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Safety & Efficacy of Zirconium Silicate Dosed for 28 Days in Hyperkalemia.

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ClinicalTrials.gov Identifier: NCT02088073
Recruitment Status : Completed
First Posted : March 14, 2014
Results First Posted : December 7, 2018
Last Update Posted : December 7, 2018
Sponsor:
Information provided by (Responsible Party):
ZS Pharma, Inc.

Tracking Information
First Submitted Date  ICMJE March 12, 2014
First Posted Date  ICMJE March 14, 2014
Results First Submitted Date  ICMJE July 18, 2017
Results First Posted Date  ICMJE December 7, 2018
Last Update Posted Date December 7, 2018
Actual Study Start Date  ICMJE March 31, 2014
Actual Primary Completion Date August 31, 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 13, 2018)
Mean Serum Potassium Between Maintenance Phase Study Days 8 to 29, Inclusive (MP-ITT Population). [ Time Frame: 22 Days; Maintenance Phase Days 8 - 29, inclusive. ]
The least squares means (LSMeans) are dervied from a mixed effects model of serial log transformed S-K values between Days 8 and 29 with patients as a random effect and the following fixed effects terms: MP treatment group; AP baseline eGFR; AP and MP baseline S-K levels, age categories (<55, 55-64, >= 65 years); and binary indicators for RAAS inhibitors use, CKD, CHF, and DM. The LSmeans estimate obtained from the above model is back-transformed and presented as the lsmeans of all available S-K values during the Maintenance phase study Days 8 to 29.
Original Primary Outcome Measures  ICMJE
 (submitted: March 12, 2014)
Maintenance of serum potassium level with once daily ZS for 28 days after establishment of normokalemia with ZS three times a day for first 48 hours. [ Time Frame: First 48 hours acute phase, then 28 days maintenance phase ]
To evaluate the safety and efficacy of three (3) different doses of ZS administered once daily (qd) for 28 days in maintaining normokalemia (serum potassium (S-K) between 3.5 - 5.0 mmol/l, inclusive) in subjects achieving normokalemia following two days of acute therapy for subjects with hyperkalemia (two consecutive i-STAT potassium values ≥ 5.1 mmol/l, taken 60 minutes apart) at baseline.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 13, 2018)
  • The Number of Normokalemic Days Between Maintenance Phase Study Days 8 to 29, Inclusive (MP-ITT). [ Time Frame: 22 days; Maintenance Phase Day 8 - 29, inclusive. ]
    The number of normokalemic days during the Maintenance Phase Study Days 8 to 29 is calculated assuming that the interval between assessments is normokalemic only if both the beginning and end assessments for that time interval display normal S-K values (i.e. 3.5 - 5.0 mmol/L)
  • Mean Change in S-K Levels From Acute Phase Baseline to Maintenance Phase Study Day 2 to Day 29/Exit . [ Time Frame: Acute Phase baseline to Maintenance Phase Study Day 2 to Day 29/Exit, inclusive. ]
  • Mean Percent Change in S-K Levels From Acute Phase Baseline to Maintenance Phase Study Day 2 to Day 29/Exit, Inclusive . [ Time Frame: Acute Phase baseline to Maintenance Phase Study Day 2 to Day 29/Exit, inclusive. ]
  • Mean Change in S-K Levels From Maintenance Phase Baseline to Maintenance Phase Day 2 to Day 29/Exit. [ Time Frame: Maintenance phase baseline to Maintenance Phase Study Day 29/Exit, inclusive. ]
  • Mean Percent Change in S-K Levels From Maintenance Phase Baseline to Maintenance Phase Day 2 to Day 29/Exit. [ Time Frame: Maintenance phase baseline to Maintenance Phase Study Day 29/Exit, inclusive. ]
  • Median Time to Hyperkalemia (S-K ≥ 5.1mmol/L) [ Time Frame: Maintenance Phase baseline to maintenance Phase Study Day 29/Exit. ]
  • Mean S-K Intra-subject Standard Deviation Calculated Among Subjects With ≥ 2 Values on or After Maintenance Phase Study Day 8 [ Time Frame: 22 days; Maintenance Phase Day 8 - 29 ]
  • Proportion of Subjects Who Remained Normokalemic During Maintenance Phase [ Time Frame: Maintenance Phase Study Days 1, 2, 5, 8, 12, 15, 19, 22, 26, 29, and 35, inclusive. ]
  • Median Time to Relapse in S-K Values [ Time Frame: Maintenance phase Study Day 1 to Study Day 29/Exit. ]
    Median time to relapse in S-K values (return to original Acute Phase S-K baseline value)
  • Exponential Rate of Change in S-K Values During the Acute Phase at 24 Hours and 48 Hours of Study Drug Treatment. [ Time Frame: Acute Phase 24 hours and Acute Phase 48 hours. ]
  • Mean Change From Baseline in S-K Values (Blood) at All Measured Time Intervals Post Dose Acute Phase. [ Time Frame: All measured time intervals post dose during the Acute Phase. ]
  • Mean Percent Change From Baseline in S-K Values (Blood) at All Measured Time Intervals Post Dose Acute Phase. [ Time Frame: All measured time intervals post dose during the Acute Phase. ]
  • Proportion of Subjects Who Achieve Normokalemia During the Acute Phase at 24 and 48 Hours After Start of Dosing [ Time Frame: Through 48 hours acute phase ]
  • Median Time to Normalization (3.50-5.0 mmol/L) in S-K Levels in the 48 Hours of Initial Treatment [ Time Frame: Through 48 hours acute phase ]
Original Secondary Outcome Measures  ICMJE
 (submitted: March 12, 2014)
Proportion of subjects who convert from hyperkalemia to normokalemia after 10g ZS three times a day. [ Time Frame: First 48 hours ]
Evaluate the safety and efficacy of ZS in pre-defined subgroups of hyperkalemia including chronic kidney disease, diabetes mellitus, congestive heart failure, and patients taking Renin-Angiotensin-Aldosterone System (RAAS) inhibitors.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety & Efficacy of Zirconium Silicate Dosed for 28 Days in Hyperkalemia.
Official Title  ICMJE Multicenter, Multi-phase, Multi-dose, Prospective, Double-blind, Placebo-controlled, Maintenance Study of Safety and Efficacy of ZS (Microporous, Fractionated, Protonated Zirconium Silicate) in Hyperkalemia.
Brief Summary It is hypothesized that ZS is more effective than placebo control (alternative hypothesis) in maintaining mean double-blind randomized maintenance phase (DBRMP) Day 8-29 serum potassium levels (3.5 - 5.0 mmol/l, inclusive) among hyperkalemic subjects in whom normokalemia was established during the open-label acute phase versus no difference between each ZS dose (highest to lowest) versus placebo control (null hypothesis).
Detailed Description

