Hyperkalemia
Conditions
Brief summary
To evaluate the efficacy of two different doses (5 and 10 g) of ZS orally administered once daily (qd) vs placebo in maintaining normokalemia in initially hyperkalemic patients having achieved normokalemia following 24 or 48 hours of initial ZS therapy (10g TID).
Detailed description
This study will be conducted in approximately 35 centers in China. Before patients are randomized to the double-blind phase, they will receive open-label ZS for 24 or 48 hours during the initial phase. It is expected that approximately 490 patients will need to be enrolled, to have approximately 280 patients entered into the open-label initial phase resulting in 250 patients being randomized in the 28-day treatment study phase. Enrolment will be stopped when 250 patients have been initiated with the 28-day randomized treatment study phase.
Interventions
DRUGSodium Zirconium Cyclosilicate 5g
Suspension administered Sodium Zirconium Cyclosilicate 5g orally once daily for 28 days after the open label initial phase with suspension administered Sodium Zirconium Cyclosilicate 10g orally three times per day for at most 2 days.
DRUGSodium Zirconium Cyclosilicate 10g
Suspension administered Sodium Zirconium Cyclosilicate 10g orally once daily for 28 days after the open label initial phase with suspension administered Sodium Zirconium Cyclosilicate 10g orally three times per day for at most 2 days.
DRUGPlacebo
Suspension administered orally placebo once daily for 28 days after the open label initial phase with suspension administered Sodium Zirconium Cyclosilicate 10g orally three times per day for at most 2 days.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
1. Provision of informed consent (pre-screening consent) prior to any study specific procedures 2. Female and male patients aged ≥18 and ≤ 90 years 3. Provision of informed consent prior to any study specific procedures 4. Two consecutive i-STAT potassium values, measured 60 minutes (± 10 minutes) apart, both ≥ 5.1 mmol/L and measured within 1 day of the first ZS dose on open-label initial phase Day 1 5. Ability to have repeated blood draws or effective venous catheterization 6. Female patients must be 1 year post-menopausal, surgically sterile, or using an acceptable method of contraception 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
1. Involvement in the planning and/or conduct of the study 2. Participation in another clinical study with an investigational product during the last 3 months 3. 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 4. Pseudohyperkalemia signs and symptoms, such as hemolyzed blood specimen due to excessive fist clenching to make veins prominent, difficult or traumatic venepuncture, or history of severe leukocytosis or thrombocytosis 5. Patients treated with lactulose, xifaxan (rifaximin) or other non-absorbed antibiotics for hyperammonemia within 7 days prior to the first dose of study drug 6. Patients treated with resins,calcium acetate,calcium carbonate, or lanthanum carbonate,within 7 days prior to the first dose of study drug 7. Patients with a life expectancy of less than 3 months 8. Patients 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 9. Female patients who are pregnant, lactating, or planning to become pregnant 10. Patients with diabetic ketoacidosis 11. Known hypersensitivity or previous anaphylaxis to ZS or to components thereof 12. Patients with cardiac arrhythmias that require immediate treatment 13. History of QT prolongation associated with other medications that required discontinuation of that medication. 14. Congenital long QT syndrome 15. Symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Subjects with atrial fibrillation controlled by medication are permitted 16. QTc(f) \> 550 msec 17. Patients on dialysis 18. Patients who are blood donors should not donate blood during the study and for 3 months following their last dose of ZS 19. Patients who need hospitalization after taking blood samples on day 1 of the open-label initial phase
