Here, we describe the rationale and design of the NEUTRALIZE study (NCT04727528), which aims to investigate whether SZC can: (1) correct hyperkalemia and maintain normal serum K + levels and (2) provide sustained increases in serum HCO 3 − in patients with CKD-associated hyperkalemia and metabolic acidosis. Thus, further study is needed to elucidate if SZC causes clinically meaningful increases in serum HCO 3 − in patients with CKD-associated hyperkalemia and metabolic acidosis. Moreover, the impact of SZC on urine NH 4 + excretion was not evaluated. In addition, the effect of SZC on serum HCO 3 − may have been confounded by patients receiving sodium bicarbonate therapy, although it should be noted that increases in serum HCO 3 − were also seen in patients not receiving sodium bicarbonate. The post hoc analyses of previous clinical studies showing dose-dependent increases in serum HCO 3 − with SZC did not systematically examine patients with CKD with a combination of hyperkalemia and low serum HCO 3 −. The mechanism(s) underlying the increase in serum HCO 3 − with SZC are not fully understood but may be due to direct binding and removal of NH 4 + by SZC in the gastrointestinal tract and/or an increase in renal ammonia (NH 3) production with correction of hyperkalemia, which would allow for increased renal acid excretion. Furthermore, SZC was associated with dose-dependent decreases in blood urea nitrogen (BUN) during correction (first 48 h) and maintenance (21 days) treatment compared with placebo in patients with CKD. The rise in serum HCO 3 − during the 48-h correction phase was independent of CKD stage and was sustained during the 29-day maintenance phase with SZC 10–15 g once daily (QD) and for 11 months of continued open-label treatment. In addition to its effects on serum K +, in post hoc analyses, SZC had acute effects on serum HCO 3 − during correction of hyperkalemia, with rapid dose-dependent placebo-adjusted increases in serum HCO 3 − of 1.02 mmol/L with SZC 5 g three times daily (TID) to 1.78 mmol/L with SZC 10 g TID within 48 h. Conclusions: NEUTRALIZE will establish whether SZC can provide sustained increases in serum HCO 3 − 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 HCO 3 − with SZC treatment. Key secondary endpoints include mean change in serum HCO 3 −, the proportion of patients with an increase in serum HCO 3 − of ≥2 or ≥3 mmol/L without rescue therapy for metabolic acidosis, and the proportion of patients with serum HCO 3 − ≥22 mmol/L at EOT. The primary endpoint is the proportion of patients with normokalemia at the end of treatment (EOT) without rescue therapy for hyperkalemia. 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. In the open-label correction phase, all eligible patients receive SZC 10 g three times daily for up to 48 h. ![]() 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 HCO 3 − (16–20 mmol/L). The NEUTRALIZE study is investigating whether SZC, in addition to correcting hyperkalemia and maintaining normal serum K +, can provide sustained increases in serum bicarbonate (HCO 3 −) in patients with hyperkalemia and metabolic acidosis associated with chronic kidney disease (CKD). Introduction: Sodium zirconium cyclosilicate (SZC) is a selective potassium (K +) binder for hyperkalemia management that provides rapid and sustained correction of hyperkalemia.
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