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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Hyperkalemia

Intervention / Treatment
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* Drug: Sodium Zirconium Cyclosilicate 5g
* Drug: Sodium Zirconium Cyclosilicate 10g
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of informed consent (pre-screening consent) prior to any study specific procedures Female and male patients aged ≥18 and ≤ 90 years Provision of informed consent prior to any study specific procedures 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 Ability to have repeated blood draws or effective venous catheterization 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: Involvement in the planning and/or conduct of the study Participation in another clinical study with an investigational product during the last 3 months 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 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 Patients treated with lactulose, xifaxan (rifaximin) or other non-absorbed antibiotics for hyperammonemia within 7 days prior to the first dose of study drug Patients treated with resins,calcium acetate,calcium carbonate, or lanthanum carbonate,within 7 days prior to the first dose of study drug Patients with a life expectancy of less than 3 months 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 Female patients who are pregnant, lactating, or planning to become pregnant Patients with diabetic ketoacidosis Known hypersensitivity or previous anaphylaxis to ZS or to components thereof Patients with cardiac arrhythmias that require immediate treatment History of QT prolongation associated with other medications that required discontinuation of that medication. Congenital long QT syndrome Symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Subjects with atrial fibrillation controlled by medication are permitted QTc(f) > 550 msec Patients on dialysis Patients who are blood donors should not donate blood during the study and for 3 months following their last dose of ZS Patients who need hospitalization after taking blood samples on day 1 of the open-label initial phase

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sodium Zirconium Cyclosilicate 10g<br>Suspension administered 10g orally once daily for 28 days after the open label initial phase. | Drug: Sodium Zirconium Cyclosilicate 10g<br>* 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.<br>|
| Experimental: Sodium Zirconium Cyclosilicate 5g<br>Suspension administered 5g orally once daily for 28 days after the open label initial phase. | Drug: Sodium Zirconium Cyclosilicate 5g<br>* 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.<br>|
| Placebo Comparator: Matching Placebo<br>Suspension administered orally placebo once daily for 28 days after the open label initial phase. | Drug: Placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Least Squares Means of S-K values during the 28-day randomized treatment study phase Study Days 8-29. | Comparison between placebo and each ZS treatment group (high to low) with regard to the mean S-K level during the 28-day randomized treatment study phase Days 8-29 | Through 28 day randomized treatment study phase day 8-29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exponential rate of change in S-K levels | Exponential rate of change in S-K levels (blood) during the open label initial phase | Through open label initial phase | 
| Mean change from baseline in S-K levels | Mean Change (absolute and percent change) from baseline in S-K levels (blood) at all measured time intervals post dose in the open label initial phase | Through open label initial phase | 
| proportion of patients achieve normokalemia | Proportion of patients who achieve normokalemia during the open label initial phase at 24 hours and at the end of the open label phase | Through open label initial phase | 
| Time to normalization in S-K levels | Time to normalization in S-K levels (normalization defined as S-K levels between 3.5-5.0 mmol/L, inclusive) in the open label initial phase | Through open label initial phase | 
| Proportion of patients remaining normokalemic | The proportion of patients who remain normokalemic (as defined by S-K between 3.5-5.0 mmol/L, inclusive) at the end of the 28-day randomized treatment study phase and during the 28-day randomized treatment study phase | Through 28-day randomized treatment study phase | 
| Mean number of Days patients remain normokalemic | The mean number of days patients remain normokalemic during the 28-day randomized treatment study phase | Through 28-day randomized treatment study phase | 
| Mean change and mean percent change in S-K levels | The mean change and mean percent change in S-K levels evaluated relative to both baselines | Through 28-day randomized treatment study phase | 
| Time to hyperkalemia | The time to hyperkalemia (defined as S-K ≥5.1mmol/L) | Through 28-day randomized treatment study phase | 
| Mean changes in S-Aldo and P-Renin levels | The mean changes in S-Aldo and P-Renin levels | Through 28-day randomized treatment study phase |