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Least Square Mean S-K Level on Days 8-29 | Days 8 to 29 (Randomized treatment study phase) used for model-based least squares mean computation | Comparison between placebo and each SZC treatment group (high to low) with regard to the mean S-K level during the randomized treatment phase days 8-29. Mixed-effects models were used to estimate least-squares means. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Exponential Rate of Change in S-K Levels | Through 24 hours post-dose in the initial phase | Exponential rate of change in S-K levels (blood) during the open-label initial phase 24 hours post-dose. Least Square Mean corresponds to the exponential rate of change i.e. the slope (for time) in terms of log-transformed S-K levels. The results in the table below are presented for OLP. |
| Absolute Change From Baseline in S-K Levels | Through open label initial phase | Absolute change from baseline in S-K levels at all measured time intervals. End of OLP is defined as Day 2 (24 hours post first dose) or Day 3 (48 hours post first dose) depending on when the subject achieved normokalemia based on the pre-dose i-STAT potassium level. The results in the table below are presented for OLP. |
| Percentage Change From Baseline in S-K Levels | Through open label initial phase | Percentage change from baseline in S-K levels at all measured time intervals. End of OLP is defined as Day 2 (24 hours post first dose) or Day 3 (48 hours post first dose) depending on when the subject achieved normokalemia based on the pre-dose i-STAT potassium level. The results in the table below are presented for OLP. |
| Proportion of Patients Who Remain Normokalemic During RTP | Through 28-day randomized treatment study phase day 8-29 | Proportion of patients who remain normokalemic (as defined by S-K between 3.5-5.0 mmol/l, inclusive) during RTP (Day 8 to Day 29). The results in the table below are presented for RTP. |
| Proportion of Normokalemic Patients at the End of RTP | The end of 28-day randomized treatment study phase | Proportion of normokalemic patients (as defined by S-K between 3.5-5.0 mmol/l, inclusive). The results in the table below are presented for RTP. |
| Percentage of Patients Who Achieve Normokalemia | Through open label initial phase | Percentage of patients who achieve normokalemia during the open label initial phase at 24 hours and at the end of the open label phase. End of OLP is defined as Day 2 (24 hours post first dose) or Day 3 (48 hours post first dose) depending on when the subject achieved normokalemia based on the pre-dose i-STAT potassium level. The results in the table below are presented for OLP. |
| Mean Change in S-K Levels | Through 28-day randomized treatment phase. | The mean change in S-K levels evaluated relative to the RTP baseline. The results in the table below are presented for RTP. |
| Mean Percent Change in S-K Levels | Through 28-day randomized treatment phase. | The mean percent change in S-K levels evaluated relative to the RTP baseline. The results in the table below are presented for RTP. |
| Least Square Mean Changes in S-Aldo and P-Renin Levels | Through 28 day randomized treatment study phase day 15-29 | Comparison between placebo and each SZC treatment group (high to low) with regard to the mean S-Aldo and P-Renin levels during the randomized treatment phase days 15-29. |
| Hyperkalaemia at Day 29 | Day 29 | The number of patients with hyperkalaemia at day 29. The results in the table below are presented for RTP. |
| Percentage of Patients Without Hyperkalemia | Day 29 of randomized treatment phase | Kaplan-Meier estimate at Day 29 of percentage of patients without hyperkalemia. The results in the table below are presented for RTP. |
| Days Patients Remain Normokalemic | Through days 8-29 of the randomized treatment phase. | The number of days patients remain normokalemic during days 8-29 of the randomized treatment study phase. The results in the table below are presented for RTP. |
Countries
China, India
Participant flow
Recruitment details
The study was conducted in 35 sites in China.
Pre-assignment details
The study consisted of two phases, an Open-label initial phase (OLP) and a Randomized treatment phase (RTP). 270 participants entered OLP, out of these 250 entered RTP & received Placebo, SZC 5g QD, or SZC 10g QD in a 1:2:2 ratio.
