Safety & Efficacy of Zirconium Silicate in Mild to Moderate Hyperkalemia

Multicenter, Two-phase, Multi-dose, Prospective, Randomized, Double-blind, Placebo-Controlled Study of Safety and Efficacy of Microporous, Fractionated, Protonated Zirconium Silicate in Mild to Moderate Hyperkalemia

Acute Phase: It is hypothesized that ZS (zirconium silicate) is more effective than placebo control (alternative hypothesis) in lowering S-K levels in subjects with S-K between 5.0 - 6.5 mmol/l versus no difference between ZS and placebo control (null hypothesis).

Subacute Phase (randomized withdrawal): It is hypothesized that ZS once daily is more effective than placebo control (alternative hypotheses) in maintaining normokalemic levels (3.5 - 4.9 mmol/l) among subjects completing the Acute Phase versus no difference between each ZS dose and respective placebo controls (null hypotheses).

Study Overview

• Status: Completed
• Conditions: Hyperkalemia
• Intervention / Treatment: Drug: Zirconium silicate (acute phase); Drug: Placebo (acute phase); Drug: Zirconium silicate (subacute phase); Drug: Placebo ( subacute phase)

Detailed Description

A total of 750 subjects with mild to moderate hyperkalemia (i- STAT potassium levels between 5.0-6.5 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 4.9 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.

• Study Type: Interventional
• Enrollment (Actual): 754
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Gosford, New South Wales, Australia, 02250
      • Renal Research
  • Victoria
    • Reservoir, Victoria, Australia, 03073
      • Melbourne Renal Research Group
• United States
  • Alabama
    • Anniston, Alabama, United States, 36207
      • Pinnacle Research Group
    • Huntsville, Alabama, United States, 35801
      • Saadat Ansari Internal Medicine
  • Arizona
    • Glendale, Arizona, United States, 85301
      • Aspire Clinical Studies, LLC
    • Tempe, Arizona, United States, 85284
      • Southwest Clinical Research Institute
  • California
    • Chula Vista, California, United States, 91910
      • California Institute of Renal Research
    • Lomita, California, United States, 90717
      • Torrance Clinical Research
    • Los Angeles, California, United States, 90022
      • Academic Medical Research Institute
    • Paramount, California, United States, 90723
      • Mohammad Ismail, Inc
    • Riverside, California, United States, 92505
      • Apex Research of Riverside
    • Sacramento, California, United States, 95825
      • Capital Nephrology Clinical Group
  • Colorado
    • Colorado Springs, Colorado, United States, 80909
      • Pikes Peak Nephrology Associates
    • Denver, Colorado, United States, 80230
      • Denver Nephrologists, PC
  • Connecticut
    • Middlebury, Connecticut, United States, 06762
      • Nephrology and Hypertension Associates
  • Florida
    • Atlantis, Florida, United States, 33462
      • JEM Research Institute
    • Brandon, Florida, United States, 33511
      • Clinical Research of Brandon
    • Brooksville, Florida, United States, 34601
      • Meridien Research
    • Edgewater, Florida, United States, 32123
      • Riverside Clinical Research
    • Lake Mary, Florida, United States, 32746
      • Endocrinology of Central Florida
    • Lakeland, Florida, United States, 33805
      • Meridien Research
    • Miami, Florida, United States, 33169
      • Elite Research Institute
    • Miami, Florida, United States, 33015
      • San Marcus Research Clinic
    • Miami, Florida, United States, 33125
      • Medical Consulting Center
    • Miramar, Florida, United States, 33023
      • Prevention & Strengthening Solutions, Inc
    • New Smyrna, Florida, United States, 32168
      • PCCC of Volusia
    • Saint Petersburg, Florida, United States, 33709
      • Meridien Research
    • Summerfield, Florida, United States, 34491
      • Lakeview Medical Research
    • Tampa, Florida, United States, 33607
      • Clinical Research Trials of Florida
    • West Palm Beach, Florida, United States, 33401
      • Metabolic Research Institute
  • Illinois
    • Evergreen Park, Illinois, United States, 60805
      • Research by Design
  • Kansas
    • Wichita, Kansas, United States, 67213
      • Professional Research Network of Kansas, LLC
  • Maryland
    • Bethesda, Maryland, United States, 20814
      • Washington Nephrology Associates
  • Michigan
    • Kalamazoo, Michigan, United States, 49007
      • Nephrology Center DBA, Paragon Health PC
  • Mississippi
    • Biloxi, Mississippi, United States, 39531
      • The Center for Clinical Trials
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Clinical Research Consultants, LLC
  • New York
    • Binghamton, New York, United States, 13903
      • United Medical Associates
    • Brooklyn, New York, United States, 11206
      • Life Medi-research and Management
  • Pennsylvania
    • Doylestown, Pennsylvania, United States, 18901
      • Doylestown Hospital Medical Research
  • South Carolina
    • Orangeburg, South Carolina, United States, 29118
      • South Carolina Nephrology & Hypertension
    • Sumter, South Carolina, United States, 29150
      • Carolina Diabetes and Kidney Center
  • Texas
    • Houston, Texas, United States, 77099
      • Southwest Houston Research, Ltd
    • San Antonio, Texas, United States, 78215
      • Clinical Advancement Center, PLLC
  • Utah
    • Saint George, Utah, United States, 84770
      • Southern Utah Kidney and Hypertension Center

