A Phase 3b, Randomized, Double-Blind, Placebo-Controlled Study of Sodium Zirconium Cyclosilicate for Reducing the Incidence of Predialysis Hyperkalemia
Authors: Fishbane Steven , Ford Martin , Fukagawa Masafumi , McCafferty Kieran , Rastogi Anjay , Spinowitz Bruce , Staroselskiy Konstantin , Vishnevskiy Konstantin , Lisovskaja Vera , Al-Shurbaji Ayman , Guzman Nicolas , Bhandari Sunil 
Published: June 2019

Significance Statement
Patients with ESRD receiving chronic hemodialysis often have persistent predialysis hyperkalemia. In the DIALIZE randomized study, the authors evaluated treatment with the potassium binder sodium zirconium cyclosilicate versus placebo in managing hyperkalemia in such patients. The authors report that compared with placebo, sodium zirconium cyclosilicate (SZC) significantly increased the proportion of patients who maintained predialysis serum potassium 4.0–5.0 mmol/L during ≥3 of 4 HD treatments following the long interdialytic interval and who did not require urgent rescue therapy. Sodium zirconium cyclosilicate was well tolerated: the two groups had comparable proportions of patients experiencing serious adverse events, comparable interdialytic weight gain, and few episodes of hypokalemia. The results indicate that sodium zirconium cyclosilicate is an option for the management of hyperkalemia in this setting.

Background
Patients with ESRD have minimal renal potassium excretion and, despite hemodialysis, often have persistent predialysis hyperkalemia. The DIALIZE study (NCT03303521) evaluated sodium zirconium cyclosilicate (SZC) in the management of hyperkalemia in hemodialysis patients.

Methods
In the DIALIZE study, a double-blind, placebo-controlled, phase 3b multicenter study, we randomized adults with ESRD who were managed by three-times weekly hemodialysis and had predialysis hyperkalemia to receive placebo or SZC 5 g once daily on non-dialysis days, and titrated towards maintaining normokalemia over 4 weeks, in 5 g increments to a maximum of 15 g. The primary efficacy outcome was proportion of patients during the 4-week stable-dose evaluation period who maintained predialysis serum potassium of 4.0–5.0 mmol/L during at least three of four hemodialysis treatments after the long interdialytic interval and did not require urgent rescue therapy to reduce serum potassium.

Results
In total, 196 patients (mean [standard deviation (SD)] age =58.1 [13.7] years old) were randomized to sodium zirconium cyclosilicate or placebo. Of 97 patients receiving sodium zirconium cyclosilicate, 41.2% met the primary end point and were deemed treatment responders compared with 1.0% of 99 patients receiving placebo (P<0.001). Rescue therapy to reduce serum potassium during the treatment period was required by 2.1% of patients taking sodium zirconium cyclosilicate versus 5.1% taking placebo. Serious adverse events occurred in 7% and 8% of patients in sodium zirconium cyclosilicate and placebo groups, respectively. The two groups displayed comparable interdialytic weight gain. There were few episodes of hypokalemia.

Conclusions
Sodium zirconium cyclosilicate is an effective and well-tolerated treatment for predialysis hyperkalemia in patients with ESRD undergoing adequate hemodialysis.