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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Hyperkalemia, Chronic Kidney Disease, Kidney Dysfunction

Intervention / Treatment
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* Drug: Zirconium silicate (ZS)
* 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. 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.

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 |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo (silicified microcrystalline cellulose) randomized to mimic escalating doses of experimental drug administered three times daily (TID) with meals. | Drug: Placebo<br>* Randomized to mimic escalating doses of experimental drug administered 3 times daily (tid) with meals.<br>* Other names: silicified microcrystalline cellulose;|
| Experimental: Zirconium silicate (ZS)<br>Randomized escalating doses (0.3g, 3g and 10g) of ZS (fractionated, protonated, microporous zirconium silicate, an oral sorbent) administered 3 times daily (tid) with meals. | Drug: Zirconium silicate (ZS)<br>* Randomized escalating doses (0.3g, 3g and 10g) of ZS (fractionated, protonated microporous Zirconium Silicate, an oral sorbent) administered 3 times daily (tid) with meals.<br>* Other names: ZS-9;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in the Exponential Rate of Change in Serum Potassium (S-K) Levels Versus Placebo During the Initial 48 Hours of Study Drug Treatment | The rate of fall in S-K levels during the initial 48 hours of study drug treatment between the placebo treated subjects and the ZS treated subjects measured on a log scale | 24 and 48 hours post first study drug dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Potassium (S-K) at Individual Time Points. | Serum potassium (S-K) at individual time points through Study day 3/0hour. | First 48 hours of study | 
| Time Specific S-K Levels to Normalization | Percent of subjects achieving S-K normalization (<=as defined by S-K levels of 3.5 to 4.9 mmol/L) from baseline at Study Days 2 and 3 at 0 hr. | 48 and 72 hours post first study drug dose | 
| Time Specific Decreases in S-K Levels of > = 0.5 mmol/L | Percentage of participants achieving a 0.5mmol/L drop from baseline at Study Days 2 and 3 at 0 hr. | 24 and 48 hours post first study drug dose | 
| Percentage of Participants With Normal S-K Levels at End of Study Day 2 | Percentage (%) of subjects who achieve S-K normalization at end of Study Day 2 | 48 hours post first study drug dose | 
| Urine Sodium Excretion | Urine sodium excretion compared between the combined placebo-treated controls and the ZS-treated subjects (measured throughout two 24-hour periods on Study Days 1 and 2). | 24 and 48 hours post first study drug dose | 
| Urine Potassium Excretion | Urine potassium excretion compared between the combined placebo-treated controls and the ZS-treated subjects (measured throughout two 24-hour periods on Study Days 1 and 2). | 24 and 48 hours post study drug dose | 
| Urea Nitrogen Excretion | Urea nitrogen excretion compared between the combined placebo-treated controls and the ZS-treated subjects (measured throughout two 24-hour periods on Study Days 1 and 2). | 24 and 48 hours post study drug dose | 
| Blood Urea Nitrogen | Blood urea nitrogen compared between the combined placebo-treated controls and the ZS-treated subjects (measured 24 & 48 hours post dose on Study Days 2 and 3). | 24 and 48 hours post study drug dose | 
| Serum Magnesium (S-Mg) Levels | Serum magnesium compared between the combined placebo-treated controls and the ZS-treated subjects (measured at 24 & 48 hours post dose on Study Days 2 and 3). | 24 and 48 hours post study drug dose | 
| Serum Calcium (S-Ca) Levels | Serum calcium compared between the combined placebo-treated controls and the ZS-treated subjects (measured at 24 & 48 hours post dose on Study Days 2 and 3). | 24 and 48 hours post study drug dose | 
| Serum Sodium (S-Na) Levels | Serum sodium compared between the combined placebo-treated controls and the ZS-treated subjects (measured at 24 & 48 hours post dose on Study Days 2 and 3). | 24 and 48 hours post study drug dose | 
| Serum Bicarbonate (HCO3) Levels | Serum bicarbonate compared between the combined placebo-treated controls and the ZS-treated subjects (measured at 24 & 48 hours post dose on Study Days 2 and 3). | 24 and 48 hours post study drug dose | 
| 24-hour Urinary Excretion of Potassium | 24-hour urinary excretion of potassium on Study Days 1 and Day 2 | 24 and 48 hours post study drug dose | 
| 24-hour Urinary Excretion of Sodium | 24-hour urinary excretion of sodium on Study Days 1 and Day 2 | 48 hours | 
| 24-hour Urinary Excretion of Urea Nitrogen | 24-hour urinary excretion of urea nitrogen on Study Days 1 and Day 2 | 48 hours | 
| 24-hour Urinary Excretion of Creatinine | 24-hour urinary excretion of creatinine on Study Days 1 and Day 2 | 48 hours |