A Study to Investigate the Safety and Efficacy of ZS in Patients With Hyperkalemia. (HARMONIZE Asia)

A Phase 3 Multicenter, Prospective, Randomized, Double-blind, Placebo-controlled Study to Investigate the Safety and Efficacy of ZS (Sodium Zirconium Cyclosilicate), in Patients With Hyperkalemia-HARMONIZE Asia

To evaluate the efficacy of two different doses (5 and 10 g) of ZS orally administered once daily (qd) vs placebo in maintaining normokalemia in initially hyperkalemic patients having achieved normokalemia following 24 or 48 hours of initial ZS therapy (10g TID).

Study Overview

• Status: Completed
• Conditions: Hyperkalemia
• Intervention / Treatment: Drug: Sodium Zirconium Cyclosilicate 10g; Drug: Sodium Zirconium Cyclosilicate 5g; Drug: Placebo

Detailed Description

This study will be conducted in approximately 35 centers in China. Before patients are randomized to the double-blind phase, they will receive open-label ZS for 24 or 48 hours during the initial phase. It is expected that approximately 490 patients will need to be enrolled, to have approximately 280 patients entered into the open-label initial phase resulting in 250 patients being randomized in the 28-day treatment study phase. Enrolment will be stopped when 250 patients have been initiated with the 28-day randomized treatment study phase.

• Study Type: Interventional
• Enrollment (Actual): 270
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Baotou, China, 14010
    • Research Site
  • Beijing, China, 100853
    • Research Site
  • Beijing, China, 100029
    • Research Site
  • Beijing, China, 102206
    • Research Site
  • Beijing, China, 100144
    • Research Site
  • Bengbu, China, 233004
    • Research Site
  • Changchun, China, 130021
    • Research Site
  • Changsha, China, 410008
    • Research Site
  • Changsha, China, 430033
    • Research Site
  • Chengdu, China, 610041
    • Research Site
  • Chengdu, China, 610072
    • Research Site
  • Dalian, China, 116027
    • Research Site
  • Dongguan, China, 523009
    • Research Site
  • Fuzhou, China, 350025
    • Research Site
  • Fuzhou, China, 350005
    • Research Site
  • Guangzhou, China, 510120
    • Research Site
  • Guangzhou, China, 510080
    • Research Site
  • Guiyang, China, 550004
    • Research Site
  • Haikou, China, 570311
    • Research Site
  • Hangzhou, China, 310003
    • Research Site
  • Hangzhou, China, 310009
    • Research Site
  • Hefei, China, 230601
    • Research Site
  • Hefei, China, 230022
    • Research Site
  • Jilin, China, 132011
    • Research Site
  • Jinan, China, 250021
    • Research Site
  • Jingzhou, China, 434020
    • Research Site
  • Kunming, China, 650021
    • Research Site
  • Kunming, China, 650011
    • Research Site
  • Lanzhou, China, 730030
    • Research Site
  • Nanchang, China, 330006
    • Research Site
  • Ningbo, China, 315010
    • Research Site
  • Qingdao, China, 266000
    • Research Site
  • Shanghai, China, 200025
    • Research Site
  • Shanghai, China, 200090
    • Research Site
  • Shanghai, China, 200127
    • Research Site
  • Suzhou, China, 215006
    • Research Site
  • Taiyuan, China, 030001
    • Research Site
  • Taiyuan, China, 030012
    • Research Site
  • Tianjin, China, 300211
    • Research Site
  • Tianjin, China, 300121
    • Research Site
  • Wuhan, China, 430030
    • Research Site
  • Wuhan, China, 430070
    • Research Site
  • Wuxi, China, 214023
    • Research Site
  • Xiamen, China, 361003
    • Research Site
  • Xian, China, 710061
    • Research Site
  • Xining, China, 810007
    • Research Site
  • Xining, China, 810001
    • Research Site
  • Yangzhou, China, 225001
    • Research Site
  • Yichang, China, 443003
    • Research Site
  • Yinchuan, China, 750004
    • Research Site
  • Zhanjiang, China, 524001
    • Research Site
  • Zhuzhou, China, 412007
    • Research Site
• India
  • Ahmedabad, India, 380016
    • Research Site
  • Ahmedabad, India, 380006
    • Research Site
  • Ahmedabad, India, 380015
    • Research Site
  • Bangalore, India, 560002
    • Research Site
  • Bangalore, India, 560004
    • Research Site
  • Bengaluru, India, 560004
    • Research Site
  • Chandigarh, India, 160030
    • Research Site
  • Chennai, India, 600001
    • Research Site
  • Hyderabad, India, 500018
    • Research Site
  • Kolkata, India, 700054
    • Research Site
  • Nagpur, India, 440012
    • Research Site
  • New Delhi, India, 110017
    • Research Site
  • New Delhi, India, 110002
    • Research Site
  • Vijayawada, India, 522002
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Provision of informed consent (pre-screening consent) prior to any study specific procedures
2. Female and male patients aged ≥18 and ≤ 90 years
3. Provision of informed consent prior to any study specific procedures
4. Two consecutive i-STAT potassium values, measured 60 minutes (± 10 minutes) apart, both ≥ 5.1 mmol/L and measured within 1 day of the first ZS dose on open-label initial phase Day 1
5. Ability to have repeated blood draws or effective venous catheterization
6. Female patients must be 1 year post-menopausal, surgically sterile, or using an acceptable method of contraception for the duration of the study (from the time they sign consent) and for 3 months after the last dose of ZS/matching placebo to prevent pregnancy. In addition, oral contraceptives, approved contraceptive implant, long-term injectable contraception, intrauterine device, or tubal ligation are allowed. Oral contraception alone is not acceptable; additional barrier methods in conjunction with spermicide must be used

