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.
Trial Registration: ClinicalTrials.gov identifier: NCT05347693; EudraCT: 2021-003527-14, registered on 19 October 2021.
Competing Interests: This information presented in this manuscript has not been published previously in whole or part, except in abstract format (Nephrol Dialysis Transplant 2022;37:gfac066.053). J.O.B. holds grant funding from the National Institute of Health Research, the British Heart Foundation, Kidney Research UK and Yakult Honsha. He has received honoraria from AstraZeneca, Napp Pharmaceutical Group Ltd, Vifor Pharma, Pfizer/Bristol-Myers Squibb and Astellas. A.M.A., J.M.E., E.L. and C.M. are employees of, and hold or may hold stock in, AstraZeneca. A.A. reports serving as principal investigator or co-investigator of clinical trials sponsored by the National Institutes of Health/National Institute of Allergy and Infectious Diseases, NeuroRx Pharma, Pulmotect, Inc., Blade Therapeutics, Novartis, Takeda, Humanigen, Eli Lilly, PTC Therapeutics, Octapharma, Fulcrum Therapeutics and Alexion, unrelated to the present study; speaker and/or consultant for Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, Portola, Sunovion, Mylan, Salix, Alexion, AstraZeneca, Novartis, Nabriva Therapeutics, Paratek Pharmaceuticals, Inc., Bayer, Tetraphase Pharmaceuticals, Inc., Achogen La Jolla, Ferring, Seres, Spero, Eli Lilly, Millennium, PeraHealth, HeartRite, AseptiScope and Sprightly, unrelated to the present study. C.L. reports consulting fees from AstraZeneca, Roche diagnostics and Bayer; and speaker honoraria from Novartis, Astra, Bayer, Medtronic, Impulse Dynamics and Vifor Pharma. M.M.S., holder of the Jindal Research Chair in the Prevention of Kidney Disease, has received honoraria from AstraZeneca.
(© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)