Efficacy and safety of sodium zirconium cyclosilicate for hyperkalaemia: the randomized, placebo-controlled HARMONIZE-Global study

Abstract

Aims: Sodium zirconium cyclosilicate (SZC, formerly ZS-9) is a selective K⁺ binder to treat adults with hyperkalaemia. HARMONIZE-Global examined the efficacy and safety of SZC among outpatients with hyperkalaemia from diverse geographic and ethnic origins.

Methods and results: This phase 3, randomized, double-blind, placebo-controlled study recruited outpatients with serum K⁺ ≥5.1 mmol/L (measured by point-of-care i-STAT device) at 45 sites in Japan, Russia, South Korea, and Taiwan. Following open-label treatment with thrice-daily SZC 10 g during a 48 h correction phase (CP), patients achieving normokalaemia (K⁺ 3.5-5.0 mmol/L) were randomized 2:2:1 to once-daily SZC 5 g, SZC 10 g, or placebo during a 28 day maintenance phase (MP). The primary endpoint was mean central-laboratory K⁺ level during days 8-29 of the MP. Of 267 patients in the CP, 248 (92.9%) entered the MP. During the CP, mean central-laboratory K⁺ was reduced by 1.28 mmol/L at 48 h vs. baseline (P < 0.001). During the MP (days 8-29), SZC 5 and 10 g once-daily significantly lowered mean central-laboratory K⁺ by 9.6% and 17.7%, respectively, vs. placebo (P < 0.001 for both). More patients had normokalaemia (central-laboratory K⁺ 3.5-5.0 mmol/L at day 29) with SZC 5 (58.6%) and 10 g (77.3%) vs. placebo (24.0%), with the greatest number of normokalaemic days in the 10-g group. The most common adverse events with SZC were mild or moderate constipation and oedema.

Conclusions: Normokalaemia achieved during the CP was maintained over 28 days with SZC treatment among outpatients with hyperkalaemia.

Keywords: Hyperkalaemia; Normokalaemia; Potassium; Sodium zirconium cyclosilicate.

Figure 1

Study design (A) and patient disposition (B). ^aDay 3 of the correction phase was also considered day 1 of the maintenance phase. ^bOff‐drug visit occurred within 7 (±1) days after last dose administration. ^cFive patients who did not meet the study inclusion/exclusion criteria were enrolled in the correction phase. DB, double‐blind; QD, once‐daily; R, randomization; SZC, sodium zirconium cyclosilicate; TID, thrice‐daily.

Figure 2

Mean central‐laboratory K⁺ over time (A) during the 48 h open‐label correction phase and (B) according to the randomized groups during the 28 day maintenance phase. Error bars are the 95% confidence interval. Grey shading indicates the normokalaemic range. BL, baseline; CP, correction phase; MP, maintenance phase; QD, once‐daily; R, randomization; SZC, sodium zirconium cyclosilicate; TID, thrice‐daily.

Figure 3

Proportion of patients with normokalaemia during the correction and maintenance phases (full analysis set). BL, baseline; CP, correction phase; MP, maintenance phase; QD, once‐daily; R, randomization; SZC, sodium zirconium cyclosilicate; TID, thrice‐daily.