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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Hyperkalaemia, Heart Failure With Reduced Ejection Fraction

Intervention / Treatment
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* Drug: Sodium zirconium cyclosilicate
* Drug: Placebo
* Other: Spironolactone


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: REALIZE-K is a Phase 4, multinational, multicenter, double-blind, placebo-controlled, randomized-withdrawal, parallel-group study.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open-label run-in phase<br>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). | Drug: Sodium zirconium cyclosilicate<br>* Investigational medicinal product<br>* Other names: SZC;Drug: Placebo<br>* Placebo comparator<br>Other: Spironolactone<br>* 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.<br>|
| Experimental: Randomized withdrawal phase (6 months)<br>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). | Drug: Sodium zirconium cyclosilicate<br>* Investigational medicinal product<br>* Other names: SZC;Drug: Placebo<br>* Placebo comparator<br>Other: Spironolactone<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | From randomization to the end of treatment (EOT) visit (approximately 6 months post-randomisation) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | From randomization to the end of treatment (EOT) visit (approximately 6 months post-randomisation) | 
| 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. | From randomization to the end of treatment (EOT) visit (approximately 6 months post-randomisation) | 
| 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. | From randomization to the end of treatment (EOT) visit (approximately 6 months post-randomisation) | 
| 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. | From randomization to the end of treatment (EOT) visit (approximately 6 months post-randomisation) | 
| 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) | From randomization to the end of treatment (EOT) visit (approximately 6 months post-randomisation) |