Continuing Sodium Zirconium Cyclosilicate (SZC) After Discharge Study

Study Overview
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Brief Summary
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This is an open-label, randomised study in participants with chronic kidney disease (CKD) treated for hyperkalaemia (HK) whilst in hospital. The study will compare SZC to standard of care (SoC) with the goal of determining: If continued use of SZC maintains normokalaemia (NK) better than SoC after participant discharge from the hospital. If continued use of SZC after discharge will reduce HK related healthcare resource utilisation compared to SoC.

Detailed Description
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This is a Phase 4, randomised, controlled, open-label, parallel-group, multicentre study in participants with CKD treated for HK whilst in hospital. Participants from 30 to 50 sites in 4 to 7 countries will be screened for enrolment. In total, 632 participants will be screened to yield 506 participants entering the inpatient phase, resulting in 430 participants discharged and randomised (215 per arm) and 344 evaluable participants. The study plans to enrol approximately equal numbers of participants with mild HK (K+ between > 5.0 and ≤ 5.5 mmol/L) and with moderate/severe HK (K+ between > 5.5 and ≤ 6.5 mmol/L), with a minimum of 30% of the enrolled participants in either group. During the in-hospital phase, participants will be treated with SZC as per local label, starting at baseline and based on local K+ measurement obtained within 24 hours of treatment initiation:). Participants treated with a K-binder other than SZC, at ED visit/hospital admission will be switched to correction treatment with SZC if they are still HK. Such a therapy modification must be based on the investigator's medical judgement of the participant's best interest. Participants who received any K-binder, including SZC at ED visit/hospital admission and are NK at baseline can directly start the maintenance dose of SZC. Participants who initiated SZC during ED visit/hospital admission and are still HK will continue on SZC correction dose (up to 72 hours). All other participants will start correction treatment with SZC as per local label. At discharge, NK participants who have been treated with SZC for between 2 and 21 days whilst in hospital and are established on SZC maintenance dose will be randomised in a 1:1 ratio to one of the following arms: Arm A: Participants discharged with SZC, as per local label, to manage HK until the end of the outpatient phase Arm B: Participants discharged with SoC, as per local practice, to manage HK until the end of study. Note: Participants intended to be discharged with a K+ binder (as per the site routine medical practice) will not be randomised and will be discontinued from the study. Still, participants randomised into Arm B may have a K-binder prescribed at, or after Day 7 post-discharge, to treat confirmed HK or in case there is an increase in K+ level since discharge that, in the investigator's opinion, requires therapy. The total duration of the study for each participant will be up to approximately 189 days, with a maximum of 208 days. Study visit schedule is as follows: In-hospital phase: - The screening visit will occur while the participant is at the hospital (up to 21 days before discharge; medical monitor's approval may be sought for allowing longer duration hospital stays for specific participants) in order to check eligibility criteria Inpatient phase: o The baseline visit (can occur the same day as the screening visit) where correction treatment with SZC will be initiated o The discharge visit, 1 to 20 days after baseline; medical monitor's approval may be sought for allowing longer duration hospital stays for specific participants). Randomisation will occur at day of discharge. Outpatient phase: - Visits will occur at 7, 30, 60, 90, 120, 150, and 180 (EOT, End of Trial) days after randomisation. Only visits at 7, 90 and 180 days after randomisation will be on-site visits, the remaining being telephone visits. If dose titration occurs at any time during the outpatient phase, unscheduled dispensation visits will be performed. Follow-up phase: - A follow-up on-site visit (end of study visit) will occur approximately 7 days after EOT. • Data will be collected at on-site visits, via telephone visits and medical chart reviews. • An adjudication committee will be involved in the study.

Official Title
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An Open-Label, Randomised, Phase 4 Study of Continuing Sodium Zirconium Cyclosilicate (SZC) After Discharge in Participants With Chronic Kidney Disease Treated for Hyperkalaemia

Conditions
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Hyperkalaemia, Chronic Kidney Disease

