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ZS Ph2/3 Dose-response Study in Japan

Primary Purpose

Hyperkalemia

Status
Completed
Phase
Phase 2
Locations
Japan
Study Type
Interventional
Intervention
Sodium Zirconium Cyclosilicate (ZS) 5g
Sodium Zirconium Cyclosilicate (ZS) 10g
Placebo
Sponsored by
AstraZeneca
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hyperkalemia

Eligibility Criteria

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

Inclusion Criteria:

  • Provision of informed consent prior to any study specific procedures.
  • Patients aged ≥18. For patients aged <20 years, a written informed consent should be obtained from the patient and his or her legally acceptable representative.
  • Two consecutive i-STAT potassium values, measured 60 (± 10) minutes apart, both values should be ≥ 5.1 mmol/L and ≤ 6.5 mmol/L and measured within 1 day before the first dose of study drug on Study Day 1.
  • Ability to have repeated blood draws or effective venous catheterization.
  • Female patients must be 1 year post-menopausal, surgically sterile, or using an acceptable method of contraception (an acceptable method of contraception is defined as a barrier method in conjunction with a spermicide) for the duration of the study (from the time they sign consent) and for 3 months after the last dose of ZS/matching placebo to prevent pregnancy. In addition, oral contraceptives, approved contraceptive implant, long-term injectable contraception, intrauterine device, or tubal ligation are allowed. Oral contraception alone is not acceptable; additional barrier methods in conjunction with spermicide must be used.

Exclusion Criteria:

  • Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)

  • Cause or symptoms of pseudohyperkalemia, such as

    1. hemolyzed blood specimen due to excessive fist clenching to make veins prominent
    2. hemolyzed blood specimen due to difficult or traumatic venepuncture
    3. history of severe leukocytosis or thrombocytosis
  • Patients treated with lactulose, rifaximin, or other non-absorbed antibiotics for hyperammonemia within 7 days prior to first dose of study drug on Study Day 1
  • Patients treated with resins (such as sevelamer hydrochloride, sodium polystyrene sulfonate [SPS; e.g. Kayexalate®] or calcium polystyrene sulfonate [CPS]), calcium acetate, calcium carbonate, or lanthanum carbonate, within 7 days prior to the first dose of study drug
  • Patients with a life expectancy of less than 3 months
  • Patients who are severely physically or mentally incapacitated and who, in the opinion of investigator, are unable to perform the patients' tasks associated with the protocol
  • Female patients who are pregnant, lactating, or planning to become pregnant
  • Patients who have an active or history of diabetic ketoacidosis
  • Presence of any condition which, in the opinion of the investigator, places the patient 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
  • Treatment with a drug or device within the last 30 days that has not received regulatory approval at the time of study entry
  • Patients with cardiac arrhythmias that require immediate treatment
  • Patients on dialysis

Sites / Locations

  • Research Site
  • Research Site
  • Research Site
  • Research Site
  • Research Site
  • Research Site
  • Research Site
  • Research Site
  • Research Site
  • Research Site
  • Research Site
  • Research Site
  • Research Site
  • Research Site
  • Research Site
  • Research Site
  • Research Site
  • Research Site
  • Research Site
  • Research Site
  • Research Site
  • Research Site
  • Research Site
  • Research Site
  • Research Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Placebo Comparator

Arm Label

Sodium Zirconium Cyclosilicate (ZS) 5g

Sodium Zirconium Cyclosilicate (ZS) 10g

Placebo

Arm Description

Suspension administered 5g orally three times daily for 48 hours.

Suspension administered 10g orally three times daily for 48 hours.

Placebo suspension administered orally placebo three times daily for 48 hours.

Outcomes

Primary Outcome Measures

Exponential Rate of Change in Serum Potassium (S-K) Values During the Initial 48 Hours of Study Drug Treatment
Blood samples for determination of potassium were collected pre-dose, and at 1, 2, and 4 hours post Dose 1 on Day 1. An additional sample was collected at 90 minutes post Dose 2 on Day 1 if i-STAT potassium values at the 4-hour post Dose 1 time point was ≥ 6.1 or <4.0 mmol/L. On Day 2 samples were analysed pre-dose, and 1 and 4 hours post Dose 1. S-K levels were analysed at the Central Laboratory. Natural logarithm of S-K from 0 to 48 hours post dose are modelled by the random coefficients model including fixed effects of intercept, time, time x treatment and patient-level random effects for time and intercept. Exponential rate of change refers to the slope estimate from the random coefficients model.

