Long-term safety and efficacy of sodium zirconium cyclosilicate for hyperkalaemia in patients with mild/moderate versus severe/end-stage chronic kidney disease: comparative results from an open-label, Phase 3 study

Abstract

Background: Sodium zirconium cyclosilicate (SZC; formerly ZS-9) is a selective potassium (K+) binder for the treatment of adults with hyperkalaemia. This post hoc analysis of an open-label, single-arm trial (NCT02163499) compared SZC efficacy and safety >12 months among outpatients with hyperkalaemia and Stages 4 and 5 chronic kidney disease (CKD) versus those with Stages 1-3 CKD.

Methods: Adults with serum K+ ≥5.1 mmol/L (measured by point-of-care i-STAT device) received SZC 10 g three times daily for 24-72 h until normokalaemia (i-STAT K+ 3.5-5.0 mmol/L) was achieved [correction phase (CP)], followed by once daily SZC 5 g for ≤12 months [maintenance phase (MP)]. Here, patients were stratified by baseline estimated glomerular filtration rate (eGFR <30 or ≥30 mL/min/1.73 m2). Study endpoints included percent achieving normokalaemia during CP and MP, mean serum K+ and bicarbonate during MP, and adverse events (AEs).

Results: Of 751 patients enrolled, 289 (39%), 453 (60%) and 9 (1%) had baseline eGFR values of <30, ≥30 mL/min/1.73 m2 or missing, respectively. During the CP, 82% of patients achieved normokalaemia in both eGFR subgroups within 24 h, and 100 and 95% with baseline eGFR <30 and ≥30 mL/min/1.73 m2, respectively, within 72 h. Corresponding proportions with normokalaemia during the MP were 82 and 90% at Day 365, respectively. Mean serum K+ reduction from baseline during the CP was sustained throughout the MP and serum bicarbonate increased. AEs during the MP were more common in the eGFR <30 ≥30 mL/min/1.73 m2 subgroup.

Conclusions: SZC corrects hyperkalaemia and maintains normokalaemia among outpatients regardless of the CKD stage.

Keywords: chronic kidney disease; estimated glomerular filtration rate; hyperkalaemia; potassium; sodium zirconium cyclosilicate.

© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.

Figures

Graphical abstract

FIGURE 1

Patient disposition. Nine patients who entered the CP did not have a study baseline eGFR measurement. ECG, electrocardiogram.

FIGURE 2

Proportion of patients with baseline eGFR (A) <30 mL/min/1.73 m2 and (B) ≥30 mL/min/1.73 m2 achieving i-STAT K+ levels in the CP ITT population. ITT population included all patients who received SZC and had any post-baseline K+ values measured during the study phase. In (B), at 24 h, 0.2% of patients had i-STAT K+ >6.0 mmol/L.

FIGURE 3

Proportion of patients with baseline eGFR (A) <30 mL/min/1.73 m2 and (B) ≥30 mL/min/1.73 m2 achieving i-STAT K+ levels in the MP ITT population. ITT population included all patients who received SZC and had any post-baseline K+ values measured during the study phase.

FIGURE 4

Mean absolute serum K+ (A) and mean change in serum K+ (B) over time in the MP ITT population. ITT population included all patients who received SZC and had any post-baseline K+ values measured during the study phase. Across study Days 8–365, absolute mean (SD) serum K+ levels were 4.8 (0.4) mmol/L in the eGFR <30 mL/min/1.73 m2 subgroup and 4.7 (0.4) mmol/L in the eGFR ≥30 mL/min/1.73 m2 subgroup (P-value for difference <0.001); corresponding values for mean (95% CI) change from CP baseline were −0.87 (−0.93 to −0.82) and −0.86 (−0.91 to −0.81), respectively (P-value for difference = 0.765). Off-drug values were recorded within 7 (±1) days following the last dose of SZC in 75 and 86% of patients with baseline eGFR <30 and ≥30 mL/min/1.73 m2, respectively. Off-drug values were recorded outside of the 7 (±1)-day window in 25 and 14% of patients with baseline eGFR <30 and ≥30 mL/min/1.73 m2, respectively. Sensitivity analyses showed that mean off-drug serum K+ values within versus outside of the 7 (±1)-day window were similar (P = 0.459 and 0.914 for patients with baseline eGFR <30 and ≥30 mL/min/1.73 m2, respectively). All bars P < 0.001 versus CP baseline. CI, confidence interval.

FIGURE 5

Distribution of SZC dosing in the safety populations of each study phase (safety population included all patients who received one or more dose of SZC during the given study phase and had any post-baseline follow-up for safety). (A) Total dose required to achieve normokalaemia during the CPa; and distribution of SZC dosing per study visit in patients with baseline eGFR B) <30, and C) ≥30 mL/min/1.73m2 in the maintenance phase. aDuring the CP, one, two and three patients in the eGFR <30 mL/min/1.73m2 subgroup received SZC 10, 20 and 50 g, respectively, while one, three, two and one patient in the eGFR ≥30 mL/min/1.73m2 subgroup received SZC 10, 20, 50 and 70 g, respectively). bMean and median dose reported are for last dose administered prior to that MP day's endpoint measurements.

FIGURE 6

Change from CP baseline in (A) eGFR, (B) serum bicarbonate and (C) serum urea over time in the MP safety population. Safety population included all patients who received one or more dose of SZC during the given study phase and had any post-baseline follow-up for safety. aTwo hundred and ninety for eGFR and serum bicarbonate data. Off-drug values were recorded within 7 (±1) days following the last dose of SZC in 75 and 87% of patients with baseline eGFR <30 and ≥30 mL/min/1.73 m2, respectively. Off-drug values were recorded outside of the 7 (±1)-day window in 25 and 13% of patients with baseline eGFR <30 and ≥30 mL/min/1.73 m2, respectively. Sensitivity analyses showed that mean off-drug eGFR values within versus outside of the 7 (±1)-day window were similar (P = 0.121 and P = 0.085 for patients with baseline eGFR <30 and ≥30 mL/min/1.73 m2, respectively).