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

• ClinicalTrials.gov Identifier: NCT04847232
• Recruitment Status: Terminated
• First Posted: April 19, 2021
• Last Update Posted: April 11, 2024
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: April 8, 2021
• First Posted Date: April 19, 2021
• Last Update Posted Date: April 11, 2024
• Actual Study Start Date: April 30, 2021
• Actual Primary Completion Date: March 7, 2024 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: August 4, 2023): 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.]) [ Time Frame: From randomization visit through study completion during study visits every 3 months, over an average of 3 years ]
• Original Primary Outcome Measures (submitted: April 14, 2021): Time to first occurrence of SCD, stroke, or hospitalization/intervention/ED visit due to arrhythmias (atrial fibrillation [AF], bradycardia, asystole, ventricular tachyarrhythmias [VT]) [ Time Frame: From randomization visit through study completion during study visits every 3 months, over an average of 2 years ]

Current Secondary Outcome Measures (submitted: August 4, 2023)

• S-K of 4.0-5.5 mmol/L (yes/no) after the long interdialytic interval (LIDI) at the 12 month visit [ Time Frame: 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.]) [ Time Frame: 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.]) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Evaluated at 12 months after randomization ]
• Time to SCD [ Time Frame: From randomization visit through study completion during study visits every 3 months, over an average of 3 years ]
• Time to first occurrence of stroke [ Time Frame: From randomization visit through study completion during study visits every 3 months, over an average of 3 years ]
• Time to cardiovascular (CV) death [ Time Frame: From randomization visit through study completion during study visits every 3 months, over an average of 3 years ]
• Time to death of any cause [ Time Frame: From randomization visit through study completion during study visits every 3 months, over an average of 3 years ]

Original Secondary Outcome Measures (submitted: April 14, 2021)

• S-K of 4.0-5.5 mmol/L (yes/no) after the long interdialytic interval (LIDI) at the 12 month visit [ Time Frame: Evaluated at 12 months after randomization ]
• Time to first occurrence of hospitalization/intervention/ED visit due to arrhythmias (AF, bradycardia, asystole, VT) [ Time Frame: From randomization visit through study completion during study visits every 3 months, over an average of 2 years ]
• Number of hospitalizations/interventions/ED visits due to arrhythmias (AF, bradycardia, asystole, or VT) [ Time Frame: From randomization visit through study completion during study visits every 3 months, over an average of 2 years ]
• Time to first instance of rescue therapy use for hyperkalemia [ Time Frame: From randomization visit through study completion during study visits every 3 months, over an average of 2 years ]
• S-K > 6.5 mmol/L (yes/no) after the LIDI at the 12 month visit [ Time Frame: Evaluated at 12 months after randomization ]
• Time to SCD [ Time Frame: From randomization visit through study completion during study visits every 3 months, over an average of 2 years ]
• Time to first occurrence of stroke [ Time Frame: From randomization visit through study completion during study visits every 3 months, over an average of 2 years ]
• Time to cardiovascular (CV) death [ Time Frame: From randomization visit through study completion during study visits every 3 months, over an average of 2 years ]
• Time to death of any cause [ Time Frame: From randomization visit through study completion during study visits every 3 months, over an average of 2 years ]

Current Other Pre-specified Outcome Measures (submitted: August 4, 2023)

• Adverse Events (AEs)/ Serious Adverse Events (SAEs) [ Time Frame: From randomization/ screening visit through study completion during study visits every 3 months, over an average of 3 years ]
• Events of pre-dialysis hypokalemia (S-K < 3.0 mmol/L) [ Time Frame: From randomization visit through study completion during study visits every 3 months, over an average of 3 years ]
• Change in interdialytic weight gain (kg) as compared to baseline [ Time Frame: From randomization visit through study completion during study visits every 3 months, over an average of 3 years ]

Original Other Pre-specified Outcome Measures (submitted: April 14, 2021)

• Adverse Events (AEs)/ Serious Adverse Events (SAEs) [ Time Frame: From randomization/ screening visit through study completion during study visits every 3 months, over an average of 2 years ]
• Events of pre-dialysis hypokalemia (S-K < 3.0 mmol/L) [ Time Frame: From randomization visit through study completion during study visits every 3 months, over an average of 2 years ]
• Change in interdialytic weight gain (kg) as compared to baseline [ Time Frame: From randomization visit through study completion during study visits every 3 months, over an average of 2 years ]

Descriptive Information

• Brief Title: Effect of Sodium Zirconium Cyclosilicate on Arrythmia-related Cardiovascular Outcomes in Participants on Chronic Hemodialysis With Recurrent Hyperkalemia (DIALIZE-Outcomes)
• Official Title: 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)
• 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.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Hyperkalemia

Intervention

• Drug: Sodium Zirconium Cyclosilicate (SZC)
  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).
  Other Name: Lokelma TM
• Drug: SZC Placebo
  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.

Study Arms

• Experimental: Sodium Zirconium Cyclosilicate
  Intervention: Drug: Sodium Zirconium Cyclosilicate (SZC)
• Placebo Comparator: Placebo
  Intervention: Drug: SZC Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: January 9, 2024): 2698
• Original Estimated Enrollment (submitted: April 14, 2021): 2300
• Actual Study Completion Date: March 7, 2024
• Actual Primary Completion Date: March 7, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol
2. Provision of signed and dated, written ICF prior to any mandatory study specific procedures, sampling, and analyses
3. Must be ≥ 18 years of age, at the time of signing the ICF.
4. Receiving hemodialysis (or hemodiafiltration) 3 times a week for treatment of ESRD for ≥ 4 months before enrollment
5. 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
6. At least 2 out of 3 pre-dialysis S K ≥ 5.5 mmol/L after the LIDI during screening
7. Negative pregnancy test for female participants of childbearing potential
8. 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:

1. 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)
2. Presence of cardiac arrhythmias or conduction defects that require immediate treatment
3. Participants who have a pacemaker or implantable cardiac defibrillator
4. 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
5. History of QT prolongation associated with other medications that required discontinuation of that medication
6. Congenital long QT syndrome
7. QTcF > 550 msec
8. Atrial fibrillation requiring immediate/urgent intervention at screening or randomizations
9. 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
10. Participation in another clinical study with an investigational product, device, or non-standard hemodialysis procedure administered within one month before screening
11. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
12. 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
13. Previous randomization in the present study
14. 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
15. Known hypersensitivity or previous anaphylaxis to SZC or to components thereof
16. Scheduled date for living donor kidney transplant
17. Sustained Ventricular Tachycardia > 30 seconds requiring assessment / intervention

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 130 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Austria, Brazil, Bulgaria, Canada, China, Czechia, Germany, Hungary, India, Italy, Japan, Malaysia, Mexico, Peru, Poland, Russian Federation, Slovakia, Spain, Taiwan, Thailand, Turkey, Ukraine, United Kingdom, United States, Vietnam

Administrative Information

• NCT Number: NCT04847232
• Other Study ID Numbers: D9487C00001; 2020-005561-14 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

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
• Supporting Materials: 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 de-identified 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

• Current Responsible Party: AstraZeneca
• Original Responsible Party: Same as current
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Steven Fishbane, Professor, MD; North Shore University Hospital, 300 Community Drive, Manhasset, NY 11030

• PRS Account: AstraZeneca
• Verification Date: April 2024