Safety & Efficacy of Zirconium Silicate in Mild to Moderate Hyperkalemia

• Change in serum potassium levels from baseline after administration of zirconium silicate three times a day. [ Time Frame: first 48 hours ] [ Designated as safety issue: Yes ]
  To perform a controlled evaluation of the safety and efficacy of four (4) different doses of ZS administered 3 times daily for 48 hours in the Acute Phase for patients with mild to moderate hyperkalemia (potassium level between 5.1-6.5 mmol/l as determined by i-STAT) at baseline.
  
  

• Change in serum potassium levels from baseline after administration of zirconium silicate once a day for patients who first completed 48 hours of dosing tid. [ Time Frame: additional 12 days ] [ Designated as safety issue: Yes ]
  To perform a controlled evaluation of the safety and efficacy of four different doses of ZS administered once daily for 12 additional days in a subsequent Subacute Phase for patients completing the Acute Phase and achieving potassium levels within the normal range (3.5 - 5.0 mmol/l, as determined by i-STAT).
  
  

• Change in serum sodium, magnesium, calcium and blood urea nitrogen (BUN) from baseline after administration of zirconium silicate three times a day. [ Time Frame: first 48 hours ] [ Designated as safety issue: Yes ]
  

A total of 750 subjects with mild to moderate hyperkalemia (i- STAT potassium levels between 5.1-6.5 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 5.0 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.