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 (STABILIZE-CKD)

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

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.

Study Overview

• Status: Terminated
• Conditions: Renal Insufficiency, Chronic; Hyperkalemia
• Intervention / Treatment: Drug: Sodium Zirconium Cyclosilicate (SZC); Drug: Lisinopril; Drug: Valsartan; Drug: Irbesartan; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 1112
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1429BWN
    • Research Site
  • Buenos Aires, Argentina, ARG 1425
    • Research Site
  • CABA, Argentina, C1440AAD
    • Research Site
  • La Plata, Argentina, 1900
    • Research Site
  • Mar del Plata, Argentina, 7600
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  • Mar del Plata, Argentina, B7600
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  • Rosario, Argentina, 2000
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  • San Vicente, Argentina, 5006
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  • Sarandí, Argentina, B1872EEC
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• Brazil
  • Curitiba, Brazil, 80440-020
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  • Fortaleza, Brazil, 60115282
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  • Joinville, Brazil, 89227-680
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  • Maringá, Brazil, 87060-040
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  • Porto Alegre, Brazil, 90020-090
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  • Porto Alegre, Brazil, 90160-093
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  • São Paulo, Brazil, 04039-000
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  • São Paulo, Brazil, 05403-9000
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• Bulgaria
  • Blagoevgrad, Bulgaria, 2700
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  • Botevgrad, Bulgaria, 2140
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  • Dupnitsa, Bulgaria, 2600
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  • Gorna Oryahovitsa, Bulgaria, 5100
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  • Gotse Delchev, Bulgaria, 2900
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  • Kozloduy, Bulgaria, 3320
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  • Lom, Bulgaria, 3600
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  • Pleven, Bulgaria, 5800
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  • Plovdiv, Bulgaria, 4000
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  • Plovdiv, Bulgaria, 4004
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  • Plovdiv, Bulgaria, 4001
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  • Samokov, Bulgaria, 2000
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  • Sandanski, Bulgaria, 2800
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  • Silistra, Bulgaria, 7500
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  • Sliven, Bulgaria, 8800
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  • Smolyan, Bulgaria, 3700
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  • Stara Zagora, Bulgaria, 6000
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  • Yambol, Bulgaria, 8600
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• Canada
  • New Brunswick
    • Saint John, New Brunswick, Canada, E2L 4L2
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  • Ontario
    • Oshawa, Ontario, Canada, L1G 2B9
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  • Quebec
    • Montreal, Quebec, Canada, H4J 1C5
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    • Montreal, Quebec, Canada, H1T 2M4
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• China
  • Baotou, China, 014010
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  • Beijing, China, 100034
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  • Beijing, China, 100029
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  • Beijing, China, 100044
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  • Beijing, China, 100191
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  • Beijing, China, 102206
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  • Beijing, China, 102218
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  • Changchun, China, 130041
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  • Changsha, China, 410013
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  • Chengdu, China, 610041
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  • Chengdu, China, 610072
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  • Chongqing, China, 400010
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  • Guangzhou, China, 510000
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  • Guangzhou, China, 510180
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  • Guangzhou, China, 510630
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  • Guangzhou, China, 510062
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  • Guiyang, China, 550002
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  • Hangzhou, China, 310014
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  • Hefei, China, 230601
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  • Hengyang, China, 421001
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  • Huizhou, China, 516001
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  • Lanzhou, China, 730030
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  • Nanchang, China, 330006
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  • Nanjing, China, 210009
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  • Nanjing, China, 210029
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  • Nanjing, China, 210011
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  • Ningbo, China, 315010
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  • Sanya, China, 572000
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  • Shanghai, China, 200025
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  • Shanghai, China, 201199
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  • Shanghai, China, 200040
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  • Shanghai, China, 201210
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  • Shantou, China, 515041
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  • Shengyang, China, 110004
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  • Shenyang, China, 110001
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  • Shenzhen, China, 518036
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  • Taiyuan, China, 030012
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  • Wuhan, China, 430060
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  • Wuhan, China, 430010
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  • Wuxi, China, 214023
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  • Xi'an, China, 710061
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  • Xuzhou, China, 221000
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  • Yantai, China, 264000
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  • Yinchuan, China, 750004
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  • Zhengzhou, China, 450052
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  • Zhuzhou, China, 412007
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  • Ürümqi, China, 830054
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• India
  • Coimbatore, India, 641018
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  • Kolkata, India, 700020
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  • Madurai, India, 625107
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  • New Delhi, India, 110029
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• Italy
  • Bari, Italy, 70124
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  • Bassano del Grappa, Italy, 36061
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  • Bologna, Italy, 40138
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  • Brescia, Italy, 25123
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  • Messina, Italy, 98125
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  • Pavia, Italy, 27100
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  • Roma, Italy, 00168
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  • Roma, Italy, 00161
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  • Rozzano, Italy, 20089
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  • San Giovanni Rotondo, Italy, 71013
