Safety & Efficacy of Zirconium Silicate Dosed for 28 Days in Hyperkalemia.

Multicenter, Multi-phase, Multi-dose, Prospective, Double-blind, Placebo-controlled, Maintenance Study of Safety and Efficacy of ZS (Microporous, Fractionated, Protonated Zirconium Silicate) in Hyperkalemia.

It is hypothesized that ZS is more effective than placebo control (alternative hypothesis) in maintaining mean double-blind randomized maintenance phase (DBRMP) Day 8-29 serum potassium levels (3.5 - 5.0 mmol/l, inclusive) among hyperkalemic subjects in whom normokalemia was established during the open-label acute phase versus no difference between each ZS dose (highest to lowest) versus placebo control (null hypothesis).

Study Overview

• Status: Completed
• Conditions: Hyperkalemia
• Intervention / Treatment: Drug: Sodium zirconium cyclosilicate; Drug: Placebo

Detailed Description

Approximately 275 subjects with hyperkalemia (two consecutive i-STAT potassium levels ≥ 5.1 mmol/l, taken 60 minutes apart at baseline) will be enrolled in the Open-label Acute Phase to provide 232 subjects in the Double Blind Randomized Maintenance Phase.

Initially all subjects will receive open-label ZS at a dose of 10g three times a day (tid) for 48 hours (AP). Subjects who achieve normokalemia (i-STAT potassium values between 3.5 to 5.0 mmol/l, inclusive) on the morning of Study Day 3 (after 6 doses of 10g ZS) will then, in a double-blind fashion, be randomized 4:4:4:7 to receive one of three doses of ZS (5g, 10g or 15g) or placebo control, qd for the following 28 days (DBRMP).

Safety and tolerability will be assessed on an ongoing basis by an Independent Data Monitoring Committee (iDMC). Each active dose group in the DBRMP will consist of 49 subjects and the placebo control group will consist of 85 subjects for a total of 232 subjects to detect a 0.6 effect size difference between each ZS dose (from highest to lowest) and placebo control; the 4:4:4:7 allocation optimizes the multiple comparisons to the placebo control for the DBRMP.

• Study Type: Interventional
• Enrollment (Actual): 258
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Gosford, New South Wales, Australia
  • Queensland
    • Woolloongabba, Queensland, Australia
  • Victoria
    • Heidelberg, Victoria, Australia
    • Melbourne, Victoria, Australia
    • Parkville, Victoria, Australia
• South Africa
  • Meyerspark, South Africa
  • Port Elizabeth, South Africa
  • Somerset West, South Africa
• United States
  • Alabama
    • Anniston, Alabama, United States
    • Huntsville, Alabama, United States
    • Scottsboro, Alabama, United States
  • Arizona
    • Phoenix, Arizona, United States
    • Tempe, Arizona, United States
  • California
    • Hawaiian Gardens, California, United States
    • Los Angeles, California, United States
    • Paramount, California, United States
    • Riverside, California, United States
  • Florida
    • Atlantis, Florida, United States
    • Bradenton, Florida, United States
    • Brandon, Florida, United States
    • Brooksville, Florida, United States
    • DeLand, Florida, United States
    • Edgewater, Florida, United States
    • Miami, Florida, United States
    • Miami Lakes, Florida, United States
    • New Smyrna Beach, Florida, United States
    • Ocala, Florida, United States
    • Summerfield, Florida, United States
    • Tampa, Florida, United States
    • Winter Park, Florida, United States
  • Georgia
    • Columbus, Georgia, United States
    • Decatur, Georgia, United States
  • Illinois
    • Evergreen Park, Illinois, United States
    • Joliet, Illinois, United States
  • Louisiana
    • Shreveport, Louisiana, United States
  • Maine
    • Auburn, Maine, United States
  • Michigan
    • Chesterfield, Michigan, United States
  • Missouri
    • Kansas City, Missouri, United States
  • Nevada
    • Las Vegas, Nevada, United States
  • New York
    • Flushing, New York, United States
  • Pennsylvania
    • Altoona, Pennsylvania, United States
  • Rhode Island
    • Providence, Rhode Island, United States
  • South Carolina
    • Orangeburg, South Carolina, United States
    • Sumter, South Carolina, United States
  • Tennessee
    • Chattanooga, Tennessee, United States
  • Texas
    • San Antonio, Texas, United States

