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

Primary Purpose

Hyperkalaemia, Heart Failure With Reduced Ejection Fraction

Status

Recruiting

Phase

Phase 4

Locations

International

Study Type

Interventional

Intervention

Sodium zirconium cyclosilicate

Placebo

Spironolactone

About this trial

This is an interventional treatment trial for Hyperkalaemia

Eligibility Criteria

18 Years - 130 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 either:
Have a history of HK (sK+ >5.0 mEq/L) within the prior 24 months and eGFR ≥30 mL/min/1.73 m2, or
sK+ ≥4.5 mEq/L and eGFR 30 to 60 mL/min/1.73 m2 and/or 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) (stable dose for ≥4 weeks)
Not on spironolactone or eplerenone, or on low-dose spironolactone (<25 mg daily).
Receiving beta-blocker (stable dose for ≥4 weeks) 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 due to HF
Previous cardiac transplantation or implantation of a ventricular assistance device (VAD) or similar device, or transplantation or implantation expected after randomisation

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Open-label run-in phase

Randomized withdrawal phase (6 months)

Arm 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).

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).

Outcomes

Primary Outcome Measures

Occurrence (yes/no) of patients on SZC compared to placebo who, at the EOT, have serum potassium (sK+) within 3.5-5.0 mEq/L are on spironolactone ≥25 mg daily, and did not use rescue therapy for HK at any point during the randomised-withdrawal phase

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)

Secondary Outcome Measures

Occurrence (yes/no) of patients on SZC compared to placebo who at the EOT visit,have sK+ within 3.5-5.0 mEq/L and are on the same dose of spironolactone as randomisation without use of rescue therapy for HK at any point in the randomised-withdrawal phase

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

Occurrence (yes/no) of patients on SZC compared to placebo who, at the EOT visit, are on spironolactone ≥25 mg daily. Patients who are lost to follow-up, including due to death, prior to the EOT visit will be treated as non-response.

To compare the SZC and placebo arms with respect to spironolactone dose.

Time to first HK episode for patients on SZC compared to placebo during the randomised withdrawal phase, 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.

Time to first instance of decrease or discontinuation of spironolactone dose due to HK for patients on SZC compared to placebo during the randomised-withdrawal phase.

To compare the SZC and placebo arms with respect to ability to prevent decreases in spironolactone dose.

Change in KCCQ-CSS at EOT visit from randomisation for patients on SZC compared to placebo.

To compare the SZC and placebo arms with respect to change from randomisation in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS)

Full Information

NCT ID

NCT04676646

First Posted

December 16, 2020

Last Updated

October 10, 2023

Sponsor

AstraZeneca

1. Study Identification

Unique Protocol Identification Number

NCT04676646

Brief Title

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

Acronym

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

Study Type

Interventional

2. Study Status

Record Verification Date

October 2023

Overall Recruitment Status

Recruiting

Study Start Date

March 8, 2021 (Actual)

Primary Completion Date

July 31, 2024 (Anticipated)

Study Completion Date

July 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

AstraZeneca

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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).

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hyperkalaemia, Heart Failure With Reduced Ejection Fraction

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Model Description

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

Masking

ParticipantInvestigator

Masking Description

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.

Allocation

Randomized

Enrollment

400 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Open-label run-in phase

Arm Type

Experimental

Arm Description

Arm Title

Randomized withdrawal phase (6 months)

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Sodium zirconium cyclosilicate

Other Intervention Name(s)

SZC

Intervention Description

Investigational medicinal product

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Placebo comparator

Intervention Type

Other

Intervention Name(s)

Spironolactone

Intervention Description

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.

Primary Outcome Measure Information:

Title

Description

Time Frame