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  • Verona, Italy, 37126
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• Japan
  • Amagasaki-shi, Japan, 660-8550
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  • Atsugi-shi, Japan, 243-0035
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  • Chiba, Japan, 260-8712
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  • Chuo-shi, Japan, 409-3898
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  • Chūōku, Japan, 104-8560
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  • Chūōku, Japan, 103-0002
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  • Fukuoka, Japan, 814-0180
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  • Kamakura-shi, Japan, 247-0056
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  • Kanoya-shi, Japan, 893-0015
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  • Kasugai-shi, Japan, 486-8510
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  • Kawachinagano-shi, Japan, 586-8521
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  • Kawasaki-shi, Japan, 211-8510
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  • Kitakyushu, Japan, 805-8508
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  • Kitakyushu-shi, Japan, 802-8555
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  • Koriyama-shi, Japan, 963-8052
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  • Koshigaya-shi, Japan, 343-8555
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  • Kumamoto, Japan, 861-8520
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  • Kure-shi, Japan, 737-0023
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  • Marugame-shi, Japan, 763-8502
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  • Matsumoto-shi, Japan, 390-8621
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  • Matsusaka-shi, Japan, 515-8557
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  • Matsuyama, Japan, 790-8524
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  • Nagoya, Japan, 466-8650
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  • Nagoya, Japan, 457-8511
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  • Naka, Japan, 311-0113
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  • Noda, Japan, 278-8501
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  • Osaka, Japan, 559-0012
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  • Osaka, Japan, 543-8922
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  • Sakaishi, Japan, 593-8304
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  • Takarazuka-shi, Japan, 665-0873
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  • Toyota, Japan, 470-0396
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  • Toyota-Shi, Japan, 471-8513
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  • Tsu, Japan, 514-8507
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  • Tsuchiura-shi, Japan, 300-0028
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  • Urayasu-shi, Japan, 279-0021
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  • Yaizu-shi, Japan, 425-8505
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  • Yokohama, Japan, 236-0004
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  • Yokohama, Japan, 227-8501
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  • Yokohama, Japan, 234-0054
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  • Yonago-shi, Japan, 683-8605
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  • Ōita, Japan, 870-0033
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  • Ōmihachiman, Japan, 523-0082
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• Malaysia
  • Alor Star, Malaysia, 5460
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  • Batu Caves, Malaysia, 68100
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  • Johor Bahru, Malaysia, 80100
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  • Kajang, Malaysia, 43000
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  • Kuala Lumpur, Malaysia, 59100
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  • Kuala Lumpur, Malaysia, 50586
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  • Kuala Lumpur, Malaysia, 56000
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  • Seri Manjung, Malaysia, 32040
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• Mexico
  • Cuauhtémoc, Mexico, 06700
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  • Culiacán, Mexico, 80230
    • Research Site
  • Guadalajara, Mexico, 44670
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  • Mazatlán, Mexico, 82000
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  • Mérida, Mexico, 97070
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  • Mérida, Mexico, 97130
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  • México, Mexico, 03100
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  • México, Mexico, 06700
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  • San Luis Potosí City, Mexico, 78250
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  • Veracruz, Mexico, 91900
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• Philippines
  • Davao City, Philippines, PH-8000
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  • Iloilo City, Philippines, 5000
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• Poland
  • Krakow, Poland, 31-156
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  • Lodz, Poland, 92-213
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  • Poznan, Poland, 61-485
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  • Rzeszów, Poland, 35-055
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  • Tczew, Poland, 83-110
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• Puerto Rico
  • Ponce, Puerto Rico, 00717
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• Russia
  • Aramil, Russia, 624002
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  • Moscow, Russia, 123182
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  • Perm, Russia, 614000
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  • Rostov-on-Don, Russia, 344022
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  • Saint Petersburg, Russia, 191167
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• Spain
  • Almería, Spain, 4009
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  • Barcelona, Spain, 08035
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  • Barcelona, Spain, 08036
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  • Barcelona, Spain, 8003
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  • Getafe, Spain, 28905
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  • L'Hospitalet de Llobregat, Spain, 08907
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  • Lugo, Spain, 27004
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  • Madrid, Spain, 28040
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  • Santa Cruz de Tenerife, Spain, 38010
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  • Seville, Spain, 41009
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  • Valencia, Spain, 46010
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  • Valencia, Spain, 46014
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• Taiwan
  • Hualien City, Taiwan, 97002
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  • Kaohsiung City, Taiwan, 82445
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  • Kaohsiung City, Taiwan, 81362
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  • Kaohsiung City, Taiwan, 833
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  • Keelung, Taiwan, 20448
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  • New Taipei City, Taiwan, 23561
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  • New Taipei City, Taiwan, 220216
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  • Taichung, Taiwan, 40705
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  • Taichung, Taiwan, 40201
    • Research Site
  • Tainan, Taiwan, 70403
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  • Tainan, Taiwan, 710
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  • Taipei, Taiwan, 10002
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  • Taipei, Taiwan, 114
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  • Taipei, Taiwan, 110
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  • Taoyuan District, Taiwan, 333
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• Thailand
  • Bangkok, Thailand, 10330
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  • Bangkok, Thailand, 10700
    • Research Site
