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

Phase 2

Completed

• Conditions: Hyperkalemia; Chronic Kidney Disease; Kidney Dysfunction
• Interventions: Drug: Zirconium silicate (ZS); Drug: Placebo

• Registration Number: NCT01493024
• Lead Sponsor: ZS Pharma, Inc.

Brief Summary

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

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.

Study Timeline

• Study Start: 2011-11-30
• Study First Submitted: 2011-12-12
• Study First Submitted QC: 2011-12-13
• Study First Posted: 2011-12-15
• Primary Completion: 2012-05-31
• Study Completion: 2012-06-30
• Disposition First Submitted: 2013-06-05
• Disposition First Submitted QC: 2013-06-05
• Disposition First Posted: 2013-06-13
• Results First Submitted: 2017-07-18
• Status Verified: 2018-05
• Results First Submitted QC: 2018-05-29
• Last Update Submitted: 2018-05-29
• Results First Posted: 2018-06-29
• Last Update Posted: 2018-06-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 90

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Zirconium silicate (ZS)	Zirconium silicate (ZS)	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.
Placebo	Placebo	Placebo (silicified microcrystalline cellulose) randomized to mimic escalating doses of experimental drug administered three times daily (TID) with meals.

Primary Outcome Measures

Name	Time	Method
Difference in the Exponential Rate of Change in Serum Potassium (S-K) Levels Versus Placebo During the Initial 48 Hours of Study Drug Treatment	24 and 48 hours post first study drug dose	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

Secondary Outcome Measures

Name	Time	Method
Urine Sodium Excretion	24 and 48 hours post first study drug dose	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).
Serum Potassium (S-K) at Individual Time Points.	First 48 hours of study	Serum potassium (S-K) at individual time points through Study day 3/0hour.
Time Specific S-K Levels to Normalization	48 and 72 hours post first study drug dose	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.
Time Specific Decreases in S-K Levels of > = 0.5 mmol/L	24 and 48 hours post first study drug dose	Percentage of participants achieving a 0.5mmol/L drop from baseline at Study Days 2 and 3 at 0 hr.
Percentage of Participants With Normal S-K Levels at End of Study Day 2	48 hours post first study drug dose	Percentage (%) of subjects who achieve S-K normalization at end of Study Day 2
Urine Potassium Excretion	24 and 48 hours post study drug dose	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).
Urea Nitrogen Excretion	24 and 48 hours post study drug dose	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).
Blood Urea Nitrogen	24 and 48 hours post study drug dose	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).
Serum Magnesium (S-Mg) Levels	24 and 48 hours post study drug dose	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).
Serum Calcium (S-Ca) Levels	24 and 48 hours post study drug dose	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).
Serum Sodium (S-Na) Levels	24 and 48 hours post study drug dose	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).
Serum Bicarbonate (HCO3) Levels	24 and 48 hours post study drug dose	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-hour Urinary Excretion of Potassium	24 and 48 hours post study drug dose	24-hour urinary excretion of potassium on Study Days 1 and Day 2
24-hour Urinary Excretion of Sodium	48 hours	24-hour urinary excretion of sodium on Study Days 1 and Day 2
24-hour Urinary Excretion of Urea Nitrogen	48 hours	24-hour urinary excretion of urea nitrogen on Study Days 1 and Day 2
24-hour Urinary Excretion of Creatinine	48 hours	24-hour urinary excretion of creatinine on Study Days 1 and Day 2

Trial Locations

Locations (9)

West Coast Clinical Trials; 🇺🇸 Costa Mesa, California, United States

Southwest Houston Research, Ltd; 🇺🇸 Houston, Texas, United States

Renal Associates, P.A.; 🇺🇸 San Antonio, Texas, United States

Johnson County Clin-Trials; 🇺🇸 Lenexa, Kansas, United States

Elite Research Institute, Inc.; 🇺🇸 Miami, Florida, United States

Lakeview Medical Research; 🇺🇸 Summerfield, Florida, United States

Riverside Clinical Research; 🇺🇸 Edgewater, Florida, United States

Southwest Clinical Research Institute; 🇺🇸 Tempe, Arizona, United States

Compass Research Phase 1, LLC; 🇺🇸 Orlando, Florida, United States