Hyperkalemia
Conditions
Keywords
Hemodialysis, Hyperkalemia, Cardiovascular Events, Atrial Fibrillation, Ventricular Tachycardia
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.
Interventions
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).
DRUGSZC 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.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Argentina, Austria, Brazil, Bulgaria, Canada, China, Czechia, Germany, Hungary, India, Italy, Japan, Malaysia, Mexico, Peru, Poland, Russia, Slovakia, Spain, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United Kingdom, United States, Vietnam
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| SZC (Active) 5 g SZC QD to 15 g SZC QD | 1,349 |
| Placebo SZC Placebo | 1,341 |
| Total | 2,690 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 123 | 115 |
| Overall Study | Lost to Follow-up | 3 | 10 |
| Overall Study | Subcategories under Other not reported. | 1,150 | 1,115 |
| Overall Study | Withdrawal by Subject | 73 | 101 |
Baseline characteristics
| Characteristic | SZC (Active) | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 55.8 Years STANDARD_DEVIATION 13.3 | 56.3 Years STANDARD_DEVIATION 13.6 | 56.1 Years STANDARD_DEVIATION 13.4 |
| Age, Customized 18 yr ≤ Age < 51 yr | 442 Participants | 441 Participants | 883 Participants |
| Age, Customized 51 yr ≤ Age < 65 yr | 526 Participants | 509 Participants | 1035 Participants |
| Age, Customized 65 yr ≤ Age < 85 yr | 373 Participants | 378 Participants | 751 Participants |
| Age, Customized Age ≥ 85 yr | 8 Participants | 13 Participants | 21 Participants |
| Dialysis vintage | 6.01 Years STANDARD_DEVIATION 5.41 | 5.82 Years STANDARD_DEVIATION 5.2 | 5.92 Years STANDARD_DEVIATION 5.31 |
| Race/Ethnicity, Customized AMERICAN INDIAN OR ALASKA NATIVE | 49 Participants | 52 Participants | 101 Participants |
| Race/Ethnicity, Customized ASIAN | 392 Participants | 389 Participants | 781 Participants |
| Race/Ethnicity, Customized BLACK OR AFRICAN AMERICAN | 121 Participants | 130 Participants | 251 Participants |
| Race/Ethnicity, Customized NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER | 3 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized NOT REPORTED | 21 Participants | 10 Participants | 31 Participants |
| Race/Ethnicity, Customized OTHER | 75 Participants | 86 Participants | 161 Participants |
| Race/Ethnicity, Customized WHITE | 688 Participants | 672 Participants | 1360 Participants |
| Sex: Female, Male Female | 498 Participants | 517 Participants | 1015 Participants |
| Sex: Female, Male Male | 851 Participants | 824 Participants | 1675 Participants |
| spKt/V | 1.48 Dimensionless STANDARD_DEVIATION 0.39 | 1.51 Dimensionless STANDARD_DEVIATION 0.47 | 1.49 Dimensionless STANDARD_DEVIATION 0.43 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 120 / 1,348 | 113 / 1,338 |
| other Total, other adverse events | 558 / 1,348 | 616 / 1,338 |
| serious Total, serious adverse events | 521 / 1,348 | 503 / 1,338 |
Outcome results
Primary
Incidence of the Composite of Cardiac Event Outcomes
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.
Time frame: From Randomization (Visit 4) up to week 129 (Randomized Study Intervention Phase)
Population: Full analysis set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SZC (Active) | Incidence of the Composite of Cardiac Event Outcomes | 119 Participants |
| Placebo | Incidence of the Composite of Cardiac Event Outcomes | 119 Participants |
p-value: 0.86795% CI: [0.76, 1.26]Regression, Cox
Secondary
Incidence of the Composite of Arrhythmia Related Events
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.
Time frame: From Randomization (Visit 4) up to week 129 (Randomized Study Intervention Phase)
Population: Full analysis set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SZC (Active) | Incidence of the Composite of Arrhythmia Related Events | 74 Participants |
| Placebo | Incidence of the Composite of Arrhythmia Related Events | 65 Participants |
p-value: 0.5195% CI: [0.8, 1.56]Regression, Cox
Secondary
Normokalemia at 12 Months Post-randomization
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.
Time frame: Randomization to 12-Month Visit
Population: Full analysis set. Only subjects with non-missing S-K value at the 12 month visit included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SZC (Active) | Normokalemia at 12 Months Post-randomization | 495 Participants with event |
| Placebo | Normokalemia at 12 Months Post-randomization | 293 Participants with event |
p-value: <0.000195% CI: [2.64, 4.26]Regression, Logistic