RESUMO
BACKGROUND: Metabolic acidosis and hyperkalemia are common in chronic kidney disease (CKD). A potential dual effect of sodium zirconium cyclosilicate (SZC), a selective binder of potassium in the gastrointestinal tract, on serum potassium (sK+) and serum bicarbonate (sHCO3-) was evaluated in patients with hyperkalemia and metabolic acidosis associated with CKD. METHODS: In the NEUTRALIZE study (NCT04727528), non-dialysis patients with stage 3-5 CKD, hyperkalemia (sK+ >5.0 to ≤5.9 mmol/l) and metabolic acidosis (sHCO3- 16-20 mmol/l) received open-label SZC 10 g three times daily for ≤48 hours. Patients achieving normokalemia (sK+ 3.5-5.0 mmol/l) were randomized 1:1 to SZC 10 g or placebo daily for 4 weeks. Primary endpoint was patients (%) maintaining normokalemia at end of treatment (EOT) without rescue. Secondary endpoints included mean change in sHCO3- at EOT (Day 29), and patients (%) normokalemic with a ≥3-mmol/l increase in sHCO3- without rescue. RESULTS: Of 229 patients screened, 37 were randomized (SZC, n = 17; placebo, n = 20). High screen failure led to early study termination. At EOT, 88.2% (SZC) versus 20.0% (placebo) of patients maintained normokalemia (odds ratio 56.2; P = 0.001). Low enrollment rendered secondary endpoint P-values nominal. SZC treatment provided nominally significant increases in sHCO3- versus placebo from Day 15 onwards. Patients who were normokalemic with a ≥3-mmol/l increase in sHCO3- without rescue were 35.3% (SZC) and 5.0% (placebo; P < 0.05). No new safety concerns were reported. CONCLUSIONS: SZC effectively lowered sK+ and maintained normokalemia, with nominally significant increases in sHCO3- observed for SZC versus placebo.
RESUMO
INTRODUCTION: 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). METHODS: 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+ >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. CONCLUSIONS: 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.