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.
• Two consecutive i-STAT potassium values, measured 60-minutes apart, both ≥5.1 mmol/l and measured within 1 day of the first ZS dose on AP Study Day 1.
• Ability to have repeated blood draws or effective venous catheterization.
• Women of childbearing potential must be using two forms of medically acceptable contraception (at least one barrier method) and have a negative pregnancy test at AP Study Day 1. Women who are surgically sterile or those who are post-menopausal for at least 2 years are not considered to be of childbearing potential.

Exclusion Criteria:

• Pseudohyperkalemia signs and symptoms, such as excessive fist clenching hemolyzed blood specimen, history of severe leukocytosis or thrombocytosis.
• Subjects treated with lactulose, Xifaxan or other non-absorbed antibiotics for hyperammonemia within 7 days prior to the first dose of study drug.
• Subjects treated with resins (such as sevelamer acetate or sodium polystyrene sulfonate [SPS; e.g. Kayexalate®]), calcium acetate, calcium carbonate, or lanthanum carbonate, within 7 days prior to the first dose of study drug.
• Subjects with a life expectancy of less than 3 months.
• 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 diabetic ketoacidosis.
• 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.
• Randomization into the previous ZS-002 or ZS-003 studies.
• 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.
• Subjects on dialysis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sodium zirconium cyclosilicate 10 g three times daily; Sodium zirconium cyclosilicate 10 g three times daily for 48 hours (acute phase)	Drug: Sodium zirconium cyclosilicate; Sodium zirconium cyclosilicate; Other Names: ZS; Microporous, Fractionated, Protonated Zirconium Silicate; Zirconium Silicate
Placebo Comparator: Placebo once daily; Randomized to mimic doses of experimental drug administered once daily with breakfast for 28 days.	Drug: Placebo; Randomized to mimic doses of experimental drug administered once daily with breakfast for 28 days (maintenance phase); Other Names: Silicilate microcrystaline cellulose
Experimental: Sodium zirconium cyclosilicate 5 g once daily; Sodium zirconium cyclosilicate (ZS) 5 g once daily for 28 days (maintenance phase)	Drug: Sodium zirconium cyclosilicate; Sodium zirconium cyclosilicate; Other Names: ZS; Microporous, Fractionated, Protonated Zirconium Silicate; Zirconium Silicate
Experimental: Sodium zirconium cyclosilicate 10 g once daily; Sodium zirconium cyclosilicate (ZS) 10 g once daily for 28 days (maintenance phase)	Drug: Sodium zirconium cyclosilicate; Sodium zirconium cyclosilicate; Other Names: ZS; Microporous, Fractionated, Protonated Zirconium Silicate; Zirconium Silicate
Experimental: Sodium zirconium cyclosilicate 15 g once daily; Sodium zirconium cyclosilicate (ZS) 15 g once daily for 28 days (maintenance phase)	Drug: Sodium zirconium cyclosilicate; Sodium zirconium cyclosilicate; Other Names: ZS; Microporous, Fractionated, Protonated Zirconium Silicate; Zirconium Silicate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Serum Potassium Between Maintenance Phase Study Days 8 to 29, Inclusive (MP-ITT Population).	The least squares means (LSMeans) are dervied from a mixed effects model of serial log transformed S-K values between Days 8 and 29 with patients as a random effect and the following fixed effects terms: MP treatment group; AP baseline eGFR; AP and MP baseline S-K levels, age categories (<55, 55-64, >= 65 years); and binary indicators for RAAS inhibitors use, CKD, CHF, and DM. The LSmeans estimate obtained from the above model is back-transformed and presented as the lsmeans of all available S-K values during the Maintenance phase study Days 8 to 29.	