Study to Assess Efficacy and Safety of SZC for the Management of High Potassium in Patients With Symptomatic HFrEF Receiving Spironolactone
NCT ID: NCT04676646
Last Updated: 2025-07-09
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE4
366 participants
INTERVENTIONAL
2021-03-08
2024-07-15
Brief Summary
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Detailed Description
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Patients meeting the following criteria will enter the 4-6 week open-label run-in phase: symptomatic heart failure with reduced ejection fraction (HFrEF); receiving an angiotensin-converting enzyme inhibitor (ACEi), angiotensin II receptor blocker (ARB), or angiotensin receptor-Neprilysin inhibitor (ARNi); receiving no spironolactone or eplerenone, or receiving low-dose spironolactone (\<25 mg daily); receiving a beta-blocker unless contraindicated; AND with hyperkalemia (sK+ 5.1-5.9 mEq/L) and an eGFR \>/= 30 mL/min/1.73m2, OR normokalemic (sK+ 3.5-5.0 mEq/L) and 'at risk' of developing hyperkalemia (ie, history of hyperkalemia within the past 36 months and eGFR \>/= 30 mL/min/1.73m2, or sK+ 4.5-5.0 mEq/L and eGFR 30-60 mL/min/1.73m2 and/or age \>75 years).
Patients who are normokalemic on SZC and receiving spironolactone \>/= 25 mg daily at the end of the open-label run-in phase will enter the 6-month double-blind, placebo-controlled, randomized withdrawal treatment phase. Eligible patients will be randomized 1:1, stratified by run-in phase sK+ cohort.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
DOUBLE
The IRT/RTSM will provide to the investigator(s) or pharmacists the kit identification number to be allocated to the participant at the dispensing visit. Routines for this will be described in the IRT/RTSM user manual that will be provided to each centre.
The randomisation code should not be broken except in medical emergencies when the appropriate management of the participant requires knowledge of the treatment randomisation.
Study Groups
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Open-label run-in phase
Cohort 1 (4 weeks duration): Patients who are hyperkalemic at study entry will begin SZC 10 g TID for up to 48 hours followed by SZC 10 g once daily to achieve and maintain normokalemia. The SZC dose will be adjusted as needed to maintain normokalemia (dose range = 5 g every other day, to 5-15 g once daily).
Cohort 2 (up to 6 weeks duration): Patients who develop hyperkalemia during the uptitration of spironolactone will receive SZC 10 g TID for up to 48 hours followed by SZC 10 g once daily to achieve and maintain normokalemia. The SZC dose will be adjusted as needed to maintain normokalemia (dose range = 5 g every other day, to 5-15 g once daily).
Sodium zirconium cyclosilicate
Investigational medicinal product
Placebo
Placebo comparator
Spironolactone
Background intervention.
During the run-in phase, spironolactone will be initiated/uptitrated up to a maximum of 50 mg per day. During the randomized withdrawal phase the spironolactone dose at the end of the run-in phase will be maintained.
Randomized withdrawal phase (6 months)
SZC arm and Placebo arm: Patients will continue on the SZC dose they were receiving at the end of the run-in phase.
The SZC / Placebo dose will be adjusted as needed to maintain normokalemia (dose range = 5 g every other day, to 5-15 g once daily).
Sodium zirconium cyclosilicate
Investigational medicinal product
Placebo
Placebo comparator
Spironolactone
Background intervention.
During the run-in phase, spironolactone will be initiated/uptitrated up to a maximum of 50 mg per day. During the randomized withdrawal phase the spironolactone dose at the end of the run-in phase will be maintained.
Interventions
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Sodium zirconium cyclosilicate
Investigational medicinal product
Placebo
Placebo comparator
Spironolactone
Background intervention.
During the run-in phase, spironolactone will be initiated/uptitrated up to a maximum of 50 mg per day. During the randomized withdrawal phase the spironolactone dose at the end of the run-in phase will be maintained.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Potassium and estimated glomerular filtration rate (eGFR):
* Cohort 1: sK+ 5.1-5.9 mEq/L at screening/study enrolment and eGFR ≥30 mL/min/1.73 m2; OR
* Cohort 2: Normokalaemic (sK+ 3.5-5.0 mEq/L) at screening and 'at risk' of developing HK defined as any of the following:
* Have a history of HK (sK+ \>5.0 mEq/L) within the prior 36 months and eGFR ≥30 mL/min/1.73 m2; or
* sK+ 4.5-5.0 mEq/L and eGFR 30 to 60 mL/min/1.73 m2; or
* sK+ 4.5-5.0 mEq/L, and age \>75 years
* Symptomatic HFrEF (New York Heart Association \[NYHA\] class II-IV), which has been present for at least 3 months
* Left ventricular ejection fraction (LVEF) ≤40%
* Receiving angiotensin-converting enzyme inhibitor (ACEi), angiotensin II receptor blocker (ARB), or angiotensin receptor-Neprilysin inhibitor (ARNi)
* Not on or on low-dose spironolactone or eplerenone (\<25 mg daily)
* Receiving beta-blocker unless contraindicated
Exclusion Criteria
* Current inpatient hospitalisation with unstable HF, defined as any of the following:
* Systolic blood pressure \<95 mmHg during the 6 hours prior to screening.
