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 two days of initial ZS therapy (10g TID).

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, in Patients With Hyperkalemia-HARMONIZE Global

Conditions
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Hyperkalemia

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of informed consent prior to any study specific procedures Female and male patients aged ≥18 and ≤ 90 years 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 48-hour 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 and for 3 months after the last dose of ZS/matching placebo to prevent pregnancy. 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 Pseudohyperkalemia signs and symptoms 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 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 Known hypersensitivity or previous anaphylaxis to ZS or to components thereof Patients with cardiac arrhythmias that require immediate treatment 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

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 (ZS) 5g<br>Suspension administered 5g orally once daily for 28 days after the first 48-hour open label initial phase. | Drug: Sodium Zirconium Cyclosilicate (ZS) 5g<br>* Suspension administered 5g orally once daily for 28 days after the first 48-hour open label initial phase.<br>|
| Experimental: Sodium Zirconium Cyclosilicate (ZS) 10g<br>Suspension administered 10g orally once daily for 28 days after the first 48-hour open label initial phase. | Drug: Sodium Zirconium Cyclosilicate (ZS) 10g<br>* Suspension administered 10g orally three times per day, in the first 48-hour of the study for all patients (48-hour open label initial phase)<br>Drug: Sodium Zirconium Cyclosilicate (ZS) 10g<br>* Suspension administered 10g orally once daily for 28 days after the first 48-hour open label initial phase.<br>|
| Placebo Comparator: Placebo<br>Suspension administered orally placebo once daily for 28 days after the first 48-hour open label initial phase. | Drug: Placebo<br>* Suspension administered orally placebo once daily for 28 days after the first 48-hour open label initial phase.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Least Square Mean S-K Level on Days 8-29 | Comparison between placebo and the active ZS treatment groups (each dose group will be sequentially compared with placebo, starting with the highest and ending with the lowest dose) with regard to the mean S-K level during the 28-day randomized treatment study phase Days 8-29. The results in the table below are presented for RTP. | Through 28-day randomized treatment study phase day 8-29. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients Achieving Normokalemia | Proportion of patients who achieve normokalemia during the initial phase at 24 and 48 hours. The results in the table below are presented for OLP. (h=hours). | Through 48-hour initial phase. | 
| Exponential Rate of Change in S-K Levels | Exponential rate of change in S-K levels (blood) during the 48-hour open-label initial phase. The results in the table below are presented for OLP. | Through 48-hour initial phase. | 
| Absolute Change From Baseline in S-K Levels | Absolute change from baseline in S-K levels at all measured time intervals. The results in the table below are presented for OLP. | Through 48-hour initial phase. | 
| Percentage Change From Baseline in S-K Levels | Percentage change from baseline in S-K levels at all measured time intervals. The results in the table below are presented for OLP. | Through 48-hour 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. 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 Day 1 Through Day 29/Exit | The proportion of patients who are normokalemic (as defined by S-K between 3.5-5.0 mmol/l, inclusive) at Day 1 through Day 29/Exit in randomization phase. The results in the table below are presented for RTP. | Through 28-day randomized treatment phase. | 
| Days Patients Remain Normokalemic | The number of days patients remain normokalemic during the 28-day randomized treatment study phase. The results in the table below are presented for RTP. | Through 28-day randomized treatment phase. | 
| Mean Change in S-K Levels | The mean change in S-K levels evaluated relative to both baselines. The results in the table below are presented for RTP. | Through 28-day randomized treatment phase. | 
| Mean Percentage Change in S-K Levels | The mean percentage change in S-K levels evaluated relative to both baselines. The results in the table below are presented for RTP. | Through 28-day randomized treatment phase. | 
| Number of Hyperkalemic Patients | The results represent number of hyperkalemic patients during the 28-day randomized treatment study phase. The results in the table below are presented for RTP. | Through 28-day randomized treatment phase. | 
| Mean Changes in S-Aldosterone and P Renin Levels | The mean changes from OLP baseline in S-Aldosterone and P-Renin levels. The results in the table below are presented for RTP. | Through 28-day randomized treatment phase. | 
| Patient Reported Health State (EQ-5D) Questionnaire | Evaluate health state of patients using EQ-5D questionnaire. This scale is numbered from 0 to 100. 0 means the worst health you can imagine. 100 means the best health you can imagine. The results in the table below are presented for RTP. | Through study completion, an average of 37 days. |