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Safety & Efficacy of Zirconium Silicate in Mild to Moderate Hyperkalemia

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ClinicalTrials.gov Identifier: NCT01737697
Recruitment Status : Completed
First Posted : November 29, 2012
Results First Posted : October 12, 2018
Last Update Posted : October 12, 2018
Sponsor:
Information provided by (Responsible Party):
ZS Pharma, Inc.

Tracking Information
First Submitted Date  ICMJE November 19, 2012
First Posted Date  ICMJE November 29, 2012
Results First Submitted Date  ICMJE October 2, 2017
Results First Posted Date  ICMJE October 12, 2018
Last Update Posted Date October 12, 2018
Actual Study Start Date  ICMJE November 30, 2012
Actual Primary Completion Date October 31, 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 14, 2018)
  • Exponential Rate of Change in Serum Potassium (S-K) Levels During the Initial 48 Hours of Study Drug Treatment. [ Time Frame: Through 48 hours acute phase ]
  • Exponential Rate of Change in S-K Levels in the Subacute Phase. [ Time Frame: Through 12 days subacute phase (Day 3 through Day 15) ]
Original Primary Outcome Measures  ICMJE
 (submitted: November 26, 2012)
Change in serum potassium levels from baseline after administration of zirconium silicate three times a day. [ Time Frame: first 48 hours ]
To perform a controlled evaluation of the safety and efficacy of four (4) different doses of ZS administered 3 times daily for 48 hours in the Acute Phase for patients with mild to moderate hyperkalemia (potassium level between 5.1-6.5 mmol/l as determined by i-STAT) at baseline.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 14, 2018)
  • Percentage of Subjects Who Achieve Normalization in S-K Levels After 48 Hours of Treatment [ Time Frame: Through 48 hours acute phase ]
  • Mean Change From Baseline in S-K at All Time Points Acute Phase [ Time Frame: 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
  • Mean Percent Change From Baseline in S-K Change at All Time Points Acute Phase [ Time Frame: 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) [ Time Frame: 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
  • Percentage of Subjects Within Each Treatment Group Who Retained Normal S-K Values at End of Subacute Phase [ Time Frame: 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. [ Time Frame: 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
  • Mean Percent Change From Subacute Baseline in Serum Potassium at All Time Points. [ Time Frame: 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
Original Secondary Outcome Measures  ICMJE
 (submitted: November 26, 2012)
Change in serum potassium levels from baseline after administration of zirconium silicate once a day for patients who first completed 48 hours of dosing tid. [ Time Frame: additional 12 days ]
To perform a controlled evaluation of the safety and efficacy of four different doses of ZS administered once daily for 12 additional days in a subsequent Subacute Phase for patients completing the Acute Phase and achieving potassium levels within the normal range (3.5 - 5.0 mmol/l, as determined by i-STAT).
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: November 26, 2012)
Change in serum sodium, magnesium, calcium and blood urea nitrogen (BUN) from baseline after administration of zirconium silicate three times a day. [ Time Frame: first 48 hours ]
 
Descriptive Information
Brief Title  ICMJE Safety & Efficacy of Zirconium Silicate in Mild to Moderate Hyperkalemia
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Supportive Care
Condition  ICMJE Hyperkalemia
Intervention  ICMJE
  • 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.
    Other Name: ZS
  • 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.
    Other Name: ZS
  • 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.
    Other Name: Silicified microcrystalline cellulose
  • 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.
    Other Name: Silicified microcrystalline cellulose
Study Arms  ICMJE
  • Experimental: 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: Drug: Zirconium silicate (acute phase)
  • Placebo Comparator: Placebo (acute phase)
    Placebo ( silicified microcrystalline cellulose) randomized to mimic doses of experimental drug administered 3 times (tid) daily with meals.
    Intervention: Drug: Placebo (acute phase)
  • Experimental: 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: Drug: Zirconium silicate (subacute phase)
  • Placebo Comparator: 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.
    Intervention: Drug: Placebo ( subacute phase)
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 14, 2018)
754
Original Estimated Enrollment  ICMJE
 (submitted: November 26, 2012)
750
Actual Study Completion Date  ICMJE November 30, 2013
Actual Primary Completion Date October 31, 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01737697
Other Study ID Numbers  ICMJE ZS-003
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party ZS Pharma, Inc.
Study Sponsor  ICMJE ZS Pharma, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Henrik Rasmussen, MD ZS Pharma, Inc.
PRS Account ZS Pharma, Inc.
Verification Date September 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP