Correction of serum potassium with sodium zirconium cyclosilicate in Japanese patients with hyperkalemia: a randomized, dose–response, phase 2/3 study

Abstract

Background Sodium zirconium cyclosilicate (SZC) is an oral potassium binder approved to treat hyperkalemia in adults in a number of countries, including Japan. Methods This phase 2/3, randomized, double-blind, placebo-controlled, dose–response study (ClinicalTrials.gov: NCT03127644) was designed to determine the efficacy and safety of SZC in Japanese adults with hyperkalemia. Patients with serum potassium (sK+) concentrations ≥ 5.1– ≤ 6.5 mmol/L were randomized 1:1:1 to SZC 5 g, SZC 10 g, or placebo three times daily for 48 h (six doses total). The primary efficacy endpoint was the exponential rate of change in sK+ over 48 h. The proportion of patients with normokalemia (sK+ 3.5–5.0 mmol/L) at 48 h and adverse events (AEs) were also evaluated. Results Overall, 103 patients (mean age, 73.2 years; range 50–89 years) received SZC 5 g (n = 34), SZC 10 g (n = 36), or placebo (n = 33). The exponential rate of sK+ change from 0 to 48 h versus placebo was − 0.00261 (SZC 5 g) and – 0.00496 (SZC 10 g; both P < 0.0001). At 48 h, the proportions of patients with normokalemia were 85.3%, 91.7%, and 15.2% with SZC 5 g, SZC 10 g, and placebo, respectively. No serious AEs were reported. Hypokalemia (sK+ < 3.5 mmol/L) occurred in two patients in the SZC 10 g group; normokalemia was re-established within 6 days and no treatment-related AEs were reported. Conclusion SZC is effective and well tolerated in Japanese patients with hyperkalemia.

A phase 3 multicenter open-label maintenance study to investigate the long-term safety of sodium zirconium cyclosilicate in Japanese subjects with hyperkalemia

“…Furthermore, subgroup analyses showed consistent results across subpopulations. These findings are consistent with those reported for shorter courses of treatment as in the dose-finding study and HARMONIZE-GLOBAL studies, which included Japanese patients [ 13 , 15 ]. Thus, the present findings confirm that SZC is effective in inducing and maintaining normokalemia long term, regardless of age, sex, renal function, concomitant medication, or comorbid conditions in Japanese patients.…”

“…The key results obtained during the maintenance phase of the present study were that SZC was well tolerated (primary objective), and the tolerability profile was consistent with previous SZC studies in Japan and other Asian countries [ 13 , 15 ]. The present safety profile was also comparable with that of previous studies conducted overseas [ 10 – 12 ].…”

“…SZC acts locally and is not absorbed systemically [ 8 ]; therefore, SZC is not associated with systemic toxicity [ 10 – 12 ]. In a multicenter, phase 2/3, dose-finding study in 103 Japanese subjects with hyperkalemia (NCT03127644), SZC dosed at 5 g and 10 g three times daily significantly reduced serum potassium levels within 48 h versus placebo and had a good safety and tolerability profile [ 13 ]. Moreover, in a subgroup analysis of the same study, consistent beneficial effects of SZC on potassium levels during the correction phase of the study were demonstrated, regardless of underlying condition (HF, DM, CKD, or RAASi treatment) [ 14 ].…”

Effects and Safety of a Novel Oral Potassium-Lowering Drug-Sodium Zirconium Cyclosilicate for the Treatment of Hyperkalemia: a Systematic Review and Meta-Analysis

“…This systematic review and meta-analysis was conducted to estimate the efficacy and safety of SZC for hyperkalemia, and eventually, 8 RCTs met our inclusion criteria [21,[23][24][25][26][27][28][29]. Our results showed that SZC effectively decreased the sK + in patients with hyperkalemia within 48 h and had benefits for the Consistent with our findings, available data showed that SZC was associated with a significant decrease in sK + within 48 h and had benefits for the long-term control of sK + .…”

“…The safety of SZC is the main issues of concern. The current research reported the side effects of SZC mainly included gastrointestinal disorders (including nausea, vomiting, diarrhea and constipation), cardiac disorders, urinary tract infection, edema and hypokalemia [20][21][22][23][24][25][26][27][28][29][30]33]. In our meta-analysis, of all adverse events mentioned above, SZC only increased the risk of edema compared with placebo.…”