Back to resultsSafety & Efficacy of Zirconium Silicate Dosed for 28 Days in Hyperkalemia.
Primary Purpose
Hyperkalemia
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Sodium zirconium cyclosilicate
Placebo
Sponsored by
About this trial
This is an interventional supportive care trial for Hyperkalemia
Eligibility Criteria
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.
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm Type
Experimental
Placebo Comparator
Experimental
Experimental
Experimental
Arm Label
Sodium zirconium cyclosilicate 10 g three times daily
Placebo once daily
Sodium zirconium cyclosilicate 5 g once daily
Sodium zirconium cyclosilicate 10 g once daily
Sodium zirconium cyclosilicate 15 g once daily
Arm Description
Sodium zirconium cyclosilicate 10 g three times daily for 48 hours (acute phase)
Randomized to mimic doses of experimental drug administered once daily with breakfast for 28 days.
Sodium zirconium cyclosilicate (ZS) 5 g once daily for 28 days (maintenance phase)
Sodium zirconium cyclosilicate (ZS) 10 g once daily for 28 days (maintenance phase)
Sodium zirconium cyclosilicate (ZS) 15 g once daily for 28 days (maintenance phase)
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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)
Mean Change in S-K Levels From Acute Phase Baseline to Maintenance Phase Study Day 2 to Day 29/Exit .
Mean Percent Change in S-K Levels From 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.
Mean Percent Change in S-K Levels From Maintenance Phase Baseline to Maintenance Phase Day 2 to Day 29/Exit.
Median Time to Hyperkalemia (S-K ≥ 5.1mmol/L)
Mean S-K Intra-subject Standard Deviation Calculated Among Subjects With ≥ 2 Values on or After Maintenance Phase Study Day 8
Proportion of Subjects Who Remained Normokalemic During Maintenance Phase
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)
Exponential Rate of Change in S-K Values During the Acute Phase at 24 Hours and 48 Hours of Study Drug Treatment.
Mean Change From Baseline in S-K Values (Blood) at All Measured Time Intervals Post Dose Acute Phase.
Mean Percent Change From Baseline in S-K Values (Blood) at All Measured Time Intervals Post Dose Acute Phase.
Proportion of Subjects Who Achieve Normokalemia During the Acute Phase at 24 and 48 Hours After Start of Dosing
Median Time to Normalization (3.50-5.0 mmol/L) in S-K Levels in the 48 Hours of Initial Treatment
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02088073
Brief Title
Safety & Efficacy of Zirconium Silicate Dosed for 28 Days in Hyperkalemia.
Official Title
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.
Study Type
Interventional
2. Study Status
Record Verification Date
November 2018
Overall Recruitment Status
Completed
Study Start Date
March 31, 2014 (Actual)
Primary Completion Date
August 31, 2014 (Actual)
Study Completion Date
January 31, 2015 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
ZS Pharma, Inc.
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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).
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hyperkalemia
7. Study Design
Primary Purpose
Supportive Care
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
258 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Sodium zirconium cyclosilicate 10 g three times daily
Arm Type
Experimental
Arm Description
Sodium zirconium cyclosilicate 10 g three times daily for 48 hours (acute phase)
Arm Title
Placebo once daily
Arm Type
Placebo Comparator
Arm Description
Randomized to mimic doses of experimental drug administered once daily with breakfast for 28 days.
Arm Title
Sodium zirconium cyclosilicate 5 g once daily
Arm Type
Experimental
Arm Description
Sodium zirconium cyclosilicate (ZS) 5 g once daily for 28 days (maintenance phase)
Arm Title
Sodium zirconium cyclosilicate 10 g once daily
Arm Type
Experimental
Arm Description
Sodium zirconium cyclosilicate (ZS) 10 g once daily for 28 days (maintenance phase)
Arm Title
Sodium zirconium cyclosilicate 15 g once daily
Arm Type
Experimental
Arm Description
Sodium zirconium cyclosilicate (ZS) 15 g once daily for 28 days (maintenance phase)
Intervention Type
Drug
Intervention Name(s)
Sodium zirconium cyclosilicate
Other Intervention Name(s)
ZS; Microporous, Fractionated, Protonated Zirconium Silicate; Zirconium Silicate
Intervention Description
Sodium zirconium cyclosilicate
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Silicilate microcrystaline cellulose
Intervention Description
Randomized to mimic doses of experimental drug administered once daily with breakfast for 28 days (maintenance phase)
Primary Outcome Measure Information:
Title
Mean Serum Potassium Between Maintenance Phase Study Days 8 to 29, Inclusive (MP-ITT Population).
Description
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.
Time Frame
22 Days; Maintenance Phase Days 8 - 29, inclusive.
Secondary Outcome Measure Information:
Title
The Number of Normokalemic Days Between Maintenance Phase Study Days 8 to 29, Inclusive (MP-ITT).
Description
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)
Time Frame
22 days; Maintenance Phase Day 8 - 29, inclusive.
Title
Mean Change in S-K Levels From Acute Phase Baseline to Maintenance Phase Study Day 2 to Day 29/Exit .
Time Frame
Acute Phase baseline to Maintenance Phase Study Day 2 to Day 29/Exit, inclusive.
Title
Mean Percent Change in S-K Levels From Acute Phase Baseline to Maintenance Phase Study Day 2 to Day 29/Exit, Inclusive .
Time Frame
Acute Phase baseline to Maintenance Phase Study Day 2 to Day 29/Exit, inclusive.