Participants by arm
| Arm | Count |
|---|---|
| Sodium Zirconium Cyclosilicate (SZC) Suspension administered 10g orally 3 times per day for the open-label initial phase | 270 |
| Sodium Zirconium Cyclosilicate (SZC) 5g QD Suspension administered 5g orally once daily for 28 days after the open-label initial phase | 100 |
| Sodium Zirconium Cyclosilicate (SZC) 10g QD Suspension administered 10g orally once daily for 28 days after the open-label initial phase | 100 |
| Placebo Suspension administered placebo orally once daily for 28 days after the open-label initial phase. | 50 |
| Total | 520 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Open-Label Phase | (Not collected) | 4 | 0 | 0 | 0 |
| Open-Label Phase | Physician Decision | 2 | 0 | 0 | 0 |
| Open-Label Phase | Withdrawal by Subject | 8 | 0 | 0 | 0 |
| Randomized Treatment Phase | Lost to Follow-up | 0 | 0 | 1 | 0 |
| Randomized Treatment Phase | (Not collected) | 0 | 4 | 6 | 5 |
| Randomized Treatment Phase | Physician Decision | 0 | 5 | 1 | 2 |
| Randomized Treatment Phase | (Study specific withdrawal criteria) | 0 | 3 | 3 | 4 |
| Randomized Treatment Phase | Withdrawal by Subject | 0 | 7 | 4 | 1 |
Baseline characteristics
| Characteristic | Sodium Zirconium Cyclosilicate (SZC) | Total | Sodium Zirconium Cyclosilicate (SZC) 5g QD | Sodium Zirconium Cyclosilicate (SZC) 10g QD | Placebo |
|---|---|---|---|---|---|
| Age, Continuous Open-label initial phase (OLP) | 56.4 Years STANDARD_DEVIATION 14.17 | 56.4 Years STANDARD_DEVIATION 14.17 | — | — | — |
| Age, Continuous Randomized treatment phase (RTP) | — | 55.9 Years STANDARD_DEVIATION 14.28 | 54.3 Years STANDARD_DEVIATION 13.92 | 55.6 Years STANDARD_DEVIATION 14.47 | 59.7 Years STANDARD_DEVIATION 14.2 |
| Race/Ethnicity, Customized Not Hispanic or Latino Open-label initial phase (OLP) | 270 Participants | 270 Participants | — | — | — |
| Race/Ethnicity, Customized Not Hispanic or Latino Randomized treatment phase (RTP) | — | 250 Participants | 100 Participants | 100 Participants | 50 Participants |
| Sex: Female, Male Open-label initial phase (OLP) Female | 103 Participants | 103 Participants | — | — | — |
| Sex: Female, Male Open-label initial phase (OLP) Male | 167 Participants | 167 Participants | — | — | — |
| Sex: Female, Male Randomized treatment phase (RTP) Female | — | 94 Participants | 35 Participants | 40 Participants | 19 Participants |
| Sex: Female, Male Randomized treatment phase (RTP) Male | — | 156 Participants | 65 Participants | 60 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 270 | 0 / 100 | 0 / 100 | 0 / 50 |
| other Total, other adverse events | 38 / 270 | 48 / 100 | 42 / 100 | 17 / 50 |
| serious Total, serious adverse events | 1 / 270 | 6 / 100 | 3 / 100 | 1 / 50 |
Outcome results
Primary
Least Square Mean S-K Level on Days 8-29
Comparison between placebo and each SZC treatment group (high to low) with regard to the mean S-K level during the randomized treatment phase days 8-29. Mixed-effects models were used to estimate least-squares means.
Time frame: Days 8 to 29 (Randomized treatment study phase) used for model-based least squares mean computation
Population: Full analysis set - Randomized Treatment Phase
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) 5g QD | Least Square Mean S-K Level on Days 8-29 | 4.859 mmol/L |
| Sodium Zirconium Cyclosilicate (SZC) 10g QD | Least Square Mean S-K Level on Days 8-29 | 4.440 mmol/L |
| Placebo | Least Square Mean S-K Level on Days 8-29 | 5.225 mmol/L |
Comparison: Results are derived from a longitudinal model applied to log-transformed S-K measurements adjusted for treatment, visit, treatment-by-visit interaction and baseline covariates. The back-transformation is to the original scale of the S-K measurementp-value: <0.00195% CI: [0.902, 0.959]Mixed Models Analysis
Comparison: Results are derived from a longitudinal model applied to log-transformed S-K measurements adjusted for treatment, visit, treatment-by-visit interaction and baseline covariates. The back-transformation is to the original scale of the S-K measurementp-value: <0.00195% CI: [0.825, 0.876]Mixed Models Analysis
Secondary
Absolute Change From Baseline in S-K Levels
Absolute change from baseline in S-K levels at all measured time intervals. End of OLP is defined as Day 2 (24 hours post first dose) or Day 3 (48 hours post first dose) depending on when the subject achieved normokalemia based on the pre-dose i-STAT potassium level. The results in the table below are presented for OLP.
Time frame: Through open label initial phase
Population: Full analysis set - Open Label Phase
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) 10g TID | Absolute Change From Baseline in S-K Levels | OLP - 24 hours | -0.936 mmol/L | Standard Deviation 0.377 |
| Sodium Zirconium Cyclosilicate (SZC) 10g TID | Absolute Change From Baseline in S-K Levels | End of OLP | -1.107 mmol/L | Standard Deviation 0.466 |
Secondary
Days Patients Remain Normokalemic
The number of days patients remain normokalemic during days 8-29 of the randomized treatment study phase. The results in the table below are presented for RTP.
