Hyperkalemia
Conditions
Brief summary
The purpose of this study is to evaluate the efficacy of ZS in the treatment of hyperkalemia in patients on hemodialysis.
Interventions
DRUGPlacebo
Suspension administered orally for a treatment period of eight weeks (4 weeks of dose adjustment, 4 weeks in stable dose) . Single dose contains from 1 to 3 sachets of Placebo depending on dose level assigned to a patient per non-dialysis days.
Suspension administered orally for a treatment period of eight weeks (4 weeks of dose adjustment, 4 weeks in stable dose) . Single dose contains from 1 to 3 sachets of ZS 5g depending on dose level assigned to a patient per non-dialysis days.
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
1. Provision of informed consent prior to any study specific procedures 2. Female or male aged ≥ 18 years at screening Visit 1. For patients aged \<20 years and enrolled in Japan, a written informed consent should be obtained from the patient and his or her legally acceptable representative. 3. Receiving hemodialysis (or hemodiafiltration) 3 times a week for treatment of endstage renal disease (ESRD) for at least 3 months before randomization. 4. Patients must have hemodialysis access consisting of an arteriovenous fistula, AV graft, or tunneled (permanent) catheter which is expected to remain in place for the entire duration of the study. 5. Pre-dialysis serum K \>5.4 mmol/L after long inter-dialytic interval and \>5.0 mmol/L after one short inter-dialytic interval during screening (as assessed by central lab). 6. Prescribed dialysate K concentration ≤ 3 mmol/L during screening 7. Sustained Qb ≥200 ml/min and spKt/V ≥1.2 (or URR ≥ 63) on stable hemodialysis/hemodiafltration prescription during screening with prescription (time, dialyzer, blood flow \[Qb\], dialysate flow rate \[Qd\] and bicarbonate concentration) expected to remain unchanged during study 8. Heparin dose (if used) must be stable during screening and expected to be stable during the study 9. Subjects must be receiving dietary counseling appropriate for ESRD patients treated with hemodialysis/hemodiafiltration as per local guidelines, which includes dietary potassium restriction.
Exclusion criteria
1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca, including ZS Pharma staff and/or staff at the study site) 2. Hemoglobin \<9 g/dL on screening (as assessed on Visit 1) 3. Lack of compliance with hemodialysis prescription (both number and duration of treatments) during the two-week period preceding screening (100% compliance required) 4. Patients treated with sodium polystyrene sulfonate (SPS, Kayexalate, Resonium), calcium polystyrene sulfonate (CPS, Resonium calcium) or patiromer (Veltassa) within 7 days before screening or anticipated in requiring any of these agents during the study 5. Myocardial infarction, acute coronary syndrome, stroke, seizure or a thrombotic/thromboembolic event (e.g., deep vein thrombosis or pulmonary embolism, but excluding vascular access thrombosis) within 12 weeks prior to randomization 6. Laboratory diagnosis of hypokalemia (K \< 3.5 mmol/L), hypocalcemia (Ca \< 8.2 mg/dL; for Japan hypocalcemia is defined as albumin-corrected Ca \< 8.0 mg/dL), hypomagnesemia (Mg \< 1.7 mg/dL) or severe acidosis (serum bicarbonate 16 mEq/L or less) in the 4 weeks preceding randomization 7. Pseudohyperkalemia secondary to hemolyzed blood specimen (this situation is not considered screening failure, sampling or full screening can be postponed to a later time as applicable). 8. Severe leukocytosis (\>20× 10\^9/L) or thrombocytosis (≥450 × 10\^9/L) during screening 9. Polycythemia (Hb \>14 g/dL) during screening 10. Diagnosis of rhabdomyolysis during the 4 weeks preceding randomization 11. Patients treated with lactulose, xifaxan (rifaximin) or other non-absorbed antibiotics for hyperammonemia within 7 days prior to the first dose of study drug 12. Patients unable to take oral ZS drug mix 13. Scheduled date for living donor kidney transplant 14. Patients with a life expectancy of less than 6 months 15. Female patients who are pregnant or breastfeeding 16. Females of childbearing potential, unless using contraception as detailed in the protocol or sexual abstinence. 17. Known hypersensitivity or previous anaphylaxis to ZS or to components thereof 18. Participation in another clinical study with an investigational product during the last 1 month before screening 19. Any medical condition, including active, clinically significant infection, that in the opinion of the investigator or Sponsor may pose a safety risk to a patient in this study, which may confound safety or efficacy assessment and jeopardize the quality of the data, or may interfere with study participation 20. Presence of cardiac arrhythmias or conduction defects that require immediate treatment 21. History of alcohol or drug abuse within 2 years prior to randomization 22. Previous randomization in the present study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Responders | Evaluation period runs over the last 4 weeks of the treatment period up to 8 weeks, starting after visit 11 and ending on visit 15, thus it comprises post-long inter-dialytic interval visits 12, 13, 14 and 15. | A subject was considered to be a responder if, during the evaluation period, they maintained a pre-dialysis serum potassium (S-K) between 4.0 and 5.0 mmol/L on at least 3 out of 4 dialysis treatments following the long inter-dialytic interval and did not receive rescue therapy. The S-K levels used for this analysis were based on the measurements obtained by the central laboratory. |
| Percentage of Responders When Accounting for Missing Central Laboratory Serum Potassium Data | Evaluation period runs over the last 4 weeks of the treatment period up to 8 weeks, starting after visit 11 and ending on visit 15, thus it comprises post-long inter-dialytic interval visits 12, 13, 14 and 15. | The sensitivity analysis assessed the impact of subjects classified as non-responders due to missing serum potassium (S-K) data. Missing central lab (c-lab) pre-dialysis values were imputed using corresponding pre-dialysis i-STAT (a portable blood analyser) measurements. In addition, a last observation carried forward (LOCF) approach was utilized to further impute missing values of pre-dialysis S-K during the evaluation period. This technique will replace missing c-lab S-K values with the last available non-missing pre-dialysis LIDI observation recorded for that patient (and this could be a c-lab value or an imputed c-lab value). The Primary endpoint analysis was repeated on the imputed data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Needing Rescue Therapy | An 8 week overall treatment period (a 4 week adjustment phase plus a 4 week evaluation phase) and a 2 week follow up period. | Patients requiring any urgent intervention consistent with local practice patterns to reduce serum potassium (S-K) including insulin/glucose, beta-adrenergic agonists, sodium bicarbonate, K binders or any form of renal replacement therapy. |
Countries
Japan, Russia, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sodium Zirconium Cyclosilicate (SZC) Suspension administered orally for a treatment period of eight weeks (4 weeks of dose adjustment, 4 weeks in stable dose).
