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

NCT04676646 | Completed Phase 4 Results DMC FDA Drug

• 2 other identifiers: D9480C000182020-003312-27
• Study Type: interventional
• Target: 366
• Locations: 8 countries
• Sites: 89

Brief 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).

Conditions

Hyperkalaemia; Heart Failure With Reduced Ejection Fraction

Outcome Measures

Primary Outcomes (1)

• 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 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

  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

  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

  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

  From randomisation to the EOT visit, up to 6 months

• Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) at EOT

  At EOT visit (approximately 6 months post-randomisation)

Other Outcomes (1)

• Location and Severity of Peripheral Oedema

  During the randomised-withdrawal period and up to 14 days after discontinuation of SZC or placebo, up to 6.5 months

Study Arms (2)

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).

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).

Drug: Sodium zirconium cyclosilicate; Drug: Placebo; Other: Spironolactone

Interventions

Sodium zirconium cyclosilicate DRUG

Investigational medicinal product

Also known as: SZC

Open-label run-in phase; Randomized withdrawal phase (6 months)

Placebo DRUG

Placebo comparator

Open-label run-in phase; Randomized withdrawal phase (6 months)

Spironolactone OTHER

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.

Open-label run-in phase; Randomized withdrawal phase (6 months)

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (89)

Research Site

Fairhope, Alabama, 36532, United States

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Los Angeles, California, 90033, United States

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Torrance, California, 90502, United States

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Evanston, Illinois, 60202, United States

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Hazel Crest, Illinois, 60429-2196, United States

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Oak Lawn, Illinois, 60453, United States

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Kansas City, Missouri, 64111, United States

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New York, New York, 10029, United States

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Winston-Salem, North Carolina, 27157, United States

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Greenville, South Carolina, 29605, United States

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Houston, Texas, 77054, United States

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Falls Church, Virginia, 22042, United States

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Belo Horizonte, 30110-017, Brazil

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Bragança Paulista, 12916-542, Brazil

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Brasília, 70390-700, Brazil

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Brasília, 71615-907, Brazil

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Campina Grande do Sul, 83430-000, Brazil

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Campinas, 13060-080, Brazil

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Canoas, 92425-020, Brazil

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Joinville, 89201-490, Brazil

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Porto Alegre, 90020-090, Brazil

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Porto Alegre, 90035-000, Brazil

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Porto Alegre, 90035-903, Brazil

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Ribeirão Preto, 14026-020, Brazil

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Salvador, 41810-011, Brazil

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Santa Cruz do Sul, 96835-090, Brazil

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São Paulo, 01321-001, Brazil

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São Paulo, 04556-100, Brazil

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São Paulo, 05652-9000, Brazil

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São Paulo, 08270-070, Brazil

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Votuporanga, 15500-003, Brazil

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Cambridge, Ontario, N1R 6V6, Canada

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Kitchener, Ontario, N2N 1B2, Canada

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Scarborough Village, Ontario, M1B 4Z8, Canada

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Scarborough Village, Ontario, M1S 4N6, Canada

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Toronto, Ontario, M5B1M8, Canada

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Whitby, Ontario, L1N 5T2, Canada

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Montreal, Quebec, H1T 1C8, Canada

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Montreal, Quebec, H2X 3E4, Canada

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Québec, Quebec, G1R 2J6, Canada

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Terrebonne, Quebec, J6V 2H2, Canada

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Brandýs nad Labem, 250 01, Czechia

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Broumov, 55001, Czechia

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Hradec Králové, 500 02, Czechia

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Jaroměř, 55101, Czechia

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Louny, 440 01, Czechia

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Ostrava, 708 52, Czechia

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Uherské Hradiště, 68601, Czechia

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Budapest, 1122, Hungary

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Budapest, 1204, Hungary

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Zalaegerszeg, 8900, Hungary

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Gdynia, 81-157, Poland

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Lodz, 90-553, Poland

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Lodz, 91-002, Poland

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Lódz, 93-513, Poland

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Skórzewo, 60-185, Poland

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Żarów, 58-130, Poland

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A Coruña, 15006, Spain

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Almería, 4009, Spain

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Barcelona, 8035, Spain

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Barcelona, 8041, Spain

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Bilbao (Vizcaya), 48013, Spain

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Granada, 18007, Spain

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Huelva, 21005, Spain

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Jaén, 23007, Spain

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Lleida, 25198, Spain

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Madrid, 28041, Spain

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Majadahonda, 28222, Spain

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Murcia, 30120, Spain

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Palma de Mallorca, 07010, Spain

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Palma de Mallorca, 07198, Spain

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Pamplona, 31008, Spain

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Sabadell, 08208, Spain

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Salamanca, 37007, Spain

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Santiago de Compostela, 15706, Spain

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Seville, 41009, Spain

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Seville, 41013, Spain

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Valencia, 46010, Spain

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Valencia, 46026, Spain

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Zaragoza, 50009, Spain

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Ashington, NE63 9JJ, United Kingdom

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Bridgend, CF31 1RQ, United Kingdom

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Bristol, BS105NB, United Kingdom

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Glasgow, G4 0SF, United Kingdom

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Leicester, LE3 9QP, United Kingdom

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Liverpool, L9 7AL, United Kingdom

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Manchester, M13 9WL, United Kingdom

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Newport, NP20 2UB, United Kingdom

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Sheffield, S5 7AU, United Kingdom

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Related Publications (2)

• 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.

  PMID: 39566872 DERIVED

• 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.

  PMID: 38878009 DERIVED

Related Links

• Redacted SAP
• Redacted CSP
• redacted CSR study synopsis

MeSH Terms

Conditions

Hyperkalemia

Interventions

sodium zirconium cyclosilicate; Spironolactone

Condition Hierarchy (Ancestors)

Water-Electrolyte Imbalance; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Lactones; Organic Chemicals; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Results Point of Contact

• Title: Global Clinical Lead
• Organization: AstraZeneca

information.center@astrazeneca.com

18772409479

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: All participants entering the double-blind, randomised treatment period will be centrally assigned to randomised study intervention using an Interactive Response Technology/Randomisation and Trial Supply Management (IRT/RTSM). Randomisation will be stratified by the sK+ cohort determined by central laboratory at the start of the open-label phase (Day 1). Before the study is initiated, the telephone number and call-in directions for the IRT and/or the log in information and directions for the RTSM will be provided to each site. 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: REALIZE-K is a Phase 4, multinational, multicenter, double-blind, placebo-controlled, randomized-withdrawal, parallel-group study.

Study Record Dates

• First Submitted: December 16, 2020
• First Posted: December 21, 2020
• Study Start: March 8, 2021
• Primary Completion: July 15, 2024
• Study Completion: July 15, 2024
• Last Updated: July 9, 2025
• Results First Posted: July 9, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• 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.
• 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.

Locations

ES (23); BR (19); PL (6); GB (9); CA (10); US (12); HU (3); CZ (7)