  • Chaingmai, Thailand, 50200
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  • Hat Yai, Thailand, 90110
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  • Ratchathewi, Thailand, 10400
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• Turkey (Türkiye)
  • Adapazarı, Turkey (Türkiye), 54100
    • Research Site
  • Ankara, Turkey (Türkiye), 06230
    • Research Site
  • Ankara, Turkey (Türkiye), 6230
    • Research Site
  • Ankara, Turkey (Türkiye), 06340
    • Research Site
  • Antalya, Turkey (Türkiye), 07059
    • Research Site
  • Gaziantep, Turkey (Türkiye), 27310
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  • Istanbul, Turkey (Türkiye)
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  • Izmir, Turkey (Türkiye), 35040
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  • Kahramanmaraş, Turkey (Türkiye), 46100
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  • Kayseri, Turkey (Türkiye), 38039
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  • Kocaeli, Turkey (Türkiye), 41380
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• Ukraine
  • Dnipropetrovsk, Ukraine, 49005
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  • Kharkiv, Ukraine, 61039
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  • Kyiv, Ukraine, 02125
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  • Kyiv, Ukraine, 04050
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  • Kyiv, Ukraine, 04053
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  • Kyiv, Ukraine, 03057
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  • Lutsk, Ukraine, 43005
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  • Vinnytsia, Ukraine, 21028
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  • Zaporizhzhia, Ukraine, 69001
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  • Zhytomyr, Ukraine, 10002
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• United States
  • Arizona
    • Surprise, Arizona, United States, 85374
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    • Tucson, Arizona, United States, 85741
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  • California
    • Canyon Country, California, United States, 91351
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    • Chula Vista, California, United States, 91910
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    • Northridge, California, United States, 91324
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    • San Dimas, California, United States, 91773
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    • South Gate, California, United States, 90280
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    • Tarzana, California, United States, 91356
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  • Colorado
    • Denver, Colorado, United States, 80230
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  • Florida
    • Boynton Beach, Florida, United States, 33435
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    • Hialeah, Florida, United States, 33012
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    • Lauderdale Lakes, Florida, United States, 33313
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    • Ocoee, Florida, United States, 34761
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    • Temple Terrace, Florida, United States, 33637
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  • Idaho
    • Nampa, Idaho, United States, 83687
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  • Illinois
    • Chicago, Illinois, United States, 60643
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    • Oak Brook, Illinois, United States, 60523
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  • Indiana
    • Fort Wayne, Indiana, United States, 46804
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  • Kentucky
    • Louisville, Kentucky, United States, 40205
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  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Research Site
    • Boston, Massachusetts, United States, 02114
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  • Michigan
    • Flint, Michigan, United States, 48532
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    • Saint Clair Shores, Michigan, United States, 48081
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  • Missouri
    • Columbia, Missouri, United States, 65201
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    • Kansas City, Missouri, United States, 64111
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  • New Mexico
    • Albuquerque, New Mexico, United States, 87109
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  • New York
    • Albany, New York, United States, 12205
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    • Great Neck, New York, United States, 11021
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  • North Carolina
    • Winston-Salem, North Carolina, United States, 27103
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  • Ohio
    • Cincinnati, Ohio, United States, 45267
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  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18017
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    • Chester, Pennsylvania, United States, 19013
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  • South Carolina
    • Columbia, South Carolina, United States, 29203
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    • Orangeburg, South Carolina, United States, 29118
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  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
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  • Texas
    • Arlington, Texas, United States, 76015
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    • Fort Worth, Texas, United States, 76164
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    • Houston, Texas, United States, 77004
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    • Houston, Texas, United States, 77054
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    • Houston, Texas, United States, 77099
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    • San Antonio, Texas, United States, 78212
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  • Virginia
    • Newport News, Virginia, United States, 23606
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• Vietnam
  • Biên Hòa, Vietnam, 810000
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  • Da Nang, Vietnam, 55000
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  • Hanoi, Vietnam, 100000
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  • Ho Chi Minh City, Vietnam, 700000
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  • Ho Chi Minh City, Vietnam, 70000
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  • Ho Chi Minh City, Vietnam, 10000
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  • Huế, Vietnam, 530000
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Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 130 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sodium Zirconium Cyclosilicate (SZC); SZC 5 g every other day to 15 g once daily + Lisinopril/Valsartan	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.; Other Names: Lokelma TM; Drug: 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.; Drug: 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.; Drug: 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.
Placebo Comparator: Placebo; Placebo + Lisinopril/Valsartan	Drug: 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.; Drug: 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.; Drug: 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.; Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total eGFR Slope (Coprimary Analysis #1)	Total eGFR slope, Baseline (Maintenance phase) to visit 17 (week 69)	Baseline (Maintenance phase) to visit 17 (week 69)
Chronic eGFR Slope (Coprimary Analysis #2)	Chronic eGFR slope, 12 weeks to visit 17 (week 69)	12 weeks to visit 17 (week 69)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From Baseline (Maintenance phase) up to week 97 (Maintenance phase)
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.	From Baseline (Maintenance phase) up to week 97 (Maintenance phase)
UACR	Urine albumin-to-creatinine ratio (UACR); mass concentration of albumin divided by mass concentration of creatinine, in urine; at visit 13 (week 24)	At visit 13 (week 24)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Glenn M. Chertow, MD, MPH, Stanford University School of Medicine, Stanford, CA USA

