A Study to Test Whether ZS (Sodium Zirconium Cyclosilicate) Can Reduce the Incidence of Increased Blood Potassium Levels Among Dialized Patients.

Inclusion criteria

• Provision of informed consent prior to any study specific procedures
• Female or male aged ≥ 18 years at screening Visit 1. For patients aged <20 years and enrolled in Japan, a written informed consent should be obtained from the patient and his or her legally acceptable representative.
• Receiving hemodialysis (or hemodiafiltration) 3 times a week for treatment of endstage renal disease (ESRD) for at least 3 months before randomization.
• Patients must have hemodialysis access consisting of an arteriovenous fistula, AV graft, or tunneled (permanent) catheter which is expected to remain in place for the entire duration of the study.
• Pre-dialysis serum K >5.4 mmol/L after long inter-dialytic interval and >5.0 mmol/L after one short inter-dialytic interval during screening (as assessed by central lab).
• Prescribed dialysate K concentration ≤ 3 mmol/L during screening
• Sustained Qb ≥200 ml/min and spKt/V ≥1.2 (or URR ≥ 63) on stable hemodialysis/hemodiafltration prescription during screening with prescription (time, dialyzer, blood flow [Qb], dialysate flow rate [Qd] and bicarbonate concentration) expected to remain unchanged during study
• Heparin dose (if used) must be stable during screening and expected to be stable during the study
• Subjects must be receiving dietary counseling appropriate for ESRD patients treated with hemodialysis/hemodiafiltration as per local guidelines, which includes dietary potassium restriction.

Exclusion criteria

• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca, including ZS Pharma staff and/or staff at the study site)
• Hemoglobin <9 g/dL on screening (as assessed on Visit 1)
• Lack of compliance with hemodialysis prescription (both number and duration of treatments) during the two-week period preceding screening (100% compliance required)
• Patients treated with sodium polystyrene sulfonate (SPS, Kayexalate, Resonium), calcium polystyrene sulfonate (CPS, Resonium calcium) or patiromer (Veltassa) within 7 days before screening or anticipated in requiring any of these agents during the study
• Myocardial infarction, acute coronary syndrome, stroke, seizure or a thrombotic/thromboembolic event (e.g., deep vein thrombosis or pulmonary embolism, but excluding vascular access thrombosis) within 12 weeks prior to randomization
• Laboratory diagnosis of hypokalemia (K < 3.5 mmol/L), hypocalcemia (Ca < 8.2 mg/dL; for Japan hypocalcemia is defined as albumin-corrected Ca < 8.0 mg/dL), hypomagnesemia (Mg < 1.7 mg/dL) or severe acidosis (serum bicarbonate 16 mEq/L or less) in the 4 weeks preceding randomization
• Pseudohyperkalemia secondary to hemolyzed blood specimen (this situation is not considered screening failure, sampling or full screening can be postponed to a later time as applicable).
• Severe leukocytosis (>20× 10^9/L) or thrombocytosis (≥450 × 10^9/L) during screening
• Polycythemia (Hb >14 g/dL) during screening
• Diagnosis of rhabdomyolysis during the 4 weeks preceding randomization
• Patients treated with lactulose, xifaxan (rifaximin) or other non-absorbed antibiotics for hyperammonemia within 7 days prior to the first dose of study drug
• Patients unable to take oral ZS drug mix
• Scheduled date for living donor kidney transplant
• Patients with a life expectancy of less than 6 months
• Female patients who are pregnant or breastfeeding
• Females of childbearing potential, unless using contraception as detailed in the protocol or sexual abstinence.
• Known hypersensitivity or previous anaphylaxis to ZS or to components thereof
• Participation in another clinical study with an investigational product during the last 1 month before screening
• Any medical condition, including active, clinically significant infection, that in the opinion of the investigator or Sponsor may pose a safety risk to a patient in this study, which may confound safety or efficacy assessment and jeopardize the quality of the data, or may interfere with study participation
• Presence of cardiac arrhythmias or conduction defects that require immediate treatment
• History of alcohol or drug abuse within 2 years prior to randomization
• Previous randomization in the present study