Secondary Outcome Measures

Percentage of Patients Who Achieved Normokalaemia at 48 Hours
The percentage of patients who achieved normokalaemia (normalisation of S-K values to between 3.5 mmol/L and 5.0 mmol/L, inclusive) at 48 hours after start of dosing was determined. Patients with missing S-K values at 48 hours were regarded as not normokalaemic.
Exponential Rate of Change in S-K Values During the Initial 24 Hours of Study Drug Treatment
Blood samples for determination of potassium were collected pre-dose, and at 1, 2, and 4 hours post Dose 1 on Day 1. An additional sample was collected at 90 minutes post Dose 2 on Day 1 if i-STAT potassium values at the 4-hour post Dose 1 time point was ≥ 6.1 or <4.0 mmol/L. On Day 2 samples were analysed pre-dose, and 1 and 4 hours post Dose 1. S-K levels were analysed at the Central Laboratory. Natural logarithm of S-K from 0 to 24 hours post dose are modelled by the random coefficients model including fixed effects of intercept, time, time x treatment and patient-level random effects for time and intercept. Exponential rate of change refers to the slope estimate from the random coefficients model.
Percentage of Patients Who Achieved Normokalaemia at 24 Hours
The percentage of patients who achieved normokalaemia (normalisation of S-K values to between 3.5 mmol/L and 5.0 mmol/L, inclusive) at 24 hours after start of dosing was determined. Patients with missing S-K values at 24 hours were regarded as not normokalaemic.
Percentage of Patients Who Achieved Normokalaemia at Each Scheduled Potassium Assessment Time Point
The percentage of patients who achieved normokalaemia (normalisation of S-K values to between 3.5 mmol/L and 5.0 mmol/L, inclusive) at each each scheduled potassium assessment time point after the start of dosing was determined. Patients with missing S-K values were regarded as not normokalaemic.
Mean Change From Baseline in S-K Values at All Measured Time Intervals
Blood samples for determination of potassium were collected pre-dose, and at 1, 2, and 4 hours post Dose 1 on Day 1. An additional sample was collected at 90 minutes post Dose 2 on Day 1 if i-STAT potassium values at the 4-hour post Dose 1 time point was ≥ 6.1 or <4.0 mmol/L. On Day 2 samples were analysed pre-dose, and 1 and 4 hours post Dose 1. S-K levels were analysed locally using i-STAT devices, and at the Central Laboratory. S-K values measured at each time point and end of study visit were recorded and mean change from baseline is displayed.
Mean Percent Change From Baseline in S-K Values at All Measured Time Intervals
Blood samples for determination of potassium were collected pre-dose, and at 1, 2, and 4 hours post Dose 1 on Day 1. An additional sample was collected at 90 minutes post Dose 2 on Day 1 if i-STAT potassium values at the 4-hour post Dose 1 time point was ≥ 6.1 or <4.0 mmol/L. On Day 2 samples were analysed pre-dose, and 1 and 4 hours post Dose 1. S-K levels were analysed locally using i-STAT devices, and at the Central Laboratory. S-K values measured at each time point and end of study visit were recorded and mean percent change from baseline is displayed.
Time to Normalisation in S-K Values
The distribution of time to normalisation of S-K values (defined as S-K values between 3.5 mmol/L and 5.0 mmol/L, inclusive) was measured. A patient who reached at least one S-K within normal range was counted as an event regardless of S-K value after that time point. Patients who did not achieve normokalaemia within 48 hours were censored.
Time to a Decrease in S-K Levels of 0.5 mmol/L
The median time (hours) for S-K values to decrease by 0.5 mmol/L was measured.

Full Information

First Posted
April 5, 2017
Last Updated
February 20, 2019
Sponsor
AstraZeneca
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1. Study Identification

Unique Protocol Identification Number
NCT03127644
Brief Title
ZS Ph2/3 Dose-response Study in Japan
Official Title
A Phase 2/3 Multicenter, Dose-response Study to Assess Efficacy and Safety of ZS (Sodium Zirconium Cyclosilicate), in Japanese Patients With Hyperkalemia
Study Type
Interventional

2. Study Status

Record Verification Date
February 2019
Overall Recruitment Status
Completed
Study Start Date
June 14, 2017 (Actual)
Primary Completion Date
February 23, 2018 (Actual)
Study Completion Date
February 23, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
AstraZeneca

