Hyperkalemia
Conditions
Brief summary
The study is designed to determine if ZS 10g administered up to three times over 10h added to insulin and glucose in patients presenting with hyperkalemia will prove tolerable and efficacious. Patients will receive ZS or Placebo on top of standard of care treatment with insulin and glucose.
Interventions
DRUGPlacebo
Suspension administered orally for a treatment period of 24h. 2 sachets administered up to three times over 10h (at 0, 4 and 10h).
DRUGSodium Zirconium Cyclosilicate(ZS)
Suspension administered orally for a treatment period of 24h. Single dose contains 2 sachets of ZS 5g. 10g administered up to three times over 10h (at 0, 4 and 10h).
DRUGInsulin
Insulin 0.1 units/kg administered as a bolus or for up to 30 minutes.
DRUGGlucose
Glucose 25g administered IV \<15 minutes before the insulin.
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 130 Years
Healthy volunteers
No
Inclusion criteria
≥ 18 years of age Potassium ≥5.8 mmol/L
Exclusion criteria
Possible pseudohyperkalaemia Hyperkalaemia caused by any condition for which a therapy directed against the underlying cause of hyperkalaemia would be a better treatment option than treatment with insulin and glucose. Dialysis session expected within 4h after randomization Treated with any therapy intended to lower S-K between arriving at the hospital and randomization during Visit 1.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Absolute Change in S-K From Baseline Until 4h After Start of Dosing With SZC/Placebo | Baseline to 4h potassium measurements. | The least squares means (LS-means) are derived from a linear regression model of absolute change in S-K at 4h with the following covariates: treatment group; baseline S-K; time from the start of dosing insulin to the start of dosing SZC/placebo and the dose (units/kg) of the first course of insulin. The 95% CI is associated with LS-Means. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Fraction of Patients Administered Additional Potassium Lowering Therapy Due to Hyperkalaemia From 0 to 4h. | Baseline to 4h potassium meansurements. | Additional therapies for hyperkalaemia are 2nd dose of insulin, Beta-agonists, Diuretics, Dialysis, Sodium bicarbonate and Potassium binders when administered with the expressed intent to lower S-K. |
| Fraction of Patients Responding to Therapy Defined as: S-K <6.0mmol/L Between 1 and 4h and S-K <5.0mmol/L at 4h; and no Additional Potassium Lowering Therapy From 0 to 4h With Exception of the Initial Insulin Treatment | Baseline to 4h potassium meansurements. | Additional therapies for hyperkalaemia are 2nd dose of insulin, Beta-agonists, Diuretics, Dialysis, Sodium bicarbonate and Potassium binders when administered with the expressed intent to lower S-K. Patients with any missing potassium value from 1h to 4h inclusive will be treated as non-responders. |
| The Fraction of Patients Achieving S-K <6.0mmol/l 1, 2, and 4h After Start of Dosing With SZC/Placebo | Baseline to 4h potassium meansurements. | — |
| The Fraction of Patients Achieving S-K <5.5mmol/l 1, 2, and 4h After Start of Dosing With SZC/Placebo | Baseline to 4h potassium meansurements. | — |
| Mean Absolute Change in S-K From Baseline to 1h and 2h After Start of Dosing With SZC/Placebo | Baseline to 2h potassium measurements. | The least squares means (LS-means) are derived from a linear regression model of absolute change in S-K at 1h and 2h with the following covariates: treatment group; baseline S-K; time from the start of dosing insulin to the start of dosing SZC/placebo and the dose (units/kg) of the first course of insulin. The 95% CI is associated with LS-Means. |
| The Fraction of Patients Achieving Normokalaemia 1, 2 and 4h After Start of Dosing With SZC/Placebo | Baseline to 4h potassium meansurements. | Proportion of patients achieving normokalaemia, S-K 3.5-5.0 mmol/L, at 1, 2 and 4h after start of dosing |
Countries
Denmark, Italy, Russia, United States
Participant flow
Recruitment details
Participants took part in the study in the United States, Russia, Denmark and Italy from 13 February 2018 to 21 December 2018.
