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A Phase 3, International, Randomised, Double-blind, Placebo-controlled Study to Evaluate the Effect of Sodium Zirconium Cyclosilicate on CKD Progression in Participants With CKD and Hyperkalaemia or at Risk of Hyperkalaemia (STABILIZE-CKD)

A Study to Evaluate the Effect of Sodium Zirconium Cyclosilicate on Chronic Kidney Disease (CKD) Progression in Participants With CKD and Hyperkalaemia or at Risk of Hyperkalaemia

Hibi Kazushige

Astrazeneka K.K

3-1, Ofuka-cho, Kita-ku, Osaka-shi

RD-clinical-information-Japan@astrazeneca.com

Hibi Kazushige

Astrazeneka K.K

3-1, Ofuka-cho, Kita-ku, Osaka-shi

+81-6-4802-3533

RD-clinical-information-Japan@astrazeneca.com

Not Recruiting

Dec. 01, 2021

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

- 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 or more at the time of signing the informed consent. For participants < 20 years of age and enrolled in Japan, a written informed consent should be obtained from the participant and his or her legally acceptable representative
- Must have eGFR 25 or more and 59 mL/min/1.73m2 or less as calculated by central laboratory (CKD-EPI formula) at screening (Visit 1)
- Must have UACR 200 or more and 5000 mg/g or less 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 or more to 6.5 mmol/L or less ) as measured by the central laboratory, and on adequate* or limited** RAASi therapy due to hyperkalaemia.
2. Cohort B: Normokalaemia (S-K 3.5 or more to 5.0 mmol/L or less ) 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 or more to 5.0 mmol/L or less.

(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 inhibitor (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.

- 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).
- Systolic blood pressure 160 mmHg or more or diastolic blood pressure 95 mmHg or less (confirmed by repeated measurement), within 2 weeks prior to screening (Visit 1). Participants may be rescreened once blood pressure is controlled.
- QTcF 550 msec or more 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.
- Type 1 diabetes mellitus.

- 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 more or 3.5 mmol/L less than 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).

Both

Chronic Kidney disease, Hyperkalemia

- initiation phase: initial dose of SZC will be administered. No changes will be made to the ACEi or ARB therapy at this stage

- run-in phase: open-label SZC and either lisinopril or valsartan

- maintenance phase: randomized to SZC or placebo

Total eGFR slope and Chronic eGFR slope [ Time Frame: Total slope: from randomisation visit to the end of the maintenance phase at Week 104; Chronic slope: from Week 12 visit to the end of the maintenance phase at Week 104 ]

+81-3-5213-0028

Oct. 18, 2021

Yes

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.

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