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
To assess efficacy of 5 g three times daily (TID) and 10 g TID ZS versus placebo in Japanese patients with hyperkalemia (serum potassium [S-K] ≥ 5.1 mmol/L and ≤ 6.5 mmol/L).
Detailed Description
Patients not receiving any therapy for hyperkalemia and with 2 consecutive i-STAT potassium values of ≥ 5.1 mmol/L and ≤ 6.5 mmol/L will be enrolled and randomized 1:1:1 to receive ZS 5 g, ZS 10 g, or placebo TID for 48 hours. Throughout the study most potassium values will be measured at fasting before taking study drug. Nothing should be taken by mouth except water, coffee or tea, with or without milk and/or sugar, and essential medications, prior to the blood collection for a minimum of 8 hours. Potassium level should be determined by both i-STAT and the Central Laboratory on all occasions. Treatment decisions (eg, stopping rules) will be made based on i-STAT potassium values, as these provide clinical sites with a real-time measurement. Statistical analyses on the study data will in principle be based on S-K values as measured by the central laboratory. Safety and tolerability will be assessed on an ongoing basis. Standard study assessments including blood potassium, clinical chemistry (including calcium, magnesium, sodium, phosphate, creatinine, bicarbonate, and blood urea nitrogen [BUN]) and hematology parameters, urinalysis, vital signs, physical examinations, and electrocardiograms (ECGs) will be assessed during the study at the time points specified in the assessments schedule. All women of childbearing potential will have a urine pregnancy test prior to enrollment and at their End of Study (EOS) visit. Stopping rules will be implemented to ensure subjects discontinue the study treatment and receive alternative therapy in case of significant hyperkalemia, hypokalemia, or significant cardiac arrhythmias.