Pre-assignment details
Patients with S-K ≥5.8 mmol/L for whom treatment with insulin and glucose to manage hyperkalaemia has been determined medically appropriate by the Investigator. The study originally recruited patients with S-K ≥6.0 mmol/L; however, this inclusion criterion was updated during CSP Amendment to allow enrolment of patients with S-K ≥5.8 mmol/L.
Participants by arm
| Arm | Count |
|---|---|
| Sodium Zirconium Cyclosilicate (SZC) 10g SZC will be administered in addition to insulin and glucose. | 33 |
| Placebo Placebo will be administered in addition to insulin and glucose. | 37 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 2 |
| Overall Study | not categorized into the listed ones | 11 | 9 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Sodium Zirconium Cyclosilicate (SZC) 10g | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 62.0 years STANDARD_DEVIATION 12.7 | 56.4 years STANDARD_DEVIATION 14.4 | 59.0 years STANDARD_DEVIATION 13.8 |
| Age, Customized >=50 - <65 years | 11 Participants | 18 Participants | 29 Participants |
| Age, Customized <50 years | 6 Participants | 11 Participants | 17 Participants |
| Age, Customized >=65 years | 16 Participants | 8 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 10 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants | 27 Participants | 54 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 9 Participants | 20 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 22 Participants | 26 Participants | 48 Participants |
| Region of Enrollment Denmark | 0 Participants | 2 Participants | 2 Participants |
| Region of Enrollment Italy | 1 Participants | 1 Participants | 2 Participants |
| Region of Enrollment Russia | 13 Participants | 14 Participants | 27 Participants |
| Region of Enrollment United States | 19 Participants | 20 Participants | 39 Participants |
| Sex: Female, Male Female | 16 Participants | 19 Participants | 35 Participants |
| Sex: Female, Male Male | 17 Participants | 18 Participants | 35 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 / 29 | 1 / 33 | 0 / 29 | 0 / 33 |
| other Total, other adverse events | 4 / 29 | 5 / 33 | 3 / 29 | 0 / 33 |
| serious Total, serious adverse events | 1 / 29 | 2 / 33 | 2 / 29 | 3 / 33 |
Outcome results
Primary
Mean Absolute Change in S-K From Baseline Until 4h After Start of Dosing With SZC/Placebo
The least squares means (LS-means) are derived from a linear regression model of absolute change in S-K at 4h with the following covariates: treatment group; baseline S-K; time from the start of dosing insulin to the start of dosing SZC/placebo and the dose (units/kg) of the first course of insulin. The 95% CI is associated with LS-Means.
Time frame: Baseline to 4h potassium measurements.
Population: Full analysis set: all randomized patients. However, patients with no baseline or/and post-baseline data (one patient in each group) were excluded from the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) 10g | Mean Absolute Change in S-K From Baseline Until 4h After Start of Dosing With SZC/Placebo | -0.41 mmol/L |
| Placebo | Mean Absolute Change in S-K From Baseline Until 4h After Start of Dosing With SZC/Placebo | -0.27 mmol/L |
Secondary
Fraction of Patients Responding to Therapy Defined as: S-K <6.0mmol/L Between 1 and 4h and S-K <5.0mmol/L at 4h; and no Additional Potassium Lowering Therapy From 0 to 4h With Exception of the Initial Insulin Treatment
Additional therapies for hyperkalaemia are 2nd dose of insulin, Beta-agonists, Diuretics, Dialysis, Sodium bicarbonate and Potassium binders when administered with the expressed intent to lower S-K. Patients with any missing potassium value from 1h to 4h inclusive will be treated as non-responders.
Time frame: Baseline to 4h potassium meansurements.
