Hyperkalemia
Conditions
Brief summary
Subjects who completed the Double-blind Randomized Maintenance Phase (DBRMP) Study Day 29 visit in ZS-004 (NCT 02088073) and have an i-STAT potassium value that is 3.5 to 6.2 mmol/l inclusive or who discontinued during ZS-004 due to hypo- or hyperkalemia in the DBRMP and have a mean i-STAT potassium value from two consecutive measurements at 0 and 60 minutes on Acute Phase Day 1/Maintenance Phase Day 1 that is 3.5 to 6.2 mmol/l inclusive may have the option to participate in ZS-004E (NCT 021070920). Subjects who discontinued from study ZS-004 due to any other reasons (e.g. adverse events, poor compliance, investigator decision) will not be entered into study ZS-004E. All subjects who continue into the extension study must begin dosing within two (2) days after the last dose of investigational product in ZS-004.
Detailed description
All subjects with i-STAT potassium values between 3.5-5.5 mmol/l, inclusive at the ZS-004 (NCT 02088073) DBRMP Study Day 29 visit, who continue directly into the open-label extension study ZS-004E (NCT 021070920), will enter the Maintenance Phase (MP) and start on open-label ZS at a dose of 10g qd. All subjects with i-STAT potassium values \> 5.5 mmol/l at the ZS-004 DBRMP Study Day 29 visit will undergo an acute treatment phase (AP) where they will receive ZS 10g three times a day (tid) for 24 (3 doses) or 48 hours (6 doses). If the subject's i-STAT potassium is between 3.5-5.0 mmol/l, inclusive after 24 (AP Study Day 2) or 48 hours (AP Study Day 3), the subject will enter the MP at a starting dose of 10g qd. For subjects who discontinued during ZS-004 DBRMP due to hypo- or hyperkalemia baseline potassium values will be determined within 1 day of administration of the first dose in the ZS-004E extension study by taking two (2) consecutive i-STAT potassium measurements at 0 and 60 minutes (± 10 minutes). If the mean i-STAT value is between 3.5 - 5.5 mmol/l, inclusive, the subject will enter directly into the MP and receive 10g ZS qd; if the mean i-STAT potassium value is \> 5.5 mmol/l, the subject will enter the AP. If i-STAT potassium values are still \>5.0 mmol/l on the morning of AP Study Day 3, subjects will not enter the MP but will be referred to their normal health care provider for standard of care. If the i-STAT potassium value increases above 5.5 mmol/l during the MP with treatment at 10g qd, the dose can be increased to15g qd. Conversely, if S-K decreases to between 3.0-3.4 mmol/l, inclusive, the dose of ZS can be decreased in 5g qd, decrements. If a subject is on a 5g qd dose and still develops blood potassium i-STAT values between 3.0 - 3.4mmol, inclusive the dose can be reduced to 5g every other day. Subjects will receive up to 11 months of treatment with open-label ZS.
Interventions
Oral 10g once daily with breakfast for 11 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. * Completed the ZS-004 DBRMP Study Day 29 visit or discontinued study ZS-004 during the DBRMP due to hypo- or hyperkalemia and able to start dosing in ZS-004E within two (2) days after the last dose of Investigational product in ZS-004. * Subject must have an i-STAT potassium value that is 3.5 to 6.2 mmol/l inclusive at the ZS-004 DBRMP Study Day 29 visit or a mean i-STAT potassium value from two consecutive measurements at 0 and 60 minutes on Acute Phase Day 1/Maintenance Phase Day 1 that is 3.5 to 6.2 mmol/l inclusive if the subject discontinued study ZS-004 during the DBRMP due to hypo- or hyperkalemia .
Exclusion criteria
* Pseudohyperkalemia signs and symptoms, such as excessive fist clenching hemolyzed blood specimen, history of severe leukocytosis or thrombocytosis. * Subjects who received alternative treatment for hyperkalemia while participating in study ZS-004. * Subjects with a life expectancy of less than 3 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 other than ZS 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Subjects With Average Serum Potassium Values ≤ 5.1 mmol/L | 11 months | The proportions of subjects with average serum potassium (S-K) values ≤ 5.1 mmol/L during Extended Dosing Study Days 8 to 337, inclusive |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Subjects With Average Serum Potassium Values ≤ 5.5 mmol/L | 11 months | The proportions of subjects with average S-K values ≤ 5.5 mmol/L during Extended Dosing Study Days 8 to 337, inclusive |
Countries
Australia, South Africa, United States
Participant flow
Recruitment details
Participants took part in the study at 30 outpatient sites in the United States, Australia and South Africa from 10 May 2014 to 14 July 2015.
Pre-assignment details
Participants that completed Study ZS-004 (NCT02088073) Extended Dosing (ED) Phase Study Day 29 Visit or discontinued Study ZS-004 during the ED Phase due to hypo- or hyperkalemia, had a mean i-STAT potassium value between 3.5 and 6.2 mmol/L, and were able to start dosing in Study ZS-004E within 2 days after the last dose of study drug in ZS-004.