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.
• Mean i-STAT potassium values between 5.0 - 6.5 mmol/l inclusive, at screening (Study Day 0).
• Ability to have repeated blood draws or effective venous catheterization.
• Women of childbearing potential must be practicing a highly effective method of birth control.

Exclusion Criteria:

• Pseudohyperkalemia signs and symptoms, such as excessive fist clinching hemolyzed blood specimen, severe leukocytosis or thrombocytosis.
• Subjects treated with lactulose, xifaxan or other nonabsorbed antibiotics for hyperammonemia within the last 7 days.
• Subjects treated with resins (such as Sevelamer acetate or Sodium polystyrene sulfonate [SPS; e.g. Kayexalate®]), calcium acetate, calcium carbonate, or lanthanum carbonate, 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.
• 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 ZS or to components thereof.
• Previous treatment with ZS
• Treatment with a drug or device within the last 30 days that has not received regulatory approval at the time of study entry.
• Subjects with cardiac arrhythmias that require immediate treatment.
• Insulin-dependent diabetes mellitus
• Subjects on dialysis

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Zirconium silicate (acute phase); Randomized oral doses (1.25g, 2.5g, 5g, and 10g) of microporous, fractionated, protonated zirconium silicate administered 3 times (tid) daily with meals for 48 hours.	Drug: Zirconium silicate (acute phase); Randomized oral doses (1.25g, 2.5g, 5g, and 10g) of microporous, fractionated, protonated zirconium silicate administered 3 times (tid) daily with meals for 48 hours.; Other Names: ZS
PLACEBO_COMPARATOR: Placebo (acute phase); Placebo ( silicified microcrystalline cellulose) randomized to mimic doses of experimental drug administered 3 times (tid) daily with meals.	Drug: Placebo (acute phase); Randomized to mimic doses of experimental drug administered 3 times (tid) daily with meals for 48 hours during the acute phase.; Other Names: Silicified microcrystalline cellulose
EXPERIMENTAL: Zirconium silicate (subacute phase); Randomized oral doses (1.25g, 2.5g, 5g, and 10g) of microporous, fractionated, protonated zirconium silicate administered once a day prior to the morning meal for 12 days.	Drug: Zirconium silicate (subacute phase); Randomized oral doses (1.25g, 2.5g, 5g, and 10g) of microporous, fractionated, protonated zirconium silicate administered once a day prior to the morning meal for 12 days.; Other Names: ZS
PLACEBO_COMPARATOR: Placebo (subacute phase); Placebo (silicified microcrystalline cellulose) randomized to mimic doses of experimental drug administered once a day (qd) prior to the morning meal for 12 days.	Drug: Placebo ( subacute phase); Randomized to mimic doses of experimental drug administered once a day prior to the morning meal for 12 days during the subacute phase.; Other Names: Silicified microcrystalline cellulose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Exponential Rate of Change in Serum Potassium (S-K) Levels During the Initial 48 Hours of Study Drug Treatment.	Through 48 hours acute phase
Exponential Rate of Change in S-K Levels in the Subacute Phase.	Through 12 days subacute phase (Day 3 through Day 15)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Subjects Who Achieve Normalization in S-K Levels After 48 Hours of Treatment		Through 48 hours acute phase
