A Phase 3b, Randomized, Double-Blind, Placebo-Controlled Study of Sodium Zirconium Cyclosilicate for Reducing the Incidence of Predialysis Hyperkalemia

Abstract

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.

Keywords: clinical trial; end-stage renal disease; hemodialysis.

Graphical abstract

Figure 1.

The DIALIZE study design. L, visit after the long interdialytic interval; PBO, placebo; R, randomization; SZC, sodium zirconium cyclosilicate.

Figure 2.

Flow diagram of patient disposition. “Other” reasons for withdrawal from study for sodium zirconium cyclosilicate (SZC): adverse event (n=1) and transferred to a nonstudy dialysis center (n=1). “Other” reasons for withdrawal from study for placebo (PBO): kidney transplantation (n=1), discontinuation of investigational product (n=1), and noncompliance to study protocol (n=1). “Other” reasons for discontinuation of intervention for SZC: transferred to a nonstudy dialysis center (n=1). “Other” reasons for discontinuation of intervention for PBO: patient hospitalized due to nontreatment-related serious adverse event and was unable to receive treatment during hospitalization and until end of treatment visit (n=1).

Figure 3.

Mean pre- and postdialysis sK⁺ values were lower with SZC than with PBO both at the end of the titration period and during the evaluation period. Postdialysis measurements after the short interdialytic interval were obtained only for some of the patients, because these were scheduled according to an earlier version of the study protocol. Dashed horizontal lines represent the upper and lower limits of normal predialysis sK⁺. Error bars indicate 2×SD of the mean. Predialysis mean (SD) sK⁺ was comparable between treatment groups at randomization (visit 4): SZC, 5.8 (0.6) mmol/L; PBO, 5.9 (0.6) mmol/L. Postdialysis mean (SD) sK⁺ at randomization was also comparable in each treatment group: SZC, 3.8 (0.6) mmol/L; PBO, 3.9 (0.6) mmol/L. L, visit after the long interdialytic interval.