Renal Insufficiency, Chronic, Hyperkalemia
Conditions
Keywords
Renal Insufficiency, Chronic, Chronic Kidney Diseases, Hyperkalemia
Brief summary
The purpose of this study is to evaluate the effect of Sodium Zirconium Cyclosilicate (SZC), as adjunct to ACEi/ARB therapy (lisinopril or valsartan), on slowing CKD progression (assessed as the reduction in participant's glomerular filtration rate \[eGFR\] decline over time) in participants with hyperkalaemia or at high risk of hyperkalaemia.
Detailed description
This is a Phase 3, international, randomised withdrawal, double-blind, parallel-group, placebo-controlled study, to evaluate the effect of SZC as adjunct to RAASi therapy (lisinopril or valsartan) in slowing CKD progression in participants with CKD and hyperkalaemia or at risk of hyperkalaemia. Specifically, the study will include participants with hyperkalaemia (S-K \> 5.0 to ≤ 6.5 mmol/L by central laboratory) who are on adequate or limited RAASi therapy due to hyperkalaemia, and participants with normokalaemia (S-K ≥ 3.5 to ≤ 5.0 mmol/L by central laboratory) who are on limited RAASi therapy due to high risk of hyperkalaemia. High risk of hyperkalaemia is defined as (1) participants with a previous medical history or record of hyperkalaemia within the prior 24 months who are on limited RAASi therapy despite indication in CKD; (2) participants in whom RAASi therapy is indicated in CKD but are on limited RAASi therapy and have S-K ≥ 4.7 to ≤ 5.0 mmol/L; and (3) participants in whom RAASi therapy has been discontinued or reduced to suboptimal doses because of hyperkalaemia. A participant is expected to be in the study for approximately 28 months, which includes up to 13 days for the screening period, 27 months for the intervention period, and 1 week for follow-up. The 27-month intervention period of the study consists of 3 phases, an initiation phase (up to 72 hours), a run-in phase (3 months/up to Day 90), and a maintenance phase (24 months/104 weeks). The initial dose of SZC will be administered to participants during the initiation phase. No changes will be made to the ACEi or ARB therapy at this stage. As soon as possible after the participant is confirmed to be normokalaemic at the end of the initiation phase, the participant will enter the run-in phase. Participants will receive open-label SZC and either lisinopril or valsartan. The aim of the run-in phase is to increase ACEi or ARB therapy stepwise to their maximum doses. After a 3-month run-in period for RAASi dose optimization while on SZC, participants will be randomized to SZC or placebo and followed during the subsequent 24 months of maintenance phase for efficacy and safety assessments.
Interventions
Powder for oral suspension in a sachet. Unit dose strength: 5 or 10 g SZC. Single dose will consist of 1-3 sachets. During Initiation Phase: * S-K \> 5 to ≤ 6.5 mmol/L (measured by L-Lab): Single dose contains 10 g SZC that should be suspended in 45 mL of water. The 10 g SZC single dose should be administered three times daily for up to 72 hours until normokalaemic (S-K 3.5-5.0 mmol/L); the total daily dose is 30 g SZC. * S-K ≥ 3.5 to ≤ 5 mmol/L (measured by L-Lab): Single dose contains 5 g SZC that should be suspended in 45 mL of water and administered once daily for 48 hours. During Run-in and Maintenance Phases: \- Single dose contains 5 g SZC administered every other day or 5, 10, or 15 g SZC administered once daily that should be suspended in 45 mL of water.
DRUGPlacebo
Powder for oral suspension in a sachet. Placebo to match 5 or 10 g. Single dose will consist of 1-3 sachets. During Maintenance Phase: \- Single dose contains 5 g placebo administered every other day or 5, 10, or 15 g placebo administered once daily that should be suspended in 45 mL of water.
DRUGLisinopril
Tablet for oral administration. Unit dose strength: 2.5, 5, 10 or 20 mg. Dosage level: 5, 10, 20, or 40 mg administered once daily.
DRUGValsartan
Tablet or capsule for oral administration. Unit dose strength: 40, 80 or 160 mg. Dosage level: 40, 80, 160, or 320 mg administered once daily.
DRUGIrbesartan
Tablet for oral administration. Unit dose strength: 75, 150 or 300 mg. Dosage level: 75, 150, or 300 mg administered once daily. The study is designed to use valsartan as the selected ARB therapy adjunct to SZC. However, if an actual shortage of valsartan in a local market jeopardises the ability of participants to enter or continue in the study, valsartan can be temporarily substituted with irbesartan until the shortage of valsartan is resolved.
