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

Phase 3

Terminated

Conditions: Hyperkalemia

Interventions: Drug: Sodium Zirconium Cyclosilicate (SZC)
Drug: SZC Placebo

Registration Number: NCT04847232

Lead Sponsor: AstraZeneca

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 2690

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Sodium Zirconium Cyclosilicate	Sodium Zirconium Cyclosilicate (SZC)	-
Placebo	SZC Placebo	-

Primary Outcome Measures

Name	Time	Method
Incidence of the Composite of Cardiac Event Outcomes	From Randomization (Visit 4) up to week 129 (Randomized Study Intervention Phase)	Incidence of the composite endpoint of SCD, all stroke, or hospitalization/intervention/emergency department (ED) visit due to arrhythmias is analyzed based on Cox regression model with treatment and region as covariates. Patients with no events are censored at final clinical assessment, death, or disposition event.

Secondary Outcome Measures

Name	Time	Method
Normokalemia at 12 Months Post-randomization	Randomization to 12-Month Visit	Logistic regression analysis of whether a subject is Normokalemic (S-K of 4.0 - 5.5 mmol/L ) after the LIDI at the 12-month visit.
Incidence of the Composite of Arrhythmia Related Events	From Randomization (Visit 4) up to week 129 (Randomized Study Intervention Phase)	Incidence of the composite endpoint of hospitalization, intervention, emergency department (ED) visit due to arrhythmias is analyzed based on Cox regression model with treatment and region as covariates. Patients with no events are censored at final clinical assessment, death, or disposition event.