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

Renal Insufficiency, Chronic Clinical Trial

— STABILIZE-CKD  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT05056727
• Other study ID #: D9488C00001
• Secondary ID: 2021-001911-96
• Status: Terminated
• Phase: Phase 3
• Start date: September 30, 2021
• Est. completion date: February 7, 2024

Study information

• Verified date: June 2024
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 716
• Est. completion date: February 7, 2024
• Est. primary completion date: February 7, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 130 Years

Eligibility

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).

Related Conditions & MeSH terms

• Hyperkalemia
• Renal Insufficiency
• Renal Insufficiency, Chronic

Intervention

Drug:
• Sodium Zirconium Cyclosilicate (SZC)
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.
• Placebo
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.
• Lisinopril
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.
• Valsartan
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.
• Irbesartan
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.

Locations

Country	Name	City	State
Argentina	Research Site	Buenos Aires
Argentina	Research Site	Buenos Aires
Argentina	Research Site	Caba
Argentina	Research Site	La Plata
Argentina	Research Site	Mar del Plata
Argentina	Research Site	Mar del Plata
Argentina	Research Site	Rosario
Argentina	Research Site	San Vicente
Argentina	Research Site	Sarandi
Brazil	Research Site	Curitiba
Brazil	Research Site	Fortaleza
Brazil	Research Site	Joinville
Brazil	Research Site	Maringá
Brazil	Research Site	Porto Alegre
Brazil	Research Site	Porto Alegre
Brazil	Research Site	Sao Paulo
Brazil	Research Site	Sao Paulo
Bulgaria	Research Site	Blagoevgrad
Bulgaria	Research Site	Botevgrad
Bulgaria	Research Site	Dupnitsa
Bulgaria	Research Site	Gorna Oryahovitsa
Bulgaria	Research Site	Gotse Delchev
Bulgaria	Research Site	Kozloduy
Bulgaria	Research Site	Lom
Bulgaria	Research Site	Pleven
Bulgaria	Research Site	Plovdiv
Bulgaria	Research Site	Plovdiv
Bulgaria	Research Site	Plovdiv
Bulgaria	Research Site	Samokov
Bulgaria	Research Site	Sandanski
Bulgaria	Research Site	Silistra
Bulgaria	Research Site	Sliven
Bulgaria	Research Site	Smolyan
Bulgaria	Research Site	Stara Zagora
Bulgaria	Research Site	Yambol
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Oshawa	Ontario
Canada	Research Site	Saint John	New Brunswick
China	Research Site	Baotou
China	Research Site	Beijing
China	Research Site	Beijing
China	Research Site	Beijing
China	Research Site	Beijing
China	Research Site	Beijing
China	Research Site	Beijing
China	Research Site	Changchun
China	Research Site	Changsha
China	Research Site	Chengdu
China	Research Site	Chengdu
China	Research Site	Chongqing
China	Research Site	Guangzhou
China	Research Site	Guangzhou
China	Research Site	Guangzhou
China	Research Site	Guangzhou
China	Research Site	Guiyang
China	Research Site	Hangzhou
China	Research Site	Hefei
China	Research Site	Hengyang
China	Research Site	Huizhou
China	Research Site	Lanzhou
China	Research Site	Nanchang
China	Research Site	Nanjing
China	Research Site	Nanjing
China	Research Site	Nanjing
China	Research Site	Ningbo
China	Research Site	Sanya
China	Research Site	Shanghai
China	Research Site	Shanghai
China	Research Site	Shanghai
China	Research Site	Shanghai
China	Research Site	Shantou
China	Research Site	Shengyang
China	Research Site	Shenyang
China	Research Site	Shenzhen
China	Research Site	Taiyuan
China	Research Site	Urumqi
China	Research Site	Wuhan
China	Research Site	Wuhan
China	Research Site	Wuxi
China	Research Site	Xi'an
China	Research Site	Xuzhou
China	Research Site	Yantai
China	Research Site	Yinchuan
China	Research Site	Zhengzhou
China	Research Site	Zhuzhou
India	Research Site	Coimbatore
India	Research Site	Kolkata
India	Research Site	Madurai
India	Research Site	New Delhi
Italy	Research Site	Bari
Italy	Research Site	Bassano del Grappa
Italy	Research Site	Bologna
Italy	Research Site	Brescia
Italy	Research Site	Messina
Italy	Research Site	Pavia
Italy	Research Site	Roma
Italy	Research Site	Roma
Italy	Research Site	Rozzano
Italy	Research Site	San Giovanni Rotondo
Italy	Research Site	Verona
Japan	Research Site	Amagasaki-shi
Japan	Research Site	Atsugi-shi
Japan	Research Site	Chiba-shi
Japan	Research Site	Chuo-ku
Japan	Research Site	Chuo-ku
Japan	Research Site	Chuo-shi
Japan	Research Site	Fukuoka-shi
Japan	Research Site	Kamakura-shi
Japan	Research Site	Kanoya-shi
Japan	Research Site	Kasugai-shi
Japan	Research Site	Kawachinagano-shi
Japan	Research Site	Kawasaki-shi
Japan	Research Site	Kitakyushu
Japan	Research Site	Kitakyushu-shi
Japan	Research Site	Koriyama-shi
Japan	Research Site	Koshigaya-shi
Japan	Research Site	Kumamoto-shi
Japan	Research Site	Kure-shi
Japan	Research Site	Marugame-shi
Japan	Research Site	Matsumoto-shi
Japan	Research Site	Matsusaka-shi
Japan	Research Site	Matsuyama-shi
Japan	Research Site	Nagoya-shi
Japan	Research Site	Nagoya-shi
Japan	Research Site	Naka-shi
Japan	Research Site	Noda-shi
Japan	Research Site	Oita-shi
Japan	Research Site	Omihachiman-shi
Japan	Research Site	Osaka-city
Japan	Research Site	Osaka-shi