Title
Mean Change in S-K Levels From Maintenance Phase Baseline to Maintenance Phase Day 2 to Day 29/Exit.
Time Frame
Maintenance phase baseline to Maintenance Phase Study Day 29/Exit, inclusive.
Title
Mean Percent Change in S-K Levels From Maintenance Phase Baseline to Maintenance Phase Day 2 to Day 29/Exit.
Time Frame
Maintenance phase baseline to Maintenance Phase Study Day 29/Exit, inclusive.
Title
Median Time to Hyperkalemia (S-K ≥ 5.1mmol/L)
Time Frame
Maintenance Phase baseline to maintenance Phase Study Day 29/Exit.
Title
Mean S-K Intra-subject Standard Deviation Calculated Among Subjects With ≥ 2 Values on or After Maintenance Phase Study Day 8
Time Frame
22 days; Maintenance Phase Day 8 - 29
Title
Proportion of Subjects Who Remained Normokalemic During Maintenance Phase
Time Frame
Maintenance Phase Study Days 1, 2, 5, 8, 12, 15, 19, 22, 26, 29, and 35, inclusive.
Title
Median Time to Relapse in S-K Values
Description
Median time to relapse in S-K values (return to original Acute Phase S-K baseline value)
Time Frame
Maintenance phase Study Day 1 to Study Day 29/Exit.
Title
Exponential Rate of Change in S-K Values During the Acute Phase at 24 Hours and 48 Hours of Study Drug Treatment.
Time Frame
Acute Phase 24 hours and Acute Phase 48 hours.
Title
Mean Change From Baseline in S-K Values (Blood) at All Measured Time Intervals Post Dose Acute Phase.
Time Frame
All measured time intervals post dose during the Acute Phase.
Title
Mean Percent Change From Baseline in S-K Values (Blood) at All Measured Time Intervals Post Dose Acute Phase.
Time Frame
All measured time intervals post dose during the Acute Phase.
Title
Proportion of Subjects Who Achieve Normokalemia During the Acute Phase at 24 and 48 Hours After Start of Dosing
Time Frame
Through 48 hours acute phase
Title
Median Time to Normalization (3.50-5.0 mmol/L) in S-K Levels in the 48 Hours of Initial Treatment
Time Frame
Through 48 hours acute phase
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Henrik Rasmussen, MD, PhD
Organizational Affiliation
ZS Pharma, Inc.
Official's Role
Study Chair
Facility Information:
City
Anniston
State/Province
Alabama
Country
United States
City
Huntsville
State/Province
Alabama
Country
United States
City
Scottsboro
State/Province
Alabama
Country
United States
City
Phoenix
State/Province
Arizona
Country
United States
City
Tempe
State/Province
Arizona
Country
United States
City
Hawaiian Gardens
State/Province
California
Country
United States
City
Los Angeles
State/Province
California
Country
United States
City
Paramount
State/Province
California
Country
United States
City
Riverside
State/Province
California
Country
United States
City
Atlantis
State/Province
Florida
Country
United States
City
Bradenton
State/Province
Florida
Country
United States
City
Brandon
State/Province
Florida
Country
United States
City
Brooksville
State/Province
Florida
Country
United States
City
DeLand
State/Province
Florida
Country
United States
City
Edgewater
State/Province
Florida
Country
United States
City
Miami Lakes
State/Province
Florida
Country
United States
City
Miami
State/Province
Florida
Country
United States
City
New Smyrna Beach
State/Province
Florida
Country
United States
City
Ocala
State/Province
Florida
Country
United States
City
Summerfield
State/Province
Florida
Country
United States
City
Tampa
State/Province
Florida
Country
United States
City
Winter Park
State/Province
Florida
Country
United States
City
Columbus
State/Province
Georgia
Country
United States
City
Decatur
State/Province
Georgia
Country
United States
City
Evergreen Park
State/Province
Illinois
Country
United States
City
Joliet
State/Province
Illinois
Country
United States
City
Shreveport
State/Province
Louisiana
Country
United States
City
Auburn
State/Province
Maine
Country
United States
City
Chesterfield
State/Province
Michigan
Country
United States
City
Kansas City
State/Province
Missouri
Country
United States
City
Las Vegas
State/Province
Nevada
Country
United States
City
Flushing
State/Province
New York
Country
United States
City
Altoona
State/Province
Pennsylvania
Country
United States
City
Providence
State/Province
Rhode Island
Country
United States
City
Orangeburg
State/Province
South Carolina
Country
United States
City
Sumter
State/Province
South Carolina
Country
United States
City
Chattanooga
State/Province
Tennessee
Country
United States
City
San Antonio
State/Province
Texas
Country
United States
City
Gosford
State/Province
New South Wales
Country
Australia
City
Woolloongabba
State/Province
Queensland
Country
Australia
City
Heidelberg
State/Province
Victoria
Country
Australia
City
Melbourne
State/Province
Victoria
Country
Australia
City
Parkville
State/Province
Victoria
Country
Australia
City
Meyerspark
Country
South Africa
City
Port Elizabeth
Country
South Africa
City
Somerset West
Country
South Africa
12. IPD Sharing Statement
Citations:
PubMed Identifier
32588430
Citation
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.
Results Reference
derived
PubMed Identifier
31791288
Citation
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.
Results Reference
derived
PubMed Identifier
25402495
Citation
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.
Results Reference
derived
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Safety & Efficacy of Zirconium Silicate Dosed for 28 Days in Hyperkalemia.
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