Hyperkalemia
Conditions
Brief summary
The Open-Label Maintenance Study contains an Acute Phase, in which subjects will be dosed with ZS 10 g three times daily (tid) for 24 to 72 hours, followed by a long-term Maintenance Phase.
Detailed description
Subjects with 2 consecutive i STAT potassium values 5.1 mmol/L will enter the Acute Phase and receive ZS 10 g tid for 24 to 72 hours, depending on potassium values. Once normokalemia (i STAT potassium between 3.5 and 5.0 mmol/L, inclusive) is restored (whether after 24, 48 or 72 hours), subjects will be enrolled in the Maintenance Phase to be dosed with ZS at a starting dose of 5 g qd. Potassium (i STAT and central laboratory) will be measured weekly throughout the first month of study and every 4 weeks thereafter through Month 12. During the Maintenance Phase, the ZS dose may be increased or decreased in increments/decrements of 5 g qd up to a maximum of 15 g qd or a minimum of 5 g every other day based on i STAT potassium measurements as outlined below: • \> 5.0 mmol/L while receiving 5 g qd or 5 g every other day or \> 5.5 mmol/L while receiving 10 g qd: increase ZS dose in 5 g qd increments to a maximum dose of 15 g qd .• Between 3.0 and 3.4 mmol/L, inclusive: decrease ZS dose in 5 g qd decrements to a minimum dose of 5 g every other day; if a subject's i STAT potassium value remains between 3.0 and 3.4 mmol/L, inclusive, on the ZS 5 g every other day dose, the subject will be withdrawn from the study and receive standard of care treatment. There is no limit to the number of dose titrations allowed. Subjects will receive up to 12 months of treatment with open-label ZS.
Interventions
Acute Phase Dosing: Sodium Zirconium Cyclosilicate 10 g three times daily (TID) for 24 to 72 Extended Dosing: Sodium Zirconium Cyclosilicate 5 g once daily (QD). Sodium Zirconium Cyclosilicate dose increased or decreased in increments/decrements of 5 g QD up to a maximum of 15 g QD or a minimum of 5 g every other day (QOD) based on i-STAT potassium measurements up to 12 months.
Sponsors
ZS Pharma, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
SUPPORTIVE_CARE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Provision of written informed consent. * Over 18 years of age. * Two consecutive i STAT potassium values, measured 60 (+/- 15) minutes apart, both \>/= 5.1 mmol/L and measured within 1 day before the first dose of ZS on Acute Phase Study Day 1. * Ability to have repeated blood draws or effective venous catheterization. * Women of childbearing potential must be using 2 forms of medically acceptable contraception (at least 1 barrier method) and have a negative pregnancy test at Acute Phase Study Day 1. Women who are surgically sterile or those who are postmenopausal for at least 2 years are not considered to be of childbearing potential. * Controlled diabetic subjects.
