Clinical trial NCT01737697: Safety & Efficacy of Zirconium Silicate in Mild to Moderate Hyperkalemia
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hyperkalemia
Lead sponsor: ZS Pharma, Inc.
Sponsor class: INDUSTRY
First posted: 2012-11-29
Enrollment: 754
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: 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.

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

Primary outcomes:
measure: Exponential Rate of Change in Serum Potassium (S-K) Levels During the Initial 48 Hours of Study Drug Treatment.
timeFrame: Through 48 hours acute phase
measure: Exponential Rate of Change in S-K Levels in the Subacute Phase.
timeFrame: Through 12 days subacute phase (Day 3 through Day 15)
Secondary outcomes:
measure: Percentage of Subjects Who Achieve Normalization in S-K Levels After 48 Hours of Treatment
timeFrame: Through 48 hours acute phase
measure: Mean Change From Baseline in S-K at All Time Points Acute Phase
timeFrame: 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.
measure: Mean Percent Change From Baseline in S-K Change at All Time Points Acute Phase
timeFrame: 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.
measure: Time Subjects Remain Normokalemic (Subacute Phase)
timeFrame: Through 18 days (12 days treatment, 6 days follow-up) of subacute phase
measure: Percentage of Subjects Within Each Treatment Group Who Retained Normal S-K Values at End of Subacute Phase
timeFrame: Through 18 days of subacute phase (12 days treatment, 6 days follow-up)
measure: Mean Change From Subacute Baseline in Serum Potassium at All Time Points.
timeFrame: Through 18 days of subacute phase (12 days treatment, 6 days follow-up)
measure: Mean Percent Change From Subacute Baseline in Serum Potassium at All Time Points.
timeFrame: Through 18 days of subacute phase (12 days treatment, 6 days follow-up)
Other outcomes:
Locations:
city: Anniston
country: United States
facility: Pinnacle Research Group
state: Alabama
city: Huntsville
country: United States
facility: Saadat Ansari Internal Medicine
state: Alabama
city: Glendale
country: United States
facility: Aspire Clinical Studies, LLC
state: Arizona
city: Tempe
country: United States
facility: Southwest Clinical Research Institute
state: Arizona
city: Chula Vista
country: United States
facility: California Institute of Renal Research
state: California
city: Lomita
country: United States
facility: Torrance Clinical Research
state: California
city: Los Angeles
country: United States
facility: Academic Medical Research Institute
state: California
city: Paramount
country: United States
facility: Mohammad Ismail, Inc
state: California
city: Riverside
country: United States
facility: Apex Research of Riverside
state: California
city: Sacramento
country: United States
facility: Capital Nephrology Clinical Group
state: California
city: Colorado Springs
country: United States
facility: Pikes Peak Nephrology Associates
state: Colorado
city: Denver
country: United States
facility: Denver Nephrologists, PC
state: Colorado
city: Middlebury
country: United States
facility: Nephrology and Hypertension Associates
state: Connecticut
city: Atlantis
country: United States
facility: JEM Research Institute
state: Florida
city: Brandon
country: United States
facility: Clinical Research of Brandon
state: Florida
city: Brooksville
country: United States
facility: Meridien Research
state: Florida
city: Edgewater
country: United States
facility: Riverside Clinical Research
state: Florida
city: Lake Mary
country: United States
facility: Endocrinology of Central Florida
state: Florida
city: Lakeland
country: United States
facility: Meridien Research
state: Florida
city: Miami
country: United States
facility: San Marcus Research Clinic
state: Florida
city: Miami
country: United States
facility: Medical Consulting Center
state: Florida
city: Miami
country: United States
facility: Elite Research Institute
state: Florida
city: Miramar
country: United States
facility: Prevention & Strengthening Solutions, Inc
state: Florida
city: New Smyrna
country: United States
facility: PCCC of Volusia
state: Florida
city: Saint Petersburg
country: United States
facility: Meridien Research
state: Florida
city: Summerfield
country: United States
facility: Lakeview Medical Research
state: Florida
city: Tampa
country: United States
facility: Clinical Research Trials of Florida
state: Florida
city: West Palm Beach
country: United States
facility: Metabolic Research Institute
state: Florida
city: Evergreen Park
country: United States
facility: Research by Design
state: Illinois
city: Wichita
country: United States
facility: Professional Research Network of Kansas, LLC
state: Kansas
city: Bethesda
country: United States
facility: Washington Nephrology Associates
state: Maryland
city: Kalamazoo
country: United States
facility: Nephrology Center DBA, Paragon Health PC
state: Michigan
city: Biloxi
country: United States
facility: The Center for Clinical Trials
state: Mississippi
city: Kansas City
country: United States
facility: Clinical Research Consultants, LLC
state: Missouri
city: Binghamton
country: United States
facility: United Medical Associates
state: New York
city: Brooklyn
country: United States
facility: Life Medi-Research and Management
state: New York
city: Doylestown
country: United States
facility: Doylestown Hospital Medical Research
state: Pennsylvania
city: Orangeburg
country: United States
facility: South Carolina Nephrology & Hypertension
state: South Carolina
city: Sumter
country: United States
facility: Carolina Diabetes and Kidney Center
state: South Carolina
city: Houston
country: United States
facility: Southwest Houston Research, Ltd
state: Texas
city: San Antonio
country: United States
facility: Clinical Advancement Center, PLLC
state: Texas
city: Saint George
country: United States
facility: Southern Utah Kidney and Hypertension Center
state: Utah
city: Gosford
country: Australia
facility: Renal Research
state: New South Wales
city: Reservoir
country: Australia
facility: Melbourne Renal Research Group
state: Victoria
Study officials:
affiliation: ZS Pharma, Inc.
name: Henrik Rasmussen, MD
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: 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.
citation: 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.