Population: Full analysis set: all randomized patients. However, patients with no baseline or/and post-baseline data (one patient in each group) were excluded from the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) 10g | Fraction of Patients Responding to Therapy Defined as: S-K <6.0mmol/L Between 1 and 4h and S-K <5.0mmol/L at 4h; and no Additional Potassium Lowering Therapy From 0 to 4h With Exception of the Initial Insulin Treatment | 0.063 Proportion of participants |
| Placebo | Fraction of Patients Responding to Therapy Defined as: S-K <6.0mmol/L Between 1 and 4h and S-K <5.0mmol/L at 4h; and no Additional Potassium Lowering Therapy From 0 to 4h With Exception of the Initial Insulin Treatment | 0.056 Proportion of participants |
Secondary
Mean Absolute Change in S-K From Baseline to 1h and 2h After Start of Dosing With SZC/Placebo
The least squares means (LS-means) are derived from a linear regression model of absolute change in S-K at 1h and 2h with the following covariates: treatment group; baseline S-K; time from the start of dosing insulin to the start of dosing SZC/placebo and the dose (units/kg) of the first course of insulin. The 95% CI is associated with LS-Means.
Time frame: Baseline to 2h potassium measurements.
Population: Full analysis set: all randomized patients. However, patients with no baseline or/and post-baseline data (one patient in each group) were excluded from the analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) 10g | Mean Absolute Change in S-K From Baseline to 1h and 2h After Start of Dosing With SZC/Placebo | 1h | -0.67 mmol/L |
| Sodium Zirconium Cyclosilicate (SZC) 10g | Mean Absolute Change in S-K From Baseline to 1h and 2h After Start of Dosing With SZC/Placebo | 2h | -0.72 mmol/L |
| Placebo | Mean Absolute Change in S-K From Baseline to 1h and 2h After Start of Dosing With SZC/Placebo | 1h | -0.67 mmol/L |
| Placebo | Mean Absolute Change in S-K From Baseline to 1h and 2h After Start of Dosing With SZC/Placebo | 2h | -0.36 mmol/L |
Secondary
The Fraction of Patients Achieving Normokalaemia 1, 2 and 4h After Start of Dosing With SZC/Placebo
Proportion of patients achieving normokalaemia, S-K 3.5-5.0 mmol/L, at 1, 2 and 4h after start of dosing
Time frame: Baseline to 4h potassium meansurements.
Population: Full analysis set: all randomized patients. However, patients with no baseline or/and post-baseline data (one patient in each group) were excluded from the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) 10g | The Fraction of Patients Achieving Normokalaemia 1, 2 and 4h After Start of Dosing With SZC/Placebo | 1h | 0.156 Proportion of participants |
| Sodium Zirconium Cyclosilicate (SZC) 10g | The Fraction of Patients Achieving Normokalaemia 1, 2 and 4h After Start of Dosing With SZC/Placebo | 2h | 0.125 Proportion of participants |
| Sodium Zirconium Cyclosilicate (SZC) 10g | The Fraction of Patients Achieving Normokalaemia 1, 2 and 4h After Start of Dosing With SZC/Placebo | 4h | 0.063 Proportion of participants |
| Placebo | The Fraction of Patients Achieving Normokalaemia 1, 2 and 4h After Start of Dosing With SZC/Placebo | 1h | 0.139 Proportion of participants |
| Placebo | The Fraction of Patients Achieving Normokalaemia 1, 2 and 4h After Start of Dosing With SZC/Placebo | 2h | 0.056 Proportion of participants |
| Placebo | The Fraction of Patients Achieving Normokalaemia 1, 2 and 4h After Start of Dosing With SZC/Placebo | 4h | 0.056 Proportion of participants |
Secondary
The Fraction of Patients Achieving S-K <5.5mmol/l 1, 2, and 4h After Start of Dosing With SZC/Placebo
Time frame: Baseline to 4h potassium meansurements.