Exclusion criteria
* Pseudohyperkalemia signs and symptoms, such as hemolyzed blood specimen due to excessive fist clenching to make veins prominent, difficult or traumatic venipuncture, or history of severe leukocytosis or thrombocytosis. * Subjects treated with lactulose, rifaximin, or other non-absorbed antibiotics for hyperammonemia within 7 days prior to first dose of ZS on Acute Phase Study Day 1. * Subjects treated with sodium polystyrene sulfonate (SPS; eg, Kayexalate®) or calcium polystyrene sulfonate (eg, Resonium®) within 3 days prior to first dose of ZS on Acute Phase Study Day 1. * Subjects with a life expectancy of less than 12 months. * Subjects 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. * Women who are pregnant, lactating, or planning to become pregnant. * Subjects with diabetic ketoacidosis. * Presence of any condition which, in the opinion of the investigator, places the subject 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. * Subjects with cardiac arrhythmias that require immediate treatment. * Subjects on dialysis. * Subjects randomized into the previous ZS-002, ZS-003, ZS-004, or ZS-004E studies. * Documented GFR \<15 mL/min within 90 days prior to study entry.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants With Restoration of Normal Serum Potassium (S-K) Values (3.5 to 5.0 mmol/L, Inclusive) at the End of the Acute Phase | 72 Hours | Percentage of subjects with S-K values between 3.5 and 5.0 mmol/L, inclusive at the end of the Acute Phase - ITT Population |
| Percentage of Participants With Mean S-K Values ≤ 5.1 mmol/L During Extended Dosing Phase Days 85 to 365 | Study Days 85 to 365 | Percentage of subjects with mean S-K values ≤ 5.1 mmol/L during Extended Dosing Phase - ITT Population |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Subjects With Mean S-K Between 3.5 and 5.5 mmol/L, Inclusive Months 3 to 12 | Study Days 85 to 365 | Proportion of Subjects with mean S-K between 3.5 and 5.5 mmol/L during Extended Dosing Phase - ITT Population |
| Mean S-K Levels Months 3 to 12, Months 6 to 9, and Months 9 to 12. | Study days 85 to 365 | Mean S-K levels months 3 to 12(EP Days 85, 113, 141, 176, 211, 239, 267, 295, 330, 365 and EOS),months 6 to 9, and months 9 to 12. |
Countries
Australia, Germany, Netherlands, Romania, South Africa, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 56 sites in the Unites States, Australia, South Africa, Germany, the United Kingdom and the Netherlands from 23 June 2014 to 04 November 2016
Participants by arm
| Arm | Count |
|---|---|
| Acute Phase: ZS | 751 |
| Total | 751 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Acute Phase: ZS 10 g TID | Hypo- or Hyperkalemia | 1 |
| Acute Phase: ZS 10 g TID | Participant's Compliance | 1 |
| Acute Phase: ZS 10 g TID | Physician Decision | 1 |
| Acute Phase: ZS 10 g TID | Protocol Violation | 1 |
| Acute Phase: ZS 10 g TID | Withdrawal by Subject | 1 |
| Extended Dosing Phase: ZS | Adverse Event | 51 |
| Extended Dosing Phase: ZS | Death | 8 |
| Extended Dosing Phase: ZS | Expected Progression of CKD | 40 |
| Extended Dosing Phase: ZS | Hyperkalemia | 5 |
| Extended Dosing Phase: ZS | Hypokalemia | 9 |
| Extended Dosing Phase: ZS | Lost to Follow-up | 31 |
| Extended Dosing Phase: ZS | Met ECG Withdrawal Criteria | 7 |
| Extended Dosing Phase: ZS | Physician Decision | 8 |
| Extended Dosing Phase: ZS | Protocol Violation | 2 |
| Extended Dosing Phase: ZS | Sponsor's Decision | 5 |
| Extended Dosing Phase: ZS | Subject Compliance | 17 |
| Extended Dosing Phase: ZS | Various reasons | 16 |
| Extended Dosing Phase: ZS | Withdrawal by Subject | 81 |
Baseline characteristics
| Characteristic | Acute Phase: ZS |
|---|---|
| Acute Phase baseline Serum Potassium 5.5<6.0 mmol/L | 338 Participants |
| Acute Phase baseline Serum Potassium <5.5 mmol/L | 287 Participants |
| Acute Phase baseline Serum Potassium ≥6.0 mmol/L | 126 Participants |
| Age, Continuous | 63.6 Years STANDARD_DEVIATION 13.03 |
| Baseline eGFR <15 | 46 Participants |
