Safety & Efficacy of Zirconium Silicate in Mild to Moderate Hyperkalemia

Hyperkalemia Clinical Trial

Official title:

Multicenter, Two-phase, Multi-dose, Prospective, Randomized, Double-blind, Placebo-Controlled Study of Safety and Efficacy of Microporous, Fractionated, Protonated Zirconium Silicate in Mild to Moderate Hyperkalemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01737697
• Other study ID #: ZS-003
• Status: Completed
• Phase: Phase 3
• Start date: November 30, 2012
• Est. completion date: November 30, 2013

Study information

• Verified date: September 2018
• Source: ZS Pharma, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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 information / eligibility

• Status: Completed
• Enrollment: 754
• Est. completion date: November 30, 2013
• Est. primary completion date: October 31, 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Hyperkalemia

Intervention

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

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
ZS Pharma, Inc.

Countries where clinical trial is conducted

United States,  Australia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Exponential Rate of Change in Serum Potassium (S-K) Levels During the Initial 48 Hours of Study Drug Treatment.		Through 48 hours acute phase
Primary	Exponential Rate of Change in S-K Levels in the Subacute Phase.		Through 12 days subacute phase (Day 3 through Day 15)
Secondary	Percentage of Subjects Who Achieve Normalization in S-K Levels After 48 Hours of Treatment		Through 48 hours acute phase
Secondary	Mean Change From Baseline in S-K at All Time Points Acute Phase	Mean change from baseline in S-K at all time points over initial 48 hours	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.
Secondary	Mean Percent Change From Baseline in S-K Change at All Time Points Acute Phase	Mean percent change from baseline in S-K at all time points over initial 48 hours	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.
Secondary	Time Subjects Remain Normokalemic (Subacute Phase)	Time (number of days) subjects remain normokalemic (3.5 - 5.0 mmol/l) subacute phase	Through 18 days (12 days treatment, 6 days follow-up) of subacute phase
Secondary	Percentage of Subjects Within Each Treatment Group Who Retained Normal S-K Values at End of Subacute Phase	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	Through 18 days of subacute phase (12 days treatment, 6 days follow-up)
Secondary	Mean Change From Subacute Baseline in Serum Potassium at All Time Points.	Mean change from subacute baseline in serum potassium at all time points during subacute phase	Through 18 days of subacute phase (12 days treatment, 6 days follow-up)
Secondary	Mean Percent Change From Subacute Baseline in Serum Potassium at All Time Points.	Mean percent change from subacute baseline in serum potassium at all time points during subacute phase	Through 18 days of subacute phase (12 days treatment, 6 days follow-up)