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

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)

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.

Study Overview

• Status: Terminated
• Conditions: Hyperkalaemia
• Intervention / Treatment: Drug: Sodium Zirconium Cyclosilicate (SZC); Other: Enhanced dietary advice; Other: Standard dietary advice including K+ restriction.

Detailed Description

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target S-K+ , and receive enhanced nutritional advice to consume fruit and vegetables (SZC arm), or SZC will be withdrawn and participants will receive SoC, including dietary K+ restriction (SoC arm).

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Florida
    • West Palm Beach, Florida, United States, 33411
      • Research Site

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Participant must be ≥18 years of age at the time of signing the informed consent.
2. Participants with prevalent HK (S-K+ >5.5 mmol/L at the end of LIDI) not requiring acute treatment.
3. Receiving haemodialysis 3 times a week with stable vascular access for at least 3 months before screening visit.
4. Participants who have and are able and willing to use smart phone (android or iOS) nutrition app.

5. 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.
6. 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:

1. 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.
2. 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.
3. Severe leucocytosis (>20 × 109 /L) or thrombocytosis (≥450 × 109 /L) during screening.
4. Polycythaemia (haemoglobin >14 g/dL) during screening.
5. Severe constipation, bowel obstruction, post-operative motility disorders.
6. Scheduled date for living donor kidney transplant.
7. Participants with a life expectancy of less than 6 months.
8. Females of childbearing potential, unless using contraception as detailed in the protocol or sexually abstinent.
9. Currently pregnant (confirmed with positive pregnancy test) or breast-feeding.
10. Presence of cardiac arrhythmias or conduction defects that require immediate treatment at HCP discretion.
11. History of alcohol or drug abuse within 2 years prior to screening visit.
12. History of QT prolongation associated with other medications that required discontinuation of that medication.
13. Congenital long QT syndrome or QT interval corrected for heart rate (QTc) using Fridericia's method (QTcF) >550 ms.
14. Symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Subjects with atrial fibrillation controlled by medication are permitted.
15. 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.
16. 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.
17. Participants with a known hypersensitivity or previous anaphylaxis to SZC or any of the excipients of the product.
18. Participants unable to take oral SZC. Prior/Concurrent Clinical Study Experience
19. Participation in another clinical study with an investigational product administered during the month before screening2 .
20. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
21. 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.
22. Previous enrolment in the present study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SZC arm with enhanced dietary advice; 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); Participants in the active arm will receive SZC dosed as per the local label to control hyperkalaemia and maintain normokalaemia.; Other Names: SZC; Other: Enhanced dietary advice; 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.
Other: SoC arm with standard dietary advice; 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.; Participants randomised to the SoC arm of the Diet Comparison Phase will receive standard dietary advice including K+ restriction.; Other Names: Standard dietary advice

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Study Director: Eric Wittbrodt, PharmD, MPH, AstraZeneca, Biopharmaceuticals Medical

Publications and helpful links

Helpful Links

• Clinical Study Protocol-redacted
• Statistical Analysis Plan-redacted
• CSR synopsis-redacted

Study record dates

Study Major Dates

• Study Start (Actual): August 17, 2021
• Primary Completion (Actual): November 17, 2021
• Study Completion (Actual): November 17, 2021

Study Registration Dates

• First Submitted: June 16, 2021
• First Submitted That Met QC Criteria: July 30, 2021
• First Posted (Actual): August 9, 2021

Study Record Updates

• Last Update Posted (Actual): January 19, 2023
• Last Update Submitted That Met QC Criteria: December 22, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: Hyperkalaemia; Dialysis Patients
• Additional Relevant MeSH Terms: Metabolic Diseases; Water-Electrolyte Imbalance; Hyperkalemia
• Other Study ID Numbers: D9480C00014; 2021-000457-81 (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 de-identified 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; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)

Drug and device information, study documents

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