Publications and helpful links

Helpful Links

• redacted CSP
• redacted SAP
• redacted CSR Synopsis

Study record dates

Study Major Dates

• Study Start (Actual): September 30, 2021
• Primary Completion (Actual): February 7, 2024
• Study Completion (Actual): February 7, 2024

Study Registration Dates

• First Submitted: September 1, 2021
• First Submitted That Met QC Criteria: September 14, 2021
• First Posted (Actual): September 24, 2021

Study Record Updates

• Last Update Posted (Estimated): January 8, 2026
• Last Update Submitted That Met QC Criteria: December 17, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Renal Insufficiency, Chronic; Hyperkalemia; Chronic Kidney Diseases
• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Chronic Disease; Disease Attributes; Metabolic Diseases; Renal Insufficiency; Water-Electrolyte Imbalance; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Renal Insufficiency, Chronic; Hyperkalemia; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Hydrocarbons; Hydrocarbons, Cyclic; Hydrocarbons, Aromatic; Polycyclic Compounds; Amino Acids; Benzene Derivatives; Amino Acids, Essential; Tetrazoles; Biphenyl Compounds; Dipeptides; Spiro Compounds; Valine; Amino Acids, Branched-Chain; Valsartan; Irbesartan; Lisinopril; sodium zirconium cyclosilicate
• Other Study ID Numbers: D9488C00001; 2021-001911-96 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD 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.

• IPD Sharing 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.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No