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Safety & Efficacy of Zirconium Silicate in Chronic Kidney Disease or Moderate Kidney Dysfunction With Mild Hyperkalemia

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ClinicalTrials.gov Identifier: NCT01493024
Recruitment Status : Completed
First Posted : December 15, 2011
Results First Posted : June 29, 2018
Last Update Posted : June 29, 2018
Sponsor:
Information provided by (Responsible Party):
ZS Pharma, Inc.

Tracking Information
First Submitted Date  ICMJE December 12, 2011
First Posted Date  ICMJE December 15, 2011
Results First Submitted Date  ICMJE July 18, 2017
Results First Posted Date  ICMJE June 29, 2018
Last Update Posted Date June 29, 2018
Actual Study Start Date  ICMJE November 30, 2011
Actual Primary Completion Date May 31, 2012   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 29, 2018)
Difference in the Exponential Rate of Change in Serum Potassium (S-K) Levels Versus Placebo During the Initial 48 Hours of Study Drug Treatment [ Time Frame: 24 and 48 hours post first study drug dose ]
The rate of fall in S-K levels during the initial 48 hours of study drug treatment between the placebo treated subjects and the ZS treated subjects measured on a log scale
Original Primary Outcome Measures  ICMJE
 (submitted: December 13, 2011)
Change in serum potassium levels from baseline after administration of zirconium silicate three times a day. [ Time Frame: during the first 48 hours ]
To evaluate the effect on serum potassium (S-K)) of 3 different doses of zirconium silicate (ZS) administered 3 times daily for 48 hours (with up to an additional 48 hours of three times a day dosing for subjects whose S-K has not normalized [3.5 - 4.9 mmol/l] after the initial 48 hours) to subjects with moderate Chronic Kidney Disease (CKD as defined by a glomerular filtration rate (GFR) between 40-60ml/min) and mild hyperkalemia (S-K between 5-6.0 mmol/l).
Change History Complete list of historical versions of study NCT01493024 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 29, 2018)
  • Serum Potassium (S-K) at Individual Time Points. [ Time Frame: First 48 hours of study ]
    Serum potassium (S-K) at individual time points through Study day 3/0hour.
  • Time Specific S-K Levels to Normalization [ Time Frame: 48 and 72 hours post first study drug dose ]
    Percent of subjects achieving S-K normalization (<=as defined by S-K levels of 3.5 to 4.9 mmol/L) from baseline at Study Days 2 and 3 at 0 hr.
  • Time Specific Decreases in S-K Levels of > = 0.5 mmol/L [ Time Frame: 24 and 48 hours post first study drug dose ]
    Percentage of participants achieving a 0.5mmol/L drop from baseline at Study Days 2 and 3 at 0 hr.
  • Percentage of Participants With Normal S-K Levels at End of Study Day 2 [ Time Frame: 48 hours post first study drug dose ]
    Percentage (%) of subjects who achieve S-K normalization at end of Study Day 2
  • Urine Sodium Excretion [ Time Frame: 24 and 48 hours post first study drug dose ]
    Urine sodium excretion compared between the combined placebo-treated controls and the ZS-treated subjects (measured throughout two 24-hour periods on Study Days 1 and 2).
  • Urine Potassium Excretion [ Time Frame: 24 and 48 hours post study drug dose ]
    Urine potassium excretion compared between the combined placebo-treated controls and the ZS-treated subjects (measured throughout two 24-hour periods on Study Days 1 and 2).
  • Urea Nitrogen Excretion [ Time Frame: 24 and 48 hours post study drug dose ]
    Urea nitrogen excretion compared between the combined placebo-treated controls and the ZS-treated subjects (measured throughout two 24-hour periods on Study Days 1 and 2).
  • Blood Urea Nitrogen [ Time Frame: 24 and 48 hours post study drug dose ]
    Blood urea nitrogen compared between the combined placebo-treated controls and the ZS-treated subjects (measured 24 & 48 hours post dose on Study Days 2 and 3).
  • Serum Magnesium (S-Mg) Levels [ Time Frame: 24 and 48 hours post study drug dose ]
    Serum magnesium compared between the combined placebo-treated controls and the ZS-treated subjects (measured at 24 & 48 hours post dose on Study Days 2 and 3).
  • Serum Calcium (S-Ca) Levels [ Time Frame: 24 and 48 hours post study drug dose ]
    Serum calcium compared between the combined placebo-treated controls and the ZS-treated subjects (measured at 24 & 48 hours post dose on Study Days 2 and 3).
  • Serum Sodium (S-Na) Levels [ Time Frame: 24 and 48 hours post study drug dose ]
    Serum sodium compared between the combined placebo-treated controls and the ZS-treated subjects (measured at 24 & 48 hours post dose on Study Days 2 and 3).
  • Serum Bicarbonate (HCO3) Levels [ Time Frame: 24 and 48 hours post study drug dose ]
    Serum bicarbonate compared between the combined placebo-treated controls and the ZS-treated subjects (measured at 24 & 48 hours post dose on Study Days 2 and 3).
  • 24-hour Urinary Excretion of Potassium [ Time Frame: 24 and 48 hours post study drug dose ]
    24-hour urinary excretion of potassium on Study Days 1 and Day 2
  • 24-hour Urinary Excretion of Sodium [ Time Frame: 48 hours ]
    24-hour urinary excretion of sodium on Study Days 1 and Day 2
  • 24-hour Urinary Excretion of Urea Nitrogen [ Time Frame: 48 hours ]
    24-hour urinary excretion of urea nitrogen on Study Days 1 and Day 2
  • 24-hour Urinary Excretion of Creatinine [ Time Frame: 48 hours ]
    24-hour urinary excretion of creatinine on Study Days 1 and Day 2
Original Secondary Outcome Measures  ICMJE
 (submitted: December 13, 2011)
Identify optimal zirconium silicate dose to normalize serum potassium levels between 3.5 - 4.9 mmol/L without causing serious adverse events [ Time Frame: 6 months ]
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 in Chronic Kidney Disease or Moderate Kidney Dysfunction With Mild Hyperkalemia
Official Title  ICMJE Multicenter, Prospective, Randomized, Placebo-Controlled, Double-blind Dose Escalating Study of Safety, Tolerability and Pharmacodynamics of Zirconium Silicate in Chronic Kidney Disease and Moderate Kidney Dysfunction With Mild Hyperkalemia
Brief Summary It is hypothesized that zirconium silicate is safe and well tolerated and more effective than placebo (alternative hypothesis) in lowering serum potassium levels in subjects with serum potassium between 5 - 6.0 mmol/l versus no difference between zirconium silicate and placebo (null hypothesis). It is hypothesized that zirconium silicate even up to the top dose of 10g three times a day is well tolerated.
Detailed Description