Population: Full analysis set: all randomized patients. However, patients with no baseline or/and post-baseline data (one patient in each group) were excluded from the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) 10g | The Fraction of Patients Achieving S-K <5.5mmol/l 1, 2, and 4h After Start of Dosing With SZC/Placebo | 1h | 0.313 Proportion of paticipants |
| Sodium Zirconium Cyclosilicate (SZC) 10g | The Fraction of Patients Achieving S-K <5.5mmol/l 1, 2, and 4h After Start of Dosing With SZC/Placebo | 2h | 0.375 Proportion of paticipants |
| Sodium Zirconium Cyclosilicate (SZC) 10g | The Fraction of Patients Achieving S-K <5.5mmol/l 1, 2, and 4h After Start of Dosing With SZC/Placebo | 4h | 0.156 Proportion of paticipants |
| Placebo | The Fraction of Patients Achieving S-K <5.5mmol/l 1, 2, and 4h After Start of Dosing With SZC/Placebo | 1h | 0.306 Proportion of paticipants |
| Placebo | The Fraction of Patients Achieving S-K <5.5mmol/l 1, 2, and 4h After Start of Dosing With SZC/Placebo | 2h | 0.167 Proportion of paticipants |
| Placebo | The Fraction of Patients Achieving S-K <5.5mmol/l 1, 2, and 4h After Start of Dosing With SZC/Placebo | 4h | 0.139 Proportion of paticipants |
Secondary
The Fraction of Patients Achieving S-K <6.0mmol/l 1, 2, and 4h After Start of Dosing With SZC/Placebo
Time frame: Baseline to 4h potassium meansurements.
Population: Full analysis set: all randomized patients. However, patients with no baseline or/and post-baseline data (one patient in each group) were excluded from the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) 10g | The Fraction of Patients Achieving S-K <6.0mmol/l 1, 2, and 4h After Start of Dosing With SZC/Placebo | 1h | 0.656 Proportion of paticipants |
| Sodium Zirconium Cyclosilicate (SZC) 10g | The Fraction of Patients Achieving S-K <6.0mmol/l 1, 2, and 4h After Start of Dosing With SZC/Placebo | 2h | 0.625 Proportion of paticipants |
| Sodium Zirconium Cyclosilicate (SZC) 10g | The Fraction of Patients Achieving S-K <6.0mmol/l 1, 2, and 4h After Start of Dosing With SZC/Placebo | 4h | 0.469 Proportion of paticipants |
| Placebo | The Fraction of Patients Achieving S-K <6.0mmol/l 1, 2, and 4h After Start of Dosing With SZC/Placebo | 2h | 0.472 Proportion of paticipants |
| Placebo | The Fraction of Patients Achieving S-K <6.0mmol/l 1, 2, and 4h After Start of Dosing With SZC/Placebo | 1h | 0.611 Proportion of paticipants |
| Placebo | The Fraction of Patients Achieving S-K <6.0mmol/l 1, 2, and 4h After Start of Dosing With SZC/Placebo | 4h | 0.361 Proportion of paticipants |
Secondary
The Fraction of Patients Administered Additional Potassium Lowering Therapy Due to Hyperkalaemia From 0 to 4h.
Additional therapies for hyperkalaemia are 2nd dose of insulin, Beta-agonists, Diuretics, Dialysis, Sodium bicarbonate and Potassium binders when administered with the expressed intent to lower S-K.
Time frame: Baseline to 4h potassium meansurements.
Population: Full analysis set: all randomized patients. However, patients with no baseline or/and post-baseline data (one patient in each group) were excluded from the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) 10g | The Fraction of Patients Administered Additional Potassium Lowering Therapy Due to Hyperkalaemia From 0 to 4h. | 0.156 Proportion of participants |
| Placebo | The Fraction of Patients Administered Additional Potassium Lowering Therapy Due to Hyperkalaemia From 0 to 4h. | 0.306 Proportion of participants |