6. Conditions and Keywords

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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
103 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Sodium Zirconium Cyclosilicate (ZS) 5g
Arm Type
Experimental
Arm Description
Suspension administered 5g orally three times daily for 48 hours.
Arm Title
Sodium Zirconium Cyclosilicate (ZS) 10g
Arm Type
Experimental
Arm Description
Suspension administered 10g orally three times daily for 48 hours.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo suspension administered orally placebo three times daily for 48 hours.
Intervention Type
Drug
Intervention Name(s)
Sodium Zirconium Cyclosilicate (ZS) 5g
Intervention Description
Suspension administered 5g orally three times daily for 48 hours.
Intervention Type
Drug
Intervention Name(s)
Sodium Zirconium Cyclosilicate (ZS) 10g
Intervention Description
Suspension administered 10g orally three times daily for 48 hours.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo suspension administered orally placebo three times daily for 48 hours.
Primary Outcome Measure Information:
Title
Exponential Rate of Change in Serum Potassium (S-K) Values During the Initial 48 Hours of Study Drug Treatment
Description
Blood samples for determination of potassium were collected pre-dose, and at 1, 2, and 4 hours post Dose 1 on Day 1. An additional sample was collected at 90 minutes post Dose 2 on Day 1 if i-STAT potassium values at the 4-hour post Dose 1 time point was ≥ 6.1 or <4.0 mmol/L. On Day 2 samples were analysed pre-dose, and 1 and 4 hours post Dose 1. S-K levels were analysed at the Central Laboratory. Natural logarithm of S-K from 0 to 48 hours post dose are modelled by the random coefficients model including fixed effects of intercept, time, time x treatment and patient-level random effects for time and intercept. Exponential rate of change refers to the slope estimate from the random coefficients model.
Time Frame
From 0 to 48 hours.
Secondary Outcome Measure Information:
Title
Percentage of Patients Who Achieved Normokalaemia at 48 Hours
Description
The percentage of patients who achieved normokalaemia (normalisation of S-K values to between 3.5 mmol/L and 5.0 mmol/L, inclusive) at 48 hours after start of dosing was determined. Patients with missing S-K values at 48 hours were regarded as not normokalaemic.
Time Frame
At 48 hours.
Title
Exponential Rate of Change in S-K Values During the Initial 24 Hours of Study Drug Treatment
Description
Blood samples for determination of potassium were collected pre-dose, and at 1, 2, and 4 hours post Dose 1 on Day 1. An additional sample was collected at 90 minutes post Dose 2 on Day 1 if i-STAT potassium values at the 4-hour post Dose 1 time point was ≥ 6.1 or <4.0 mmol/L. On Day 2 samples were analysed pre-dose, and 1 and 4 hours post Dose 1. S-K levels were analysed at the Central Laboratory. Natural logarithm of S-K from 0 to 24 hours post dose are modelled by the random coefficients model including fixed effects of intercept, time, time x treatment and patient-level random effects for time and intercept. Exponential rate of change refers to the slope estimate from the random coefficients model.
Time Frame
From 0 to 24 hours.
Title
Percentage of Patients Who Achieved Normokalaemia at 24 Hours
Description
The percentage of patients who achieved normokalaemia (normalisation of S-K values to between 3.5 mmol/L and 5.0 mmol/L, inclusive) at 24 hours after start of dosing was determined. Patients with missing S-K values at 24 hours were regarded as not normokalaemic.
Time Frame
At 24 hours.
Title
Percentage of Patients Who Achieved Normokalaemia at Each Scheduled Potassium Assessment Time Point
Description
The percentage of patients who achieved normokalaemia (normalisation of S-K values to between 3.5 mmol/L and 5.0 mmol/L, inclusive) at each each scheduled potassium assessment time point after the start of dosing was determined. Patients with missing S-K values were regarded as not normokalaemic.
Time Frame
From baseline to end of study (9 days).
Title
Mean Change From Baseline in S-K Values at All Measured Time Intervals
Description
Blood samples for determination of potassium were collected pre-dose, and at 1, 2, and 4 hours post Dose 1 on Day 1. An additional sample was collected at 90 minutes post Dose 2 on Day 1 if i-STAT potassium values at the 4-hour post Dose 1 time point was ≥ 6.1 or <4.0 mmol/L. On Day 2 samples were analysed pre-dose, and 1 and 4 hours post Dose 1. S-K levels were analysed locally using i-STAT devices, and at the Central Laboratory. S-K values measured at each time point and end of study visit were recorded and mean change from baseline is displayed.
Time Frame
From baseline to end of study (9 days).
Title
Mean Percent Change From Baseline in S-K Values at All Measured Time Intervals
Description
Blood samples for determination of potassium were collected pre-dose, and at 1, 2, and 4 hours post Dose 1 on Day 1. An additional sample was collected at 90 minutes post Dose 2 on Day 1 if i-STAT potassium values at the 4-hour post Dose 1 time point was ≥ 6.1 or <4.0 mmol/L. On Day 2 samples were analysed pre-dose, and 1 and 4 hours post Dose 1. S-K levels were analysed locally using i-STAT devices, and at the Central Laboratory. S-K values measured at each time point and end of study visit were recorded and mean percent change from baseline is displayed.
Time Frame
From baseline to end of study (9 days).
Title
Time to Normalisation in S-K Values
Description
The distribution of time to normalisation of S-K values (defined as S-K values between 3.5 mmol/L and 5.0 mmol/L, inclusive) was measured. A patient who reached at least one S-K within normal range was counted as an event regardless of S-K value after that time point. Patients who did not achieve normokalaemia within 48 hours were censored.
