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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).
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Sodium Zirconium Cyclosilicate (ZS) 5g | Experimental | Suspension administered 5g orally three times daily for 48 hours. |
|
| Sodium Zirconium Cyclosilicate (ZS) 10g | Experimental | Suspension administered 10g orally three times daily for 48 hours. |
|
| Placebo | Placebo Comparator | Placebo suspension administered orally placebo three times daily for 48 hours. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sodium Zirconium Cyclosilicate (ZS) 5g | Drug | Suspension administered 5g orally three times daily for 48 hours. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | From 0 to 48 hours. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | At 48 hours. |
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Inclusion Criteria:
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
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
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Research Site | Chiba | 260-8712 | Japan | |||
| Research Site |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32779057 | Derived | 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. |
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103 patients were randomised 1:1:1 to receive double-blind treatment of sodium zirconium cyclosilicate (ZS) 5 grams (g) three times daily (TID), ZS 10 g TID, or placebo TID for 48 hours.
Patients not receiving any therapy for hyperkalaemia and with 2 consecutive potassium values of ≥ 5.1 millimoles/litre (mmol/L) and ≤ 6.5 mmol/L (as measured by i-STAT, a portable blood analyser) were enrolled into 24 study sites in Japan from June 2017 to February 2018.
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| ID | Title | Description |
|---|---|---|
| FG000 | ZS 5 g TID | ZS suspension was administered 5 g orally TID for 48 hours. |
| FG001 | ZS 10 g TID | ZS suspension was administered 10 g orally TID for 48 hours. |
| FG002 | Placebo TID | Placebo suspension was administered orally TID for 48 hours. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
The full analysis set included all patients randomised in the study.
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| ID | Title | Description |
|---|---|---|
| BG000 | ZS 5 g TID | ZS suspension was administered 5 g orally TID for 48 hours. |
| BG001 | ZS 10 g TID | ZS suspension was administered 10 g orally TID for 48 hours. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | The full analysis set included all patients randomised in the study. | Posted | Mean | Standard Error | log (mmol/L) / hour | From 0 to 48 hours. |
|
Treatment-emergent adverse events (TEAEs) were reported from Day 1 to Day 3 inclusive.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | ZS 5 g TID | ZS suspension was administered 5 g orally TID for 48 hours. | 0 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Respiratory tract infection | Infections and infestations | MedDRA version 20.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Global Clinical Lead | AstraZeneca | +1 302 885 1180 | ClinicalTrialTransparency@astrazeneca.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Sep 26, 2017 | Feb 19, 2019 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Feb 19, 2018 | Feb 20, 2019 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D006947 | Hyperkalemia |
| ID | Term |
|---|---|
| D014883 | Water-Electrolyte Imbalance |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| C000597310 | sodium zirconium cyclosilicate |
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| Sodium Zirconium Cyclosilicate (ZS) 10g | Drug | Suspension administered 10g orally three times daily for 48 hours. |
|
| Placebo | Drug | Placebo suspension administered orally placebo three times daily for 48 hours. |
|
| 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. |
| From 0 to 24 hours. |
| 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. | At 24 hours. |
| 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. | From baseline to end of study (9 days). |
| 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. | From baseline to end of study (9 days). |
| 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. | From baseline to end of study (9 days). |
| 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. | From 0 to 48 hours. |
| 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. | From 0 to 48 hours. |
| Chiba |
| 263-0043 |
| Japan |
| Research Site | Hanyu-shi | 348-8505 | Japan |
| Research Site | Higashiibaraki-gun | 311-3193 | Japan |
| Research Site | Hitachi-Naka | 312-0057 | Japan |
| Research Site | Ina-shi | 396-8555 | Japan |
| Research Site | Kagoshima | 892-8580 | Japan |
| Research Site | Kahoku-gun | 920-0293 | Japan |
| Research Site | Kamakura-shi | 247-8533 | Japan |
| Research Site | Kanazawa | 920-8650 | Japan |
| Research Site | Kasugai-shi | 486-8510 | Japan |
| Research Site | Kawachinagano-shi | 586-8521 | Japan |
| Research Site | Kawasaki-shi | 216-8511 | Japan |
| Research Site | Kitakyushu-shi | 802-0001 | Japan |
| Research Site | Koga-shi | 306-0041 | Japan |
| Research Site | Kusatsu-shi | 525-8585 | Japan |
| Research Site | Matsudo-shi | 271-0077 | Japan |