Japan	Research Site	Sakai-shi
Japan	Research Site	Takarazuka-shi
Japan	Research Site	Toyota City
Japan	Research Site	Toyota-Shi
Japan	Research Site	Tsu-shi
Japan	Research Site	Tsuchiura-shi
Japan	Research Site	Urayasu-shi
Japan	Research Site	Yaizu-shi
Japan	Research Site	Yokohama-shi
Japan	Research Site	Yokohama-shi
Japan	Research Site	Yokohama-shi
Japan	Research Site	Yonago-shi
Malaysia	Research Site	Alor Setar
Malaysia	Research Site	Batu Caves
Malaysia	Research Site	Johor Bahru
Malaysia	Research Site	Kajang
Malaysia	Research Site	Kuala Lumpur
Malaysia	Research Site	Kuala Lumpur
Malaysia	Research Site	Kuala Lumpur
Malaysia	Research Site	Seri Manjung
Mexico	Research Site	Cuauhtemoc
Mexico	Research Site	Culiacán
Mexico	Research Site	Guadalajara
Mexico	Research Site	Mazatlán
Mexico	Research Site	Merida
Mexico	Research Site	Merida
Mexico	Research Site	Mexico
Mexico	Research Site	Mexico
Mexico	Research Site	San Luis Potosí
Mexico	Research Site	Veracruz
Philippines	Research Site	Davao City
Philippines	Research Site	Iloilo City
Poland	Research Site	Kraków
Poland	Research Site	Lódz
Poland	Research Site	Poznan
Poland	Research Site	Rzeszow
Poland	Research Site	Tczew
Puerto Rico	Research Site	Ponce
Russian Federation	Research Site	Aramil
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Perm
Russian Federation	Research Site	Rostov-on-Don
Russian Federation	Research Site	Saint Petersburg
Spain	Research Site	Almeria
Spain	Research Site	Barcelona
Spain	Research Site	Barcelona
Spain	Research Site	Barcelona
Spain	Research Site	Getafe
Spain	Research Site	L'Hospitalet de Llobregat
Spain	Research Site	Lugo
Spain	Research Site	Madrid
Spain	Research Site	Sevilla
Spain	Research Site	Tenerife
Spain	Research Site	Valencia
Spain	Research Site	Valencia
Taiwan	Research Site	Hualien City
Taiwan	Research Site	Kaohsiung
Taiwan	Research Site	Kaohsiung
Taiwan	Research Site	Kaohsiung
Taiwan	Research Site	Keelung
Taiwan	Research Site	New Taipei
Taiwan	Research Site	New-Taipei
Taiwan	Research Site	Taichung
Taiwan	Research Site	Taichung
Taiwan	Research Site	Tainan
Taiwan	Research Site	Tainan City
Taiwan	Research Site	Taipei
Taiwan	Research Site	Taipei City
Taiwan	Research Site	Taipei City
Taiwan	Research Site	Taoyuan
Thailand	Research Site	Bangkok
Thailand	Research Site	Bangkok
Thailand	Research Site	Chaingmai
Thailand	Research Site	Hat Yai
Thailand	Research Site	Ratchathewi
Turkey	Research Site	Adapazari
Turkey	Research Site	Ankara
Turkey	Research Site	Ankara
Turkey	Research Site	Ankara
Turkey	Research Site	Antalya
Turkey	Research Site	Gaziantep
Turkey	Research Site	Istanbul
Turkey	Research Site	Izmir
Turkey	Research Site	Kahramanmaras
Turkey	Research Site	Kayseri
Turkey	Research Site	Kocaeli
Ukraine	Research Site	Dnipropetrovsk
Ukraine	Research Site	Kharkiv
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Lutsk
Ukraine	Research Site	Vinnytsya
Ukraine	Research Site	Zaporizhzhia
Ukraine	Research Site	Zhytomyr
United States	Research Site	Albany	New York
United States	Research Site	Albuquerque	New Mexico
United States	Research Site	Arlington	Texas
United States	Research Site	Bethlehem	Pennsylvania
United States	Research Site	Boston	Massachusetts
United States	Research Site	Boston	Massachusetts
United States	Research Site	Boynton Beach	Florida
United States	Research Site	Canyon Country	California
United States	Research Site	Chattanooga	Tennessee
United States	Research Site	Chester	Pennsylvania
United States	Research Site	Chicago	Illinois
United States	Research Site	Chula Vista	California
United States	Research Site	Cincinnati	Ohio
United States	Research Site	Columbia	South Carolina
United States	Research Site	Columbia	Missouri
United States	Research Site	Denver	Colorado
United States	Research Site	Flint	Michigan
United States	Research Site	Fort Wayne	Indiana
United States	Research Site	Fort Worth	Texas
United States	Research Site	Great Neck	New York
United States	Research Site	Hialeah	Florida
United States	Research Site	Houston	Texas
United States	Research Site	Houston	Texas
United States	Research Site	Houston	Texas
United States	Research Site	Kansas City	Missouri
United States	Research Site	Lauderdale Lakes	Florida
United States	Research Site	Louisville	Kentucky
United States	Research Site	Nampa	Idaho
United States	Research Site	Newport News	Virginia
United States	Research Site	Northridge	California
United States	Research Site	Oak Brook	Illinois
United States	Research Site	Ocoee	Florida
United States	Research Site	Orangeburg	South Carolina
United States	Research Site	S. Gate	California
United States	Research Site	Saint Clair Shores	Michigan
United States	Research Site	San Antonio	Texas
United States	Research Site	San Dimas	California
United States	Research Site	Surprise	Arizona
United States	Research Site	Tarzana	California
United States	Research Site	Temple Terrace	Florida
United States	Research Site	Tucson	Arizona
United States	Research Site	Winston-Salem	North Carolina
Vietnam	Research Site	Bien Hoa
Vietnam	Research Site	Da Nang
Vietnam	Research Site	Hanoi
Vietnam	Research Site	Ho Chi Minh
Vietnam	Research Site	Ho Chi Minh
Vietnam	Research Site	Ho Chi Minh City
Vietnam	Research Site	Hue