Time frame: Through days 8-29 of the randomized treatment phase.
Population: Full analysis set - Randomized Treatment Phase
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) 5g QD | Days Patients Remain Normokalemic | 9.11 Day | Standard Error 1.413 |
| Sodium Zirconium Cyclosilicate (SZC) 10g QD | Days Patients Remain Normokalemic | 14.54 Day | Standard Error 1.397 |
| Placebo | Days Patients Remain Normokalemic | 3.40 Day | Standard Error 1.473 |
Comparison: Results derived from a linear regression model with the following covariates: treatment group; baseline S-K values (Open-label phase and Randomized treatment phase); baseline eGFR; age category; country; baseline RAAS inhibitor, chronic kidney disease, heart failure, and diabetes mellitus statuses.p-value: <0.00195% CI: [3.13, 8.31]Regression, Linear
Comparison: Results derived from a linear regression model with the following covariates: treatment group; baseline S-K values (Open-label phase and Randomized treatment phase); baseline eGFR; age category; country; baseline RAAS inhibitor, chronic kidney disease, heart failure, and diabetes mellitus statuses.p-value: <0.00195% CI: [8.57, 13.71]Regression, Linear
Secondary
Exponential Rate of Change in S-K Levels
Exponential rate of change in S-K levels (blood) during the open-label initial phase 24 hours post-dose. Least Square Mean corresponds to the exponential rate of change i.e. the slope (for time) in terms of log-transformed S-K levels. The results in the table below are presented for OLP.
Time frame: Through 24 hours post-dose in the initial phase
Population: Full analysis set - Open Label Phase
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) 10g TID | Exponential Rate of Change in S-K Levels | -0.0051 log(mmol/L)/h | Standard Error 0.00027 |
Secondary
Hyperkalaemia at Day 29
The number of patients with hyperkalaemia at day 29. The results in the table below are presented for RTP.
Time frame: Day 29
Population: Full analysis set - Randomized Treatment Phase
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) 5g QD | Hyperkalaemia at Day 29 | 77 Participants |
| Sodium Zirconium Cyclosilicate (SZC) 10g QD | Hyperkalaemia at Day 29 | 50 Participants |
| Placebo | Hyperkalaemia at Day 29 | 48 Participants |
Secondary
Least Square Mean Changes in S-Aldo and P-Renin Levels
Comparison between placebo and each SZC treatment group (high to low) with regard to the mean S-Aldo and P-Renin levels during the randomized treatment phase days 15-29.
Time frame: Through 28 day randomized treatment study phase day 15-29
Population: Full analysis set - Randomized Treatment Phase
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) 5g QD | Least Square Mean Changes in S-Aldo and P-Renin Levels | S-Aldo | -21.926 pmol/L |
| Sodium Zirconium Cyclosilicate (SZC) 5g QD | Least Square Mean Changes in S-Aldo and P-Renin Levels | P-Renin | -0.348 pmol/L |
| Sodium Zirconium Cyclosilicate (SZC) 10g QD | Least Square Mean Changes in S-Aldo and P-Renin Levels | S-Aldo | -53.945 pmol/L |
| Sodium Zirconium Cyclosilicate (SZC) 10g QD | Least Square Mean Changes in S-Aldo and P-Renin Levels | P-Renin | -0.424 pmol/L |
| Placebo | Least Square Mean Changes in S-Aldo and P-Renin Levels | S-Aldo | 83.322 pmol/L |
| Placebo | Least Square Mean Changes in S-Aldo and P-Renin Levels | P-Renin | -0.362 pmol/L |
Comparison: S-Aldo Results derived from a longitudinal mixed model adjusted for treatment, visit, treatment-by-visit interaction and baseline covariatesp-value: <0.00195% CI: [-161.293, -49.203]Mixed Models Analysis
Comparison: S-Aldo Results derived from a longitudinal mixed model adjusted for treatment, visit, treatment-by-visit interaction and baseline covariatesp-value: <0.00195% CI: [-192.596, -81.937]Mixed Models Analysis
Comparison: P-Renin Results derived from a longitudinal mixed model adjusted for treatment, visit, treatment-by-visit interaction and baseline covariatesp-value: 0.83995% CI: [-0.12, 0.147]Mixed Models Analysis
Comparison: P-Renin Results derived from a longitudinal mixed model adjusted for treatment, visit, treatment-by-visit interaction and baseline covariatesp-value: 0.35595% CI: [-0.195, 0.07]Mixed Models Analysis
Secondary
Mean Change in S-K Levels
The mean change in S-K levels evaluated relative to the RTP baseline. The results in the table below are presented for RTP.
Time frame: Through 28-day randomized treatment phase.
Population: Full analysis set - Randomized Treatment Phase
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) 5g QD | Mean Change in S-K Levels | Day 2 change from RTP baseline | -0.04 mmol/L | Standard Deviation 0.299 |
| Sodium Zirconium Cyclosilicate (SZC) 5g QD | Mean Change in S-K Levels | Day 5 change from RTP baseline | 0.09 mmol/L | Standard Deviation 0.434 |
| Sodium Zirconium Cyclosilicate (SZC) 5g QD | Mean Change in S-K Levels | Day 8 change from RTP baseline | 0.20 mmol/L | Standard Deviation 0.481 |
| Sodium Zirconium Cyclosilicate (SZC) 5g QD | Mean Change in S-K Levels | Day 12 change from RTP baseline | 0.25 mmol/L | Standard Deviation 0.539 |
| Sodium Zirconium Cyclosilicate (SZC) 5g QD | Mean Change in S-K Levels | Day 15 change from RTP baseline | 0.26 mmol/L | Standard Deviation 0.557 |
| Sodium Zirconium Cyclosilicate (SZC) 5g QD | Mean Change in S-K Levels | Day 19 change from RTP baseline | 0.41 mmol/L | Standard Deviation 0.606 |
| Sodium Zirconium Cyclosilicate (SZC) 5g QD | Mean Change in S-K Levels | Day 22 change from RTP baseline | 0.32 mmol/L | Standard Deviation 0.543 |
| Sodium Zirconium Cyclosilicate (SZC) 5g QD | Mean Change in S-K Levels | Day 26 change from RTP baseline | 0.22 mmol/L | Standard Deviation 0.556 |
| Sodium Zirconium Cyclosilicate (SZC) 5g QD | Mean Change in S-K Levels | Day 29 change from RTP baseline | 0.23 mmol/L | Standard Deviation 0.494 |
| Sodium Zirconium Cyclosilicate (SZC) 5g QD | Mean Change in S-K Levels | EOS change from RTP baseline | 0.57 mmol/L | Standard Deviation 0.499 |
| Sodium Zirconium Cyclosilicate (SZC) 10g QD | Mean Change in S-K Levels | Day 29 change from RTP baseline | 0.01 mmol/L | Standard Deviation 0.578 |
| Sodium Zirconium Cyclosilicate (SZC) 10g QD | Mean Change in S-K Levels | Day 2 change from RTP baseline | -0.15 mmol/L | Standard Deviation 0.314 |
| Sodium Zirconium Cyclosilicate (SZC) 10g QD | Mean Change in S-K Levels | Day 19 change from RTP baseline | -0.19 mmol/L | Standard Deviation 0.616 |
| Sodium Zirconium Cyclosilicate (SZC) 10g QD | Mean Change in S-K Levels | Day 15 change from RTP baseline | -0.24 mmol/L | Standard Deviation 0.581 |
| Sodium Zirconium Cyclosilicate (SZC) 10g QD | Mean Change in S-K Levels | Day 5 change from RTP baseline | -0.27 mmol/L | Standard Deviation 0.464 |
| Sodium Zirconium Cyclosilicate (SZC) 10g QD | Mean Change in S-K Levels | EOS change from RTP baseline | 0.67 mmol/L | Standard Deviation 0.688 |
| Sodium Zirconium Cyclosilicate (SZC) 10g QD | Mean Change in S-K Levels | Day 26 change from RTP baseline | -0.05 mmol/L | Standard Deviation 0.627 |
| Sodium Zirconium Cyclosilicate (SZC) 10g QD | Mean Change in S-K Levels | Day 8 change from RTP baseline | -0.29 mmol/L | Standard Deviation 0.541 |
| Sodium Zirconium Cyclosilicate (SZC) 10g QD | Mean Change in S-K Levels | Day 22 change from RTP baseline | -0.13 mmol/L | Standard Deviation 0.538 |
| Sodium Zirconium Cyclosilicate (SZC) 10g QD | Mean Change in S-K Levels | Day 12 change from RTP baseline | -0.23 mmol/L | Standard Deviation 0.597 |
| Placebo | Mean Change in S-K Levels | Day 26 change from RTP baseline | 0.55 mmol/L | Standard Deviation 0.447 |
| Placebo | Mean Change in S-K Levels | Day 12 change from RTP baseline | 0.67 mmol/L | Standard Deviation 0.452 |
| Placebo | Mean Change in S-K Levels | Day 15 change from RTP baseline | 0.67 mmol/L | Standard Deviation 0.494 |