| Research Site | Matsuyama | 791-8026 | Japan |
| Research Site | Nagoya | 457-8511 | Japan |
| Research Site | Naka | 311-0113 | Japan |
| Research Site | Omura-shi | 856-8562 | Japan |
| Research Site | Shimajiri-gun | 901-0493 | Japan |
| Research Site | Shizuoka | 421-0117 | Japan |
| Research Site | Yakushi | 581-0011 | Japan |
| Research Site | Yotsukaido-shi | 284-0027 | Japan |
| BG002 | Placebo TID | Placebo suspension was administered orally TID for 48 hours. |
| BG003 | Total | Total of all reporting groups |
| Years |
|
| Age, Customized | Number | Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
ZS suspension was administered 5 g orally TID for 48 hours. |
| OG001 | ZS 10 g TID | ZS suspension was administered 10 g orally TID for 48 hours. |
| OG002 | Placebo TID | Placebo suspension was administered orally TID for 48 hours. |
|
|
|
| Secondary | 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. | The full analysis set included all patients randomised in the study. | Posted | Number | Percentage of Patients | At 48 hours. |
|
|
|
|
| Secondary | 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. | The full analysis set included all patients randomised in the study. | Posted | Mean | Standard Error | log (mmol/L) / hour | From 0 to 24 hours. |
|
|
|
|
| Secondary | 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. | The full analysis set included all patients randomised in the study. | Posted | Number | Percentage of Patients | At 24 hours. |
|
|
|
|
| Secondary | 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. | The full analysis set included all patients randomised in the study. | Posted | Number | Percentage of Patients | From baseline to end of study (9 days). |
|
|
|
| Secondary | 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. | The full analysis set included all patients randomised in the study. | Posted | Mean | Standard Deviation | mmol/L | From baseline to end of study (9 days). |
|
|
|
| Secondary | 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. | The full analysis set included all patients randomised in the study. | Posted | Mean | Standard Deviation | Percent change | From baseline to end of study (9 days). |
|
|
|
| Secondary | 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. | The full analysis set included all patients randomised in the study. | Posted | Median | 95% Confidence Interval | Hours | From 0 to 48 hours. |
|
|
|
|
| Secondary | 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. | The full analysis set included all patients randomised in the study. | Posted | Median | 95% Confidence Interval | Hours | From 0 to 48 hours. |
|
|
|
|
| 34 |
| 0 |
| 34 |
| 4 |
| 34 |
| EG001 | ZS 10 g TID | ZS suspension was administered 10 g orally TID for 48 hours. | 0 | 36 | 0 | 36 | 5 | 36 |
| EG002 | Placebo TID | Placebo suspension was administered orally TID for 48 hours. | 0 | 33 | 0 | 33 | 1 | 33 |
| Viral upper respiratory tract infection | Infections and infestations | MedDRA version 20.0 | Systematic Assessment |
|
| Nephrogenic anaemia | Blood and lymphatic system disorders | MedDRA version 20.0 | Systematic Assessment |
|
| Hypoglycaemia | Metabolism and nutrition disorders | MedDRA version 20.0 | Systematic Assessment |
|
| Tension headache | Nervous system disorders | MedDRA version 20.0 | Systematic Assessment |
|
| Tremor | Nervous system disorders | MedDRA version 20.0 | Systematic Assessment |
|
| Ventricular extrasystoles | Cardiac disorders | MedDRA version 20.0 | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA version 20.0 | Systematic Assessment |
|
| Erythema | Skin and subcutaneous tissue disorders | MedDRA version 20.0 | Systematic Assessment |
|
| Thirst | General disorders | MedDRA version 20.0 | Systematic Assessment |
|
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| Regression, Logistic |
| <0.0001 |
| Odds Ratio (OR) |
| 71.835 |
| 2-Sided |
| 95 |
| 13.497 |
| 382.337 |
| Superiority |
|
Exponential rate of change in S-K through to 24 hours was analysed with a mixed effect model (random slope model). |
| Mixed Models Analysis |
| <0.0001 |
| Treatment difference in slopes |
| -0.00401 |
| Standard Error of the Mean |
| 0.000637 |
| 2-Sided |
| 95 |
| -0.00527 |
| -0.00275 |
Negative exponential rate of change relative to placebo indicates more rapid reduction (correction) of S-K. |
| Other |
| Regression, Logistic |
| <0.0001 |
| Odds Ratio (OR) |
| 15.334 |
| 2-Sided |
| 95 |
| 4.006 |
| 58.697 |
| Superiority |
| Title | Measurements |
|---|---|
|
| 2 hours after first dose |
|
| 4 hours after first dose |
|
| 24 hours after first dose |
|
| 25 hours after first dose |
|
| 28 hours after first dose |
|
| 48 hours after first dose |
|
| End of study (Last dose + 7 days) |
|
| 2 hours after first dose |
|
|
| 4 hours after first dose |
|
|
| 24 hours after first dose |
|
|
| 25 hours after first dose |
|
|
| 28 hours after first dose |
|
|
| 48 hours after first dose |
|
|
| End of study (Last dose + 7 days) |
|
|
| 2 hours after first dose |
|
|
| 4 hours after first dose |
|
|
| 24 hours after first dose |
|
|
| 25 hours after first dose |
|
|
| 28 hours after first dose |
|
|
| 48 hours after first dose |
|
|
| End of study (Last dose + 7 days) |
|
|
Nominal p value
| Superiority |
Nominal p value
| Superiority |