A total of 90 subjects with moderate CKD (defined as GFR between 40- 60ml/min) and mild hyperkalemia (S-K between 5-6 mmol/l) will be enrolled in the study where, in a double-blind dose-escalating fashion (three separate cohorts), they will be randomized to receive one of the doses of ZS (0.3g, 3g and 10g) or placebo, administered 3 times (tid) daily with meals. The first cohort will have 18 subjects while both of the second and third cohorts will have 36 subjects for a total of 90 subjects.

Safety and tolerability will be assessed by an Independent Data Safety Monitoring Board (DSMB) after completion of each cohort, before escalation to the next dose level will be allowed. The next dose escalation will happen no sooner than one week after the last dose of study drug at the previous dosing level has been administered. Safety stopping rules will be specified for this study. Within the first dose level (300 mg dose), 12 subjects will be randomized to receive ZS, whereas 6 subjects will be randomized to receive placebo for a total of 18 subjects in this first cohort. In the next two cohorts (3 g and 10 g doses), 24 subjects per cohort will be randomized to receive ZS, whereas 12 subjects per cohort will be randomized to receive placebo for a total of 36 subjects in each of the second and third cohorts.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Supportive Care
Condition  ICMJE
  • Hyperkalemia
  • Chronic Kidney Disease
  • Kidney Dysfunction
Intervention  ICMJE
  • Drug: Zirconium silicate (ZS)
    Randomized escalating doses (0.3g, 3g and 10g) of ZS (fractionated, protonated microporous Zirconium Silicate, an oral sorbent) administered 3 times daily (tid) with meals.
    Other Name: ZS-9
  • Drug: Placebo
    Randomized to mimic escalating doses of experimental drug administered 3 times daily (tid) with meals.
    Other Name: silicified microcrystalline cellulose
Study Arms  ICMJE
  • Placebo Comparator: Placebo
    Placebo (silicified microcrystalline cellulose) randomized to mimic escalating doses of experimental drug administered three times daily (TID) with meals.
    Intervention: Drug: Placebo
  • Experimental: Zirconium silicate (ZS)
    Randomized escalating doses (0.3g, 3g and 10g) of ZS (fractionated, protonated, microporous zirconium silicate, an oral sorbent) administered 3 times daily (tid) with meals.
    Intervention: Drug: Zirconium silicate (ZS)
Publications * Not Provided

*   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: December 13, 2011)
90
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE June 30, 2012
Actual Primary Completion Date May 31, 2012   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Provision of written informed consent.
  • Over 18 years of age.
  • GFR between 40-60 ml/min as estimated by the CKD-EPI equation. After screening two additional GFR values of between 40-60ml/min must be repeated within 24 hours before inclusion is allowed.
  • S-K between 5.0 - 6.0 mmol/l (inclusive) during Study Day 0.
  • Ability to have repeated blood draws or effective venous catheterization.
  • Women of child bearing potential must be practicing a highly effective method of birth control.

Exclusion Criteria:

  • Pseudohyperkalemia such as excessive fist clinching hemolyzed blood specimen, severe leukocytosis or thrombocytosis.
  • Subjects treated with lactulose, xifaxan or other non-absorbed antibiotics for hyperammonemia within the last 7 days.
  • Subjects treated with resins (such as sevelamer acetate, calcium acetate or calcium carbonate, lanthanum carbonate, Sodium polystyrene sulfonate (SPS; e.g. Kayexalate®) 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.
  • Cancer within the last 5 years (other than successfully treated basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or early stage prostate cancer).
  • 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 Zirconium Silicate or to components thereof.
  • Subjects who have cardiac arrhythmias that require immediate treatment.
  • Subjects with ECG changes associated with hyperkalemia.
  • Subjects with acute kidney injury.
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 United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01493024
Other Study ID Numbers  ICMJE ZS-002
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 May 2018

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