Study of SZC and Enhanced Nutrition Advice Compared to SoC in Dialysis Patients With Hyperkalaemia

Study Overview
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Brief Summary
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Prescribing Sodium zirconium cyclosilicate (SZC) with enhanced nutritional advice to participants with hyperkalaemia on haemodialysis will reduce serum K+ (S-K+ ) and enable the consumption of more fruit and vegetables and more satisfying diet. The study aims to show that participants using SZC achieve S-K+ reduction as well as participants on SoC (other than K+ binders), without the need for restricting K+ in the diet.

Detailed Description
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This is a Phase IV, randomised, controlled, open-label, parallel-group, multicentre, prospective study to evaluate the effect of the combination of SZC and enhanced nutritional advice to consume fruit and vegetables as compared to SoC in reducing S-K+ levels in participants with hyperkalaemia on haemodialysis. Following 7-day screening, all participants who are enrolled will begin an up to 1-month HK Treatment Phase with SZC as per local label. Participants will receive dietary advice consistent with SoC at that site, including K+ restriction. A 4-month Diet Comparison Phase will begin next with participants being randomised to either continue taking SZC, which can be titrated as needed to maintain target S-K+ , and receive enhanced nutritional advice to consume fruit and vegetables (SZC arm), or SZC will be withdrawn and participants will receive SoC, including dietary K+ restriction (SoC arm).

Official Title
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An Open-Label, Randomised, Controlled, Parallel-Design, Multicentre, Phase IV Study of Sodium Zirconium Cyclosilicate and Enhanced Nutrition Advice Compared to Standard of Care in Dialysis Patients With Hyperkalaemia (GRAZE)

