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

Abstract

Background Hyperkalemia is associated with many chronic diseases and renin-angiotensin-aldosterone system inhibitor therapy. Sodium zirconium cyclosilicate (SZC), an oral, highly selective cation-exchanger, is approved for the treatment of hyperkalemia. Methods This phase 3, multicenter, open-label, single-arm, flexible-dose study assessed the safety and efficacy of SZC in Japanese patients with hyperkalemia during a correction phase of up to 3 days and long-term (1 year) maintenance phase (NCT03172702). Results Overall, 150 patients received treatment during both study phases; the study population was generally representative of hyperkalemic Japanese patients in clinical practice. Most patients (78.7%) had three doses of SZC during the correction phase. All but one patient received SZC for ≤ 48 h before transitioning to the maintenance phase. In the maintenance phase, mean (standard deviation; SD) exposure to the study drug was 319.4 (98.1) days and mean (SD) dose was 7.38 (2.85) g/day. Adverse events (AEs) were reported in 131 patients (87.3%); most were mild. The most common treatment-related AEs as evaluated by investigators were constipation (6.7%), peripheral edema (4.0%), and hypertension (2.7%). In the correction phase, 78.7% of patients were normokalemic at 24 h and 98.7% within 48 h; ≥ 65.5% maintained normokalemia throughout the maintenance phase. Conclusion After a year of exposure, SZC treatment was well tolerated by Japanese patients and potassium levels were well controlled.

Evaluation of safety, effectiveness and treatment patterns of sodium zirconium cyclosilicate in management of hyperkalaemia in China: a real-world study protocol

“…A phase III study carried out on Japanese patients with HK evaluated the long-term safety, tolerability and efficacy of SZC after 1 year of administration. SZC treatment was well tolerated with controlled sK levels and a positive safety profile which was consistent with previous studies carried out in Japan and other Asian countries as well as throughout the world 16 28 32 33. The most common AEs reported in this study were constipation (6.7%), peripheral oedema (4.0%) and hypertension (2.7%).…”

Phase I Study of the Pharmacodynamics and Safety of Sodium Zirconium Cyclosilicate in Healthy Chinese Adults

“…27 Indeed, the ability of SZC to provide significant and clinically meaningful reductions in serum potassium concentration and maintain normokalemia among patients with hyperkalemia has been demonstrated for up to 12 months in phase II/III clinical trials, [20][21][22][23][24] including among Asian patients. 25,26 The primary focus of phase II and III clinical trials of SZC to date has been on reductions in serum potassium levels in patients with hyperkalemia and comorbidities. However, several of these studies have also reported an absence of clinically relevant effects on serum sodium concentrations.…”

“…20 Among Japanese patients with hyperkalemia, SZC also provided rapid attainment of normokalemia, with no new safety concerns and favorable tolerability throughout a year of exposure in phase II/III clinical trials. 25,26 The effect of SZC on the excretion of sodium and potassium in healthy American adults receiving a standardized diet was evaluated in a recent phase I study. 27 The results confirmed that treatment with SZC did not significantly affect urinary or fecal sodium excretion.…”

Risk Factors for Rapid Recurrence of Hyperkalemia following Cessation of Sodium Zirconium Cyclosilicate

“…Potassium-binding agents are now available to manage hyperkalemia [ 9 ]. Of note, SZC has recently been introduced as a novel potassium-binding agent with robust evidence to rapidly normalize hyperkalemia and maintain serum potassium levels within the normal range with few drug-related adverse events [ 5 ].…”

“…Before day 0, SZC was administered to all patients. SZC was initiated to treat hyperkalemia at a loading dose for 2 days, in principle, followed by a maintenance dose of 5–15 g/day [ 5 ]. SZC was considered to be terminated following the amelioration of hyperkalemia at the discretion of the treating physicians.…”