| Baseline eGFR 15-<30 | 243 Participants |
| Baseline eGFR 30-<60 | 263 Participants |
| Baseline eGFR ≥60 | 190 Participants |
| Baseline eGFR Missing | 9 Participants |
| Co-morbidities at baseline Chronic kidney disease | 513 Participants |
| Co-morbidities at baseline Diabetes mellitus | 471 Participants |
| Co-morbidities at baseline Heart Failure | 285 Participants |
| Race/Ethnicity, Customized Asian | 25 Participants |
| Race/Ethnicity, Customized Black or African American | 89 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 3 Participants |
| Race/Ethnicity, Customized Other | 10 Participants |
| Race/Ethnicity, Customized White | 624 Participants |
| Sex: Female, Male Female | 303 Participants |
| Sex: Female, Male Male | 448 Participants |
| Use of RAAS inhibitor medication | 527 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 751 | 8 / 746 |
| other Total, other adverse events | 11 / 751 | 386 / 746 |
| serious Total, serious adverse events | 1 / 751 | 161 / 746 |
Outcome results
Primary
Percentage of Participants With Mean S-K Values ≤ 5.1 mmol/L During Extended Dosing Phase Days 85 to 365
Percentage of subjects with mean S-K values ≤ 5.1 mmol/L during Extended Dosing Phase - ITT Population
Time frame: Study Days 85 to 365
Population: The Extended Phase Intent To Treat populations (EP-ITT) included subjects who received at least one dose of ZS in the EP and have at least one S-K assessment after administration of Extended Phase ZS.~Efficacy: Separate analyses were performed for the Acute and Extended Dosing Phases.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Proportion | Percentage of Participants With Mean S-K Values ≤ 5.1 mmol/L During Extended Dosing Phase Days 85 to 365 | 88.4 Percentage of participants |
Primary
Percent of Participants With Restoration of Normal Serum Potassium (S-K) Values (3.5 to 5.0 mmol/L, Inclusive) at the End of the Acute Phase
Percentage of subjects with S-K values between 3.5 and 5.0 mmol/L, inclusive at the end of the Acute Phase - ITT Population
Time frame: 72 Hours
Population: The Intent To Treat populations for the Acute Phase (AP-ITT) included subjects who received at least one dose of ZS with at least one S-K assessment after administration of Acute Phase ZS.~Efficacy: Separate analyses were performed for the Acute and Extended Dosing Phases.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Proportion | Percent of Participants With Restoration of Normal Serum Potassium (S-K) Values (3.5 to 5.0 mmol/L, Inclusive) at the End of the Acute Phase | 77.9 Percentage of participants |
Secondary
Mean S-K Levels Months 3 to 12, Months 6 to 9, and Months 9 to 12.
Mean S-K levels months 3 to 12(EP Days 85, 113, 141, 176, 211, 239, 267, 295, 330, 365 and EOS),months 6 to 9, and months 9 to 12.
Time frame: Study days 85 to 365
Population: Extended phase ITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Proportion | Mean S-K Levels Months 3 to 12, Months 6 to 9, and Months 9 to 12. | Extended Dosing Days 85 to 365/End of Study | 4.66 mmol/L | Standard Deviation 0.379 |
| Proportion | Mean S-K Levels Months 3 to 12, Months 6 to 9, and Months 9 to 12. | Extended Dosing Days 211 to 267 | 4.68 mmol/L | Standard Deviation 0.404 |
| Proportion | Mean S-K Levels Months 3 to 12, Months 6 to 9, and Months 9 to 12. | Acute Phase Baseline | 5.59 mmol/L | Standard Deviation 0.425 |
| Proportion | Mean S-K Levels Months 3 to 12, Months 6 to 9, and Months 9 to 12. | Extended Dosing Days 295 to 365 | 4.62 mmol/L | Standard Deviation 0.401 |
Secondary
Proportion of Subjects With Mean S-K Between 3.5 and 5.5 mmol/L, Inclusive Months 3 to 12
Proportion of Subjects with mean S-K between 3.5 and 5.5 mmol/L during Extended Dosing Phase - ITT Population
Time frame: Study Days 85 to 365
Population: Extended phase ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Proportion | Proportion of Subjects With Mean S-K Between 3.5 and 5.5 mmol/L, Inclusive Months 3 to 12 | 0.985 Proportion of participants |