Clinical trial NCT04676646: Study to Assess Efficacy and Safety of SZC for the Management of High Potassium in Patients With Symptomatic HFrEF Receiving Spironolactone
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
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hyperkalaemia
Heart Failure With Reduced Ejection Fraction
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2020-12-21
Enrollment: 366
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: REALIZE-K is a Phase 4, multinational, multicenter, double-blind, placebo-controlled, randomized-withdrawal, parallel-group study.
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: 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
timeFrame: The monthly visits are used for response assessment from month 1 to month 6
Secondary outcomes:
measure: 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
timeFrame: The monthly visits are used for response assessment from month 1 to month 6
measure: Response is defined by Being on spironolactone ≥25 mg daily The treatment effect concerns the overall OR
timeFrame: The monthly visits are used for response assessment from month 1 to month 6
measure: 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.
timeFrame: From randomization to the end of treatment (EOT) visit (approximately 6 months post-randomisation)
measure: Time to first instance of decrease or discontinuation of spironolactone dose due to HK. SZC compared to placebo using HR.
timeFrame: From randomization to the end of treatment (EOT) visit (approximately 6 months post-randomisation)
measure: Change in KCCQ-CSS at EOT visit (approximately 6 months post-randomisation) from randomisation. SZC compared with placebo using difference in mean
timeFrame: From randomization to the end of treatment (EOT) visit (approximately 6 months post-randomisation)
Other outcomes:
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Study officials:
References: