Hyperkalemia
Conditions
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.
Interventions
Suspension administered 5g orally three times daily for 48 hours.
Suspension administered 10g orally three times daily for 48 hours.
DRUGPlacebo
Placebo suspension administered orally placebo three times daily for 48 hours.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Exponential Rate of Change in Serum Potassium (S-K) Values During the Initial 48 Hours of Study Drug Treatment | From 0 to 48 hours. | 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
| Measure | Time frame | Description |
|---|---|---|
| Exponential Rate of Change in S-K Values During the Initial 24 Hours of Study Drug Treatment | From 0 to 24 hours. | 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 | 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 | From baseline to end of study (9 days). | 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. |
| Percentage of Patients Who Achieved Normokalaemia at 48 Hours | 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. |
| Mean Percent Change From Baseline in S-K Values at All Measured Time Intervals | From baseline to end of study (9 days). | 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 | From 0 to 48 hours. | 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 | From 0 to 48 hours. | The median time (hours) for S-K values to decrease by 0.5 mmol/L was measured. |
| Mean Change From Baseline in S-K Values at All Measured Time Intervals | From baseline to end of study (9 days). | 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. |
Countries
Japan
Participant flow
Recruitment details
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.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| ZS 5 g TID ZS suspension was administered 5 g orally TID for 48 hours. | 34 |
| ZS 10 g TID ZS suspension was administered 10 g orally TID for 48 hours. | 36 |
| Placebo TID Placebo suspension was administered orally TID for 48 hours. | 33 |
| Total | 103 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Study-specific withdrawal criteria | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | ZS 5 g TID | ZS 10 g TID | Placebo TID | Total |
|---|---|---|---|---|
| Age, Continuous | 72.4 Years STANDARD_DEVIATION 7.9 | 71.1 Years STANDARD_DEVIATION 7.6 | 76.1 Years STANDARD_DEVIATION 6.8 | 73.2 Years STANDARD_DEVIATION 7.7 |
| Age, Customized 55 to 64 years | 7 Participants | 4 Participants | 1 Participants | 12 Participants |
| Age, Customized <55 years | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Age, Customized ≥65 years | 27 Participants | 31 Participants | 32 Participants | 90 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 34 Participants | 36 Participants | 33 Participants | 103 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 34 Participants | 36 Participants | 33 Participants | 103 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 8 Participants | 8 Participants | 10 Participants | 26 Participants |
| Sex: Female, Male Male | 26 Participants | 28 Participants | 23 Participants | 77 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 34 | 0 / 36 | 0 / 33 |
| other Total, other adverse events | 4 / 34 | 5 / 36 | 1 / 33 |
| serious Total, serious adverse events | 0 / 34 | 0 / 36 | 0 / 33 |
Outcome results
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.
Time frame: From 0 to 48 hours.
Population: The full analysis set included all patients randomised in the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ZS 5 g TID | Exponential Rate of Change in Serum Potassium (S-K) Values During the Initial 48 Hours of Study Drug Treatment | -0.00273 log (mmol/L) / hour | Standard Error 0.000276 |
| ZS 10 g TID | Exponential Rate of Change in Serum Potassium (S-K) Values During the Initial 48 Hours of Study Drug Treatment | -0.00508 log (mmol/L) / hour | Standard Error 0.000269 |
| Placebo TID | Exponential Rate of Change in Serum Potassium (S-K) Values During the Initial 48 Hours of Study Drug Treatment | -0.00012 log (mmol/L) / hour | Standard Error 0.000288 |
Comparison: Exponential rate of change in S-K through to 48 hours was analysed with a mixed effect model (random slope model).p-value: <0.000195% CI: [-0.00571, -0.0042]Mixed Models Analysis
Comparison: Exponential rate of change in S-K through to 48 hours was analysed with a mixed effect model (random slope model).p-value: <0.00195% CI: [-0.00337, -0.00185]Mixed Models Analysis
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.
Time frame: From 0 to 24 hours.
