Safety & Efficacy of Zirconium Silicate in Mild to Moderate Hyperkalemia

Study Overview
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Brief Summary
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Acute Phase: It is hypothesized that ZS (zirconium silicate) is more effective than placebo control (alternative hypothesis) in lowering S-K levels in subjects with S-K between 5.0 - 6.5 mmol/l versus no difference between ZS and placebo control (null hypothesis). Subacute Phase (randomized withdrawal): It is hypothesized that ZS once daily is more effective than placebo control (alternative hypotheses) in maintaining normokalemic levels (3.5 - 4.9 mmol/l) among subjects completing the Acute Phase versus no difference between each ZS dose and respective placebo controls (null hypotheses).

Detailed Description
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A total of 750 subjects with mild to moderate hyperkalemia (i- STAT potassium levels between 5.0-6.5 mmol/l, inclusive) will be enrolled in the study where they, in a double-blind fashion, will be randomized 1:1:1:1:1 to receive one of four (4) doses of ZS (1.25g, 2.5g, 5g, and 10g) or placebo control, administered 3 times daily (tid) with meals for the initial 48 hours (Acute Phase), followed by a Subacute Phase (randomized withdrawal) during which patients treated with active doses in the Acute Phase, who achieve normokalemia (i-STAT potassium values 3.5 to 4.9 mmol/l, inclusive) will be randomized to 12 days of subacute, once a day (qd) dosing. There will be a one-time randomization to assign the Acute Phase treatment and the Subacute Phase treatment. The Subacute Phase will include subjects who became normokalemic on active drug and those who became normokalemic on placebo. The former will be randomized in a 1:1 ratio between the same dose of ZS they received during the acute phase but only administered once a day (qd) or placebo, qd. Subjects on placebo during the Acute Phase who are normokalemic in the morning of Study Day 3, will be randomized to receive either 1.25 or 2.5 g ZS, qd as Subacute Phase treatment. Safety and tolerability will be assessed on an ongoing basis by an Independent Data Safety Monitoring Board (DSMB). Each active dose group will consist of 150 patients per treatment group including the placebo control group for a total of 750 patients; the 1:1:1:1:1 allocation helps to optimize the multiple active dose comparisons to the respective placebo controls for the Subacute Phase.

Official Title
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Multicenter, Two-phase, Multi-dose, Prospective, Randomized, Double-blind, Placebo-Controlled Study of Safety and Efficacy of Microporous, Fractionated, Protonated Zirconium Silicate in Mild to Moderate Hyperkalemia

