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

Primary Purpose

Hyperkalemia, Chronic Kidney Disease, Kidney Dysfunction

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Zirconium silicate (ZS)

Placebo

About this trial

This is an interventional supportive care trial for Hyperkalemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Experimental

Arm Label

Placebo

Zirconium silicate (ZS)

Arm Description

Placebo (silicified microcrystalline cellulose) randomized to mimic escalating doses of experimental drug administered three times daily (TID) with meals.

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.

Outcomes

Primary Outcome Measures

Difference in the Exponential Rate of Change in Serum Potassium (S-K) Levels Versus Placebo During the Initial 48 Hours of Study Drug Treatment

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

Secondary Outcome Measures

Serum Potassium (S-K) at Individual Time Points.

Serum potassium (S-K) at individual time points through Study day 3/0hour.

Time Specific S-K Levels to Normalization

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

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

Percentage (%) of subjects who achieve S-K normalization at end of Study Day 2

Urine Sodium Excretion

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

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

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

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

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

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

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

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

24-hour urinary excretion of potassium on Study Days 1 and Day 2

24-hour Urinary Excretion of Sodium

24-hour urinary excretion of sodium on Study Days 1 and Day 2

24-hour Urinary Excretion of Urea Nitrogen

24-hour urinary excretion of urea nitrogen on Study Days 1 and Day 2

24-hour Urinary Excretion of Creatinine

24-hour urinary excretion of creatinine on Study Days 1 and Day 2

Full Information

NCT ID

NCT01493024

First Posted

December 12, 2011

Last Updated

May 29, 2018

Sponsor

ZS Pharma, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT01493024

Brief Title

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

2. Study Status

Record Verification Date

May 2018

Overall Recruitment Status

Completed

Study Start Date

November 30, 2011 (Actual)

Primary Completion Date

May 31, 2012 (Actual)

Study Completion Date

June 30, 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

ZS Pharma, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hyperkalemia, Chronic Kidney Disease, Kidney Dysfunction

7. Study Design

Primary Purpose

Supportive Care

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

90 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Placebo (silicified microcrystalline cellulose) randomized to mimic escalating doses of experimental drug administered three times daily (TID) with meals.

Arm Title

Zirconium silicate (ZS)

Arm Type

Experimental

Arm Description

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 Type

Drug

Intervention Name(s)

Zirconium silicate (ZS)

Other Intervention Name(s)

ZS-9

Intervention Description

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 Type

Drug

Intervention Name(s)

Placebo

Other Intervention Name(s)

silicified microcrystalline cellulose

Intervention Description

Randomized to mimic escalating doses of experimental drug administered 3 times daily (tid) with meals.

Primary Outcome Measure Information:

Title

Difference in the Exponential Rate of Change in Serum Potassium (S-K) Levels Versus Placebo During the Initial 48 Hours of Study Drug Treatment

Description

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

Time Frame

24 and 48 hours post first study drug dose

Secondary Outcome Measure Information:

Title

Serum Potassium (S-K) at Individual Time Points.

Description

Serum potassium (S-K) at individual time points through Study day 3/0hour.

Time Frame

First 48 hours of study

Title

Time Specific S-K Levels to Normalization

Description

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 Frame

48 and 72 hours post first study drug dose

Title

Time Specific Decreases in S-K Levels of > = 0.5 mmol/L

Description

Percentage of participants achieving a 0.5mmol/L drop from baseline at Study Days 2 and 3 at 0 hr.

Time Frame

24 and 48 hours post first study drug dose

Title

Percentage of Participants With Normal S-K Levels at End of Study Day 2

Description

Percentage (%) of subjects who achieve S-K normalization at end of Study Day 2

Time Frame

48 hours post first study drug dose

Title

Urine Sodium Excretion

Description

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).

Time Frame

24 and 48 hours post first study drug dose

Title

Urine Potassium Excretion

Description

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).

Time Frame