Safety & Efficacy of Zirconium Silicate Dosed for 28 Days in Hyperkalemia.

Study Overview
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Brief Summary
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It is hypothesized that ZS is more effective than placebo control (alternative hypothesis) in maintaining mean double-blind randomized maintenance phase (DBRMP) Day 8-29 serum potassium levels (3.5 - 5.0 mmol/l, inclusive) among hyperkalemic subjects in whom normokalemia was established during the open-label acute phase versus no difference between each ZS dose (highest to lowest) versus placebo control (null hypothesis).

Detailed Description
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Approximately 275 subjects with hyperkalemia (two consecutive i-STAT potassium levels ≥ 5.1 mmol/l, taken 60 minutes apart at baseline) will be enrolled in the Open-label Acute Phase to provide 232 subjects in the Double Blind Randomized Maintenance Phase. Initially all subjects will receive open-label ZS at a dose of 10g three times a day (tid) for 48 hours (AP). Subjects who achieve normokalemia (i-STAT potassium values between 3.5 to 5.0 mmol/l, inclusive) on the morning of Study Day 3 (after 6 doses of 10g ZS) will then, in a double-blind fashion, be randomized 4:4:4:7 to receive one of three doses of ZS (5g, 10g or 15g) or placebo control, qd for the following 28 days (DBRMP). Safety and tolerability will be assessed on an ongoing basis by an Independent Data Monitoring Committee (iDMC). Each active dose group in the DBRMP will consist of 49 subjects and the placebo control group will consist of 85 subjects for a total of 232 subjects to detect a 0.6 effect size difference between each ZS dose (from highest to lowest) and placebo control; the 4:4:4:7 allocation optimizes the multiple comparisons to the placebo control for the DBRMP.

Official Title
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Multicenter, Multi-phase, Multi-dose, Prospective, Double-blind, Placebo-controlled, Maintenance Study of Safety and Efficacy of ZS (Microporous, Fractionated, Protonated Zirconium Silicate) in Hyperkalemia.

Conditions
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Hyperkalemia

Intervention / Treatment
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* Drug: Sodium zirconium cyclosilicate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of written informed consent. Over 18 years of age. Two consecutive i-STAT potassium values, measured 60-minutes apart, both ≥5.1 mmol/l and measured within 1 day of the first ZS dose on AP Study Day 1. Ability to have repeated blood draws or effective venous catheterization. Women of childbearing potential must be using two forms of medically acceptable contraception (at least one barrier method) and have a negative pregnancy test at AP Study Day 1. Women who are surgically sterile or those who are post-menopausal for at least 2 years are not considered to be of childbearing potential. Exclusion Criteria: Pseudohyperkalemia signs and symptoms, such as excessive fist clenching hemolyzed blood specimen, history of severe leukocytosis or thrombocytosis. Subjects treated with lactulose, Xifaxan or other non-absorbed antibiotics for hyperammonemia within 7 days prior to the first dose of study drug. Subjects treated with resins (such as sevelamer acetate or sodium polystyrene sulfonate [SPS; e.g. Kayexalate®]), calcium acetate, calcium carbonate, or lanthanum carbonate, within 7 days prior to the first dose of study drug. Subjects with a life expectancy of less than 3 months. Subjects 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. Women who are pregnant, lactating, or planning to become pregnant. Subjects with diabetic ketoacidosis. Presence of any condition which, in the opinion of the investigator, places the subject 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. Randomization into the previous ZS-002 or ZS-003 studies. Treatment with a drug or device within the last 30 days that has not received regulatory approval at the time of study entry. Subjects with cardiac arrhythmias that require immediate treatment. Subjects on dialysis.

