Clinical trial NCT01493024: Safety & Efficacy of Zirconium Silicate in Chronic Kidney Disease or Moderate Kidney Dysfunction With Mild Hyperkalemia
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hyperkalemia
Chronic Kidney Disease
Kidney Dysfunction
Lead sponsor: ZS Pharma, Inc.
Sponsor class: INDUSTRY
First posted: 2011-12-15
Enrollment: 90
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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Difference in the Exponential Rate of Change in Serum Potassium (S-K) Levels Versus Placebo During the Initial 48 Hours of Study Drug Treatment
timeFrame: 24 and 48 hours post first study drug dose
Secondary outcomes:
measure: Serum Potassium (S-K) at Individual Time Points.
timeFrame: First 48 hours of study
measure: Time Specific S-K Levels to Normalization
timeFrame: 48 and 72 hours post first study drug dose
measure: Time Specific Decreases in S-K Levels of > = 0.5 mmol/L
timeFrame: 24 and 48 hours post first study drug dose
measure: Percentage of Participants With Normal S-K Levels at End of Study Day 2
timeFrame: 48 hours post first study drug dose
measure: Urine Sodium Excretion
timeFrame: 24 and 48 hours post first study drug dose
measure: Urine Potassium Excretion
timeFrame: 24 and 48 hours post study drug dose
measure: Urea Nitrogen Excretion
timeFrame: 24 and 48 hours post study drug dose
measure: Blood Urea Nitrogen
timeFrame: 24 and 48 hours post study drug dose
measure: Serum Magnesium (S-Mg) Levels
timeFrame: 24 and 48 hours post study drug dose
measure: Serum Calcium (S-Ca) Levels
timeFrame: 24 and 48 hours post study drug dose
measure: Serum Sodium (S-Na) Levels
timeFrame: 24 and 48 hours post study drug dose
measure: Serum Bicarbonate (HCO3) Levels
timeFrame: 24 and 48 hours post study drug dose
measure: 24-hour Urinary Excretion of Potassium
timeFrame: 24 and 48 hours post study drug dose
measure: 24-hour Urinary Excretion of Sodium
timeFrame: 48 hours
measure: 24-hour Urinary Excretion of Urea Nitrogen
timeFrame: 48 hours
measure: 24-hour Urinary Excretion of Creatinine
timeFrame: 48 hours
Other outcomes:
Locations:
city: Tempe
country: United States
facility: Southwest Clinical Research Institute
state: Arizona
city: Costa Mesa
country: United States
facility: West Coast Clinical Trials
state: California
city: Edgewater
country: United States
facility: Riverside Clinical Research
state: Florida
city: Miami
country: United States
facility: Elite Research Institute, Inc.
state: Florida
city: Orlando
country: United States
facility: Compass Research Phase 1, LLC
state: Florida
city: Summerfield
country: United States
facility: Lakeview Medical Research
state: Florida
city: Lenexa
country: United States
facility: Johnson County Clin-Trials
state: Kansas
city: Houston
country: United States
facility: Southwest Houston Research, Ltd
state: Texas
city: San Antonio
country: United States
facility: Renal Associates, P.A.
state: Texas
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.