HyperkalaemiaPhase 4REALIZE-KNCT04676646
Study to Assess Efficacy and Safety of SZC for the Management of High Potassium in Patients With Symptomatic HFrEF Receiving Spironolactone
A Phase 4 study testing Sodium zirconium cyclosilicate and Spironolactone in people with Hyperkalaemia and Heart Failure With Reduced Ejection Fraction, run by AstraZeneca at 89 sites in 8 countries.
Trial summary
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). Read more about this study
- Who is it for?
- Ages 18 to 130 years
- Conditions the study is for
- Hyperkalaemia, Heart Failure With Reduced Ejection Fraction
- What is being tested?
- Sodium zirconium cyclosilicate and Spironolactone
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 366 participants
- Where
- 89 sitesin 8 countries
- Study dates
- 8 Mar 2021to 15 Jul 2024
- Phase
- Phase 4
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 130 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 12Show fewer
- 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
Who cannot join
- 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
Trial locations and contacts
89 sites in 8 countries.
89 sites in 8 countries
Spain23 sites
Research Site
A Coruña, 15006
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Almería, 4009
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Barcelona, 8035
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Barcelona, 8041
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Bilbao (Vizcaya), 48013
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Granada, 18007
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Huelva, 21005
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Jaén, 23007
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Lleida, 25198
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Madrid, 28041
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Majadahonda, 28222
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Murcia, 30120
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Palma de Mallorca, 07010
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Palma de Mallorca, 07198
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Pamplona, 31008
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Sabadell, 08208
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Salamanca, 37007
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Santiago de Compostela, 15706
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Seville, 41009
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Seville, 41013
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Valencia, 46010
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Valencia, 46026
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Zaragoza, 50009
Brazil19 sites
Research Site
Belo Horizonte, 30110-017
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Bragança Paulista, 12916-542
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Brasília, 70390-700
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Brasília, 71615-907
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Campina Grande do Sul, 83430-000
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Campinas, 13060-080
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Canoas, 92425-020
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Joinville, 89201-490
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Porto Alegre, 90020-090
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Porto Alegre, 90035-000
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Porto Alegre, 90035-903
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Ribeirão Preto, 14026-020
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Salvador, 41810-011
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Santa Cruz do Sul, 96835-090
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São Paulo, 01321-001
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São Paulo, 04556-100
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São Paulo, 05652-9000
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São Paulo, 08270-070
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Votuporanga, 15500-003
United States12 sites
Research Site
Evanston, Illinois, 60202
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Fairhope, Alabama, 36532
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Falls Church, Virginia, 22042
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Greenville, South Carolina, 29605
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Hazel Crest, Illinois, 60429-2196
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Houston, Texas, 77054
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Kansas City, Missouri, 64111
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Los Angeles, California, 90033
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New York, New York, 10029
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Oak Lawn, Illinois, 60453
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Torrance, California, 90502
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Winston-Salem, North Carolina, 27157
Canada10 sites
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Cambridge, Ontario, N1R 6V6
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Kitchener, Ontario, N2N 1B2
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Montreal, Quebec, H1T 1C8
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Montreal, Quebec, H2X 3E4
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Québec, Quebec, G1R 2J6
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Scarborough Village, Ontario, M1B 4Z8
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Scarborough Village, Ontario, M1S 4N6
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Terrebonne, Quebec, J6V 2H2
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Toronto, Ontario, M5B1M8
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Whitby, Ontario, L1N 5T2
United Kingdom9 sites
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Ashington, NE63 9JJ
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Bridgend, CF31 1RQ
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Bristol, BS105NB
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Glasgow, G4 0SF
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Leicester, LE3 9QP
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Liverpool, L9 7AL
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Manchester, M13 9WL
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Newport, NP20 2UB
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Sheffield, S5 7AU
Czechia7 sites
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Brandýs nad Labem, 250 01
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Broumov, 55001
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Hradec Králové, 500 02
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Jaroměř, 55101
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Louny, 440 01
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Ostrava, 708 52
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Uherské Hradiště, 68601
Poland6 sites
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Gdynia, 81-157
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Lodz, 90-553
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Lodz, 91-002
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Lódz, 93-513
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Skórzewo, 60-185
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Żarów, 58-130
Hungary3 sites
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Budapest, 1122
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Budapest, 1204
Research Site
Zalaegerszeg, 8900
About this study
Official title: 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).
Read the 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.
- Being tested
- Sodium zirconium cyclosilicate, Placebo, Spironolactone
- Medical subject headings
- Hyperkalemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Sodium zirconium cyclosilicateDrug
Also called SZC
Investigational medicinal product
PlaceboDrug
Placebo comparator
SpironolactoneOther
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.
| Study group | Role | What they receive |
|---|---|---|
| Open-label run-in phase | Experimental | 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). Receives: Drug: Sodium zirconium cyclosilicate; Drug: Placebo; Other: Spironolactone |
| Randomized withdrawal phase (6 months) | Experimental | 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). Receives: Drug: Sodium zirconium cyclosilicate; Drug: Placebo; Other: Spironolactone |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: From Month 1 (Visit 9) to Month 6 (Visit 14), up to 6 months
Secondary outcomes (5)
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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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.
Measured: At EOT visit (approximately 6 months post-randomisation)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Dec 2020
- Study start8 Mar 2021
- Primary completion15 Jul 2024
- Study completion15 Jul 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for HyperkalaemiaStudies of the same condition, open and under way.
- More trials run by AstraZenecaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- REALIZE-K is a Phase 4, multinational, multicenter, double-blind, placebo-controlled, randomized-withdrawal, parallel-group study.
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 366 participants (actual)
Sponsor and investigators
- Lead sponsor
- AstraZeneca
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04676646
- Sponsor's protocol ID
- D9480C00018
- Other IDs
- 2020-003312-27
- Acronym
- REALIZE-K
- Status last verified
- Jul 2025
- First submitted
- 16 Dec 2020
- Last updated
- 9 Jul 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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.
Publications
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.
PubMed 39566872Kosiborod 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.
PubMed 38878009