CTRI/2023/04/051363暂停3 期
A Phase 3, International, Randomised, Double-blind, Placebo-controlled 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)
试验速览
- 阶段
- 3 期
- 状态
- 暂停
- 入组人数
- 1,360
- 试验地点
- 11
- 主要终点
- To determine if treatment with SZC as adjunct to ACEi/ARB therapy (lisinopril or valsartan) is superior to placebo in slowing CKD progression, assessed as the reduction in participant’s expected eGFR decline over time
研究概览
简要总结
| 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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Stratified block randomization
- 盲法
- Participant, Investigator and Outcome Assessor Blinded
入排标准
- 年龄范围
- 18.00 Year(s) 至 90.00 Year(s)（—）
- 性别
- All
入选标准
- •1 Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol 2 Must be more than or equal to 18 years of age at the time of signing the informed consent 3 Must have eGFR more than or equal to 25 and less than or equal to 59 mLmin1.73m2 as calculated by central laboratory CKDEPI formula at screening Visit 1 4 Must have UACR more than or equal to 200 and less than or equal to 5000 mg per 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 5 Any of the following criteria a or b at screening Visit 1 a Cohort A Hyperkalaemia SK more than 5 to less than or equal to 6 point 5 mmol per L as measured by the central laboratory and on adequate or limited RAASi therapy due to hyperkalaemia.
- •b Cohort B Normokalaemia SK more than or equal to 3 point 5 to less than or equal to 5 mmol per 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 SK more than or equal to 4 point 7 to less than or equal to 5 mmol per L iii Participants in whom RAASi therapy has been discontinued or reduced to suboptimal doses because of hyperkalaemia Adequate RAASi dose levels doses lower than these are considered as suboptimal Limited RAASi therapy is defined as no or suboptimal RAASi therapy according to dosing guidance provided 6 If on thiazide or loop diuretics, the dose must have been stable for 2 weeks prior to screening Visit
- •7 If on RAASi therapy, the dose must have been stable for one month prior to screening Visit 1 and remain stable during screening 8 If on an SGLT2 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 Contraceptive use by participants of childbearing potential should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies 9 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 percentage 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.
排除标准
- •1 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 2 Myocardial infarction unstable angina stroke or transient ischaemic attack within 3 months prior to screening Visit 1 3 Participants with a known history of systolic blood pressure more than or equal to 160 mmHg or diastolic blood pressure more than or equal to 95 mmHg within 2 weeks prior to screening Visit 1 are excluded In addition any participant with systolic blood pressure more than or equal to 160 mmHg or diastolic blood pressure more than or equal to 95 mmHg as measured at screening Visit 1 and confirmed by repeated measurement is excluded Participants may be rescreened once blood pressure is controlled 4 QTcF more than 550 msec at screening Visit 1 5 History of QT prolongation associated with other medications that required discontinuation of that medication 6 Congenital long QT syndrome 7 Symptomatic or uncontrolled atrial fibrillation despite treatment or asymptomatic sustained ventricular tachycardia Participants with atrial fibrillation and heart rate controlled by medication are permitted 9 Lupus nephritis or anti-neutrophil cytoplasmic antibody associated vasculitis 10 Change in renal function requiring hospitalisation or dialysis within 3 months prior to screening Visit 1 11 History of renal transplant or anticipated need for renal transplant during the study 12 Severe hepatic impairment biliary cirrhosis or cholestasis 13 History of hereditary or idiopathic angioedema 14 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 15 Known hypersensitivity or previous anaphylaxis to SZC or to components thereof 16 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 investigators clinical judgment 17 Active malignancy requiring treatment at the time of screening Visit 1 except for successfully treated basal cell or treated squamous cell carcinoma 18 SK more than 6 point 5 or less than 3 point 5 mmol per L by local laboratory within 1 day prior to the scheduled first dose of SZC in the initiation phase 19 Evidence of COVID-19 infection within 2 weeks prior to screening Visit 1 20 Treated with dual blockade of RAAS combined use of an ACEi and ARB within 3 months prior to screening Visit 1 21 Treated with an angiotensin receptor neprilysin inhibitor ARNI sacubitril or valsartan within 3 months prior to screening Visit 1 22 Treated with an MRA not approved for CKD within 3 months prior to screening Visit 1 23 Treated with aliskiren containing products with 3 months prior to screening Visit 1 24 Treated with SPS CPS patiromer or SZC within 7 days prior to screening Visit 1 25 Participation in another clinical study with an investigational product administered within one month prior to screening Visit 1 26 Not willing or not able to change to lisinopril or valsartan or 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 27 Previous dosing with SZC in the present study 28 Currently pregnant confirmed with positive pregnancy test at screening Visit 1 or breastfeeding 29 Judgment by the investigator that the participant is unlikely to comply with study procedures restrictions and requirements 30 Involvement in the planning and or or conduct of the study applies to both AstraZeneca staff and/or staff at the study site.
结局指标
主要结局
To determine if treatment with SZC as adjunct to ACEi/ARB therapy (lisinopril or valsartan) is superior to placebo in slowing CKD progression, assessed as the reduction in participant’s expected eGFR decline over time
时间窗: Co-primary | Total slope- eGFR measurements starting at randomisation | Chronic slope- eGFR measurements, starting at 12 weeks after randomisation
次要结局
- To determine if treatment with SZC, as adjunct to ACEi/ARB therapy (lisinopril or valsartan a), is superior to placebo in reducing the incidence of the composite of kidney failure outcomes comprising: sustained ≥ 40% decline in eGFR, onset of ESKD, and death from kidney failure(Time from randomisation to the first occurrence)
- To determine if treatment with SZC, as adjunct to ACEi/ARB therapy (lisinopril or valsartan a), is superior to placebo in reducing albuminuria(At scheduled visits after randomisation)
- To determine if treatment with SZC, as adjunct to ACEi/ARB therapy (lisinopril or valsartan a), is superior to placebo in reducing the incidence of lisinopril/valsartan dose decrease, in participants on lisinopril/valsartan at randomisation(Time from randomisation to first dose decrease)
- To determine if treatment with SZC, as adjunct to ACEi/ARB therapy (lisinopril or valsartan a), is superior to placebo in increasing serum bicarbonate levels(At scheduled visits after randomization)
- To determine if treatment with SZC, as adjunct to ACEi/ARB therapy (lisinopril or valsartan a), is superior to placebo on maintenance of normokalaemia(At scheduled visits after randomisation)
研究者
研究点 (11)
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