Conditions
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Hyperkalemia

Intervention / Treatment
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* Drug: Zirconium silicate (acute phase)
* Drug: Zirconium silicate (subacute phase)
* Drug: Placebo (acute phase)
* Drug: Placebo ( subacute phase)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of written informed consent. Over 18 years of age. Mean i-STAT potassium values between 5.0 - 6.5 mmol/l inclusive, at screening (Study Day 0). Ability to have repeated blood draws or effective venous catheterization. Women of childbearing potential must be practicing a highly effective method of birth control. Exclusion Criteria: Pseudohyperkalemia signs and symptoms, such as excessive fist clinching hemolyzed blood specimen, severe leukocytosis or thrombocytosis. Subjects treated with lactulose, xifaxan or other nonabsorbed antibiotics for hyperammonemia within the last 7 days. Subjects treated with resins (such as Sevelamer acetate or Sodium polystyrene sulfonate [SPS; e.g. Kayexalate®]), calcium acetate, calcium carbonate, or lanthanum carbonate, within the last 7 days. Subjects with a life expectancy of less than 3 months. Subjects who are HIV positive. 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 Ketoacidosis/Acidemia. 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. Previous treatment with ZS 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. Insulin-dependent diabetes mellitus 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: Zirconium silicate (acute phase)<br>Randomized oral doses (1.25g, 2.5g, 5g, and 10g) of microporous, fractionated, protonated zirconium silicate administered 3 times (tid) daily with meals for 48 hours. | Drug: Zirconium silicate (acute phase)<br>* Randomized oral doses (1.25g, 2.5g, 5g, and 10g) of microporous, fractionated, protonated zirconium silicate administered 3 times (tid) daily with meals for 48 hours.<br>* Other names: ZS;|
| Placebo Comparator: Placebo (acute phase)<br>Placebo ( silicified microcrystalline cellulose) randomized to mimic doses of experimental drug administered 3 times (tid) daily with meals. | Drug: Placebo (acute phase)<br>* Randomized to mimic doses of experimental drug administered 3 times (tid) daily with meals for 48 hours during the acute phase.<br>* Other names: Silicified microcrystalline cellulose;|
| Experimental: Zirconium silicate (subacute phase)<br>Randomized oral doses (1.25g, 2.5g, 5g, and 10g) of microporous, fractionated, protonated zirconium silicate administered once a day prior to the morning meal for 12 days. | Drug: Zirconium silicate (subacute phase)<br>* Randomized oral doses (1.25g, 2.5g, 5g, and 10g) of microporous, fractionated, protonated zirconium silicate administered once a day prior to the morning meal for 12 days.<br>* Other names: ZS;|
| Placebo Comparator: Placebo (subacute phase)<br>Placebo (silicified microcrystalline cellulose) randomized to mimic doses of experimental drug administered once a day (qd) prior to the morning meal for 12 days. | Drug: Placebo ( subacute phase)<br>* Randomized to mimic doses of experimental drug administered once a day prior to the morning meal for 12 days during the subacute phase.<br>* Other names: Silicified microcrystalline cellulose;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exponential Rate of Change in Serum Potassium (S-K) Levels During the Initial 48 Hours of Study Drug Treatment. |  | Through 48 hours acute phase | 
| Exponential Rate of Change in S-K Levels in the Subacute Phase. |  | Through 12 days subacute phase (Day 3 through Day 15) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects Who Achieve Normalization in S-K Levels After 48 Hours of Treatment |  | Through 48 hours acute phase | 
| Mean Change From Baseline in S-K at All Time Points Acute Phase | Mean change from baseline in S-K at all time points over initial 48 hours | Through 48 hours acute phase. In particular, at Baseline; 1, 2, 4 hour Post 1st Dose on Study Day 1; 0 hour Pre-dose, 1, 4 hour Post 1st Dose on Study Day 2; and 0 hour Pre-dose on Study Day 3. | 
| Mean Percent Change From Baseline in S-K Change at All Time Points Acute Phase | Mean percent change from baseline in S-K at all time points over initial 48 hours | Through 48 hours acute phase. In particular, 1, 2, 4 hour Post 1st Dose on Study Day 1; 0 hour Pre-dose, 1, 4 hour Post 1st Dose on Study Day 2; and 0 hour Pre-dose on Study Day 3. | 
| Time Subjects Remain Normokalemic (Subacute Phase) | Time (number of days) subjects remain normokalemic (3.5 - 5.0 mmol/l) subacute phase | Through 18 days (12 days treatment, 6 days follow-up) of subacute phase | 
| Percentage of Subjects Within Each Treatment Group Who Retained Normal S-K Values at End of Subacute Phase | Percentage of subjects within each treatment group who retained normal S-K values (values between 3.5-5.0 mmol/L) at end of subacute phase | Through 18 days of subacute phase (12 days treatment, 6 days follow-up) | 
| Mean Change From Subacute Baseline in Serum Potassium at All Time Points. | Mean change from subacute baseline in serum potassium at all time points during subacute phase | Through 18 days of subacute phase (12 days treatment, 6 days follow-up) | 
| Mean Percent Change From Subacute Baseline in Serum Potassium at All Time Points. | Mean percent change from subacute baseline in serum potassium at all time points during subacute phase | Through 18 days of subacute phase (12 days treatment, 6 days follow-up) |