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Vietnam,  Argentina,  Brazil,  Bulgaria,  Canada,  China,  India,  Italy,  Japan,  Malaysia,  Mexico,  Philippines,  Poland,  Puerto Rico,  Russian Federation,  Spain,  Taiwan,  Thailand,  Turkey,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	AEs/SAEs	During screening only SAEs will be collected.; Assessments related to AEs cover: Occurrence/frequency; Relationship to study intervention as assessed by investigator; Intensity; Seriousness; Death; AEs leading to discontinuation of study intervention	From screening visit to follow-up visit at Week 105
Primary	Co-primary: Total eGFR slope and Chronic eGFR slope	Both of the primary endpoints must be met in order for the study to be declared successful, i.e., co-primary endpoints	Co-primary: 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
Secondary	Time from randomisation to the first occurrence of any component in the composite of: Sustained = 40% decline in eGFR; Onset of ESKD (kidney transplantation, maintenance dialysis, or sustained low eGFR); Death from kidney failure		From randomisation visit to the end of the maintenance phase at Week 104
Secondary	Time from randomisation to first lisinopril/valsartan dose decrease		From randomisation visit to the end of the maintenance phase at Week 104
Secondary	UACR measurements		From randomisation visit to the end of the maintenance phase at Week 104
Secondary	Serum bicarbonate measurements		From randomisation visit to the end of the maintenance phase at Week 104
Secondary	S-K level classification	Normal (3.5-5.0 mmol/L) or non-normal (< 3.5 or > 5.0 mmol/L)	From randomisation visit to the end of the maintenance phase at Week 104