Study to Assess Efficacy and Safety of SZC for the Management of High Potassium in Patients With Symptomatic HFrEF Receiving Spironolactone (REALIZE-K)
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| ClinicalTrials.gov Identifier: NCT04676646 |
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Recruitment Status :
Active, not recruiting
First Posted : December 21, 2020
Last Update Posted : April 23, 2024
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Hyperkalaemia Heart Failure With Reduced Ejection Fraction | Drug: Sodium zirconium cyclosilicate Drug: Placebo Other: Spironolactone | Phase 4 |
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 (Clinical Trial) |
| Actual Enrollment : | 366 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Intervention Model Description: | REALIZE-K is a Phase 4, multinational, multicenter, double-blind, placebo-controlled, randomized-withdrawal, parallel-group study. |
| Masking: | Double (Participant, Investigator) |
| 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. |
| Primary Purpose: | Treatment |
| 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 |
| Actual Study Start Date : | March 8, 2021 |
| Estimated Primary Completion Date : | July 31, 2024 |
| Estimated Study Completion Date : | July 31, 2024 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Open-label run-in phase
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
Investigational medicinal product
Other Name: SZC Drug: Placebo Placebo comparator Other: Spironolactone 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. |
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Experimental: Randomized withdrawal phase (6 months)
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
Investigational medicinal product
Other Name: SZC Drug: Placebo Placebo comparator Other: Spironolactone 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. |
- 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 [ Time Frame: The monthly visits are used for response assessment from month 1 to month 6 ]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)
- 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 [ Time Frame: The monthly visits are used for response assessment from month 1 to month 6 ]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
- Response is defined by Being on spironolactone ≥25 mg daily The treatment effect concerns the overall OR [ Time Frame: The monthly visits are used for response assessment from month 1 to month 6 ]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 last month, with HK defined as sK+ >5.0 mEq/L. [ Time Frame: From randomization to the end of treatment (EOT) visit (approximately 6 months post-randomisation) ]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. SZC compared to placebo using HR. [ Time Frame: From randomization to the end of treatment (EOT) visit (approximately 6 months post-randomisation) ]To compare the SZC and placebo arms with respect to ability to prevent decreases in spironolactone dose.
- Change in KCCQ-CSS at EOT visit (approximately 6 months post-randomisation) from randomisation. SZC compared with placebo using difference in mean [ Time Frame: From randomization to the end of treatment (EOT) visit (approximately 6 months post-randomisation) ]To compare the SZC and placebo arms with respect to change from randomisation in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS)
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| Ages Eligible for Study: | 18 Years to 130 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04676646
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| Responsible Party: | AstraZeneca |
| ClinicalTrials.gov Identifier: | NCT04676646 |
| Other Study ID Numbers: |
D9480C00018 2020-003312-27 ( EudraCT Number ) |
| First Posted: | December 21, 2020 Key Record Dates |
| Last Update Posted: | April 23, 2024 |
| Last Verified: | April 2024 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared. |
| Supporting Materials: |
Study Protocol Statistical Analysis Plan (SAP) |
| Time Frame: | AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. |
| Access Criteria: | When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. |
| URL: | https://astrazenecagroup-dt.pharmacm.com/DT/Home |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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Heart Failure Hyperkalemia Heart Diseases Cardiovascular Diseases Water-Electrolyte Imbalance Metabolic Diseases Spironolactone |
Mineralocorticoid Receptor Antagonists Hormone Antagonists Hormones, Hormone Substitutes, and Hormone Antagonists Physiological Effects of Drugs Diuretics, Potassium Sparing Diuretics Natriuretic Agents |