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.

Study Overview

• Status: Completed
• Conditions: Chronic Kidney Disease; Hyperkalemia; Kidney Dysfunction
• Intervention / Treatment: Drug: Placebo; Drug: Zirconium silicate (ZS)

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 Type: Interventional
• Enrollment (Actual): 90
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tempe, Arizona, United States, 85284
      • Southwest Clinical Research Institute
  • California
    • Costa Mesa, California, United States, 92626
      • West Coast Clinical Trials
  • Florida
    • Edgewater, Florida, United States, 32132
      • Riverside Clinical Research
    • Miami, Florida, United States, 33169
      • Elite Research Institute, Inc.
    • Orlando, Florida, United States, 32806
      • Compass Research Phase 1, LLC
    • Summerfield, Florida, United States, 34491
      • Lakeview Medical Research
  • Kansas
    • Lenexa, Kansas, United States, 66219
      • Johnson County Clin-Trials
  • Texas
    • Houston, Texas, United States, 77099
      • Southwest Houston Research, Ltd
    • San Antonio, Texas, United States, 78215
      • Renal Associates, P.A.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: SUPPORTIVE_CARE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo; Placebo (silicified microcrystalline cellulose) randomized to mimic escalating doses of experimental drug administered three times daily (TID) with meals.	Drug: Placebo; Randomized to mimic escalating doses of experimental drug administered 3 times daily (tid) with meals.; Other Names: silicified microcrystalline cellulose
EXPERIMENTAL: 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.	Drug: 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.; Other Names: ZS-9

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: ZS Pharma, Inc.

Publications and helpful links

General Publications

• Natale P, Palmer SC, Ruospo M, Saglimbene VM, Strippoli GF. Potassium binders for chronic hyperkalaemia in people with chronic kidney disease. Cochrane Database Syst Rev. 2020 Jun 26;6(6):CD013165. doi: 10.1002/14651858.CD013165.pub2.

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 30, 2011
• Primary Completion (ACTUAL): May 31, 2012
• Study Completion (ACTUAL): June 30, 2012

Study Registration Dates

• First Submitted: December 12, 2011
• First Submitted That Met QC Criteria: December 13, 2011
• First Posted (ESTIMATE): December 15, 2011

Study Record Updates

• Last Update Posted (ACTUAL): June 29, 2018
• Last Update Submitted That Met QC Criteria: May 29, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Urologic Diseases; Water-Electrolyte Imbalance; Kidney Diseases; Renal Insufficiency, Chronic; Renal Insufficiency; Hyperkalemia
• Other Study ID Numbers: ZS-002

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No