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

AstraZeneca

Status and phase: Completed; Phase 4

Conditions: Hyperkalaemia; Heart Failure With Reduced Ejection Fraction

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

Study type: Interventional

Funder types: Industry

Identifiers

NCT04676646

D9480C00018

2020-003312-27 (EudraCT Number)

Details and patient eligibility

About

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).

Full 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.

Enrollment: 366 patients

Sex: All

Ages: 18 to 130 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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366 participants in 2 patient groups

Open-label run-in phase

Experimental group

Description:

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).

Treatment:

Drug: Sodium zirconium cyclosilicate

Other: Spironolactone

Drug: Placebo

Randomized withdrawal phase (6 months)

Experimental group

Description:

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).

Treatment:

Drug: Sodium zirconium cyclosilicate

Other: Spironolactone

Drug: Placebo