Population: The full analysis set included all patients randomised in the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ZS 5 g TID | Exponential Rate of Change in S-K Values During the Initial 24 Hours of Study Drug Treatment | -0.00234 log (mmol/L) / hour | Standard Error 0.000468 |
| ZS 10 g TID | Exponential Rate of Change in S-K Values During the Initial 24 Hours of Study Drug Treatment | -0.00403 log (mmol/L) / hour | Standard Error 0.000457 |
| Placebo TID | Exponential Rate of Change in S-K Values During the Initial 24 Hours of Study Drug Treatment | -0.00002 log (mmol/L) / hour | Standard Error 0.000489 |
Comparison: Exponential rate of change in S-K through to 24 hours was analysed with a mixed effect model (random slope model).p-value: 0.000495% CI: [-0.00359, -0.00104]Mixed Models Analysis
Comparison: Exponential rate of change in S-K through to 24 hours was analysed with a mixed effect model (random slope model).p-value: <0.000195% CI: [-0.00527, -0.00275]Mixed Models Analysis
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.
Time frame: From baseline to end of study (9 days).
Population: The full analysis set included all patients randomised in the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ZS 5 g TID | Mean Change From Baseline in S-K Values at All Measured Time Intervals | 1 hour after first dose | -0.20 mmol/L | Standard Deviation 0.34 |
| ZS 5 g TID | Mean Change From Baseline in S-K Values at All Measured Time Intervals | 2 hours after first dose | -0.41 mmol/L | Standard Deviation 0.28 |
| ZS 5 g TID | Mean Change From Baseline in S-K Values at All Measured Time Intervals | 4 hours after first dose | -0.40 mmol/L | Standard Deviation 0.32 |
| ZS 5 g TID | Mean Change From Baseline in S-K Values at All Measured Time Intervals | 24 hours after first dose | -0.51 mmol/L | Standard Deviation 0.3 |
| ZS 5 g TID | Mean Change From Baseline in S-K Values at All Measured Time Intervals | 25 hours after first dose | -0.74 mmol/L | Standard Deviation 0.31 |
| ZS 5 g TID | Mean Change From Baseline in S-K Values at All Measured Time Intervals | 28 hours after first dose | -0.72 mmol/L | Standard Deviation 0.35 |
| ZS 5 g TID | Mean Change From Baseline in S-K Values at All Measured Time Intervals | 48 hours after first dose | -0.83 mmol/L | Standard Deviation 0.31 |
| ZS 5 g TID | Mean Change From Baseline in S-K Values at All Measured Time Intervals | End of study (Last dose + 7 days) | -0.56 mmol/L | Standard Deviation 0.38 |
| ZS 10 g TID | Mean Change From Baseline in S-K Values at All Measured Time Intervals | 4 hours after first dose | -0.53 mmol/L | Standard Deviation 0.36 |
| ZS 10 g TID | Mean Change From Baseline in S-K Values at All Measured Time Intervals | 48 hours after first dose | -1.30 mmol/L | Standard Deviation 0.48 |
| ZS 10 g TID | Mean Change From Baseline in S-K Values at All Measured Time Intervals | 24 hours after first dose | -0.69 mmol/L | Standard Deviation 0.38 |
| ZS 10 g TID | Mean Change From Baseline in S-K Values at All Measured Time Intervals | 25 hours after first dose | -1.00 mmol/L | Standard Deviation 0.45 |
| ZS 10 g TID | Mean Change From Baseline in S-K Values at All Measured Time Intervals | 28 hours after first dose | -1.12 mmol/L | Standard Deviation 0.39 |
| ZS 10 g TID | Mean Change From Baseline in S-K Values at All Measured Time Intervals | 1 hour after first dose | -0.37 mmol/L | Standard Deviation 0.35 |
| ZS 10 g TID | Mean Change From Baseline in S-K Values at All Measured Time Intervals | 2 hours after first dose | -0.50 mmol/L | Standard Deviation 0.4 |
| ZS 10 g TID | Mean Change From Baseline in S-K Values at All Measured Time Intervals | End of study (Last dose + 7 days) | -0.66 mmol/L | Standard Deviation 0.52 |
| Placebo TID | Mean Change From Baseline in S-K Values at All Measured Time Intervals | 4 hours after first dose | -0.43 mmol/L | Standard Deviation 0.31 |
| Placebo TID | Mean Change From Baseline in S-K Values at All Measured Time Intervals | 2 hours after first dose | -0.33 mmol/L | Standard Deviation 0.3 |
| Placebo TID | Mean Change From Baseline in S-K Values at All Measured Time Intervals | 1 hour after first dose | -0.13 mmol/L | Standard Deviation 0.32 |
| Placebo TID | Mean Change From Baseline in S-K Values at All Measured Time Intervals | 24 hours after first dose | -0.22 mmol/L | Standard Deviation 0.35 |
| Placebo TID | Mean Change From Baseline in S-K Values at All Measured Time Intervals | 48 hours after first dose | -0.24 mmol/L | Standard Deviation 0.34 |
| Placebo TID | Mean Change From Baseline in S-K Values at All Measured Time Intervals | 28 hours after first dose | -0.41 mmol/L | Standard Deviation 0.43 |
| Placebo TID | Mean Change From Baseline in S-K Values at All Measured Time Intervals | 25 hours after first dose | -0.27 mmol/L | Standard Deviation 0.31 |
| Placebo TID | Mean Change From Baseline in S-K Values at All Measured Time Intervals | End of study (Last dose + 7 days) | -0.20 mmol/L | Standard Deviation 0.59 |
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.
Time frame: From baseline to end of study (9 days).
Population: The full analysis set included all patients randomised in the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ZS 5 g TID | Mean Percent Change From Baseline in S-K Values at All Measured Time Intervals | 1 hour after first dose | -3.61 Percent change | Standard Deviation 6.28 |
| ZS 5 g TID | Mean Percent Change From Baseline in S-K Values at All Measured Time Intervals | 2 hours after first dose | -7.46 Percent change | Standard Deviation 5.04 |
| ZS 5 g TID | Mean Percent Change From Baseline in S-K Values at All Measured Time Intervals | 4 hours after first dose | -7.08 Percent change | Standard Deviation 5.65 |
| ZS 5 g TID | Mean Percent Change From Baseline in S-K Values at All Measured Time Intervals | 24 hours after first dose | -8.98 Percent change | Standard Deviation 5.33 |
| ZS 5 g TID | Mean Percent Change From Baseline in S-K Values at All Measured Time Intervals | 25 hours after first dose | -13.20 Percent change | Standard Deviation 5.42 |
| ZS 5 g TID | Mean Percent Change From Baseline in S-K Values at All Measured Time Intervals | 28 hours after first dose | -12.90 Percent change | Standard Deviation 6.1 |
| ZS 5 g TID | Mean Percent Change From Baseline in S-K Values at All Measured Time Intervals | 48 hours after first dose | -14.81 Percent change | Standard Deviation 5.08 |
| ZS 5 g TID | Mean Percent Change From Baseline in S-K Values at All Measured Time Intervals | End of study (Last dose + 7 days) | -9.85 Percent change | Standard Deviation 6.51 |
| ZS 10 g TID | Mean Percent Change From Baseline in S-K Values at All Measured Time Intervals | 4 hours after first dose | -9.70 Percent change | Standard Deviation 6.53 |
| ZS 10 g TID | Mean Percent Change From Baseline in S-K Values at All Measured Time Intervals | 48 hours after first dose | -23.64 Percent change | Standard Deviation 8.27 |
| ZS 10 g TID | Mean Percent Change From Baseline in S-K Values at All Measured Time Intervals | 24 hours after first dose | -12.51 Percent change | Standard Deviation 6.3 |
| ZS 10 g TID | Mean Percent Change From Baseline in S-K Values at All Measured Time Intervals | 25 hours after first dose | -18.06 Percent change | Standard Deviation 7.05 |
| ZS 10 g TID | Mean Percent Change From Baseline in S-K Values at All Measured Time Intervals | 28 hours after first dose | -20.47 Percent change | Standard Deviation 6.38 |
| ZS 10 g TID | Mean Percent Change From Baseline in S-K Values at All Measured Time Intervals | 1 hour after first dose | -6.72 Percent change | Standard Deviation 6.29 |
| ZS 10 g TID | Mean Percent Change From Baseline in S-K Values at All Measured Time Intervals | 2 hours after first dose | -9.07 Percent change | Standard Deviation 6.88 |
| ZS 10 g TID | Mean Percent Change From Baseline in S-K Values at All Measured Time Intervals | End of study (Last dose + 7 days) | -11.89 Percent change | Standard Deviation 9.07 |
| Placebo TID | Mean Percent Change From Baseline in S-K Values at All Measured Time Intervals | 4 hours after first dose | -7.77 Percent change | Standard Deviation 5.62 |
| Placebo TID | Mean Percent Change From Baseline in S-K Values at All Measured Time Intervals | 2 hours after first dose | -6.06 Percent change | Standard Deviation 5.4 |
| Placebo TID | Mean Percent Change From Baseline in S-K Values at All Measured Time Intervals | 1 hour after first dose | -2.32 Percent change | Standard Deviation 5.6 |
| Placebo TID | Mean Percent Change From Baseline in S-K Values at All Measured Time Intervals | 24 hours after first dose | -3.81 Percent change | Standard Deviation 6.24 |
| Placebo TID | Mean Percent Change From Baseline in S-K Values at All Measured Time Intervals | 48 hours after first dose | -4.06 Percent change | Standard Deviation 5.93 |
| Placebo TID | Mean Percent Change From Baseline in S-K Values at All Measured Time Intervals | 28 hours after first dose | -7.21 Percent change | Standard Deviation 7.61 |
| Placebo TID | Mean Percent Change From Baseline in S-K Values at All Measured Time Intervals | 25 hours after first dose | -4.77 Percent change | Standard Deviation 5.66 |
| Placebo TID | Mean Percent Change From Baseline in S-K Values at All Measured Time Intervals | End of study (Last dose + 7 days) | -3.15 Percent change | Standard Deviation 9.99 |
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.
Time frame: At 24 hours.
Population: The full analysis set included all patients randomised in the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ZS 5 g TID | Percentage of Patients Who Achieved Normokalaemia at 24 Hours | 35.3 Percentage of Patients |
| ZS 10 g TID | Percentage of Patients Who Achieved Normokalaemia at 24 Hours | 83.3 Percentage of Patients |
| Placebo TID | Percentage of Patients Who Achieved Normokalaemia at 24 Hours | 27.3 Percentage of Patients |
Comparison: Logistic regression model including treatment and baseline S-K as explanatory variables was used.p-value: 0.616795% CI: [0.419, 4.329]Regression, Logistic
Comparison: Logistic regression model including treatment and baseline S-K as explanatory variables was used.p-value: <0.000195% CI: [4.006, 58.697]Regression, Logistic
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.
Time frame: At 48 hours.
Population: The full analysis set included all patients randomised in the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ZS 5 g TID | Percentage of Patients Who Achieved Normokalaemia at 48 Hours | 85.3 Percentage of Patients |
| ZS 10 g TID | Percentage of Patients Who Achieved Normokalaemia at 48 Hours | 91.7 Percentage of Patients |
| Placebo TID | Percentage of Patients Who Achieved Normokalaemia at 48 Hours | 15.2 Percentage of Patients |
Comparison: Logistic regression model including treatment and baseline S-K as explanatory variables was used.p-value: <0.000195% CI: [10.142, 213.152]Regression, Logistic
Comparison: Logistic regression model including treatment and baseline S-K as explanatory variables was used.p-value: <0.000195% CI: [13.497, 382.337]Regression, Logistic
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.
Time frame: From baseline to end of study (9 days).
Population: The full analysis set included all patients randomised in the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ZS 5 g TID | Percentage of Patients Who Achieved Normokalaemia at Each Scheduled Potassium Assessment Time Point | 4 hours after first dose | 44.1 Percentage of Patients |
| ZS 5 g TID | Percentage of Patients Who Achieved Normokalaemia at Each Scheduled Potassium Assessment Time Point | End of study (Last dose + 7 days) | 55.9 Percentage of Patients |
| ZS 5 g TID | Percentage of Patients Who Achieved Normokalaemia at Each Scheduled Potassium Assessment Time Point | 25 hours after first dose | 73.5 Percentage of Patients |
| ZS 5 g TID | Percentage of Patients Who Achieved Normokalaemia at Each Scheduled Potassium Assessment Time Point | 24 hours after first dose | 35.3 Percentage of Patients |
| ZS 5 g TID | Percentage of Patients Who Achieved Normokalaemia at Each Scheduled Potassium Assessment Time Point | Baseline | 2.9 Percentage of Patients |
| ZS 5 g TID | Percentage of Patients Who Achieved Normokalaemia at Each Scheduled Potassium Assessment Time Point | 48 hours after first dose | 85.3 Percentage of Patients |
| ZS 5 g TID | Percentage of Patients Who Achieved Normokalaemia at Each Scheduled Potassium Assessment Time Point | 2 hours after first dose | 41.2 Percentage of Patients |
| ZS 5 g TID | Percentage of Patients Who Achieved Normokalaemia at Each Scheduled Potassium Assessment Time Point | 1 hour after first dose | 29.4 Percentage of Patients |
| ZS 5 g TID | Percentage of Patients Who Achieved Normokalaemia at Each Scheduled Potassium Assessment Time Point | 28 hours after first dose | 67.6 Percentage of Patients |
| ZS 10 g TID | Percentage of Patients Who Achieved Normokalaemia at Each Scheduled Potassium Assessment Time Point | 24 hours after first dose | 83.3 Percentage of Patients |
| ZS 10 g TID | Percentage of Patients Who Achieved Normokalaemia at Each Scheduled Potassium Assessment Time Point | Baseline | 5.6 Percentage of Patients |
| ZS 10 g TID | Percentage of Patients Who Achieved Normokalaemia at Each Scheduled Potassium Assessment Time Point | 1 hour after first dose | 47.2 Percentage of Patients |
| ZS 10 g TID | Percentage of Patients Who Achieved Normokalaemia at Each Scheduled Potassium Assessment Time Point | 2 hours after first dose | 58.3 Percentage of Patients |
| ZS 10 g TID | Percentage of Patients Who Achieved Normokalaemia at Each Scheduled Potassium Assessment Time Point | 4 hours after first dose | 63.9 Percentage of Patients |
| ZS 10 g TID | Percentage of Patients Who Achieved Normokalaemia at Each Scheduled Potassium Assessment Time Point | 25 hours after first dose | 97.2 Percentage of Patients |
| ZS 10 g TID | Percentage of Patients Who Achieved Normokalaemia at Each Scheduled Potassium Assessment Time Point | 28 hours after first dose | 97.2 Percentage of Patients |
| ZS 10 g TID | Percentage of Patients Who Achieved Normokalaemia at Each Scheduled Potassium Assessment Time Point | 48 hours after first dose | 91.7 Percentage of Patients |
| ZS 10 g TID | Percentage of Patients Who Achieved Normokalaemia at Each Scheduled Potassium Assessment Time Point | End of study (Last dose + 7 days) | 61.1 Percentage of Patients |
| Placebo TID | Percentage of Patients Who Achieved Normokalaemia at Each Scheduled Potassium Assessment Time Point | 2 hours after first dose | 42.4 Percentage of Patients |
| Placebo TID | Percentage of Patients Who Achieved Normokalaemia at Each Scheduled Potassium Assessment Time Point | Baseline | 0.0 Percentage of Patients |
| Placebo TID | Percentage of Patients Who Achieved Normokalaemia at Each Scheduled Potassium Assessment Time Point | 28 hours after first dose | 36.4 Percentage of Patients |
| Placebo TID | Percentage of Patients Who Achieved Normokalaemia at Each Scheduled Potassium Assessment Time Point | 1 hour after first dose | 21.2 Percentage of Patients |
| Placebo TID | Percentage of Patients Who Achieved Normokalaemia at Each Scheduled Potassium Assessment Time Point | End of study (Last dose + 7 days) | 27.3 Percentage of Patients |
| Placebo TID | Percentage of Patients Who Achieved Normokalaemia at Each Scheduled Potassium Assessment Time Point | 24 hours after first dose | 27.3 Percentage of Patients |
| Placebo TID | Percentage of Patients Who Achieved Normokalaemia at Each Scheduled Potassium Assessment Time Point | 4 hours after first dose | 42.4 Percentage of Patients |
| Placebo TID | Percentage of Patients Who Achieved Normokalaemia at Each Scheduled Potassium Assessment Time Point | 48 hours after first dose | 15.2 Percentage of Patients |
| Placebo TID | Percentage of Patients Who Achieved Normokalaemia at Each Scheduled Potassium Assessment Time Point | 25 hours after first dose | 18.2 Percentage of Patients |
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.
Time frame: From 0 to 48 hours.
Population: The full analysis set included all patients randomised in the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ZS 5 g TID | Time to a Decrease in S-K Levels of 0.5 mmol/L | 3.883 Hours |
| ZS 10 g TID | Time to a Decrease in S-K Levels of 0.5 mmol/L | 2.892 Hours |
| Placebo TID | Time to a Decrease in S-K Levels of 0.5 mmol/L | 4.050 Hours |
p-value: 0.025Log Rank
p-value: 0.0064Log Rank
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.
Time frame: From 0 to 48 hours.
Population: The full analysis set included all patients randomised in the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ZS 5 g TID | Time to Normalisation in S-K Values | 3.883 Hours |
| ZS 10 g TID | Time to Normalisation in S-K Values | 1.758 Hours |
| Placebo TID | Time to Normalisation in S-K Values | 3.867 Hours |
p-value: 0.0586Log Rank
p-value: 0.0006Log Rank