Conditions
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Hyperkalaemia

Intervention / Treatment
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* Drug: Sodium Zirconium Cyclosilicate (SZC)
* Other: Enhanced dietary advice
* Other: Standard dietary advice including K+ restriction.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be ≥18 years of age at the time of signing the informed consent. Participants with prevalent HK (S-K+ >5.5 mmol/L at the end of LIDI) not requiring acute treatment. Receiving haemodialysis 3 times a week with stable vascular access for at least 3 months before screening visit. Participants who have and are able and willing to use smart phone (android or iOS) nutrition app. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Female participants of childbearing potential must have a negative pregnancy test. Female participants must be 1 year post-menopausal, surgically sterile, or using 1 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 3 months before entering the study and willing to remain on the birth control until 12 weeks after the last dose. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the Informed Consent Form (ICF) and in the protocol. Exclusion Criteria: As judged by the investigator or sponsor, any medical condition (including active, clinically significant infection) that may pose a safety risk to the participant in this study, may confound safety or efficacy assessments and jeopardise the quality of data, or may interfere with study participation. Myocardial infarction, acute coronary syndrome (ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, or unstable angina), stroke, seizure, thrombotic/thromboembolic event (eg, deep vein thrombosis or pulmonary embolism, but excluding vascular access thrombosis), percutaneous transluminal coronary angioplasty, or coronary artery bypass graft within 12 weeks prior to screening visit. Severe leucocytosis (>20 × 109 /L) or thrombocytosis (≥450 × 109 /L) during screening. Polycythaemia (haemoglobin >14 g/dL) during screening. Severe constipation, bowel obstruction, post-operative motility disorders. Scheduled date for living donor kidney transplant. Participants with a life expectancy of less than 6 months. Females of childbearing potential, unless using contraception as detailed in the protocol or sexually abstinent. Currently pregnant (confirmed with positive pregnancy test) or breast-feeding. Presence of cardiac arrhythmias or conduction defects that require immediate treatment at HCP discretion. History of alcohol or drug abuse within 2 years prior to screening visit. History of QT prolongation associated with other medications that required discontinuation of that medication. Congenital long QT syndrome or QT interval corrected for heart rate (QTc) using Fridericia's method (QTcF) >550 ms. Symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Subjects with atrial fibrillation controlled by medication are permitted. If the participant has evidence of Coronavirus disease 2019 (COVID-19) within 2 weeks prior to screening (see Appendix D), the participant cannot be enrolled in the study. Participants treated with SZC, sodium polystyrene sulfonate (SPS: Kayexalate™; Resonium™ A), calcium polystyrene sulfonate (CPS: Calcium Resonium™), or patiromer (Veltassa™) 1 within 4 weeks before screening. Participants with a known hypersensitivity or previous anaphylaxis to SZC or any of the excipients of the product. Participants unable to take oral SZC. Prior/Concurrent Clinical Study Experience Participation in another clinical study with an investigational product administered during the month before screening2 . Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements. Previous enrolment in the present study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel: Participants are assigned to two groups in parallel for the duration of the study. Following 7-day screening, all participants who are enrolled will begin an up to 1-month HK Treatment Phase with SZC as per local label. Participants will receive dietary advice consistent with SoC at that site, including K+ restriction. A 4-month Diet Comparison Phase will begin next with participants being randomised to either continue taking SZC, which can be titrated as needed to maintain target S-K+ , and receive enhanced nutritional advice to consume fruit and vegetables (SZC arm), or SZC will be withdrawn and participants will receive SoC, including dietary K+ restriction (SoC arm).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SZC arm with enhanced dietary advice<br>Participants will continue taking Sodium Zirconium Cyclosilicate (SZC), which can be titrated up or down to maintain S-K+ in the range 3.5-5.5 mmol/L; participants will also receive enhanced nutritional advice to consume fruit and vegetables. Advice will be provided by dietitians at study visits and by Noom app between visits. | Drug: Sodium Zirconium Cyclosilicate (SZC)<br>* Participants in the active arm will receive SZC dosed as per the local label to control hyperkalaemia and maintain normokalaemia.<br>* Other names: SZC;Other: Enhanced dietary advice<br>* Participants will receive enhanced dietary advice in addition to taking SZC. This will include advice from dietitians to consume fruit and vegetables. Participants will be encouraged to consume up to 70 mmol K+ per day.<br>|
| Other: SoC arm with standard dietary advice<br>SZC will be withdrawn and participants will receive SoC as per site practice, including dietary K+ restriction. Dietary advice will be given by dietitians at study visits and by Noom app between study visits. | Other: Standard dietary advice including K+ restriction.<br>* Participants randomised to the SoC arm of the Diet Comparison Phase will receive standard dietary advice including K+ restriction.<br>* Other names: Standard dietary advice;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Serum Potassium | Change in serum potassium taken at long interdialytic-dialysis interval visits Month 3, Month 4, and Month 5 compared to baseline | Baseline to Month 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Fruit and Vegetable Consumption Determined by Participant-reported Intake Using Noom App From Month 2 to Month 5 | Change from baseline in fruit and vegetable consumption determined by participant-reported intake using Noom app from Month 2 to Month 5 | Month 2 to Month 5 | 
| Effect of the Combination of Sodium Zirconium Cyclosilicate and Enhanced Nutritional Advice as Compared to Standard of Care on Participant-reported Chronic Kidney Disease Symptoms, Physical and Mental Health, and Satisfaction With Treatment | Electronic versions of the following: Kidney Disease and Quality of Life-36 item (KDQOL-36; symptoms/problems, Physical Component Summary and Mental Component Summary, Burden of Kidney Disease and Effects of Kidney Disease) EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Abbreviated Treatment Satisfaction Questionnaire for Medication (9 items) (TSQM-9) Patients' Global Impression of Change (PGIC) | From study start to study end | 
| Effect of the Combination of Sodium Zirconium Cyclosilicate and Enhanced Nutritional Advice to Consume Fruit and Vegetables as Compared to Standard of Care in Maintaining Serum Potassium Levels | Effect of the combination of sodium zirconium cyclosilicate and enhanced nutritional advice to consume fruit and vegetables as compared to standard of care in maintaining serum potassium levels within a range of 3.5 to 5.5 mmol/L, without requiring rescue therapy for hyperkalaemia. Binary response (responder/non-responder) with criteria that at least 66% of serum potassium values taken at long interdialytic-dialysis interval visits in Months 3, 4, and 5 fall between 3.5 and 5.5 mmol/L. Receiving rescue therapy or a potassium binder for hyperkalaemia during the final 3 months of the study was to result in a non-response. | From study start to study end | 
| Safety and Tolerability of Sodium Zirconium Cyclosilicate and Enhanced Nutritional Advice as Compared to Standard of Care | Safety and tolerability were to be evaluated in terms of adverse events (AEs), vital signs, clinical laboratory, interdialytic weight gain, and electrocardiograms. Assessments related to AEs covered occurrence/frequency, relationship to sodium zirconium cyclosilicate as assessed by Investigator, intensity, seriousness, death, and AEs leading to discontinuation of sodium zirconium cyclosilicate. | From study start to study end | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hyperkalaemia, Dialysis Patients