of signing the informed consent.

• Must have eGFR ≥ 25 and ≤ 59 mL/min/1.73m2 as calculated by central laboratory (CKD-EPI formula) at screening (Visit 1)

• Must have UACR ≥ 200 and ≤ 5000 mg/g as calculated by central laboratory atscreening (Visit 1). If the first sample does not fulfil eligibility criteria, asecond sample can be obtained during the screening period; if so, the UACRmeasurement 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 centrallaboratory, 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 centrallaboratory 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 withinthe 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.

• If on thiazide or loop diuretics, the dose must have been stable for 2 weeks priorto screening (Visit 1).

• If on RAASi therapy, the dose must have been stable for one month prior to screening (Visit 1) and remain stable during screening.

• If on an SGLT2i treatment (ie, dapagliflozin and canagliflozin), finerenone, or anyother medications in these 2 classes that are approved for CKD, the dose must havebeen stable for 3 months prior to screening (Visit 1).

• Participants must be one-year postmenopausal, surgically sterile, or using onehighly effective form of birth control (defined as one that can achieve a failurerate of less than 1% per year when used consistently and correctly). They shouldhave been stable on their chosen method of birth control for a minimum of one monthprior to screening (Visit 1) and willing to remain on the birth control until onemonth after the last dose of study intervention.

Exclusion Criteria:

• New York Heart Association class III to IV congestive heart failure at the time ofscreening (Visit 1) or previous history of severe or symptomatic heart failure.

• Myocardial infarction, unstable angina, stroke, or transient ischaemic attack within 3 months prior to screening (Visit 1).

• Participants with a known history of systolic blood pressure ≥ 160 mmHg or diastolicblood pressure ≥ 95 mmHg within 2 weeks prior to screening (Visit 1) are excluded.In addition, any participant with systolic blood pressure ≥ 160 mmHg or diastolicblood pressure ≥ 95 mmHg as measured at screening (Visit 1) and confirmed byrepeated measurement is excluded. Participants may be rescreened once blood pressureis controlled.

• QTcF > 550 msec at screening (Visit 1).

• History of QT prolongation associated with other medications that requireddiscontinuation of that medication.

• Congenital long QT syndrome.

• Symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomaticsustained ventricular tachycardia. Participants with atrial fibrillation and heartrate controlled by medication are permitted.

• Lupus nephritis or anti-neutrophil cytoplasmic antibody-associated vasculitis.

• Change in renal function requiring hospitalisation or dialysis within 3 months priorto screening (Visit 1).

• History of renal transplant (or anticipated need for renal transplant during thestudy).

• Severe hepatic impairment, biliary cirrhosis, or cholestasis.

• History of hereditary or idiopathic angioedema.

• Any prior hypersensitivity to ACEi or ARB that in the investigator's judgmentprecludes use of lisinopril and valsartan/irbesartan. Prior hypersensitivityreactions to consider include, but are not limited to, development of angioedema,icterus, hepatitis, or neutropaenia or thrombocytopaenia requiring treatmentmodification.

• Known hypersensitivity or previous anaphylaxis to SZC or to components thereof.

• 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´sclinical judgment.

• Active malignancy requiring treatment at the time of screening (Visit 1), except forsuccessfully treated basal cell or treated squamous cell carcinoma.

• S-K > 6.5 or < 3.5 mmol/L by local laboratory within 1 day prior to the scheduledfirst dose of SZC in the initiation phase.

• Evidence of COVID-19 infection within 2 weeks prior to screening (Visit 1).

• Treated with dual blockade of RAAS (combined use of an ACEi and ARB) within 3 monthsprior to screening (Visit 1).

• Treated with an angiotensin receptor neprilysin inhibitor (ARNI;sacubitril/valsartan [Entresto®]) within 3 months prior to screening (Visit 1).

• Treated with an MRA not approved for CKD within 3 months prior to screening (Visit 1).

• Treated with aliskiren-containing products with 3 months prior to screening (Visit 1).

• Treated with SPS (eg, Kayexalate, Resonium), CPS (Resonium Calcium), patiromer (Veltassa®), or SZC (Lokelma®) within 7 days prior to screening (Visit 1).

• Participation in another clinical study with an investigational product administeredwithin one month prior to screening (Visit 1).

• Not willing or not able to change to lisinopril or valsartan/irbesartan, theprotocol-mandated RAASi study intervention. Note: For participants taking a fixedcombination 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 efficaciousfor such participants to change to the study ACEi or ARB and to the other drug asseparate agents.

• Previous dosing with SZC in the present study.

• Currently pregnant (confirmed with positive pregnancy test at screening [Visit 1])or breastfeeding.

• Judgment by the investigator that the participant is unlikely to comply with studyprocedures, restrictions, and requirements.

• Involvement in the planning and/or conduct of the study (applies to both AstraZenecastaff and/or staff at the study site).