| Placebo | Mean Change in S-K Levels | Day 19 change from RTP baseline | 0.61 mmol/L | Standard Deviation 0.506 |
| Placebo | Mean Change in S-K Levels | Day 29 change from RTP baseline | 0.47 mmol/L | Standard Deviation 0.52 |
| Placebo | Mean Change in S-K Levels | Day 22 change from RTP baseline | 0.62 mmol/L | Standard Deviation 0.536 |
| Placebo | Mean Change in S-K Levels | Day 2 change from RTP baseline | 0.02 mmol/L | Standard Deviation 0.315 |
| Placebo | Mean Change in S-K Levels | EOS change from RTP baseline | 0.55 mmol/L | Standard Deviation 0.667 |
| Placebo | Mean Change in S-K Levels | Day 5 change from RTP baseline | 0.40 mmol/L | Standard Deviation 0.423 |
| Placebo | Mean Change in S-K Levels | Day 8 change from RTP baseline | 0.53 mmol/L | Standard Deviation 0.485 |
Secondary
Mean Percent Change in S-K Levels
The mean percent change in S-K levels evaluated relative to the RTP baseline. The results in the table below are presented for RTP.
Time frame: Through 28-day randomized treatment phase.
Population: Full analysis set - Randomized Treatment Phase
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) 5g QD | Mean Percent Change in S-K Levels | Day 2 change from RTP baseline | -0.81 Percent change | Standard Deviation 6.308 |
| Sodium Zirconium Cyclosilicate (SZC) 5g QD | Mean Percent Change in S-K Levels | Day 5 change from RTP baseline | 2.10 Percent change | Standard Deviation 9.009 |
| Sodium Zirconium Cyclosilicate (SZC) 5g QD | Mean Percent Change in S-K Levels | Day 8 change from RTP baseline | 4.45 Percent change | Standard Deviation 10.26 |
| Sodium Zirconium Cyclosilicate (SZC) 5g QD | Mean Percent Change in S-K Levels | Day 12 change from RTP baseline | 5.55 Percent change | Standard Deviation 11.564 |
| Sodium Zirconium Cyclosilicate (SZC) 5g QD | Mean Percent Change in S-K Levels | Day 15 change from RTP baseline | 5.85 Percent change | Standard Deviation 11.84 |
| Sodium Zirconium Cyclosilicate (SZC) 5g QD | Mean Percent Change in S-K Levels | Day 19 change from RTP baseline | 9.01 Percent change | Standard Deviation 13.285 |
| Sodium Zirconium Cyclosilicate (SZC) 5g QD | Mean Percent Change in S-K Levels | Day 22 change from RTP baseline | 7.09 Percent change | Standard Deviation 11.952 |
| Sodium Zirconium Cyclosilicate (SZC) 5g QD | Mean Percent Change in S-K Levels | Day 26 change from RTP baseline | 5.12 Percent change | Standard Deviation 12.13 |
| Sodium Zirconium Cyclosilicate (SZC) 5g QD | Mean Percent Change in S-K Levels | Day 29 change from RTP baseline | 5.24 Percent change | Standard Deviation 10.941 |
| Sodium Zirconium Cyclosilicate (SZC) 5g QD | Mean Percent Change in S-K Levels | EOS change from RTP baseline | 12.42 Percent change | Standard Deviation 11.054 |
| Sodium Zirconium Cyclosilicate (SZC) 10g QD | Mean Percent Change in S-K Levels | Day 29 change from RTP baseline | 0.48 Percent change | Standard Deviation 12.142 |
| Sodium Zirconium Cyclosilicate (SZC) 10g QD | Mean Percent Change in S-K Levels | Day 2 change from RTP baseline | -3.13 Percent change | Standard Deviation 6.627 |
| Sodium Zirconium Cyclosilicate (SZC) 10g QD | Mean Percent Change in S-K Levels | Day 19 change from RTP baseline | -3.76 Percent change | Standard Deviation 12.797 |
| Sodium Zirconium Cyclosilicate (SZC) 10g QD | Mean Percent Change in S-K Levels | Day 15 change from RTP baseline | -4.85 Percent change | Standard Deviation 12.107 |
