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

AstraZeneca366 enrolled

Overview

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).

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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

366

Conditions

Hyperkalaemia Heart Failure With Reduced Ejection Fraction

Interventions

Sodium zirconium cyclosilicateDRUG

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.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 130 Years

Medical Language ↔ Plain English

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

Locations (89)

Outcomes

Primary Outcomes

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.

Time frame: From Month 1 (Visit 9) to Month 6 (Visit 14), up to 6 months

Secondary Outcomes

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.

Time frame: 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.

Data from ClinicalTrials.gov

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