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

• ClinicalTrials.gov Identifier: NCT02088073
• Recruitment Status: Completed
• First Posted: March 14, 2014
• Results First Posted: December 7, 2018
• Last Update Posted: December 7, 2018
• Sponsor: ZS Pharma, Inc.
• Information provided by (Responsible Party): ZS Pharma, Inc.

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).

Condition or disease	Intervention/treatment	Phase
Hyperkalemia	Drug: Sodium zirconium cyclosilicate; Drug: Placebo	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 258 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Supportive Care
• 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.
• Actual Study Start Date: March 31, 2014
• Actual Primary Completion Date: August 31, 2014
• Actual Study Completion Date: January 31, 2015

Arms and Interventions

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 Name: 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 Name: 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 Name: 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 Name: 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 Name: ZS; Microporous, Fractionated, Protonated Zirconium Silicate; Zirconium Silicate

Outcome Measures

Primary Outcome Measures :

1. Mean Serum Potassium Between Maintenance Phase Study Days 8 to 29, Inclusive (MP-ITT Population). [ Time Frame: 22 Days; Maintenance Phase Days 8 - 29, inclusive. ]
   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 :

1. The Number of Normokalemic Days Between Maintenance Phase Study Days 8 to 29, Inclusive (MP-ITT). [ Time Frame: 22 days; Maintenance Phase Day 8 - 29, inclusive. ]
   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)
2. 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. ]
3. 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. ]
4. 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. ]
5. 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. ]
6. Median Time to Hyperkalemia (S-K ≥ 5.1mmol/L) [ Time Frame: Maintenance Phase baseline to maintenance Phase Study Day 29/Exit. ]
7. 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 ]
8. 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. ]
9. Median Time to Relapse in S-K Values [ Time Frame: Maintenance phase Study Day 1 to Study Day 29/Exit. ]
   Median time to relapse in S-K values (return to original Acute Phase S-K baseline value)
10. 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. ]
11. 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. ]
12. 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. ]
13. 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 ]
14. 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 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Alabama

Anniston, Alabama, United States

Huntsville, Alabama, United States

Scottsboro, Alabama, United States

United States, Arizona

Phoenix, Arizona, United States

Tempe, Arizona, United States

United States, California

Hawaiian Gardens, California, United States

Los Angeles, California, United States

Paramount, California, United States

Riverside, California, United States

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 Lakes, Florida, United States

Miami, 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

United States, Georgia

Columbus, Georgia, United States

Decatur, Georgia, United States

United States, Illinois

Evergreen Park, Illinois, United States

Joliet, Illinois, United States

United States, Louisiana

Shreveport, Louisiana, United States

United States, Maine

Auburn, Maine, United States

United States, Michigan

Chesterfield, Michigan, United States

United States, Missouri

Kansas City, Missouri, United States

United States, Nevada

Las Vegas, Nevada, United States

United States, New York

Flushing, New York, United States

United States, Pennsylvania

Altoona, Pennsylvania, United States

United States, Rhode Island

Providence, Rhode Island, United States

United States, South Carolina

Orangeburg, South Carolina, United States

Sumter, South Carolina, United States

United States, Tennessee

Chattanooga, Tennessee, United States

United States, Texas

San Antonio, Texas, United States

Australia, New South Wales

Gosford, New South Wales, Australia

Australia, Queensland

Woolloongabba, Queensland, Australia

Australia, Victoria

Heidelberg, Victoria, Australia

Melbourne, Victoria, Australia

Parkville, Victoria, Australia

South Africa

Meyerspark, South Africa

Port Elizabeth, South Africa

Somerset West, South Africa

Sponsors and Collaborators

ZS Pharma, Inc.

Investigators

• Study Chair: Henrik Rasmussen, MD, PhD; ZS Pharma, Inc.

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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: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.

• Responsible Party: ZS Pharma, Inc.
• ClinicalTrials.gov Identifier: NCT02088073
• Other Study ID Numbers: ZS-004
• First Posted: March 14, 2014
• Results First Posted: December 7, 2018
• Last Update Posted: December 7, 2018
• Last Verified: November 2018

Additional relevant MeSH terms:

Hyperkalemia; Water-Electrolyte Imbalance; Metabolic Diseases