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

Heart Failure With Reduced Ejection Fraction Clinical Trial

— REALIZE-K  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04676646
• Other study ID #: D9480C00018
• Secondary ID: 2020-003312-27
• Status: Active, not recruiting
• Phase: Phase 4
• Start date: March 8, 2021
• Est. completion date: July 31, 2024

Study information

• Verified date: April 2024
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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).

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 366
• Est. completion date: July 31, 2024
• Est. primary completion date: July 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 130 Years

Eligibility

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

Related Conditions & MeSH terms

• Heart Failure
• Heart Failure With Reduced Ejection Fraction
• Hyperkalaemia
• Hyperkalemia

Intervention

Drug:
• Sodium zirconium cyclosilicate
Investigational medicinal product
• Placebo
Placebo comparator

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.

Locations

Country	Name	City	State
Brazil	Research Site	Belo Horizonte
Brazil	Research Site	Bragança Paulista
Brazil	Research Site	Brasilia
Brazil	Research Site	Brasília
Brazil	Research Site	Campina Grande do Sul
Brazil	Research Site	Campinas
Brazil	Research Site	Canoas
Brazil	Research Site	Joinville
Brazil	Research Site	Porto Alegre
Brazil	Research Site	Porto Alegre
Brazil	Research Site	Porto Alegre
Brazil	Research Site	Ribeirao Preto
Brazil	Research Site	Salvador
Brazil	Research Site	Santa Cruz Do Sul
Brazil	Research Site	Sao Paulo
Brazil	Research Site	Sao Paulo
Brazil	Research Site	São Paulo
Brazil	Research Site	São Paulo
Brazil	Research Site	Votuporanga
Canada	Research Site	Cambridge	Ontario
Canada	Research Site	Kitchener	Ontario
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Quebec
Canada	Research Site	Scarborough	Ontario
Canada	Research Site	Scarborough	Ontario
Canada	Research Site	Terrebonne	Quebec
Canada	Research Site	Toronto	Ontario
Canada	Research Site	Whitby	Ontario
Czechia	Research Site	Brandys nad Labem
Czechia	Research Site	Broumov
Czechia	Research Site	Hradec Kralove
Czechia	Research Site	Jaromer
Czechia	Research Site	Louny
Czechia	Research Site	Ostrava
Czechia	Research Site	Uherske Hradiste
Hungary	Research Site	Budapest
Hungary	Research Site	Budapest
Hungary	Research Site	Zalaegerszeg
Poland	Research Site	Gdynia
Poland	Research Site	Lodz
Poland	Research Site	Lodz
Poland	Research Site	Lódz
Poland	Research Site	Poznan
Poland	Research Site	Zarów
Spain	Research Site	A Coruna
Spain	Research Site	Almeria
Spain	Research Site	Barcelona
Spain	Research Site	Barcelona
Spain	Research Site	Bilbao (Vizcaya)
Spain	Research Site	Granada
Spain	Research Site	Huelva
Spain	Research Site	Jaen
Spain	Research Site	Lleida
Spain	Research Site	Madrid
Spain	Research Site	Majadahonda
Spain	Research Site	Murcia
Spain	Research Site	Palma de Mallorca
Spain	Research Site	Palma de Mallorca
Spain	Research Site	Pamplona
Spain	Research Site	Sabadell
Spain	Research Site	Salamanca
Spain	Research Site	Santiago de Compostela
Spain	Research Site	Sevilla
Spain	Research Site	Sevilla
Spain	Research Site	Valencia
Spain	Research Site	Valencia
Spain	Research Site	Zaragoza
Ukraine	Research Site	Cherkasy
Ukraine	Research Site	Ivano-Frankivsk
Ukraine	Research Site	Ivano-Frankivsk
Ukraine	Research Site	Kharkiv
Ukraine	Research Site	Kharkiv Region
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Lutsk
Ukraine	Research Site	Lviv
Ukraine	Research Site	Odesa
Ukraine	Research Site	Ternopil
Ukraine	Research Site	Uzhgorod
United Kingdom	Research Site	Ashington
United Kingdom	Research Site	Bridgend
United Kingdom	Research Site	Bristol
United Kingdom	Research Site	Glasgow
United Kingdom	Research Site	Leicester
United Kingdom	Research Site	Liverpool
United Kingdom	Research Site	Manchester
United Kingdom	Research Site	Newport
United Kingdom	Research Site	Sheffield
United States	Research Site	Evanston	Illinois
United States	Research Site	Fairhope	Alabama
United States	Research Site	Falls Church	Virginia
United States	Research Site	Greenville	South Carolina
United States	Research Site	Hazel Crest	Illinois
United States	Research Site	Houston	Texas
United States	Research Site	Kansas City	Missouri
United States	Research Site	Los Angeles	California
United States	Research Site	New York	New York
United States	Research Site	Oak Lawn	Illinois
United States	Research Site	Torrance	California
United States	Research Site	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Brazil,  Canada,  Czechia,  Hungary,  Poland,  Spain,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)