Participants by arm
| Arm | Count |
|---|---|
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD ZS 10g QD starting dose. ZS dose was increased or decreased in increments/ decrements of 5g QD to maximum of 15g QD or minimum of 5g every other day (QOD) if i-STAT potassium values increased to \> 5.5 mmol/L or decreased to between 3.0 and 3.4 mmol/L, respectively. | 121 |
| Total | 121 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 7 |
| Overall Study | Expected progression of CKD | 12 |
| Overall Study | Hypo-or hyperkalemia | 2 |
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Met ECG withdrawal criteria | 3 |
| Overall Study | Miscellaneous | 3 |
| Overall Study | Physician Decision | 3 |
| Overall Study | Subject compliance | 3 |
| Overall Study | Withdrawal by Subject | 9 |
Baseline characteristics
| Characteristic | Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD |
|---|---|
| Acute Phase eGFR at baseline <60 mL/min | 90 Participants |
| Acute Phase eGFR at baseline ≥ 60 mL/min | 31 Participants |
| Age, Continuous | 63.7 Years STANDARD_DEVIATION 12.29 |
| Cormordid conditions and concomitant medications which may contirubute to hyperkalemia Chronic kidney disease | 76 Participants |
| Cormordid conditions and concomitant medications which may contirubute to hyperkalemia Diabetes mellitus | 80 Participants |
| Cormordid conditions and concomitant medications which may contirubute to hyperkalemia Heart failure | 50 Participants |
| Cormordid conditions and concomitant medications which may contirubute to hyperkalemia RAAS inhibitor medication | 83 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 11 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Race/Ethnicity, Customized White | 107 Participants |
| Sex: Female, Male Female | 51 Participants |
| Sex: Female, Male Male | 70 Participants |
| Study ZS-004 Acute Phase S-K baseline 5.5-< 6.0 mmol/L | 53 Participants |
| Study ZS-004 Acute Phase S-K baseline < 5.5 mmol/L | 54 Participants |
| Study ZS-004 Acute Phase S-K baseline ≥ 6.0 mmol/L | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 82 / 123 |
| serious Total, serious adverse events | 24 / 123 |
Outcome results
Primary
Proportion of Subjects With Average Serum Potassium Values ≤ 5.1 mmol/L
The proportions of subjects with average serum potassium (S-K) values ≤ 5.1 mmol/L during Extended Dosing Study Days 8 to 337, inclusive
Time frame: 11 months
Population: Entered Extended Dosing Phase, received study drug and had post baseline S-K values during the Extended Dosing Phase. The analysis population includes 121 subjects, where there is one subject who only had end-of-study post-baseline measurement and therefore was not presented in the participants analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.1 mmol/L | ED Study Day 8 | 0.875 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.1 mmol/L | ED Study Day 15 | 0.822 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.1 mmol/L | ED Study Day 22 | 0.797 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.1 mmol/L | ED Study Day 29 | 0.862 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.1 mmol/L | ED Study Day 36 | 0.848 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.1 mmol/L | ED Study Day 43 | 0.793 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.1 mmol/L | ED Study Day 50 | 0.796 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.1 mmol/L | ED Study Day 57 | 0.766 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.1 mmol/L | ED Study Day 281 | 0.833 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.1 mmol/L | ED Study Day 309 | 0.828 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.1 mmol/L | ED Study Day 337 | 0.843 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.1 mmol/L | ED Study Day 337/Exit | 0.783 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.1 mmol/L | ED Study Days 8-337 Average | 0.883 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.1 mmol/L | ED Study Day 85 | 0.807 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.1 mmol/L | ED Study Day 113 | 0.798 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.1 mmol/L | ED Study Day 141 | 0.815 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.1 mmol/L | ED Study Day 169 | 0.771 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.1 mmol/L | ED Study Day 197 | 0.809 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.1 mmol/L | ED Day Study 225 | 0.846 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.1 mmol/L | ED Study Day 253 | 0.778 Proportion of Participants |
Secondary
Proportion of Subjects With Average Serum Potassium Values ≤ 5.5 mmol/L
The proportions of subjects with average S-K values ≤ 5.5 mmol/L during Extended Dosing Study Days 8 to 337, inclusive
Time frame: 11 months
Population: Entered Extended Dosing Phase, received study drug and had post baseline S-K values during the Extended Dosing Phase. The analysis population includes 121 subjects, where there is one subject who only had end-of-study post-baseline measurement and therefore was not presented in the participants analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.5 mmol/L | ED Study Day 22 | 0.975 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.5 mmol/L | ED Study Day 29 | 0.957 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.5 mmol/L | ED Study Day 36 | 0.955 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.5 mmol/L | ED Study Day 43 | 0.946 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.5 mmol/L | ED Study Day 50 | 0.935 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.5 mmol/L | ED Study Day 57 | 0.944 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.5 mmol/L | ED Study Day 85 | 0.943 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.5 mmol/L | ED Study Day 197 | 0.941 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.5 mmol/L | ED Day Study 225 | 0.985 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.5 mmol/L | ED Study Day 253 | 0.937 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.5 mmol/L | ED Study Day 281 | 0.950 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.5 mmol/L | ED Study Day 309 | 0.914 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.5 mmol/L | ED Study Day 337 | 0.980 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.5 mmol/L | ED Study Day 337/Exit | 0.942 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.5 mmol/L | ED Study Days 8-337 Average | 1.000 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.5 mmol/L | ED Study Day 8 | 0.950 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.5 mmol/L | ED Study Day 15 | 0.932 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.5 mmol/L | ED Study Day 113 | 0.940 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.5 mmol/L | ED Study Day 141 | 0.938 Proportion of Participants |
| Extended Dosing Phase: ZS (Sodium Zirconium Cyclosilicate) QD | Proportion of Subjects With Average Serum Potassium Values ≤ 5.5 mmol/L | ED Study Day 169 | 0.929 Proportion of Participants |