* Intravenous diuretic therapy during the 12 hours prior to screening.
* Use of intravenous inotropic drugs during the 24 hours prior to screening.
* Received mechanical circulatory support during the 48 hours prior to screening
* Previous cardiac transplantation or implantation of a ventricular assistance device (VAD) or similar device, or transplantation or implantation expected after randomisation
18 Years
130 Years
ALL
No
Sponsors
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AstraZeneca
INDUSTRY
Responsible Party
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Locations
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Research Site
Fairhope, Alabama, United States
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Los Angeles, California, United States
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Torrance, California, United States
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Evanston, Illinois, United States
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Hazel Crest, Illinois, United States
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Oak Lawn, Illinois, United States
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Kansas City, Missouri, United States
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New York, New York, United States
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Winston-Salem, North Carolina, United States
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Greenville, South Carolina, United States
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Houston, Texas, United States
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Falls Church, Virginia, United States
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Belo Horizonte, , Brazil
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Bragança Paulista, , Brazil
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Brasília, , Brazil
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Brasília, , Brazil
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Campina Grande do Sul, , Brazil
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Campinas, , Brazil
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Canoas, , Brazil
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Joinville, , Brazil
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Porto Alegre, , Brazil
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Porto Alegre, , Brazil
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Porto Alegre, , Brazil
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Ribeirão Preto, , Brazil
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Salvador, , Brazil
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Santa Cruz do Sul, , Brazil
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São Paulo, , Brazil
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São Paulo, , Brazil
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São Paulo, , Brazil
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São Paulo, , Brazil
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Votuporanga, , Brazil
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Cambridge, Ontario, Canada
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Kitchener, Ontario, Canada
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Scarborough Village, Ontario, Canada
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Scarborough Village, Ontario, Canada
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Toronto, Ontario, Canada
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Whitby, Ontario, Canada
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Montreal, Quebec, Canada
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Montreal, Quebec, Canada
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Québec, Quebec, Canada
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Terrebonne, Quebec, Canada
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Brandýs nad Labem, , Czechia
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Broumov, , Czechia
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Hradec Králové, , Czechia
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Jaroměř, , Czechia
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Louny, , Czechia
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Ostrava, , Czechia
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Uherské Hradiště, , Czechia
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Budapest, , Hungary
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Budapest, , Hungary
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Zalaegerszeg, , Hungary
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Gdynia, , Poland
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Lodz, , Poland
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Lodz, , Poland
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Lódz, , Poland
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Skórzewo, , Poland
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Żarów, , Poland
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A Coruña, , Spain
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Almería, , Spain
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Barcelona, , Spain
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Barcelona, , Spain
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Bilbao (Vizcaya), , Spain
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Granada, , Spain
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Huelva, , Spain
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Jaén, , Spain
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Lleida, , Spain
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Madrid, , Spain
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Majadahonda, , Spain
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Murcia, , Spain
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Palma de Mallorca, , Spain
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Palma de Mallorca, , Spain
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Pamplona, , Spain
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Sabadell, , Spain
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Salamanca, , Spain
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Santiago de Compostela, , Spain
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Seville, , Spain
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Seville, , Spain
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Valencia, , Spain
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Valencia, , Spain
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Zaragoza, , Spain
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Ashington, , United Kingdom
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Bridgend, , United Kingdom
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Bristol, , United Kingdom
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Glasgow, , United Kingdom
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Leicester, , United Kingdom
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Liverpool, , United Kingdom
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Manchester, , United Kingdom
Research Site
Newport, , United Kingdom
Research Site
Sheffield, , United Kingdom
Countries
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References
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Kosiborod MN, Cherney DZI, Desai AS, Testani JM, Verma S, Chinnakondepalli K, Dolling D, Patel S, Dahl M, Eudicone JM, Friberg L, Ouwens M, Antunes MO, Connelly KA, Madrini V Jr, Kuthi L, Lala A, Lorenzo M, Guimaraes PO, Marcos MC, Merkely B, Nunez J, Squire I, Vaclavik J, Wranicz J, Petrie MC. Sodium Zirconium Cyclosilicate for Management of Hyperkalemia During Spironolactone Optimization in Patients With Heart Failure. J Am Coll Cardiol. 2025 Mar 18;85(10):971-984. doi: 10.1016/j.jacc.2024.11.014. Epub 2024 Nov 18.
Kosiborod MN, Cherney D, Connelly K, Desai AS, Guimaraes PO, Kuthi L, Lala A, Madrini V Jr, Merkely B, Villota JN, Squire I, Testani JM, Vaclavik J, Verma S, Wranicz J, Dahl M, Eudicone JM, Friberg L, Petrie MC. Sodium Zirconium Cyclosilicate in HFrEF and Hyperkalemia: REALIZE-K Design and Baseline Characteristics. JACC Heart Fail. 2024 Oct;12(10):1707-1716. doi: 10.1016/j.jchf.2024.05.003. Epub 2024 May 13.
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Related Links
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Other Identifiers
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2020-003312-27
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
D9480C00018
Identifier Type: -
Identifier Source: org_study_id
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