Safety & Efficacy of Zirconium Silicate in Chronic Kidney Disease or Moderate Kidney Dysfunction With Mild Hyperkalemia

Multicenter, Prospective, Randomized, Placebo-Controlled, Double-blind Dose Escalating Study of Safety, Tolerability and Pharmacodynamics of Zirconium Silicate in Chronic Kidney Disease and Moderate Kidney Dysfunction With Mild Hyperkalemia

It is hypothesized that zirconium silicate is safe and well tolerated and more effective than placebo (alternative hypothesis) in lowering serum potassium levels in subjects with serum potassium between 5 - 6.0 mmol/l versus no difference between zirconium silicate and placebo (null hypothesis). It is hypothesized that zirconium silicate even up to the top dose of 10g three times a day is well tolerated.

A total of 90 subjects with moderate CKD (defined as GFR between 40- 60ml/min) and mild hyperkalemia (S-K between 5-6 mmol/l) will be enrolled in the study where, in a double-blind dose-escalating fashion (three separate cohorts), they will be randomized to receive one of the doses of ZS (0.3g, 3g and 10g) or placebo, administered 3 times (tid) daily with meals. The first cohort will have 18 subjects while both of the second and third cohorts will have 36 subjects for a total of 90 subjects.

Safety and tolerability will be assessed by an Independent Data Safety Monitoring Board (DSMB) after completion of each cohort, before escalation to the next dose level will be allowed. The next dose escalation will happen no sooner than one week after the last dose of study drug at the previous dosing level has been administered. Safety stopping rules will be specified for this study. Within the first dose level (300 mg dose), 12 subjects will be randomized to receive ZS, whereas 6 subjects will be randomized to receive placebo for a total of 18 subjects in this first cohort. In the next two cohorts (3 g and 10 g doses), 24 subjects per cohort will be randomized to receive ZS, whereas 12 subjects per cohort will be randomized to receive placebo for a total of 36 subjects in each of the second and third cohorts.

Inclusion Criteria:

• Provision of written informed consent.
• Over 18 years of age.
• GFR between 40-60 ml/min as estimated by the CKD-EPI equation. After screening two additional GFR values of between 40-60ml/min must be repeated within 24 hours before inclusion is allowed.
• S-K between 5.0 - 6.0 mmol/l (inclusive) during Study Day 0.
• Ability to have repeated blood draws or effective venous catheterization.
• Women of child bearing potential must be practicing a highly effective method of birth control.

Exclusion Criteria:

• Pseudohyperkalemia such as excessive fist clinching hemolyzed blood specimen, severe leukocytosis or thrombocytosis.
• Subjects treated with lactulose, xifaxan or other non-absorbed antibiotics for hyperammonemia within the last 7 days.
• Subjects treated with resins (such as sevelamer acetate, calcium acetate or calcium carbonate, lanthanum carbonate, Sodium polystyrene sulfonate (SPS; e.g. Kayexalate®) 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.
• Cancer within the last 5 years (other than successfully treated basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or early stage prostate cancer).
• 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 Zirconium Silicate or to components thereof.
• Subjects who have cardiac arrhythmias that require immediate treatment.
• Subjects with ECG changes associated with hyperkalemia.
• Subjects with acute kidney injury.