A Study to Investigate the Safety and Efficacy of ZS in Patients With Hyperkalemia.

Phase 3

Completed

• Conditions: Hyperkalemia
• Interventions: Drug: Placebo; Drug: Sodium Zirconium Cyclosilicate 10g; Drug: Sodium Zirconium Cyclosilicate 5g

• Registration Number: NCT03528681
• Lead Sponsor: AstraZeneca

Brief Summary

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).

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 Timeline

• Study First Submitted: 2018-04-16
• Study First Submitted QC: 2018-05-09
• Study First Posted: 2018-05-18
• Study Start: 2021-05-06
• Primary Completion: 2022-09-15
• Study Completion: 2022-09-15
• Results First Submitted: 2023-09-14
• Status Verified: 2025-05
• Results First Submitted QC: 2025-05-13
• Last Update Submitted: 2025-05-13
• Results First Posted: 2025-05-14
• Last Update Posted: 2025-05-14

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 270

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Matching Placebo	Placebo	Suspension administered orally placebo once daily for 28 days after the open label initial phase.
Sodium Zirconium Cyclosilicate 10g	Sodium Zirconium Cyclosilicate 10g	Suspension administered 10g orally once daily for 28 days after the open label initial phase.
Sodium Zirconium Cyclosilicate 5g	Sodium Zirconium Cyclosilicate 5g	Suspension administered 5g orally once daily for 28 days after the open label initial phase.

Primary Outcome Measures

Name	Time	Method
Least Square Mean S-K Level on Days 8-29	Days 8 to 29 (Randomized treatment study phase) used for model-based least squares mean computation	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.

Secondary Outcome Measures

Name	Time	Method
Percentage of Patients Without Hyperkalemia	Day 29 of randomized treatment phase	Kaplan-Meier estimate at Day 29 of percentage of patients without hyperkalemia. The results in the table below are presented for RTP.
Percentage of Patients Who Achieve Normokalemia	Through open label initial phase	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.
Exponential Rate of Change in S-K Levels	Through 24 hours post-dose in the initial phase	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.
Proportion of Patients Who Remain Normokalemic During RTP	Through 28-day randomized treatment study phase day 8-29	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.
Proportion of Normokalemic Patients at the End of RTP	The end of 28-day randomized treatment study phase	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.
Absolute Change From Baseline in S-K Levels	Through open label initial phase	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.
Days Patients Remain Normokalemic	Through days 8-29 of the randomized treatment phase.	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.
Mean Change in S-K Levels	Through 28-day randomized treatment phase.	The mean change in S-K levels evaluated relative to the RTP baseline. The results in the table below are presented for RTP.
Percentage Change From Baseline in S-K Levels	Through open label initial phase	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.
Mean Percent Change in S-K Levels	Through 28-day randomized treatment phase.	The mean percent change in S-K levels evaluated relative to the RTP baseline. The results in the table below are presented for RTP.
Least Square Mean Changes in S-Aldo and P-Renin Levels	Through 28 day randomized treatment study phase day 15-29	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.
Hyperkalaemia at Day 29	Day 29	The number of patients with hyperkalaemia at day 29. The results in the table below are presented for RTP.

Trial Locations

Locations (1)

Research Site; 🇮🇳 Vijayawada, India