22 Days; Maintenance Phase Days 8 - 29, inclusive.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Number of Normokalemic Days Between Maintenance Phase Study Days 8 to 29, Inclusive (MP-ITT).	The number of normokalemic days during the Maintenance Phase Study Days 8 to 29 is calculated assuming that the interval between assessments is normokalemic only if both the beginning and end assessments for that time interval display normal S-K values (i.e. 3.5 - 5.0 mmol/L)	22 days; Maintenance Phase Day 8 - 29, inclusive.
Mean Change in S-K Levels From Acute Phase Baseline to Maintenance Phase Study Day 2 to Day 29/Exit .		Acute Phase baseline to Maintenance Phase Study Day 2 to Day 29/Exit, inclusive.
Mean Percent Change in S-K Levels From Acute Phase Baseline to Maintenance Phase Study Day 2 to Day 29/Exit, Inclusive .		Acute Phase baseline to Maintenance Phase Study Day 2 to Day 29/Exit, inclusive.
Mean Change in S-K Levels From Maintenance Phase Baseline to Maintenance Phase Day 2 to Day 29/Exit.		Maintenance phase baseline to Maintenance Phase Study Day 29/Exit, inclusive.
Mean Percent Change in S-K Levels From Maintenance Phase Baseline to Maintenance Phase Day 2 to Day 29/Exit.		Maintenance phase baseline to Maintenance Phase Study Day 29/Exit, inclusive.
Median Time to Hyperkalemia (S-K ≥ 5.1mmol/L)		Maintenance Phase baseline to maintenance Phase Study Day 29/Exit.
Mean S-K Intra-subject Standard Deviation Calculated Among Subjects With ≥ 2 Values on or After Maintenance Phase Study Day 8		22 days; Maintenance Phase Day 8 - 29
Proportion of Subjects Who Remained Normokalemic During Maintenance Phase		Maintenance Phase Study Days 1, 2, 5, 8, 12, 15, 19, 22, 26, 29, and 35, inclusive.
Median Time to Relapse in S-K Values	Median time to relapse in S-K values (return to original Acute Phase S-K baseline value)	Maintenance phase Study Day 1 to Study Day 29/Exit.
Exponential Rate of Change in S-K Values During the Acute Phase at 24 Hours and 48 Hours of Study Drug Treatment.		Acute Phase 24 hours and Acute Phase 48 hours.
Mean Change From Baseline in S-K Values (Blood) at All Measured Time Intervals Post Dose Acute Phase.		All measured time intervals post dose during the Acute Phase.
Mean Percent Change From Baseline in S-K Values (Blood) at All Measured Time Intervals Post Dose Acute Phase.		All measured time intervals post dose during the Acute Phase.
Proportion of Subjects Who Achieve Normokalemia During the Acute Phase at 24 and 48 Hours After Start of Dosing		Through 48 hours acute phase
Median Time to Normalization (3.50-5.0 mmol/L) in S-K Levels in the 48 Hours of Initial Treatment		Through 48 hours acute phase

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.
• Kosiborod M, Rasmussen HS, Lavin P, Qunibi WY, Spinowitz B, Packham D, Roger SD, Yang A, Lerma E, Singh B. Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia: the HARMONIZE randomized clinical trial. JAMA. 2014 Dec 3;312(21):2223-33. doi: 10.1001/jama.2014.15688. Erratum In: JAMA. 2015 Feb 3;313(5):526. Dosage error in text.

Study record dates

Study Major Dates

• Study Start (Actual): March 31, 2014
• Primary Completion (Actual): August 31, 2014
• Study Completion (Actual): January 31, 2015

Study Registration Dates

• First Submitted: March 12, 2014
• First Submitted That Met QC Criteria: March 12, 2014
• First Posted (Estimate): March 14, 2014

Study Record Updates

• Last Update Posted (Actual): December 7, 2018
• Last Update Submitted That Met QC Criteria: November 13, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Water-Electrolyte Imbalance; Hyperkalemia
• Other Study ID Numbers: ZS-004