| Sodium Zirconium Cyclosilicate (SZC) 10g QD | Mean Percent Change in S-K Levels | Day 5 change from RTP baseline | -5.57 Percent change | Standard Deviation 9.688 |
| Sodium Zirconium Cyclosilicate (SZC) 10g QD | Mean Percent Change in S-K Levels | EOS change from RTP baseline | 14.47 Percent change | Standard Deviation 14.797 |
| Sodium Zirconium Cyclosilicate (SZC) 10g QD | Mean Percent Change in S-K Levels | Day 26 change from RTP baseline | -0.76 Percent change | Standard Deviation 13.278 |
| Sodium Zirconium Cyclosilicate (SZC) 10g QD | Mean Percent Change in S-K Levels | Day 8 change from RTP baseline | -6.05 Percent change | Standard Deviation 11.352 |
| Sodium Zirconium Cyclosilicate (SZC) 10g QD | Mean Percent Change in S-K Levels | Day 22 change from RTP baseline | -2.59 Percent change | Standard Deviation 11.292 |
| Sodium Zirconium Cyclosilicate (SZC) 10g QD | Mean Percent Change in S-K Levels | Day 12 change from RTP baseline | -4.65 Percent change | Standard Deviation 12.604 |
| Placebo | Mean Percent Change in S-K Levels | Day 26 change from RTP baseline | 11.95 Percent change | Standard Deviation 9.809 |
| Placebo | Mean Percent Change in S-K Levels | Day 12 change from RTP baseline | 14.39 Percent change | Standard Deviation 9.908 |
| Placebo | Mean Percent Change in S-K Levels | Day 15 change from RTP baseline | 14.50 Percent change | Standard Deviation 10.775 |
| Placebo | Mean Percent Change in S-K Levels | Day 19 change from RTP baseline | 13.34 Percent change | Standard Deviation 11.266 |
| Placebo | Mean Percent Change in S-K Levels | Day 29 change from RTP baseline | 10.20 Percent change | Standard Deviation 11.438 |
| Placebo | Mean Percent Change in S-K Levels | Day 22 change from RTP baseline | 13.15 Percent change | Standard Deviation 11.686 |
| Placebo | Mean Percent Change in S-K Levels | Day 2 change from RTP baseline | 0.41 Percent change | Standard Deviation 6.67 |
| Placebo | Mean Percent Change in S-K Levels | EOS change from RTP baseline | 11.74 Percent change | Standard Deviation 14.477 |
| Placebo | Mean Percent Change in S-K Levels | Day 5 change from RTP baseline | 8.56 Percent change | Standard Deviation 8.989 |
| Placebo | Mean Percent Change in S-K Levels | Day 8 change from RTP baseline | 11.24 Percent change | Standard Deviation 9.989 |
Secondary
Percentage Change From Baseline in S-K Levels
Percentage change from baseline in S-K levels at all measured time intervals. End of OLP is defined as Day 2 (24 hours post first dose) or Day 3 (48 hours post first dose) depending on when the subject achieved normokalemia based on the pre-dose i-STAT potassium level. The results in the table below are presented for OLP.
Time frame: Through open label initial phase
Population: Full analysis set - Open Label Phase
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) 10g TID | Percentage Change From Baseline in S-K Levels | OLP - 24 hours | -15.880 Percentage | Standard Deviation 5.98 |
| Sodium Zirconium Cyclosilicate (SZC) 10g TID | Percentage Change From Baseline in S-K Levels | End of OLP | -18.588 Percentage | Standard Deviation 6.701 |
Secondary
Percentage of Patients Who Achieve Normokalemia
Percentage of patients who achieve normokalemia during the open label initial phase at 24 hours and at the end of the open label phase. End of OLP is defined as Day 2 (24 hours post first dose) or Day 3 (48 hours post first dose) depending on when the subject achieved normokalemia based on the pre-dose i-STAT potassium level. The results in the table below are presented for OLP.