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
* Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and protocol * Must be ≥ 18 years of age at the time of signing the informed consent. * Must have eGFR ≥ 25 and ≤ 59 mL/min/1.73m2 as calculated by central laboratory (CKD-EPI formula) at screening (Visit 1) * Must have UACR ≥ 200 and ≤ 5000 mg/g as calculated by central laboratory at screening (Visit 1). If the first sample does not fulfil eligibility criteria, a second sample can be obtained during the screening period; if so, the UACR measurement from the second sample must be within the eligibility range. * Any of the following criteria, a or b, at screening (Visit 1): 1. Cohort A: Hyperkalaemia (S-K \> 5.0 to ≤ 6.5 mmol/L) as measured by the central laboratory, and on adequate\* or limited\*\* RAASi therapy due to hyperkalaemia. 2. Cohort B: Normokalaemia (S-K ≥ 3.5 to ≤ 5.0 mmol/L) as measured by the central laboratory and on limited\*\* RAASi therapy due to high risk of hyperkalaemia. High risk of hyperkalaemia is defined as: (i) Participants with a previous medical history or record of hyperkalaemia within the prior 24 months, who are on limited\*\* RAASi therapy despite indication in CKD. (ii) Participants in whom RAASi therapy is indicated in CKD, who are on limited\*\* RAASi therapy and have S-K ≥ 4.7 to ≤ 5.0 mmol/L. (iii) Participants in whom RAASi therapy has been discontinued or reduced to suboptimal\* doses because of hyperkalaemia. \*Adequate RAASi dose levels are defined in protocol; doses lower than these are considered as suboptimal. \*\*Limited RAASi therapy is defined as no or suboptimal RAASi therapy according to dosing guidance provided in protocol. * If on thiazide or loop diuretics, the dose must have been stable for 2 weeks prior to screening (Visit 1). * If on RAASi therapy, the dose must have been stable for one month prior to screening (Visit 1) and remain stable during screening. * If on an SGLT2i treatment (ie, dapagliflozin and canagliflozin), finerenone, or any other medications in these 2 classes that are approved for CKD, the dose must have been stable for 3 months prior to screening (Visit 1). * Participants must be one-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 one month prior to screening (Visit 1) and willing to remain on the birth control until one month after the last dose of study intervention.
Exclusion criteria
* New York Heart Association class III to IV congestive heart failure at the time of screening (Visit 1) or previous history of severe or symptomatic heart failure. * Myocardial infarction, unstable angina, stroke, or transient ischaemic attack within 3 months prior to screening (Visit 1). * Participants with a known history of systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 95 mmHg within 2 weeks prior to screening (Visit 1) are excluded. In addition, any participant with systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 95 mmHg as measured at screening (Visit 1) and confirmed by repeated measurement is excluded. Participants may be rescreened once blood pressure is controlled. * QTcF \> 550 msec at screening (Visit 1). * 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. Participants with atrial fibrillation and heart rate controlled by medication are permitted. * Lupus nephritis or anti-neutrophil cytoplasmic antibody-associated vasculitis. * Change in renal function requiring hospitalisation or dialysis within 3 months prior to screening (Visit 1). * History of renal transplant (or anticipated need for renal transplant during the study). * Severe hepatic impairment, biliary cirrhosis, or cholestasis. * History of hereditary or idiopathic angioedema. * Any prior hypersensitivity to ACEi or ARB that in the investigator's judgment precludes use of lisinopril and valsartan/irbesartan. Prior hypersensitivity reactions to consider include, but are not limited to, development of angioedema, icterus, hepatitis, or neutropaenia or thrombocytopaenia requiring treatment modification. * Known hypersensitivity or previous anaphylaxis to SZC or to components thereof. * Any condition outside the CV and renal disease area such as, but not limited to, malignancy, with a life expectancy of less than 2 years based on investigator´s clinical judgment. * Active malignancy requiring treatment at the time of screening (Visit 1), except for successfully treated basal cell or treated squamous cell carcinoma. * S-K \> 6.5 or \< 3.5 mmol/L by local laboratory within 1 day prior to the scheduled first dose of SZC in the initiation phase. * Evidence of COVID-19 infection within 2 weeks prior to screening (Visit 