Study to Assess Efficacy and Safety of SZC for the Management of High Potassium in Patients With Symptomatic HFrEF Receiving Spironolactone (REALIZE-K)

Phase IV, Double-Blind, Placebo-Controlled, Randomized-Withdrawal Trial Evaluating Sodium Zirconium Cyclosilicate (SZC) for the Management of Hyperkalaemia in Patients With Symptomatic Heart Failure With Reduced Ejection Fraction and Receiving Spironolactone

The main objective of this study is to evaluate the efficacy of SZC as compared with placebo in keeping potassium levels within the normal range (3.5-5.0 mEq/L) while on spironolactone ≥25 mg daily without assistance of rescue therapy for hyperkalaemia (HK).

Study Overview

• Status: Completed
• Conditions: Heart Failure With Reduced Ejection Fraction; Hyperkalaemia
• Intervention / Treatment: Drug: Placebo; Drug: Sodium zirconium cyclosilicate; Other: Spironolactone

Detailed Description

REALIZE-K is a Phase 4, multinational, multicenter, double-blind, placebo-controlled, randomized-withdrawal, parallel-group study that includes the following 3 phases: screening, 4-6 week open-label run-in phase where sodium zirconium cyclosilicate (SZC) and spironolactone will be optimized, followed by a 6-month double-blind, placebo-controlled, randomized withdrawal treatment phase.

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.

• Study Type: Interventional
• Enrollment (Actual): 366
• Phase: Phase 4

Contacts and Locations

Study Locations

• Brazil
  • Belo Horizonte, Brazil, 30110-017
    • Research Site
  • Bragança Paulista, Brazil, 12916-542
    • Research Site
  • Brasilia, Brazil, 70390-700
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  • Brasília, Brazil, 71615-907
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  • Campina Grande do Sul, Brazil, 83430-000
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  • Campinas, Brazil, 13060-080
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  • Canoas, Brazil, 92425-020
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  • Joinville, Brazil, 89201-490
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  • Porto Alegre, Brazil, 90020-090
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  • Porto Alegre, Brazil, 90035-903
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  • Porto Alegre, Brazil, 90035-000
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  • Ribeirao Preto, Brazil, 14026-020
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  • Salvador, Brazil, 41810-011
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  • Santa Cruz Do Sul, Brazil, 96835-090
    • Research Site
  • Sao Paulo, Brazil, 01321-001
    • Research Site
  • Sao Paulo, Brazil, 05652-9000
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  • São Paulo, Brazil, 08270-070
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  • São Paulo, Brazil, 04556-100
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  • Votuporanga, Brazil, 15500-003
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• Canada
  • Quebec, Canada, G1R 2J6
    • Research Site
  • Ontario
    • Cambridge, Ontario, Canada, N1R 6V6
      • Research Site
    • Kitchener, Ontario, Canada, N2N 1B2
      • Research Site
    • Scarborough, Ontario, Canada, M1B 4Z8
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    • Scarborough, Ontario, Canada, M1S 4N6
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    • Toronto, Ontario, Canada, M5B1M8
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    • Whitby, Ontario, Canada, L1N 5T2
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  • Quebec
    • Montreal, Quebec, Canada, H2X 3E4
      • Research Site
    • Montreal, Quebec, Canada, H1T 1C8
      • Research Site
    • Terrebonne, Quebec, Canada, J6V 2H2
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• Czechia
  • Brandys nad Labem, Czechia, 250 01
    • Research Site
  • Broumov, Czechia, 55001
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  • Hradec Kralove, Czechia, 500 02
