Rationale and design of CONTINUITY: a Phase 4 randomized controlled trial of continued post-discharge sodium zirconium cyclosilicate treatment versus standard of care for hyperkalemia in chronic kidney disease

Background. Individuals with chronic kidney disease (CKD) hospitalized with hyperkalemia are at risk of hyperkalemia recurrence and re-hospitalization. We present the rationale and design of CONTINUITY, a study to examine the efficacy of continuing sodium zirconium cyclosilicate (SZC)-an oral, highly selective potassium (K+) binder-compared with standard of care (SoC) on maintaining normokalemia and reducing re-hospitalization and resource utilization among participants with CKD hospitalized with hyperkalemia. Methods. This Phase 4, randomized, open-label, multicenter study will enroll adults with Stage 3b-5 CKD and/or estimated glomerular filtration rate <45 mL/min/1.73 m(2), within 3 months of eligibility screening, hospitalized with a serum potassium (sK(+)) level of >5.0-<= 6.5 mmol/L, without ongoing K+ binder treatment. The study will include an in-hospital phase, where participants receive SZC for 2-21 days, and an outpatient (post-discharge) phase. At discharge, participants with sK(+) 3.5-5.0 mmol/L will be randomized (1:1) to SZC or SoC and monitored for 180 days. The primary endpoint is the occurrence of normokalemia at 180 days. Secondary outcomes include incidence and number of hospital admissions or emergency department visits both with hyperkalemia as a contributing factor, and renin-angiotensin-aldosterone system inhibitor down-titration. The safety and tolerability of SZC will be evaluated. Ethics approval has been received from all relevant ethics committees. Enrollment started March 2022 and the estimated study end date is December 2023. Conclusions. This study will assess the potential of SZC versus SoC in managing people with CKD and hyperkalemia post-discharge. LAY SUMMARY High levels of potassium in the blood are potentially life-threatening and are more common in people who have chronic kidney disease. When people with chronic kidney disease are hospitalized because blood potassium levels are elevated, the likelihood of this problem recurring is high, potentially resulting in more hospital admissions. The CONTINUITY study is designed to investigate whether a new potassium-lowering therapy-sodium zirconium cyclosilicate-could prevent a recurrence of high blood potassium levels after discharge from hospital. People with advanced kidney disease in hospital with high blood potassium levels will be randomly allocated to one of two groups: those taking sodium zirconium cyclosilicate and those receiving standard treatment. CONTINUITY is the first study of this design to investigate the effectiveness and safety of a new potassium-lowering treatment for people with chronic kidney disease admitted to hospital with high potassium levels. The study is estimated to complete in December 2023. [GRAPHICS] .