Approximately 275 subjects with hyperkalemia (two consecutive i-STAT potassium levels ≥ 5.1 mmol/l, taken 60 minutes apart at baseline) will be enrolled in the Open-label Acute Phase to provide 232 subjects in the Double Blind Randomized Maintenance Phase.

Initially all subjects will receive open-label ZS at a dose of 10g three times a day (tid) for 48 hours (AP). Subjects who achieve normokalemia (i-STAT potassium values between 3.5 to 5.0 mmol/l, inclusive) on the morning of Study Day 3 (after 6 doses of 10g ZS) will then, in a double-blind fashion, be randomized 4:4:4:7 to receive one of three doses of ZS (5g, 10g or 15g) or placebo control, qd for the following 28 days (DBRMP).

Safety and tolerability will be assessed on an ongoing basis by an Independent Data Monitoring Committee (iDMC). Each active dose group in the DBRMP will consist of 49 subjects and the placebo control group will consist of 85 subjects for a total of 232 subjects to detect a 0.6 effect size difference between each ZS dose (from highest to lowest) and placebo control; the 4:4:4:7 allocation optimizes the multiple comparisons to the placebo control for the DBRMP.

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: Sodium zirconium cyclosilicate
    Sodium zirconium cyclosilicate
    Other Name: ZS; Microporous, Fractionated, Protonated Zirconium Silicate; Zirconium Silicate
  • Drug: Placebo
    Randomized to mimic doses of experimental drug administered once daily with breakfast for 28 days (maintenance phase)
    Other Name: Silicilate microcrystaline cellulose
Study Arms  ICMJE
  • Experimental: Sodium zirconium cyclosilicate 10 g three times daily
    Sodium zirconium cyclosilicate 10 g three times daily for 48 hours (acute phase)
    Intervention: Drug: Sodium zirconium cyclosilicate
  • Placebo Comparator: Placebo once daily
    Randomized to mimic doses of experimental drug administered once daily with breakfast for 28 days.
    Intervention: Drug: Placebo
  • Experimental: Sodium zirconium cyclosilicate 5 g once daily
    Sodium zirconium cyclosilicate (ZS) 5 g once daily for 28 days (maintenance phase)
    Intervention: Drug: Sodium zirconium cyclosilicate
  • Experimental: Sodium zirconium cyclosilicate 10 g once daily
    Sodium zirconium cyclosilicate (ZS) 10 g once daily for 28 days (maintenance phase)
    Intervention: Drug: Sodium zirconium cyclosilicate
  • Experimental: Sodium zirconium cyclosilicate 15 g once daily
    Sodium zirconium cyclosilicate (ZS) 15 g once daily for 28 days (maintenance phase)
    Intervention: Drug: Sodium zirconium cyclosilicate
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: June 1, 2015)
258
Original Estimated Enrollment  ICMJE
 (submitted: March 12, 2014)
275
Actual Study Completion Date  ICMJE January 31, 2015
Actual Primary Completion Date August 31, 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Provision of written informed consent.
  • Over 18 years of age.
  • Two consecutive i-STAT potassium values, measured 60-minutes apart, both ≥5.1 mmol/l and measured within 1 day of the first ZS dose on AP Study Day 1.
  • Ability to have repeated blood draws or effective venous catheterization.
  • Women of childbearing potential must be using two forms of medically acceptable contraception (at least one barrier method) and have a negative pregnancy test at AP Study Day 1. Women who are surgically sterile or those who are post-menopausal for at least 2 years are not considered to be of childbearing potential.

Exclusion Criteria:

  • Pseudohyperkalemia signs and symptoms, such as excessive fist clenching hemolyzed blood specimen, history of severe leukocytosis or thrombocytosis.
  • Subjects treated with lactulose, Xifaxan or other non-absorbed antibiotics for hyperammonemia within 7 days prior to the first dose of study drug.
  • Subjects treated with resins (such as sevelamer acetate or sodium polystyrene sulfonate [SPS; e.g. Kayexalate®]), calcium acetate, calcium carbonate, or lanthanum carbonate, within 7 days prior to the first dose of study drug.
  • Subjects with a life expectancy of less than 3 months.
  • 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 diabetic ketoacidosis.
  • 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.
  • Randomization into the previous ZS-002 or ZS-003 studies.
  • 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.
  • 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,   South Africa,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02088073
Other Study ID Numbers  ICMJE ZS-004
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party ZS Pharma, Inc.
Original Responsible Party Same as current
Current Study Sponsor  ICMJE ZS Pharma, Inc.
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Henrik Rasmussen, MD, PhD ZS Pharma, Inc.
PRS Account ZS Pharma, Inc.
Verification Date November 2018

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