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  • Jaromer, Czechia, 55101
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  • Louny, Czechia, 440 01
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  • Ostrava, Czechia, 708 52
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  • Uherske Hradiste, Czechia, 68601
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• Hungary
  • Budapest, Hungary, 1122
    • Research Site
  • Budapest, Hungary, 1204
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  • Zalaegerszeg, Hungary, 8900
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• Poland
  • Gdynia, Poland, 81-157
    • Research Site
  • Lodz, Poland, 91-002
    • Research Site
  • Lodz, Poland, 90-553
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  • Lódz, Poland, 93-513
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  • Skórzewo, Poland, 60-185
    • Research Site
  • Żarów, Poland, 58-130
    • Research Site
• Spain
  • A Coruna, Spain, 15006
    • Research Site
  • Almeria, Spain, 4009
    • Research Site
  • Barcelona, Spain, 8035
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  • Barcelona, Spain, 8041
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  • Bilbao (Vizcaya), Spain, 48013
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  • Granada, Spain, 18007
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  • Huelva, Spain, 21005
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  • Jaen, Spain, 23007
    • Research Site
  • Lleida, Spain, 25198
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  • Madrid, Spain, 28041
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  • Majadahonda, Spain, 28222
    • Research Site
  • Murcia, Spain, 30120
    • Research Site
  • Palma de Mallorca, Spain, 07010
    • Research Site
  • Palma de Mallorca, Spain, 07198
    • Research Site
  • Pamplona, Spain, 31008
    • Research Site
  • Sabadell, Spain, 08208
    • Research Site
  • Salamanca, Spain, 37007
    • Research Site
  • Santiago de Compostela, Spain, 15706
    • Research Site
  • Sevilla, Spain, 41009
    • Research Site
  • Sevilla, Spain, 41013
    • Research Site
  • Valencia, Spain, 46010
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  • Valencia, Spain, 46026
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  • Zaragoza, Spain, 50009
    • Research Site
• United Kingdom
  • Ashington, United Kingdom, NE63 9JJ
    • Research Site
  • Bridgend, United Kingdom, CF31 1RQ
    • Research Site
  • Bristol, United Kingdom, BS105NB
    • Research Site
  • Glasgow, United Kingdom, G4 0SF
    • Research Site
  • Leicester, United Kingdom, LE3 9QP
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  • Liverpool, United Kingdom, L9 7AL
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  • Manchester, United Kingdom, M13 9WL
    • Research Site
  • Newport, United Kingdom, NP20 2UB
    • Research Site
  • Sheffield, United Kingdom, S5 7AU
    • Research Site
• United States
  • Alabama
    • Fairhope, Alabama, United States, 36532
      • Research Site
  • California
    • Los Angeles, California, United States, 90033
      • Research Site
    • Torrance, California, United States, 90502
      • Research Site
  • Illinois
    • Evanston, Illinois, United States, 60202
      • Research Site
    • Hazel Crest, Illinois, United States, 60429-2196
      • Research Site
    • Oak Lawn, Illinois, United States, 60453
      • Research Site
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Research Site
  • New York
    • New York, New York, United States, 10029
      • Research Site
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Research Site
  • South Carolina
    • Greenville, South Carolina, United States, 29605
      • Research Site
  • Texas
    • Houston, Texas, United States, 77054
      • Research Site
  • Virginia
    • Falls Church, Virginia, United States, 22042
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 130 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

INCLUSION CRITERIA

• Adults aged ≥18 years
• 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

• Heart failure due to restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, hypertrophic (obstructive) cardiomyopathy, or severe stenotic valve disease as a primary cause of HF
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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).	Drug: Placebo; Placebo comparator; Drug: Sodium zirconium cyclosilicate; Investigational medicinal product; Other Names: SZC; Other: 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.
Experimental: 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).	Drug: Placebo; Placebo comparator; Drug: Sodium zirconium cyclosilicate; Investigational medicinal product; Other Names: SZC; Other: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Participants Who Achieved Response, Defined as Serum Potassium (sK+) Within 3.5 to 5.0 mEq/L, Spironolactone Greater Than or Equal to 25 mg Daily, no Rescue Therapy for Hyperkalaemia	The median percentages of participants having a response are presented. Response means all three requirements were met. Non-response was indicated for participants lost to follow-up, including death. The treatment effect was analysed using a generalised estimating equation (GEE) model with a binomial family and a log link, a dependent variable of response per visit, fixed independent variables of randomised treatment, subject recruitment country, a per visit indicator variable and open-label period cohort. The common odds ratio was derived together with two-sided 95% confidence intervals.	From Month 1 (Visit 9) to Month 6 (Visit 14), up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Participants Who Achieved Response, Defined as sK+ Within 3.5-5.0 mEq/L, on the Same Dose of Spironolactone as Randomisation, no Rescue Therapy for Hyperkalaemia	The median percentages of participants who achieved a response are presented. Response means all three requirements were met. Non-response was indicated for participants lost to follow-up, including death. The analysis was performed using a GEE model with a binomial family and a log link, a dependent variable of response per visit, fixed independent variables of randomised treatment, subject recruitment country, a per visit indicator variable and open-label period cohort. The common odds ratio was derived together with two-sided 95% confidence intervals.	From Month 1 (Visit 9) to Month 6 (Visit 14), up to 6 months
Participants Who Achieved Response, Defined as Spironolactone Greater Than or Equal to 25 mg Daily	The median percentages of participants who achieved a response are presented. Response means that the requirement was met. Non-response was indicated for subjects lost to follow-up, including death. The analysis was performed using a GEE model with a binomial family and a log link, a dependent variable of response per visit, fixed independent variables of randomised treatment, subject recruitment country, a per visit indicator variable and open-label period cohort. The common odds ratio was derived together with two-sided 95% confidence intervals.	From Month 1 (Visit 9) to Month 6 (Visit 14), up to 6 months
Time to First Hyperkalaemia (sK+ Greater Than 5.0mEq/L) Episode	The time to first hyperkalaemia episode for participants on SZC compared to placebo during the randomised-withdrawal period, with hyperkalaemia defined as sK+ greater than 5.0 mEq/L as assessed by central laboratory, is presented in median time (days). The analysis was performed using a Cox regression model including randomised treatment group and subject recruitment country, adjusted for the stratification factor (hyperkalaemia vs normokalaemia at study entry). Placebo group used as reference level in Cox model.	From randomisation to the end of treatment (EOT) visit, up to 6 months
Time to First Instance of Decrease or Discontinuation of Spironolactone Dose Due to Hyperkalaemia	The time to first instance of decrease or discontinuation of spironolactone dose due to hyperkalaemia is presented in median time (days). The analysis was performed using a Cox regression model, adjusted for the stratification factor (hyperkalaemia vs normokalaemia at study entry).	From randomisation to the EOT visit, up to 6 months
Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) at EOT	The KCCQ is a 23-item instrument measuring, from the patients' perspectives, their heart failure-related symptoms, physical and social limitations, self-efficacy, and health-related quality of life (QoL) over the prior 2 weeks. It was scored as follows: Physical Limitation (items 1a-f), Symptom Stability (item 2), Symptom Frequency (items 3, 5, 7, and 9), Symptom Burden (items 4, 6, and 8), Self Efficacy (items 10 and 11), QoL (items 12, 13, and 14), and Social Limitation (items 15a-d). Scores were calculated by summing the responses within each domain and by taking the average. Scale scores were transformed to a 0 to 100 range, with 0 implying the lowest level of functioning and 100 for the highest level of functioning. The CSS was calculated as the average of Physical Limitation Score and Total Symptom Score (TSS) and the TSS was calculated as the average of Symptom Frequency and Symptom Burden Scores. The change from randomisation in KCCQ-CSS is reported.	At EOT visit (approximately 6 months post-randomisation)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Location and Severity of Peripheral Oedema	The location and severity of peripheral oedema that occurred during the randomised-withdrawal phase are presented. Participants with multiple peripheral oedema events were counted only once. The location of oedema is not mutually exclusive so multiple locations may apply for each participant.	During the randomised-withdrawal period and up to 14 days after discontinuation of SZC or placebo, up to 6.5 months

Collaborators and Investigators

• Sponsor: AstraZeneca

Publications and helpful links

Helpful Links

• Redacted SAP
• Redacted CSP
• redacted CSR study synopsis

Study record dates

Study Major Dates

• Study Start (Actual): March 8, 2021
• Primary Completion (Actual): July 15, 2024
• Study Completion (Actual): July 15, 2024

Study Registration Dates

• First Submitted: December 16, 2020
• First Submitted That Met QC Criteria: December 16, 2020
• First Posted (Actual): December 21, 2020

Study Record Updates

• Last Update Posted (Actual): July 9, 2025
• Last Update Submitted That Met QC Criteria: July 8, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Metabolic Diseases; Water-Electrolyte Imbalance; Heart Failure; Hyperkalemia; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Diuretics; Natriuretic Agents; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Spironolactone
• Other Study ID Numbers: D9480C00018; 2020-003312-27 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal.

All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No