Effect of Sodium Zirconium Cyclosilicate on Serum Potassium and Bicarbonate in Patients with Hyperkalemia and Metabolic Acidosis Associated with Chronic Kidney Disease: Rationale and Design of the NEUTRALIZE Study

Abstract

<b><i>Introduction:</i></b> Sodium zirconium cyclosilicate (SZC) is a selective potassium (K⁺) binder for hyperkalemia management that provides rapid and sustained correction of hyperkalemia. The NEUTRALIZE study is investigating whether SZC, in addition to correcting hyperkalemia and maintaining normal serum K⁺, can provide sustained increases in serum bicarbonate (HCO₃⁻) in patients with hyperkalemia and metabolic acidosis associated with chronic kidney disease (CKD). <b><i>Methods:</i></b> This is a prospective, randomized, double-blind, placebo-controlled phase 3b study of US adults with stage 3–5 CKD not on dialysis with hyperkalemia (K⁺ &#x3e;5.0–≤5.9 mmol/L) and low-serum HCO₃⁻ (16–20 mmol/L). In the open-label correction phase, all eligible patients receive SZC 10 g three times daily for up to 48 h. Patients who achieve normokalemia (K⁺ ≥3.5–≤5.0 mmol/L) are then randomized 1:1 to once-daily SZC 10 g or placebo for a 4-week, double-blind, placebo-controlled maintenance phase. The primary endpoint is the proportion of patients with normokalemia at the end of treatment (EOT) without rescue therapy for hyperkalemia. Key secondary endpoints include mean change in serum HCO₃⁻, the proportion of patients with an increase in serum HCO₃⁻ of ≥2 or ≥3 mmol/L without rescue therapy for metabolic acidosis, and the proportion of patients with serum HCO₃⁻ ≥22 mmol/L at EOT. <b><i>Conclusions:</i></b> NEUTRALIZE will establish whether SZC can provide sustained increases in serum HCO₃⁻ while lowering serum K⁺ in patients with hyperkalemia and CKD-associated metabolic acidosis and may provide insights on the mechanism(s) underlying the increased serum HCO₃⁻ with SZC treatment.