Mean Change From Baseline in S-K at All Time Points Acute Phase	Mean change from baseline in S-K at all time points over initial 48 hours	Through 48 hours acute phase. In particular, at Baseline; 1, 2, 4 hour Post 1st Dose on Study Day 1; 0 hour Pre-dose, 1, 4 hour Post 1st Dose on Study Day 2; and 0 hour Pre-dose on Study Day 3.
Mean Percent Change From Baseline in S-K Change at All Time Points Acute Phase	Mean percent change from baseline in S-K at all time points over initial 48 hours	Through 48 hours acute phase. In particular, 1, 2, 4 hour Post 1st Dose on Study Day 1; 0 hour Pre-dose, 1, 4 hour Post 1st Dose on Study Day 2; and 0 hour Pre-dose on Study Day 3.
Time Subjects Remain Normokalemic (Subacute Phase)	Time (number of days) subjects remain normokalemic (3.5 - 5.0 mmol/l) subacute phase	Through 18 days (12 days treatment, 6 days follow-up) of subacute phase
Percentage of Subjects Within Each Treatment Group Who Retained Normal S-K Values at End of Subacute Phase	Percentage of subjects within each treatment group who retained normal S-K values (values between 3.5-5.0 mmol/L) at end of subacute phase	Through 18 days of subacute phase (12 days treatment, 6 days follow-up)
Mean Change From Subacute Baseline in Serum Potassium at All Time Points.	Mean change from subacute baseline in serum potassium at all time points during subacute phase	Through 18 days of subacute phase (12 days treatment, 6 days follow-up)
Mean Percent Change From Subacute Baseline in Serum Potassium at All Time Points.	Mean percent change from subacute baseline in serum potassium at all time points during subacute phase	Through 18 days of subacute phase (12 days treatment, 6 days follow-up)

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.
• Amin AN, Menoyo J, Singh B, Kim CS. Efficacy and safety of sodium zirconium cyclosilicate in patients with baseline serum potassium level >/= 5.5 mmol/L: pooled analysis from two phase 3 trials. BMC Nephrol. 2019 Dec 2;20(1):440. doi: 10.1186/s12882-019-1611-8.
• Friedman PA, Scott CG, Bailey K, Baumann NA, Albert D, Attia ZI, Ladewig DJ, Yasin O, Dillon JJ, Singh B. Errors of Classification With Potassium Blood Testing: The Variability and Repeatability of Critical Clinical Tests. Mayo Clin Proc. 2018 May;93(5):566-572. doi: 10.1016/j.mayocp.2018.03.013.
• Packham DK, Rasmussen HS, Lavin PT, El-Shahawy MA, Roger SD, Block G, Qunibi W, Pergola P, Singh B. Sodium zirconium cyclosilicate in hyperkalemia. N Engl J Med. 2015 Jan 15;372(3):222-31. doi: 10.1056/NEJMoa1411487. Epub 2014 Nov 21.

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 30, 2012
• Primary Completion (ACTUAL): October 31, 2013
• Study Completion (ACTUAL): November 30, 2013

Study Registration Dates

• First Submitted: November 19, 2012
• First Submitted That Met QC Criteria: November 26, 2012
• First Posted (ESTIMATE): November 29, 2012

Study Record Updates

• Last Update Posted (ACTUAL): October 12, 2018
• Last Update Submitted That Met QC Criteria: September 14, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Water-Electrolyte Imbalance; Hyperkalemia
• Other Study ID Numbers: ZS-003

Drug and device information, study documents

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