Time Frame
From 0 to 48 hours.
Title
Time to a Decrease in S-K Levels of 0.5 mmol/L
Description
The median time (hours) for S-K values to decrease by 0.5 mmol/L was measured.
Time Frame
From 0 to 48 hours.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Provision of informed consent prior to any study specific procedures. Patients aged ≥18. For patients aged <20 years, a written informed consent should be obtained from the patient and his or her legally acceptable representative. Two consecutive i-STAT potassium values, measured 60 (± 10) minutes apart, both values should be ≥ 5.1 mmol/L and ≤ 6.5 mmol/L and measured within 1 day before the first dose of study drug on Study Day 1. Ability to have repeated blood draws or effective venous catheterization. Female patients must be 1 year post-menopausal, surgically sterile, or using an acceptable method of contraception (an acceptable method of contraception is defined as a barrier method in conjunction with a spermicide) for the duration of the study (from the time they sign consent) and for 3 months after the last dose of ZS/matching placebo to prevent pregnancy. In addition, oral contraceptives, approved contraceptive implant, long-term injectable contraception, intrauterine device, or tubal ligation are allowed. Oral contraception alone is not acceptable; additional barrier methods in conjunction with spermicide must be used. Exclusion Criteria: Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site) Cause or symptoms of pseudohyperkalemia, such as hemolyzed blood specimen due to excessive fist clenching to make veins prominent hemolyzed blood specimen due to difficult or traumatic venepuncture history of severe leukocytosis or thrombocytosis Patients treated with lactulose, rifaximin, or other non-absorbed antibiotics for hyperammonemia within 7 days prior to first dose of study drug on Study Day 1 Patients treated with resins (such as sevelamer hydrochloride, sodium polystyrene sulfonate [SPS; e.g. Kayexalate®] or calcium polystyrene sulfonate [CPS]), calcium acetate, calcium carbonate, or lanthanum carbonate, within 7 days prior to the first dose of study drug Patients with a life expectancy of less than 3 months Patients who are severely physically or mentally incapacitated and who, in the opinion of investigator, are unable to perform the patients' tasks associated with the protocol Female patients who are pregnant, lactating, or planning to become pregnant Patients who have an active or history of diabetic ketoacidosis Presence of any condition which, in the opinion of the investigator, places the patient 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 Treatment with a drug or device within the last 30 days that has not received regulatory approval at the time of study entry Patients with cardiac arrhythmias that require immediate treatment Patients on dialysis
Facility Information:
Facility Name
Research Site
City
Chiba-shi
ZIP/Postal Code
260-8712
Country
Japan
Facility Name
Research Site
City
Chiba-shi
ZIP/Postal Code
263-0043
Country
Japan
Facility Name
Research Site
City
Hanyu-shi
ZIP/Postal Code
348-8505
Country
Japan
Facility Name
Research Site
City
Higashiibaraki-gun
ZIP/Postal Code
311-3193
Country
Japan
Facility Name
Research Site
City
Hitachinaka-shi
ZIP/Postal Code
312-0057
Country
Japan
Facility Name
Research Site
City
Ina-shi
ZIP/Postal Code
396-8555
Country
Japan
Facility Name
Research Site
City
Kagoshima-shi
ZIP/Postal Code
892-8580
Country
Japan
Facility Name
Research Site
City
Kahoku-gun
ZIP/Postal Code
920-0293
Country
Japan
Facility Name
Research Site
City
Kamakura-shi
ZIP/Postal Code
247-8533
Country
Japan
Facility Name
Research Site
City
Kanazawa-shi
ZIP/Postal Code
920-8650
Country
Japan
Facility Name
Research Site
City
Kasugai-shi
ZIP/Postal Code
486-8510
Country
Japan
Facility Name
Research Site
City
Kawachinagano-shi
ZIP/Postal Code
586-8521
Country
Japan
Facility Name
Research Site
City
Kawasaki-shi
ZIP/Postal Code
216-8511
Country
Japan
Facility Name
Research Site
City
Kitakyushu-shi
ZIP/Postal Code
802-0001
Country
Japan
Facility Name
Research Site
City
Koga-shi
ZIP/Postal Code
306-0041
Country
Japan
Facility Name
Research Site
City
Kusatsu-shi
ZIP/Postal Code
525-8585
Country
Japan
Facility Name
Research Site
City
Matsudo-shi
ZIP/Postal Code
271-0077
Country
Japan
Facility Name
Research Site
City
Matsuyama-shi
ZIP/Postal Code
791-8026
Country
Japan
Facility Name
Research Site
City
Nagoya-shi
ZIP/Postal Code
457-8511
Country
Japan
Facility Name
Research Site
City
Naka-shi
ZIP/Postal Code
311-0113
Country
Japan
Facility Name
Research Site
City
Omura-shi
ZIP/Postal Code
856-8562
Country
Japan
Facility Name
Research Site
City
Shimajiri-gun
ZIP/Postal Code
901-0493
Country
Japan
Facility Name
Research Site
City
Shizuoka-shi
ZIP/Postal Code
421-0117
Country
Japan
Facility Name
Research Site
City
Yao-shi
ZIP/Postal Code
581-0011
Country
Japan
Facility Name
Research Site
City
Yotsukaido-shi
ZIP/Postal Code
284-0027
Country
Japan

12. IPD Sharing Statement

Citations:
PubMed Identifier
32779057
Citation
Kashihara N, Nishio T, Osonoi T, Saka Y, Imasawa T, Ohtake T, Mizuno H, Shibagaki Y, Kim H, Yajima T, Sarai N. Correction of serum potassium with sodium zirconium cyclosilicate in Japanese patients with hyperkalemia: a randomized, dose-response, phase 2/3 study. Clin Exp Nephrol. 2020 Dec;24(12):1144-1153. doi: 10.1007/s10157-020-01937-1. Epub 2020 Aug 10.
Results Reference
derived

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ZS Ph2/3 Dose-response Study in Japan

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