1). * Treated with dual blockade of RAAS (combined use of an ACEi and ARB) within 3 months prior to screening (Visit 1). * Treated with an angiotensin receptor neprilysin inhibitor (ARNI; sacubitril/valsartan \[Entresto®\]) within 3 months prior to screening (Visit 1). * Treated with an MRA not approved for CKD within 3 months prior to screening (Visit 1). * Treated with aliskiren-containing products with 3 months prior to screening (Visit 1). * Treated with SPS (eg, Kayexalate, Resonium), CPS (Resonium Calcium), patiromer (Veltassa®), or SZC (Lokelma®) within 7 days prior to screening (Visit 1). * Participation in another clinical study with an investigational product administered within one month prior to screening (Visit 1). * Not willing or not able to change to lisinopril or valsartan/irbesartan, the protocol-mandated RAASi study intervention. Note: For participants taking a fixed combination of an ACEi or ARB with another agent (eg, calcium blockers or diuretics) as SoC, the investigator must make a judgment that it will be safe and efficacious for such participants to change to the study ACEi or ARB and to the other drug as separate agents. * Previous dosing with SZC in the present study. * Currently pregnant (confirmed with positive pregnancy test at screening \[Visit 1\]) or breastfeeding. * Judgment by the investigator that the participant is unlikely to comply with study procedures, restrictions, and requirements. * Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total eGFR Slope (Coprimary Analysis #1) | Baseline (Maintenance phase) to visit 17 (week 69) | Total eGFR slope, Baseline (Maintenance phase) to visit 17 (week 69) |
| Chronic eGFR Slope (Coprimary Analysis #2) | 12 weeks to visit 17 (week 69) | Chronic eGFR slope, 12 weeks to visit 17 (week 69) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of the Composite of Kidney Failure Outcomes | From Baseline (Maintenance phase) up to week 97 (Maintenance phase) | Incidence of the composite of kidney failure outcomes comprising: sustained ≥ 40% decline in eGFR, onset of ESKD, and death from kidney failure is analyzed based on Cox regression model. Patients with no events are censored at end of maintenance phase or premature discontinuation. |
| Incidence of RAASi Reduction | From Baseline (Maintenance phase) up to week 97 (Maintenance phase) | Incidence of RAASi (lisinopril/valsartan) dose decrease is analyzed based on Cox regression model. Patients with no events are censored at end of maintenance phase or premature discontinuation. |
| UACR | At visit 13 (week 24) | Urine albumin-to-creatinine ratio (UACR); mass concentration of albumin divided by mass concentration of creatinine, in urine; at visit 13 (week 24) |
Countries
Argentina, Brazil, Bulgaria, Canada, China, India, Italy, Japan, Malaysia, Mexico, Philippines, Poland, Puerto Rico, Russia, Spain, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United States, Vietnam
Participant flow
Recruitment details
The study was conducted from 30 September 2021 to 07 February 2024 at 286 sites in 20 countries worldwide.
Pre-assignment details
1112 participants entered the initiation phase of the study. 1049 of those participants entered the run-in phase of the study, and a total of 716 participants were randomized to treatment or placebo in the maintenance phase.
Participants by arm
| Arm | Count |
|---|---|
| Maintenance Phase: SZC Maintenance phase only:
5 g SZC QOD to 15 g SZC QD, + Lisinopril/Valsartan | 361 |
| Maintenance Phase: Placebo Maintenance phase only:
Placebo (for SZC), + Lisinopril/Valsartan | 355 |
| Total | 716 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Initiation Phase | Lost to Follow-up | 1 | 0 | 0 | 0 |
| Initiation Phase | Physician Decision | 4 | 0 | 0 | 0 |
| Initiation Phase | Study-specific; Study terminated; Other | 20 | 0 | 0 | 0 |
| Initiation Phase | Withdrawal by Subject | 9 | 0 | 0 | 0 |
| Maintenance Phase | Death | 0 | 0 | 4 | 2 |
| Maintenance Phase | Lost to Follow-up | 0 | 0 | 2 | 2 |
| Maintenance Phase | Physician Decision | 0 | 0 | 4 | 16 |
| Maintenance Phase | Site terminated; Study terminated; Other | 0 | 0 | 332 | 314 |
| Maintenance Phase | Withdrawal by Subject | 0 | 0 | 19 | 21 |
| Run-in Phase | Death | 0 | 3 | 0 | 0 |
| Run-in Phase | Lost to Follow-up | 0 | 1 | 0 | 0 |
| Run-in Phase | Physician Decision | 0 | 20 | 0 | 0 |
| Run-in Phase | Study-specific; Site terminated; Screen failure; Study terminated; Other | 0 | 237 | 0 | 0 |
| Run-in Phase | Withdrawal by Subject | 0 | 25 | 0 | 0 |
Baseline characteristics
| Characteristic | Maintenance Phase: SZC | Maintenance Phase: Placebo | Total |
|---|---|---|---|