Time frame: Through open label initial phase
Population: Full analysis set - Open Label Phase
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) 10g TID | Percentage of Patients Who Achieve Normokalemia | Normokalemic at 24h | 180 Participants |
| Sodium Zirconium Cyclosilicate (SZC) 10g TID | Percentage of Patients Who Achieve Normokalemia | Normokalemic at End of OLP | 228 Participants |
Secondary
Percentage of Patients Without Hyperkalemia
Kaplan-Meier estimate at Day 29 of percentage of patients without hyperkalemia. The results in the table below are presented for RTP.
Time frame: Day 29 of randomized treatment phase
Population: Full analysis set - Randomized Treatment Phase
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) 5g QD | Percentage of Patients Without Hyperkalemia | 20.3 Percentage |
| Sodium Zirconium Cyclosilicate (SZC) 10g QD | Percentage of Patients Without Hyperkalemia | 47.1 Percentage |
| Placebo | Percentage of Patients Without Hyperkalemia | 4.0 Percentage |
Comparison: The model included time to reoccurrence of hyperkalaemia as response variable (event: hyperkalaemia or discontinue treatment in RTP due to high S-K levels), baseline eGFR, OLP and RTP baseline S-K values as well as age (\< 55, 55-64, \> 64 years) and baseline binary indicators for RAASi, chronic kidney disease, heart failure, and diabetes mellitus as covariates. Placebo is the reference groupp-value: <0.00195% CI: [0.27, 0.57]Regression, Cox
Comparison: The model included time to reoccurrence of hyperkalaemia as response variable (event: hyperkalaemia or discontinue treatment in RTP due to high S-K levels), baseline eGFR, OLP and RTP baseline S-K values as well as age (\< 55, 55-64, \> 64 years) and baseline binary indicators for RAASi, chronic kidney disease, heart failure, and diabetes mellitus as covariates. Placebo is the reference groupp-value: <0.00195% CI: [0.1, 0.25]Regression, Cox
Secondary
Proportion of Normokalemic Patients at the End of RTP
Proportion of normokalemic patients (as defined by S-K between 3.5-5.0 mmol/l, inclusive). The results in the table below are presented for RTP.
Time frame: The end of 28-day randomized treatment study phase
Population: Full analysis set - Randomized Treatment Phase
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) 5g QD | Proportion of Normokalemic Patients at the End of RTP | 47 Participants |
| Sodium Zirconium Cyclosilicate (SZC) 10g QD | Proportion of Normokalemic Patients at the End of RTP | 65 Participants |
| Placebo | Proportion of Normokalemic Patients at the End of RTP | 14 Participants |
p-value: 0.03595% CI: [1.07, 6.05]Regression, Logistic
Comparison: The model included normokalaemia status (yes, no) on Day 29 as binary response variables, and baseline covariates. Placebo is the reference group.p-value: <0.00195% CI: [2.56, 15.27]Regression, Logistic
Secondary
Proportion of Patients Who Remain Normokalemic During RTP
Proportion of patients who remain normokalemic (as defined by S-K between 3.5-5.0 mmol/l, inclusive) during RTP (Day 8 to Day 29). The results in the table below are presented for RTP.
Time frame: Through 28-day randomized treatment study phase day 8-29
Population: Full analysis set - Randomized Treatment Phase
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) 5g QD | Proportion of Patients Who Remain Normokalemic During RTP | 0.596 Average probability |
| Sodium Zirconium Cyclosilicate (SZC) 10g QD | Proportion of Patients Who Remain Normokalemic During RTP | 0.818 Average probability |
| Placebo | Proportion of Patients Who Remain Normokalemic During RTP | 0.279 Average probability |
p-value: <0.00195% CI: [2.17, 6.67]Mixed Models Analysis
Comparison: The analysis uses a generalized mixed model which includes a random intercept and logit link. The model includes all S-K data values collected at the scheduled visits between Days 8-29, dichotomized as normal and abnormal, as response variables, and baseline covariates. Placebo is the reference group.p-value: <0.00195% CI: [6.45, 21]Mixed Models Analysis