Ages Eligible for Study
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Minimum Age: 18 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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sodium zirconium cyclosilicate 10 g three times daily<br>Sodium zirconium cyclosilicate 10 g three times daily for 48 hours (acute phase) | Drug: Sodium zirconium cyclosilicate<br>* Sodium zirconium cyclosilicate<br>* Other names: ZS; Microporous, Fractionated, Protonated Zirconium Silicate; Zirconium Silicate;|
| Placebo Comparator: Placebo once daily<br>Randomized to mimic doses of experimental drug administered once daily with breakfast for 28 days. | Drug: Placebo<br>* Randomized to mimic doses of experimental drug administered once daily with breakfast for 28 days (maintenance phase)<br>* Other names: Silicilate microcrystaline cellulose;|
| Experimental: Sodium zirconium cyclosilicate 5 g once daily<br>Sodium zirconium cyclosilicate (ZS) 5 g once daily for 28 days (maintenance phase) | Drug: Sodium zirconium cyclosilicate<br>* Sodium zirconium cyclosilicate<br>* Other names: ZS; Microporous, Fractionated, Protonated Zirconium Silicate; Zirconium Silicate;|
| Experimental: Sodium zirconium cyclosilicate 10 g once daily<br>Sodium zirconium cyclosilicate (ZS) 10 g once daily for 28 days (maintenance phase) | Drug: Sodium zirconium cyclosilicate<br>* Sodium zirconium cyclosilicate<br>* Other names: ZS; Microporous, Fractionated, Protonated Zirconium Silicate; Zirconium Silicate;|
| Experimental: Sodium zirconium cyclosilicate 15 g once daily<br>Sodium zirconium cyclosilicate (ZS) 15 g once daily for 28 days (maintenance phase) | Drug: Sodium zirconium cyclosilicate<br>* Sodium zirconium cyclosilicate<br>* Other names: ZS; Microporous, Fractionated, Protonated Zirconium Silicate; Zirconium Silicate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Serum Potassium Between Maintenance Phase Study Days 8 to 29, Inclusive (MP-ITT Population). | The least squares means (LSMeans) are dervied from a mixed effects model of serial log transformed S-K values between Days 8 and 29 with patients as a random effect and the following fixed effects terms: MP treatment group; AP baseline eGFR; AP and MP baseline S-K levels, age categories (<55, 55-64, >= 65 years); and binary indicators for RAAS inhibitors use, CKD, CHF, and DM. The LSmeans estimate obtained from the above model is back-transformed and presented as the lsmeans of all available S-K values during the Maintenance phase study Days 8 to 29. | 22 Days; Maintenance Phase Days 8 - 29, inclusive. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Normokalemic Days Between Maintenance Phase Study Days 8 to 29, Inclusive (MP-ITT). | The number of normokalemic days during the Maintenance Phase Study Days 8 to 29 is calculated assuming that the interval between assessments is normokalemic only if both the beginning and end assessments for that time interval display normal S-K values (i.e. 3.5 - 5.0 mmol/L) | 22 days; Maintenance Phase Day 8 - 29, inclusive. | 
| Mean Change in S-K Levels From Acute Phase Baseline to Maintenance Phase Study Day 2 to Day 29/Exit . |  | Acute Phase baseline to Maintenance Phase Study Day 2 to Day 29/Exit, inclusive. | 
| Mean Percent Change in S-K Levels From Acute Phase Baseline to Maintenance Phase Study Day 2 to Day 29/Exit, Inclusive . |  | Acute Phase baseline to Maintenance Phase Study Day 2 to Day 29/Exit, inclusive. | 
| Mean Change in S-K Levels From Maintenance Phase Baseline to Maintenance Phase Day 2 to Day 29/Exit. |  | Maintenance phase baseline to Maintenance Phase Study Day 29/Exit, inclusive. | 
| Mean Percent Change in S-K Levels From Maintenance Phase Baseline to Maintenance Phase Day 2 to Day 29/Exit. |  | Maintenance phase baseline to Maintenance Phase Study Day 29/Exit, inclusive. | 
| Median Time to Hyperkalemia (S-K ≥ 5.1mmol/L) |  | Maintenance Phase baseline to maintenance Phase Study Day 29/Exit. | 
| Mean S-K Intra-subject Standard Deviation Calculated Among Subjects With ≥ 2 Values on or After Maintenance Phase Study Day 8 |  | 22 days; Maintenance Phase Day 8 - 29 | 
| Proportion of Subjects Who Remained Normokalemic During Maintenance Phase |  | Maintenance Phase Study Days 1, 2, 5, 8, 12, 15, 19, 22, 26, 29, and 35, inclusive. | 
| Median Time to Relapse in S-K Values | Median time to relapse in S-K values (return to original Acute Phase S-K baseline value) | Maintenance phase Study Day 1 to Study Day 29/Exit. | 
| Exponential Rate of Change in S-K Values During the Acute Phase at 24 Hours and 48 Hours of Study Drug Treatment. |  | Acute Phase 24 hours and Acute Phase 48 hours. | 
| Mean Change From Baseline in S-K Values (Blood) at All Measured Time Intervals Post Dose Acute Phase. |  | All measured time intervals post dose during the Acute Phase. | 
| Mean Percent Change From Baseline in S-K Values (Blood) at All Measured Time Intervals Post Dose Acute Phase. |  | All measured time intervals post dose during the Acute Phase. | 
| Proportion of Subjects Who Achieve Normokalemia During the Acute Phase at 24 and 48 Hours After Start of Dosing |  | Through 48 hours acute phase | 
| Median Time to Normalization (3.50-5.0 mmol/L) in S-K Levels in the 48 Hours of Initial Treatment |  | Through 48 hours acute phase |