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).
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
SUPPORTIVE_CARE
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.
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.
Randomized to mimic doses of experimental drug administered 3 times (tid) daily with meals for 48 hours during the acute phase.
Exponential Rate of Change in Serum Potassium (S-K) Levels During the Initial 48 Hours of Study Drug Treatment.
Time frame: Through 48 hours acute phase
Exponential Rate of Change in S-K Levels in the Subacute Phase.
Time frame: Through 12 days subacute phase (Day 3 through Day 15)
Percentage of Subjects Who Achieve Normalization in S-K Levels After 48 Hours of Treatment
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
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Masking
QUADRUPLE
Enrollment
754
Randomized to mimic doses of experimental drug administered once a day prior to the morning meal for 12 days during the subacute phase.
Pinnacle Research Group
Anniston, Alabama, United States
Saadat Ansari Internal Medicine
Huntsville, Alabama, United States
Aspire Clinical Studies, LLC
Glendale, Arizona, United States
Southwest Clinical Research Institute
Tempe, Arizona, United States
California Institute of Renal Research
Chula Vista, California, United States
Torrance Clinical Research
Lomita, California, United States
Academic Medical Research Institute
Los Angeles, California, United States
Mohammad Ismail, Inc
Paramount, California, United States
Apex Research of Riverside
Riverside, California, United States
Capital Nephrology Clinical Group
Sacramento, California, United States
...and 34 more locations
Time frame: 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
Time frame: 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
Time frame: Through 18 days of subacute phase (12 days treatment, 6 days follow-up)