Exclusion Criteria:

1. Involvement in the planning and/or conduct of the study
2. Participation in another clinical study with an investigational product during the last 3 months
3. Presence of any condition which, in the opinion of the investigator, places the patient at undue risk or potentially jeopardizes the quality of the data to be generated
4. Pseudohyperkalemia signs and symptoms, such as hemolyzed blood specimen due to excessive fist clenching to make veins prominent, difficult or traumatic venepuncture, or history of severe leukocytosis or thrombocytosis
5. Patients treated with lactulose, xifaxan (rifaximin) or other non-absorbed antibiotics for hyperammonemia within 7 days prior to the first dose of study drug
6. Patients treated with resins,calcium acetate,calcium carbonate, or lanthanum carbonate,within 7 days prior to the first dose of study drug
7. Patients with a life expectancy of less than 3 months
8. Patients who are severely physically or mentally incapacitated and who in the opinion of investigator are unable to perform the subjects' tasks associated with the protocol
9. Female patients who are pregnant, lactating, or planning to become pregnant
10. Patients with diabetic ketoacidosis
11. Known hypersensitivity or previous anaphylaxis to ZS or to components thereof
12. Patients with cardiac arrhythmias that require immediate treatment
13. History of QT prolongation associated with other medications that required discontinuation of that medication.
14. Congenital long QT syndrome
15. Symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Subjects with atrial fibrillation controlled by medication are permitted
16. QTc(f) > 550 msec
17. Patients on dialysis
18. Patients who are blood donors should not donate blood during the study and for 3 months following their last dose of ZS
19. Patients who need hospitalization after taking blood samples on day 1 of the open-label initial phase

