Effect of Sodium Zirconium Cyclosilicate on Arrythmia-related Cardiovascular Outcomes in Participants on Chronic Hemodialysis With Recurrent Hyperkalemia (DIALIZE-Outcomes)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effect of Sodium Zirconium Cyclosilicate (SZC) on arrhythmia-related cardiovascular outcomes in participants on chronic hemodialysis with recurrent hyperkalemia.

Detailed Description
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This is an international, multicenter, event-driven, randomized, double-blind, parallel group, placebo-controlled study, evaluating the utility of SZC versus placebo to reduce the incidence of sudden cardiac death (SCD), stroke, and arrhythmia-related hospitalizations, interventions, and emergency department (ED) visits in participants on chronic hemodialysis with recurrent hyperkalemia.

Official Title
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An International, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Effect of Sodium Zirconium Cyclosilicate on Arrythmia-related Cardiovascular Outcomes in Participants on Chronic Hemodialysis With Recurrent Hyperkalemia (DIALIZE-Outcomes)

Conditions
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Hyperkalemia

Intervention / Treatment
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* Drug: Sodium Zirconium Cyclosilicate (SZC)
* Drug: SZC Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol Provision of signed and dated, written ICF prior to any mandatory study specific procedures, sampling, and analyses Must be ≥ 18 years of age, at the time of signing the ICF. Receiving hemodialysis (or hemodiafiltration) 3 times a week for treatment of ESRD for ≥ 4 months before enrollment Must have hemodialysis access consisting of an arteriovenous fistula, arteriovenous graft, or tunneled (permanent) catheter which is expected to remain in place for the entire duration of the study At least 2 out of 3 pre-dialysis S K ≥ 5.5 mmol/L after the LIDI during screening Negative pregnancy test for female participants of childbearing potential Female participants must be 1 year postmenopausal, surgically sterile, or using one highly effective form of birth control (defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly). They should have been stable on their chosen method of birth control for a minimum of 3 months before entering the study and willing to remain on the birth control until 12 weeks after the last dose Exclusion Criteria: Pseudohyperkalemia secondary to hemolyzed blood specimen (this situation is not considered screening failure, sampling or full screening can be postponed to a later time as applicable) Presence of cardiac arrhythmias or conduction defects that require immediate treatment Participants who have a pacemaker or implantable cardiac defibrillator Any medical condition, including active, clinically significant infection or liver disease, that in the opinion of the investigator or sponsor may pose a safety risk to a participant in this study, confound safety or efficacy assessment and jeopardize the quality of the data, or interfere with study participation, or any other restrictions or contraindications in the local prescribing information for SZC History of QT prolongation associated with other medications that required discontinuation of that medication Congenital long QT syndrome QTcF > 550 msec Atrial fibrillation requiring immediate/urgent intervention at screening or randomizations Treated with sodium polystyrene sulfonate (SPS, Kayexalate, Resonium), calcium polystyrene sulfonate (CPS Resonium Calcium), patiromer (Veltassa), or SZC (Lokelma) within 7 days before screening or anticipated requiring chronic use of any of these agents during the study. If participant requires rescue therapy (potassium binder or dialysate S-K change during screening period), the participant will be screen failed Participation in another clinical study with an investigational product, device, or non-standard hemodialysis procedure administered within one month before screening 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 randomization in the present study Females who are pregnant (confirmed with positive pregnancy test or a uterine ultrasound if pregnancy test result is questionable), breastfeeding, or planning to become pregnant during the study Known hypersensitivity or previous anaphylaxis to SZC or to components thereof Scheduled date for living donor kidney transplant Sustained Ventricular Tachycardia > 30 seconds requiring assessment / intervention

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sodium Zirconium Cyclosilicate<br> | Drug: Sodium Zirconium Cyclosilicate (SZC)<br>* Powder for oral suspension in a sachet. A dose is titrated in 5 g increments during a period of 4 weeks from 5 g up to 15 g qd on non-dialysis days. Afterward, the dose is adjusted monthly (or more frequent based on clinical judgment) depending on the current potassium value as measured after the long interdialytic interval (LIDI).<br>* Other names: Lokelma TM;|
| Placebo Comparator: Placebo<br> | Drug: SZC Placebo<br>* Powder for oral suspension in a sachet. A dose is titrated in 5 g increments during a period of 4 weeks from 5 g up to 15 g qd on non-dialysis days. Afterward, the dose is adjusted monthly (or more frequent based on clinical judgment) depending on the current potassium value as measured after the LIDI.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first occurrence of SCD, stroke, or hospitalization/intervention/ED visit due to arrhythmias (atrial fibrillation [AF], bradycardia, asystole, ventricular tachyarrhythmia [VF, VT, etc.]) |  | From randomization visit through study completion during study visits every 3 months, over an average of 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| S-K of 4.0-5.5 mmol/L (yes/no) after the long interdialytic interval (LIDI) at the 12 month visit |  | Evaluated at 12 months after randomization | 
| Time to first occurrence of hospitalization/intervention/ED visit due to arrhythmias (AF, bradycardia, asystole, Ventricular tachyarrhythmia [VF, VT etc.]) |  | From randomization visit through study completion during study visits every 3 months, over an average of 3 years | 
| Number of hospitalizations/interventions/ED visits due to arrhythmias (AF, bradycardia, asystole, Ventricular tachyarrhythmia [VF, VT etc.]) |  | From randomization visit through study completion during study visits every 3 months, over an average of 3 years | 
| Time to first instance of rescue therapy use for hyperkalemia |  | From randomization visit through study completion during study visits every 3 months, over an average of 3 years | 
| S-K > 6.5 mmol/L (yes/no) after the LIDI at the 12 month visit |  | Evaluated at 12 months after randomization | 
| Time to SCD |  | From randomization visit through study completion during study visits every 3 months, over an average of 3 years | 
| Time to first occurrence of stroke |  | From randomization visit through study completion during study visits every 3 months, over an average of 3 years | 
| Time to cardiovascular (CV) death |  | From randomization visit through study completion during study visits every 3 months, over an average of 3 years | 
| Time to death of any cause |  | From randomization visit through study completion during study visits every 3 months, over an average of 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hemodialysis, Hyperkalemia, Cardiovascular Events, Atrial Fibrillation, Ventricular Tachycardia