Sodium Zirconium Cyclosilicate in Chronic Kidney Disease, Hyperkalemia, and Metabolic Acidosis: NEUTRALIZE Randomized Study.

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.