Safety & Efficacy of Zirconium Silicate in Mild to Moderate Hyperkalemia

NCT ID: NCT01737697

Last Updated: 2018-10-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 754 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-11-30
• Study Completion Date: 2013-11-30

Brief Summary

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).

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.

Conditions

Hyperkalemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: SUPPORTIVE_CARE
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: EXPERIMENTAL

Zirconium silicate (acute phase)

Intervention Type: DRUG

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.

Placebo (acute phase)

Placebo ( silicified microcrystalline cellulose) randomized to mimic doses of experimental drug administered 3 times (tid) daily with meals.

Group Type: PLACEBO_COMPARATOR

Placebo (acute phase)

Intervention Type: DRUG

Randomized to mimic doses of experimental drug administered 3 times (tid) daily with meals for 48 hours during the acute phase.

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.

Group Type: EXPERIMENTAL

Zirconium silicate (subacute phase)

Intervention Type: DRUG

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.

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.

Group Type: PLACEBO_COMPARATOR

Placebo ( subacute phase)

Intervention Type: DRUG

Randomized to mimic doses of experimental drug administered once a day prior to the morning meal for 12 days during the subacute phase.

Interventions

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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

ZS; ZS; Silicified microcrystalline cellulose; Silicified microcrystalline cellulose

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

ZS Pharma, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Henrik Rasmussen, MD

Role: STUDY_CHAIR

ZS Pharma, Inc.

Locations

Pinnacle Research Group

Anniston, Alabama, United States

Saadat Ansari Internal Medicine

Huntsville, Alabama, United States

Aspire Clinical Studies, LLC

Glendale, Arizona, United States

Southwest Clinical Research Institute

Tempe, Arizona, United States

California Institute of Renal Research

Chula Vista, California, United States

Torrance Clinical Research

Lomita, California, United States

Academic Medical Research Institute

Los Angeles, California, United States

Mohammad Ismail, Inc

Paramount, California, United States

Apex Research of Riverside

Riverside, California, United States

Capital Nephrology Clinical Group

Sacramento, California, United States

Pikes Peak Nephrology Associates

Colorado Springs, Colorado, United States

Denver Nephrologists, PC

Denver, Colorado, United States

Nephrology and Hypertension Associates

Middlebury, Connecticut, United States

JEM Research Institute

Atlantis, Florida, United States

Clinical Research of Brandon

Brandon, Florida, United States

Meridien Research

Brooksville, Florida, United States

Riverside Clinical Research

Edgewater, Florida, United States

Endocrinology of Central Florida

Lake Mary, Florida, United States

Meridien Research

Lakeland, Florida, United States

San Marcus Research Clinic

Miami, Florida, United States

Medical Consulting Center

Miami, Florida, United States

Elite Research Institute

Miami, Florida, United States

Prevention & Strengthening Solutions, Inc

Miramar, Florida, United States

PCCC of Volusia

New Smyrna Beach, Florida, United States

Meridien Research

St. Petersburg, Florida, United States

Lakeview Medical Research

Summerfield, Florida, United States

Clinical Research Trials of Florida

Tampa, Florida, United States

Metabolic Research Institute

West Palm Beach, Florida, United States

Research by Design

Evergreen Park, Illinois, United States

Professional Research Network of Kansas, LLC

Wichita, Kansas, United States

Washington Nephrology Associates

Bethesda, Maryland, United States

Nephrology Center DBA, Paragon Health PC

Kalamazoo, Michigan, United States

The Center for Clinical Trials

Biloxi, Mississippi, United States

Clinical Research Consultants, LLC

Kansas City, Missouri, United States

United Medical Associates

Binghamton, New York, United States

Life Medi-Research and Management

Brooklyn, New York, United States

Doylestown Hospital Medical Research

Doylestown, Pennsylvania, United States

South Carolina Nephrology & Hypertension

Orangeburg, South Carolina, United States

Carolina Diabetes and Kidney Center

Sumter, South Carolina, United States

Southwest Houston Research, Ltd

Houston, Texas, United States

Clinical Advancement Center, PLLC

San Antonio, Texas, United States

Southern Utah Kidney and Hypertension Center

St. George, Utah, United States

Renal Research

Gosford, New South Wales, Australia

Melbourne Renal Research Group

Reservoir, Victoria, Australia

Countries

United States; Australia

References

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.

Reference Type: DERIVED

PMID: 32588430 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31791288 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 29728199 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 25415807 (View on PubMed)

Other Identifiers

ZS-003

Identifier Type: -

Identifier Source: org_study_id