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: Active, not recruiting
• 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 Contact: Name: AstraZeneca Clinical Study Information Center; Phone Number: 1-877-240-9479; Email: information.center@astrazeneca.com

Study Locations

• Brazil
  • Belo Horizonte, Brazil, 30110-017
    • Research Site
  • Bragança Paulista, Brazil, 12916-542
    • Research Site
  • Brasilia, Brazil, 70390-700
    • Research Site
  • Brasília, Brazil, 71615-907
    • Research Site
  • Campina Grande do Sul, Brazil, 83430-000
    • Research Site
  • Campinas, Brazil, 13060-080
    • Research Site
  • Canoas, Brazil, 92425-020
    • Research Site
  • Joinville, Brazil, 89201-490
    • Research Site
  • Porto Alegre, Brazil, 90020-090
    • Research Site
  • Porto Alegre, Brazil, 90035-903
    • Research Site
  • Porto Alegre, Brazil, 90035-000
    • Research Site
  • Ribeirao Preto, Brazil, 14026-020
    • Research Site
  • Salvador, Brazil, 41810-011
    • Research Site
  • Santa Cruz Do Sul, Brazil, 96835-090
    • Research Site
  • Sao Paulo, Brazil, 01321-001
    • Research Site
  • Sao Paulo, Brazil, 05652-9000
    • Research Site
  • São Paulo, Brazil, 08270-070
    • Research Site
  • São Paulo, Brazil, 04556-100
    • Research Site
  • Votuporanga, Brazil, 15500-003
    • Research Site
• 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
      • Research Site
    • Scarborough, Ontario, Canada, M1S 4N6
      • Research Site
    • Toronto, Ontario, Canada, M5B1M8
      • Research Site
    • Whitby, Ontario, Canada, L1N 5T2
      • Research Site
  • Quebec
    • Montreal, Quebec, Canada, H2X 3E4
      • Research Site
    • Montreal, Quebec, Canada, H1T 1C8
      • Research Site
    • Terrebonne, Quebec, Canada, J6V 2H2
      • Research Site
• Czechia
  • Brandys nad Labem, Czechia, 250 01
    • Research Site
  • Broumov, Czechia, 55001
    • Research Site
  • Hradec Kralove, Czechia, 500 02
    • Research Site
  • Jaromer, Czechia, 55101
    • Research Site
  • Louny, Czechia, 440 01
    • Research Site
  • Ostrava, Czechia, 708 52
    • Research Site
  • Uherske Hradiste, Czechia, 68601
    • Research Site
• Hungary
  • Budapest, Hungary, 1122
    • Research Site
  • Budapest, Hungary, 1204
    • Research Site
  • Zalaegerszeg, Hungary, 8900
    • Research Site
• Poland
  • Gdynia, Poland, 81-157
    • Research Site
  • Lodz, Poland, 91-002
    • Research Site
  • Lodz, Poland, 90-553
    • Research Site
  • Lódz, Poland, 93-513
    • Research Site
  • Poznań, Poland, 60-192
    • Research Site
  • Żarów, Poland, 58-130
    • Research Site
• Spain
  • A Coruna, Spain, 15006
    • Research Site
  • Almeria, Spain, 4009
    • Research Site
  • Barcelona, Spain, 8035
    • Research Site
  • Barcelona, Spain, 8041
    • Research Site
  • Bilbao (Vizcaya), Spain, 48013
    • Research Site
  • Granada, Spain, 18016
    • Research Site
  • Huelva, Spain, 21005
    • Research Site
  • Jaen, Spain, 23007
    • Research Site
  • Lleida, Spain, 25198
    • Research Site
  • Madrid, Spain, 28041
    • Research Site
  • 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
    • Research Site
  • Valencia, Spain, 46026
    • Research Site
  • Zaragoza, Spain, 50009
    • Research Site
• Ukraine
  • Cherkasy, Ukraine, 18009
    • Research Site
  • Ivano-Frankivsk, Ukraine, 76008
    • Research Site
  • Ivano-Frankivsk, Ukraine, 76005
    • Research Site
  • Kharkiv, Ukraine, 61176
    • Research Site
  • Kharkiv Region, Ukraine, 61058
    • Research Site
  • Kyiv, Ukraine, 04050
    • Research Site
  • Kyiv, Ukraine, 02660
    • Research Site
  • Kyiv, Ukraine, 03049
    • Research Site
  • Kyiv, Ukraine, 03151
    • Research Site
  • Kyiv, Ukraine, 3680
    • Research Site
  • Kyiv, Ukraine, 03015
    • Research Site
  • Lutsk, Ukraine, 43024
    • Research Site
  • Lviv, Ukraine, 79015
    • Research Site
  • Odesa, Ukraine, 65025
    • Research Site
  • Ternopil, Ukraine, 46001
    • Research Site
  • Uzhgorod, Ukraine, 88014
    • 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
    • Research Site
  • Liverpool, United Kingdom, L9 7AL
    • Research Site
  • 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
Response is defined by Having(sK+) within 3.5-5.0 mEq/L AND Being on spironolactone ≥25 mg daily AND Not using rescue therapy for HK during the last month. The treatment effect concerns the overall OR	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)	The monthly visits are used for response assessment from month 1 to month 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Per visit, response is defined by Having potassium (sK+) within 3.5-5.0 mEq/L as assessed by central laboratory AND Being on the same spironolactone dose as they were at randomisation AND Not using rescue therapy for HK during the last month	To compare the SZC and placebo arms with respect to keeping potassium levels within a normal range (3.5-5.0 mEq/L), keeping same spironolactone dose as used at randomisation, and without having had assistance of rescue therapy for HK	The monthly visits are used for response assessment from month 1 to month 6
Response is defined by Being on spironolactone ≥25 mg daily The treatment effect concerns the overall OR	To compare the SZC and placebo arms with respect to spironolactone dose.	The monthly visits are used for response assessment from month 1 to month 6
Time to first HK episode for patients on SZC compared to placebo during the last month, with HK defined as sK+ >5.0 mEq/L.	To evaluate the efficacy of SZC as compared to placebo in keeping potassium levels ≤5.0 mEq/L.	From randomization to the end of treatment (EOT) visit (approximately 6 months post-randomisation)
Time to first instance of decrease or discontinuation of spironolactone dose due to HK. SZC compared to placebo using HR.	To compare the SZC and placebo arms with respect to ability to prevent decreases in spironolactone dose.	From randomization to the end of treatment (EOT) visit (approximately 6 months post-randomisation)
Change in KCCQ-CSS at EOT visit (approximately 6 months post-randomisation) from randomisation. SZC compared with placebo using difference in mean	To compare the SZC and placebo arms with respect to change from randomisation in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS)	From randomization to the end of treatment (EOT) visit (approximately 6 months post-randomisation)

Collaborators and Investigators

• Sponsor: AstraZeneca

Study record dates

Study Major Dates

• Study Start (Actual): March 8, 2021
• Primary Completion (Estimated): July 31, 2024
• Study Completion (Estimated): July 31, 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): February 6, 2024
• Last Update Submitted That Met QC Criteria: February 2, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Metabolic Diseases; Water-Electrolyte Imbalance; Heart Failure; Hyperkalemia; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; 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