Intervention / Treatment
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* Drug: Sodium Zirconium Cyclosilicate (SZC)
* Drug: Local standard of care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must be 18 years of age or older, at the time of signing the informed consent Admitted to hospital (inpatient care; directly or from ED) With: diagnosed stage 3b to 5 CKD And/or eGFR < 45 ml/min/1.73 m2 at, or within 3 months of, study screening, based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (Levey et al, 2009). Note: Race/ethnicity should not be included in CKD-EPI equation calculation. Hyperkalaemia at current ED visit/hospital admission as defined by site's local practice and K+ must be between > 5.0 and ≤ 6.5 mmol/L. Male or female Capable and willing of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Exclusion Criteria: Myocardial infarction, stroke, seizure, or a thrombotic/thromboembolic event (eg, deep vein thrombosis or pulmonary embolism, but excluding vascular access thrombosis) within 12 weeks prior to screening Unable to take oral SZC drug mix With a life expectancy of less than 6 months Any medical condition (including active, clinically significant infection) that, in the opinion of the investigator or sponsor, may pose a safety risk to the participant in this study, which may confound safety or efficacy assessments and jeopardise the quality of data, or may interfere with study participation Presence of cardiac arrhythmias or conduction defects that require immediate treatment QT interval corrected by the Fridericia method (QTcF) > 550 msec History of QT prolongation associated with other medications that required discontinuation of that medication Congenital long QT syndrome Symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participant with atrial fibrillation controlled by medication is permitted. History of alcohol or drug abuse within 2 years prior to screening Ongoing treatment with any K-binder before current ED visit/hospital admission. Note: Initiation of any K-binder therapy (including SZC) during the current ED visit/hospital admission is allowed. Chronic haemodialysis or peritoneal dialysis or the recipient of or scheduled date for a kidney transplant. Participation in another clinical study with an investigational product (IP) administered during the month before screening. Note: Participant vaccinated with COVID-19 vaccine whilst still under Emergency Use Utilisation will not be excluded from the study. Known hypersensitivity to SZC or any of the excipients of the product Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site) Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements Previous randomisation in the present study For women only: Women of child-bearing potential (WOCBP; ie, those who are not chemically or surgically sterilised or who are not post-menopausal) who are not willing to use one of the methods of contraception described hereafter, from the time of signing the informed consent throughout the study and 4 weeks thereafter: (a) Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, transdermal (b) Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable (c) Intrauterine device (IUD) (d) Intrauterine hormone-releasing system (IUS) (e) Bilateral tubal occlusion (f) Vasectomised partner (vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of the WOCBP participant and that the vasectomised partner has received medical assessment of the surgical success (g) Sexual abstinence: it is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant. For WOCBP only: Women who have a positive pregnancy test at screening OR women who are breastfeeding.

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: This is a Phase 4, randomised, controlled, open-label, parallel-group, multicentre study in participants with CKD treated for HK whilst in hospital. During the in-hospital phase, participants will be treated with SZC as per local label At discharge, NK participants who have been treated with SZC for between 2 and 21 days whilst in hospital and are established on SZC maintenance dose will be randomised in a 1:1 ratio to one of the following arms: Arm A: Participants discharged with SZC, as per local label, to manage HK until the end of the outpatient phase Arm B: Participants discharged with SoC, as per local practice, to manage HK until the end of study. Note: Participants intended to be discharged with a K+ binder (as per the site routine medical practice) will not be randomised and will be discontinued from the study. The total duration of the study for each participant will be up to approximately 189 days, with a maximum of 208 days.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sodium Zirconium Cyclosilicate (SZC)<br>Participants discharged with SZC, as per local label, to manage HK until the end of the outpatient phase | Drug: Sodium Zirconium Cyclosilicate (SZC)<br>* White to grey crystalline powder for oral suspension in 5 g sachets. Each sachet will be labeled in accordance with Good Manufacturing Practice Annex 13 and per country regulatory requirement. Label text will be translated into local language.<br>* Other names: Lokelma;|
| Active Comparator: Local standard of care (SoC)<br>Participants discharged with SoC, as per local practice, to manage HK until the end of study. | Drug: Local standard of care<br>* Local SoC in the country to be used as per local label<br>* Other names: SoC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence (yes/no) of normokalaemia (NK) (potassium [K+] between 3.5 and 5.0 mmol/L, inclusive) | To evaluate the efficacy of continuing SZC as part of the discharge medications, compared to SoC, in maintaining NK | Up to 180 days post-discharge | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first occurrence of hospital admissions or ED visits with HK as a contributing factor, all-cause death, or use of rescue therapy for HK | To evaluate the effect of continuing SZC as part of the discharge medications, compared to SoC, in reducing the incidence of the composite outcome of hospital admissions or ED visits with HK as a contributing factor, all-cause death, or use of rescue therapy for HK | Up to 180 days post-discharge | 
| Time to first occurrence of hospital admission or ED visit, both with HK as a contributing factor | To evaluate the effect of continuing SZC as part of the discharge medications, compared to SoC, in reducing the incidence of hospital admissions or ED visit with HK as a contributing factor | Up to 180 days post-discharge | 
| Number of hospital admission or ED visits, both with HK as a contributing factor | To evaluate the effect of continuing SZC as part of the discharge medications, compared to SoC, in reducing the number of hospital admission or ED visits with HK as a contributing factor | Up to 180 days post-discharge | 
| Time to first occurrence of RAASi down-titration (or discontinuation) | To evaluate the effect of continuing SZC as part of the discharge medications compared to SoC on reducing the risk of RAASi down-titration (or discontinuation) | Up to 180 days post-discharge | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sodium zirconium cyclosilicate, Hyperkalaemia after discharge at the hospital