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sodium Zirconium Cyclosilicate 10g; Suspension administered 10g orally once daily for 28 days after the open label initial phase.	Drug: Sodium Zirconium Cyclosilicate 10g; Suspension administered Sodium Zirconium Cyclosilicate 10g orally once daily for 28 days after the open label initial phase with suspension administered Sodium Zirconium Cyclosilicate 10g orally three times per day for at most 2 days.
Experimental: Sodium Zirconium Cyclosilicate 5g; Suspension administered 5g orally once daily for 28 days after the open label initial phase.	Drug: Sodium Zirconium Cyclosilicate 5g; Suspension administered Sodium Zirconium Cyclosilicate 5g orally once daily for 28 days after the open label initial phase with suspension administered Sodium Zirconium Cyclosilicate 10g orally three times per day for at most 2 days.
Placebo Comparator: Matching Placebo; Suspension administered orally placebo once daily for 28 days after the open label initial phase.	Drug: Placebo; Suspension administered orally placebo once daily for 28 days after the open label initial phase with suspension administered Sodium Zirconium Cyclosilicate 10g orally three times per day for at most 2 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Least Square Mean S-K Level on Days 8-29	Comparison between placebo and each SZC treatment group (high to low) with regard to the mean S-K level during the randomized treatment phase days 8-29. Mixed-effects models were used to estimate least-squares means.	Days 8 to 29 (Randomized treatment study phase) used for model-based least squares mean computation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients Who Achieve Normokalemia	Percentage of patients who achieve normokalemia during the open label initial phase at 24 hours and at the end of the open label phase. End of OLP is defined as Day 2 (24 hours post first dose) or Day 3 (48 hours post first dose) depending on when the subject achieved normokalemia based on the pre-dose i-STAT potassium level. The results in the table below are presented for OLP.	Through open label initial phase
Exponential Rate of Change in S-K Levels	Exponential rate of change in S-K levels (blood) during the open-label initial phase 24 hours post-dose. Least Square Mean corresponds to the exponential rate of change i.e. the slope (for time) in terms of log-transformed S-K levels. The results in the table below are presented for OLP.	Through 24 hours post-dose in the initial phase
Absolute Change From Baseline in S-K Levels	Absolute change from baseline in S-K levels at all measured time intervals. End of OLP is defined as Day 2 (24 hours post first dose) or Day 3 (48 hours post first dose) depending on when the subject achieved normokalemia based on the pre-dose i-STAT potassium level. The results in the table below are presented for OLP.	Through open label initial phase
Percentage Change From Baseline in S-K Levels	Percentage change from baseline in S-K levels at all measured time intervals. End of OLP is defined as Day 2 (24 hours post first dose) or Day 3 (48 hours post first dose) depending on when the subject achieved normokalemia based on the pre-dose i-STAT potassium level. The results in the table below are presented for OLP.	Through open label initial phase
Proportion of Patients Who Remain Normokalemic During RTP	Proportion of patients who remain normokalemic (as defined by S-K between 3.5-5.0 mmol/l, inclusive) during RTP (Day 8 to Day 29). The results in the table below are presented for RTP.	Through 28-day randomized treatment study phase day 8-29
Proportion of Normokalemic Patients at the End of RTP	Proportion of normokalemic patients (as defined by S-K between 3.5-5.0 mmol/l, inclusive). The results in the table below are presented for RTP.	The end of 28-day randomized treatment study phase
Days Patients Remain Normokalemic	The number of days patients remain normokalemic during days 8-29 of the randomized treatment study phase. The results in the table below are presented for RTP.	Through days 8-29 of the randomized treatment phase.
Mean Change in S-K Levels	The mean change in S-K levels evaluated relative to the RTP baseline. The results in the table below are presented for RTP.	Through 28-day randomized treatment phase.
Mean Percent Change in S-K Levels	The mean percent change in S-K levels evaluated relative to the RTP baseline. The results in the table below are presented for RTP.	Through 28-day randomized treatment phase.
Least Square Mean Changes in S-Aldo and P-Renin Levels	Comparison between placebo and each SZC treatment group (high to low) with regard to the mean S-Aldo and P-Renin levels during the randomized treatment phase days 15-29.	Through 28 day randomized treatment study phase day 15-29
Hyperkalaemia at Day 29	The number of patients with hyperkalaemia at day 29. The results in the table below are presented for RTP.	Day 29
Percentage of Patients Without Hyperkalemia	Kaplan-Meier estimate at Day 29 of percentage of patients without hyperkalemia. The results in the table below are presented for RTP.	Day 29 of randomized treatment phase

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vital signs	Vital signs include pulse rate and blood pressure	Throughout the study, from the time of signature of the main study informed consent form up to study completion.
ECG measurements	ECG measurements include heart rate, P and QRS durations, PR and QTc(f) intervals. Collected from standard lead of the computerized quantitative 12- lead ECG.	Throughout the study, from the time of signature of the main study informed consent form up to study completion.
AEs, including SAEs	The evaluation of AE will include, but not be limited to, a classification by SOC/PT, an assessment of severity and causality with regards to the IP, as well as action taken as the response to the AE, e.g. IP discontinuation	Throughout the study, from the time of signature of the main study informed consent form up to study completion.
Safety laboratory evaluations, including determination of hypokalaemia	Include, but are not limited to, serum potassium, calcium, magnesium, sodium, phosphate, bicarbonate, as well as blood urea nitrogen.	Throughout the study, from the time of signature of the main study informed consent form up to study completion.

Collaborators and Investigators

• Sponsor: AstraZeneca

Publications and helpful links

Helpful Links

• CSP Redacted
• SAP Redacted
• CSR Synopsis Redacted

Study record dates

Study Major Dates

• Study Start (Actual): May 6, 2021
• Primary Completion (Actual): September 15, 2022
• Study Completion (Actual): September 15, 2022

Study Registration Dates

• First Submitted: April 16, 2018
• First Submitted That Met QC Criteria: May 9, 2018
• First Posted (Actual): May 18, 2018

Study Record Updates

• Last Update Posted (Actual): May 14, 2025
• Last Update Submitted That Met QC Criteria: May 13, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Water-Electrolyte Imbalance; Hyperkalemia
• Other Study ID Numbers: D9480C00001

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; SAP

Drug and device information, study documents

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