Safety & Efficacy of Zirconium Silicate in Mild to Moderate Hyperkalemia

Phase 3

Completed

Conditions: Hyperkalemia

Interventions: Drug: Zirconium silicate (acute phase)
Drug: Zirconium silicate (subacute phase)
Drug: Placebo ( subacute phase)
Drug: Placebo (acute phase)

Registration Number: NCT01737697

Lead Sponsor: ZS Pharma, Inc.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 754

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Zirconium silicate (acute phase)	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.
Zirconium silicate (subacute 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.
Placebo (subacute phase)	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.
Placebo (acute phase)	Placebo (acute phase)	Placebo ( silicified microcrystalline cellulose) randomized to mimic doses of experimental drug administered 3 times (tid) daily with meals.

Primary Outcome Measures

Name	Time	Method
Exponential Rate of Change in Serum Potassium (S-K) Levels During the Initial 48 Hours of Study Drug Treatment.	Through 48 hours acute phase
Exponential Rate of Change in S-K Levels in the Subacute Phase.	Through 12 days subacute phase (Day 3 through Day 15)

Secondary Outcome Measures

Name	Time	Method
Mean Change From Baseline in S-K at All Time Points Acute Phase	Through 48 hours acute phase. In particular, at Baseline; 1, 2, 4 hour Post 1st Dose on Study Day 1; 0 hour Pre-dose, 1, 4 hour Post 1st Dose on Study Day 2; and 0 hour Pre-dose on Study Day 3.	Mean change from baseline in S-K at all time points over initial 48 hours
Percentage of Subjects Within Each Treatment Group Who Retained Normal S-K Values at End of Subacute Phase	Through 18 days of subacute phase (12 days treatment, 6 days follow-up)	Percentage of subjects within each treatment group who retained normal S-K values (values between 3.5-5.0 mmol/L) at end of subacute phase
Mean Change From Subacute Baseline in Serum Potassium at All Time Points.	Through 18 days of subacute phase (12 days treatment, 6 days follow-up)	Mean change from subacute baseline in serum potassium at all time points during subacute phase
Percentage of Subjects Who Achieve Normalization in S-K Levels After 48 Hours of Treatment	Through 48 hours acute phase
Mean Percent Change From Baseline in S-K Change at All Time Points Acute Phase	Through 48 hours acute phase. In particular, 1, 2, 4 hour Post 1st Dose on Study Day 1; 0 hour Pre-dose, 1, 4 hour Post 1st Dose on Study Day 2; and 0 hour Pre-dose on Study Day 3.	Mean percent change from baseline in S-K at all time points over initial 48 hours
Time Subjects Remain Normokalemic (Subacute Phase)	Through 18 days (12 days treatment, 6 days follow-up) of subacute phase	Time (number of days) subjects remain normokalemic (3.5 - 5.0 mmol/l) subacute phase
Mean Percent Change From Subacute Baseline in Serum Potassium at All Time Points.	Through 18 days of subacute phase (12 days treatment, 6 days follow-up)	Mean percent change from subacute baseline in serum potassium at all time points during subacute phase

Trial Locations

Locations (42): Carolina Diabetes and Kidney Center
🇺🇸
Sumter, South Carolina, United States
Nephrology and Hypertension Associates
🇺🇸
Middlebury, Connecticut, United States
South Carolina Nephrology & Hypertension
🇺🇸
Orangeburg, South Carolina, United States
Clinical Advancement Center, PLLC
🇺🇸
San Antonio, Texas, United States
Southwest Clinical Research Institute
🇺🇸
Tempe, Arizona, United States
Apex Research of Riverside
🇺🇸
Riverside, California, United States
San Marcus Research Clinic
🇺🇸
Miami, Florida, United States
Academic Medical Research Institute
🇺🇸
Los Angeles, California, United States
Denver Nephrologists, PC
🇺🇸
Denver, Colorado, United States
Prevention & Strengthening Solutions, Inc
🇺🇸
Miramar, Florida, United States
Medical Consulting Center
🇺🇸
Miami, Florida, United States
Clinical Research Trials of Florida
🇺🇸
Tampa, Florida, United States
Clinical Research of Brandon
🇺🇸
Brandon, Florida, United States
Research by Design
🇺🇸
Evergreen Park, Illinois, United States
Elite Research Institute
🇺🇸
Miami, Florida, United States
PCCC of Volusia
🇺🇸
New Smyrna, Florida, United States
Metabolic Research Institute
🇺🇸
West Palm Beach, Florida, United States
Lakeview Medical Research
🇺🇸
Summerfield, Florida, United States
Professional Research Network of Kansas, LLC
🇺🇸
Wichita, Kansas, United States
Life Medi-Research and Management
🇺🇸
Brooklyn, New York, United States
Doylestown Hospital Medical Research
🇺🇸
Doylestown, Pennsylvania, United States
The Center for Clinical Trials
🇺🇸
Biloxi, Mississippi, United States
United Medical Associates
🇺🇸
Binghamton, New York, United States
Nephrology Center DBA, Paragon Health PC
🇺🇸
Kalamazoo, Michigan, United States
Southern Utah Kidney and Hypertension Center
🇺🇸
Saint George, Utah, United States
Melbourne Renal Research Group
🇦🇺
Reservoir, Victoria, Australia
Clinical Research Consultants, LLC
🇺🇸
Kansas City, Missouri, United States
Riverside Clinical Research
🇺🇸
Edgewater, Florida, United States
JEM Research Institute
🇺🇸
Atlantis, Florida, United States
Pinnacle Research Group
🇺🇸
Anniston, Alabama, United States
Saadat Ansari Internal Medicine
🇺🇸
Huntsville, Alabama, United States
Torrance Clinical Research
🇺🇸
Lomita, California, United States
California Institute of Renal Research
🇺🇸
Chula Vista, California, United States
Mohammad Ismail, Inc
🇺🇸
Paramount, California, United States
Pikes Peak Nephrology Associates
🇺🇸
Colorado Springs, Colorado, United States
Capital Nephrology Clinical Group
🇺🇸
Sacramento, California, United States
Endocrinology of Central Florida
🇺🇸
Lake Mary, Florida, United States
Meridien Research
🇺🇸
Saint Petersburg, Florida, United States
Washington Nephrology Associates
🇺🇸
Bethesda, Maryland, United States
Southwest Houston Research, Ltd
🇺🇸
Houston, Texas, United States
Renal Research
🇦🇺
Gosford, New South Wales, Australia
Aspire Clinical Studies, LLC
🇺🇸
Glendale, Arizona, United States