Single dose contains 1 to 3 sachets that should be suspended in 45 mL of water by patient and administered on non-dialysis days. | 97 |
| Placebo Suspension administered orally for a treatment period of eight weeks (4 weeks of dose adjustment, 4 weeks in stable dose).
Single dose contains 1 to 3 sachets that should be suspended in 45 mL of water by patient and administered on non-dialysis days. | 99 |
| Total | 196 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Investigational product discontinuation | 0 | 1 |
| Overall Study | Kidney transplantation | 0 | 1 |
| Overall Study | Non-comliance to study protocol | 0 | 1 |
| Overall Study | Transferred to non-study dialysis center | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Sodium Zirconium Cyclosilicate (SZC) | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 55.7 Years STANDARD_DEVIATION 13.84 | 60.4 Years STANDARD_DEVIATION 13.2 | 58.1 Years STANDARD_DEVIATION 13.69 |
| Race/Ethnicity, Customized American Indian Or Alasa Native | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Asian | 33 Participants | 33 Participants | 66 Participants |
| Race/Ethnicity, Customized Black Or African American | 11 Participants | 8 Participants | 19 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 4 Participants | 6 Participants |
| Race/Ethnicity, Customized White | 50 Participants | 52 Participants | 102 Participants |
| Sex: Female, Male Female | 40 Participants | 41 Participants | 81 Participants |
| Sex: Female, Male Male | 57 Participants | 58 Participants | 115 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 96 | 0 / 99 |
| other Total, other adverse events | 7 / 96 | 11 / 99 |
| serious Total, serious adverse events | 7 / 96 | 8 / 99 |
Outcome results
Primary
Percentage of Responders
A subject was considered to be a responder if, during the evaluation period, they maintained a pre-dialysis serum potassium (S-K) between 4.0 and 5.0 mmol/L on at least 3 out of 4 dialysis treatments following the long inter-dialytic interval and did not receive rescue therapy. The S-K levels used for this analysis were based on the measurements obtained by the central laboratory.
Time frame: Evaluation period runs over the last 4 weeks of the treatment period up to 8 weeks, starting after visit 11 and ending on visit 15, thus it comprises post-long inter-dialytic interval visits 12, 13, 14 and 15.
Population: Full Analysis Set (all randomized patients)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) | Percentage of Responders | 41.2 Percentage of participants |
| Placebo | Percentage of Responders | 1.0 Percentage of participants |
p-value: <0.00195% CI: [10.85, 2810.85]Fisher Exact
Primary
Percentage of Responders When Accounting for Missing Central Laboratory Serum Potassium Data
The sensitivity analysis assessed the impact of subjects classified as non-responders due to missing serum potassium (S-K) data. Missing central lab (c-lab) pre-dialysis values were imputed using corresponding pre-dialysis i-STAT (a portable blood analyser) measurements. In addition, a last observation carried forward (LOCF) approach was utilized to further impute missing values of pre-dialysis S-K during the evaluation period. This technique will replace missing c-lab S-K values with the last available non-missing pre-dialysis LIDI observation recorded for that patient (and this could be a c-lab value or an imputed c-lab value). The Primary endpoint analysis was repeated on the imputed data.
Time frame: Evaluation period runs over the last 4 weeks of the treatment period up to 8 weeks, starting after visit 11 and ending on visit 15, thus it comprises post-long inter-dialytic interval visits 12, 13, 14 and 15.
Population: Full Analysis Set (all randomized patients)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) | Percentage of Responders When Accounting for Missing Central Laboratory Serum Potassium Data | 42.3 Percentage of participants |
| Placebo | Percentage of Responders When Accounting for Missing Central Laboratory Serum Potassium Data | 2.0 Percentage of participants |
p-value: <0.00195% CI: [8.53, 309.48]Fisher Exact
Secondary
Percentage of Patients Needing Rescue Therapy
Patients requiring any urgent intervention consistent with local practice patterns to reduce serum potassium (S-K) including insulin/glucose, beta-adrenergic agonists, sodium bicarbonate, K binders or any form of renal replacement therapy.
Time frame: An 8 week overall treatment period (a 4 week adjustment phase plus a 4 week evaluation phase) and a 2 week follow up period.
Population: Full Analysis Set (all randomized patients)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) | Percentage of Patients Needing Rescue Therapy | 2.1 Percentage of participants |
| Placebo | Percentage of Patients Needing Rescue Therapy | 5.1 Percentage of participants |