| Age, Continuous | 64.5 Years STANDARD_DEVIATION 12.3 | 63.6 Years STANDARD_DEVIATION 11.9 | 64.0 Years STANDARD_DEVIATION 12.1 |
| Age, Customized 18 yr ≤ Age < 65 yr | 163 Participants | 168 Participants | 331 Participants |
| Age, Customized Age ≥ 65 yr | 198 Participants | 187 Participants | 385 Participants |
| eGFR | 41.0 mL/min/(1.73 m2) STANDARD_DEVIATION 12.9 | 40.4 mL/min/(1.73 m2) STANDARD_DEVIATION 12.4 | 40.7 mL/min/(1.73 m2) STANDARD_DEVIATION 12.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 65 Participants | 79 Participants | 144 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 296 Participants | 276 Participants | 572 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 140 Participants | 133 Participants | 273 Participants |
| Race/Ethnicity, Customized Black or African American | 12 Participants | 13 Participants | 25 Participants |
| Race/Ethnicity, Customized Other | 12 Participants | 14 Participants | 26 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 4 Participants | 3 Participants | 7 Participants |
| Race/Ethnicity, Customized White | 193 Participants | 192 Participants | 385 Participants |
| Sex: Female, Male Female | 122 Participants | 132 Participants | 254 Participants |
| Sex: Female, Male Male | 239 Participants | 223 Participants | 462 Participants |
| S-K | 4.41 mmol/L STANDARD_DEVIATION 0.43 | 4.45 mmol/L STANDARD_DEVIATION 0.48 | 4.43 mmol/L STANDARD_DEVIATION 0.46 |
| UACR | 1032.5 mg/g | 1017.0 mg/g | 1018.0 mg/g |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1,112 | 3 / 1,049 | 4 / 359 | 2 / 355 |
| other Total, other adverse events | 12 / 1,112 | 221 / 1,049 | 106 / 359 | 120 / 355 |
| serious Total, serious adverse events | 0 / 1,112 | 56 / 1,049 | 66 / 359 | 42 / 355 |
Outcome results
Primary
Chronic eGFR Slope (Coprimary Analysis #2)
Chronic eGFR slope, 12 weeks to visit 17 (week 69)
Time frame: 12 weeks to visit 17 (week 69)
Population: Full analysis set.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Maintenance Phase: SZC | Chronic eGFR Slope (Coprimary Analysis #2) | -4.8705 mL/min/(1.73 m2)/yr |
| Maintenance Phase: Placebo | Chronic eGFR Slope (Coprimary Analysis #2) | -2.8285 mL/min/(1.73 m2)/yr |
p-value: 0.133895% CI: [-4.7156, 0.6314]Mixed Models Analysis
Primary
Total eGFR Slope (Coprimary Analysis #1)
Total eGFR slope, Baseline (Maintenance phase) to visit 17 (week 69)
Time frame: Baseline (Maintenance phase) to visit 17 (week 69)
Population: Full analysis set.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Maintenance Phase: SZC | Total eGFR Slope (Coprimary Analysis #1) | -5.2975 mL/min/(1.73 m2)/yr |
| Maintenance Phase: Placebo | Total eGFR Slope (Coprimary Analysis #1) | -4.5622 mL/min/(1.73 m2)/yr |
p-value: 0.469195% CI: [-2.7311, 1.2604]Mixed Models Analysis
Secondary
Incidence of RAASi Reduction
Incidence of RAASi (lisinopril/valsartan) dose decrease is analyzed based on Cox regression model. Patients with no events are censored at end of maintenance phase or premature discontinuation.
Time frame: From Baseline (Maintenance phase) up to week 97 (Maintenance phase)
Population: Full analysis set. Subjects on Valsartan/Lisinopril (RAASi) at randomisation.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Maintenance Phase: SZC | Incidence of RAASi Reduction | 55 Participants |
| Maintenance Phase: Placebo | Incidence of RAASi Reduction | 128 Participants |
p-value: <0.00195% CI: [0.25, 0.47]Regression, Cox
Secondary
Incidence of the Composite of Kidney Failure Outcomes
Incidence of the composite of kidney failure outcomes comprising: sustained ≥ 40% decline in eGFR, onset of ESKD, and death from kidney failure is analyzed based on Cox regression model. Patients with no events are censored at end of maintenance phase or premature discontinuation.
Time frame: From Baseline (Maintenance phase) up to week 97 (Maintenance phase)
Population: Full analysis set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Maintenance Phase: SZC | Incidence of the Composite of Kidney Failure Outcomes | 7 Participants |
| Maintenance Phase: Placebo | Incidence of the Composite of Kidney Failure Outcomes | 4 Participants |
p-value: 0.3995% CI: [0.5, 5.9]Regression, Cox
Secondary
UACR
Urine albumin-to-creatinine ratio (UACR); mass concentration of albumin divided by mass concentration of creatinine, in urine; at visit 13 (week 24)
Time frame: At visit 13 (week 24)
Population: Full analysis set.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Maintenance Phase: SZC | UACR | 1513.07 mg/g |
| Maintenance Phase: Placebo | UACR | 1211.94 mg/g |
p-value: 0.03495% CI: [23.15, 579.11]Regression, Linear