Clinical trial NCT02088073: 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
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hyperkalemia
Lead sponsor: ZS Pharma, Inc.
Sponsor class: INDUSTRY
First posted: 2014-03-14
Enrollment: 258
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

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.

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.

Primary outcomes:
measure: Mean Serum Potassium Between Maintenance Phase Study Days 8 to 29, Inclusive (MP-ITT Population).
timeFrame: 22 Days; Maintenance Phase Days 8 - 29, inclusive.
Secondary outcomes:
measure: The Number of Normokalemic Days Between Maintenance Phase Study Days 8 to 29, Inclusive (MP-ITT).
timeFrame: 22 days; Maintenance Phase Day 8 - 29, inclusive.
measure: Mean Change in S-K Levels From Acute Phase Baseline to Maintenance Phase Study Day 2 to Day 29/Exit .
timeFrame: Acute Phase baseline to Maintenance Phase Study Day 2 to Day 29/Exit, inclusive.
measure: Mean Percent Change in S-K Levels From Acute Phase Baseline to Maintenance Phase Study Day 2 to Day 29/Exit, Inclusive .
timeFrame: Acute Phase baseline to Maintenance Phase Study Day 2 to Day 29/Exit, inclusive.
measure: Mean Change in S-K Levels From Maintenance Phase Baseline to Maintenance Phase Day 2 to Day 29/Exit.
timeFrame: Maintenance phase baseline to Maintenance Phase Study Day 29/Exit, inclusive.
measure: Mean Percent Change in S-K Levels From Maintenance Phase Baseline to Maintenance Phase Day 2 to Day 29/Exit.
timeFrame: Maintenance phase baseline to Maintenance Phase Study Day 29/Exit, inclusive.
measure: Median Time to Hyperkalemia (S-K ≥ 5.1mmol/L)
timeFrame: Maintenance Phase baseline to maintenance Phase Study Day 29/Exit.
measure: Mean S-K Intra-subject Standard Deviation Calculated Among Subjects With ≥ 2 Values on or After Maintenance Phase Study Day 8
timeFrame: 22 days; Maintenance Phase Day 8 - 29
measure: Proportion of Subjects Who Remained Normokalemic During Maintenance Phase
timeFrame: Maintenance Phase Study Days 1, 2, 5, 8, 12, 15, 19, 22, 26, 29, and 35, inclusive.
measure: Median Time to Relapse in S-K Values
timeFrame: Maintenance phase Study Day 1 to Study Day 29/Exit.
measure: Exponential Rate of Change in S-K Values During the Acute Phase at 24 Hours and 48 Hours of Study Drug Treatment.
timeFrame: Acute Phase 24 hours and Acute Phase 48 hours.
measure: Mean Change From Baseline in S-K Values (Blood) at All Measured Time Intervals Post Dose Acute Phase.
timeFrame: All measured time intervals post dose during the Acute Phase.
measure: Mean Percent Change From Baseline in S-K Values (Blood) at All Measured Time Intervals Post Dose Acute Phase.
timeFrame: All measured time intervals post dose during the Acute Phase.
measure: Proportion of Subjects Who Achieve Normokalemia During the Acute Phase at 24 and 48 Hours After Start of Dosing
timeFrame: Through 48 hours acute phase
measure: Median Time to Normalization (3.50-5.0 mmol/L) in S-K Levels in the 48 Hours of Initial Treatment
timeFrame: Through 48 hours acute phase
Other outcomes:
Locations:
city: Anniston
country: United States
state: Alabama
city: Huntsville
country: United States
state: Alabama
city: Scottsboro
country: United States
state: Alabama
city: Phoenix
country: United States
state: Arizona
city: Tempe
country: United States
state: Arizona
city: Hawaiian Gardens
country: United States
state: California
city: Los Angeles
country: United States
state: California
city: Paramount
country: United States
state: California
city: Riverside
country: United States
state: California
city: Atlantis
country: United States
state: Florida
city: Bradenton
country: United States
state: Florida
city: Brandon
country: United States
state: Florida
city: Brooksville
country: United States
state: Florida
city: DeLand
country: United States
state: Florida
city: Edgewater
country: United States
state: Florida
city: Miami Lakes
country: United States
state: Florida
city: Miami
country: United States
state: Florida
city: New Smyrna Beach
country: United States
state: Florida
city: Ocala
country: United States
state: Florida
city: Summerfield
country: United States
state: Florida
city: Tampa
country: United States
state: Florida
city: Winter Park
country: United States
state: Florida
city: Columbus
country: United States
state: Georgia
city: Decatur
country: United States
state: Georgia
city: Evergreen Park
country: United States
state: Illinois
city: Joliet
country: United States
state: Illinois
city: Shreveport
country: United States
state: Louisiana
city: Auburn
country: United States
state: Maine
city: Chesterfield
country: United States
state: Michigan
city: Kansas City
country: United States
state: Missouri
city: Las Vegas
country: United States
state: Nevada
city: Flushing
country: United States
state: New York
city: Altoona
country: United States
state: Pennsylvania
city: Providence
country: United States
state: Rhode Island
city: Orangeburg
country: United States
state: South Carolina
city: Sumter
country: United States
state: South Carolina
city: Chattanooga
country: United States
state: Tennessee
city: San Antonio
country: United States
state: Texas
city: Gosford
country: Australia
state: New South Wales
city: Woolloongabba
country: Australia
state: Queensland
city: Heidelberg
country: Australia
state: Victoria
city: Melbourne
country: Australia
state: Victoria
city: Parkville
country: Australia
state: Victoria
city: Meyerspark
country: South Africa
city: Port Elizabeth
country: South Africa
city: Somerset West
country: South Africa
Study officials:
affiliation: ZS Pharma, Inc.
name: Henrik Rasmussen, MD, PhD
role: STUDY_CHAIR
References:
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.
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.
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.