Hyperkalemia
Conditions
Brief summary
The purpose of this study is to evaluate the efficacy and safety of Sodium Zirconium Cyclosilicate (SZC), as well as the appropriateness of the dosing mechanism, in Chinese end-stage renal disease (ESRD) patients on chronic haemodialysis.
Detailed description
This is a randomized, double-blind, placebo-controlled study to determine the safety and efficacy of SZC in ESRD subjects with hyperkalaemia and on stable haemodialysis. This study consists of a screening period, an 8-week randomized treatment period, and a follow-up period. Approximately 134 stable haemodialysis subjects with persistent pre-dialysis hyperkalaemia will be enrolled in the study across research sites in China.
Interventions
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 SZC 5g depending on dose level assigned to a patient per non-dialysis days.
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.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
1. Provision of signed and dated, written informed consent form prior to any mandatory study specific procedures, sampling, and analyses. 2. Subject must be ≥ 18 years of age inclusive, at the time of signing the informed consent form. 3. Subjects must have haemodialysis access consisting of an arteriovenous fistula, AV graft, or tunnelled (permanent) catheter which is expected to remain in place for the entire duration of the study. 4. Receiving haemodialysis (or hemodiafiltration) 3 times a week for treatment of end-stage renal disease (ESRD) for at least 3 months before randomization. 5. Pre-dialysis S-K \> 5.4 mmol/L after long inter-dialytic interval and \> 5.0 mmol/L after at least 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 haemodialysis / haemodiafltration prescription during screening with prescription (time, dialyzer, blood flow \[Qb\], dialysate flow rate \[Qd\] and bicarbonate concentration) expected to remain unchanged during study. 8. Subjects must be receiving dietary counselling appropriate for ESRD subjects treated with haemodialysis / haemodiafiltration as per local guidelines, which includes dietary potassium restriction.
Exclusion criteria
1. 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. 2. Pseudohyperkalaemia secondary to haemolyzed blood specimen (this situation is not considered screening failure, sampling or full screening can be postponed to a later time as applicable). 3. Diagnosis of rhabdomyolysis during the 4 weeks preceding randomization. 4. Presence of cardiac arrhythmias or conduction defects that require immediate treatment. 5. Any medical condition, including active, clinically significant infection or liver disease, that in the opinion of the investigator or Sponsor may pose a safety risk to a subject in this study, which may confound safety or efficacy assessment and jeopardize the quality of the data, or may interfere with study participation. 6. History of QT prolongation associated with other medications that required discontinuation of that medication; congenital long QT syndrome or QTc(f) \> 550 msec; uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Subjects with atrial fibrillation controlled by medication or with transient atrial fibrillation associated with dialysis or peridialytic period are permitted. 7. Subjects treated with sodium polystyrene sulfonate (e.g. 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. 8. Participation in another clinical study with an investigational product administered in the last 1 month before screening. 9. Haemoglobin \< 9 g/dL on screening (as assessed on Visit 1). 10. Laboratory diagnosis of hypokalaemia (K \< 3.5 mmol/L), hypocalcemia (Ca \< 8.2 mg/d or albumin-corrected Ca \< 8.0 mg/dL if the latter is used in local practice), hypomagnesemia (Mg \< 1.7 mg/dL) or severe acidosis (serum bicarbonate 16 mEq/L or less) in the 4 weeks preceding randomization. 11. Severe leukocytosis (\> 20 × 109/L) or thrombocytosis (≥ 450 × 109/L) during screening. 12. Polycythaemia (Hb \> 14 g/dL) during screening. 13. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). 14. Judgment by the investigator that the subject should not participate in the study if the subject is unlikely to comply with study procedures, restrictions and requirements. 15. Previous randomisation in the present study. 16. For women only - currently pregnant (confirmed with positive pregnancy test or uterine ultrasound if pregnancy test is questionable) or breast-feeding. 17. Females of childbearing potential, unless using contraception as detailed in the protocol or sexual abstinence. 18. Lack of compliance with haemodialysis prescription (both number and duration of treatments) during the two-week period preceding screening (100% compliance required). 19. Subjects unable to take investigational product drug mix. 20. Scheduled date for living donor kidney transplant. 21. Subjects with a life expectancy of less than 6 months. 22. Known hypersensitivity or previous anaphylaxis to SZC or to components thereof. 23. History of alcohol or drug abuse within 2 years prior to randomization.
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. | 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 (LIDI) and did not receive rescue therapy. Subjects with no data during the evaluation period were classified as non-responders. The S-K levels used for this analysis were based on the measurements obtained by the central laboratory. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Pre-dialysis S-K Values After SIDI and LIDI Below or Equal to 5.5 mmol/L During Evaluation Period | Evaluation period runs over the last 4 weeks of the treatment period up to 8 weeks. | Probability of maintaining maximum S-K value \<= 5.5 mmol/L was evaluated. Each subject's maximum pre-dialysis S-K at long inter-dialytic interval (LIDI) and short inter-dialytic interval (SIDI) visits during the evaluation period were categorised into \<= 5.5 or \> 5.5 mmol/L. Missing S-K values including those omitted due to coinciding with rescue therapy use or records omitted that are not true LIDI (i.e. records which do not occur \>= 55 hours after the previous dialysis starting time) were imputed using multiple imputation (MI). |
| Pre-dialysis S-K After LIDI Between 3.5 and 5.5 mmol/L During the Evaluation Period | Evaluation period runs over the last 4 weeks of the treatment period up to 8 weeks. | Probability of all S-K values between 3.5 and 5.5 mmol/L was evaluated. Subjects were categorised to either having all pre-dialysis LIDI values between 3.5 and 5.5 mmol/L during the evaluation period or not. Missing S-K values including those omitted due to coinciding with rescue therapy use or records omitted that are not true LIDI (i.e. records which do not occur \>= 55 hours after the previous dialysis starting time) were imputed using multiple imputation (MI). |
| Instances of Pre-dialysis S-K After LIDI Between 4.0 and 5.0 mmol/L During the Evaluation Period | Evaluation period runs over the last 4 weeks of the treatment period up to 8 weeks. | The probability of maintaining instances of pre-dialysis S-K between 4.0 and 5.0 mmol/L (normokalaemia) was evaluated at each LIDI visit during the evaluation period, by categorisation of pre-dialysis S-K into values between 4.0 and 5.0 mmol/L or not. Values coinciding with rescue therapy or not true LIDI (i.e. records which do not occur \>= 55 hours after the previous dialysis starting time) were excluded. |
| Expected Number of Normokalaemic (S-K 4.0-5.0 mmol/L) Instances | Evaluation period runs over the last 4 weeks of the treatment period up to 8 weeks. | The expected number of normokalemic instances is the sum of the probabilities of normokalaemic instance at each visit during the evaluation period. Normokalaemic is defined as S-K between 4.0 and 5.0 mmol/L. |
| Instances of Potassium Gradient of < 3.0 mmol/L After LIDI During the Evaluation Period | Evaluation period runs over the last 4 weeks of the treatment period up to 8 weeks. | The probability of maintaining instances of potassium gradient of \< 3.0 mmol/L was evaluated at each LIDI visit during the evaluation period, by categorisation of potassium gradient into \< 3.0 or \>=3.0 mmol/L. Values coinciding with rescue therapy or not true LIDI (i.e. records which do not occur \>= 55 hours after the previous dialysis starting time) were excluded. |
Countries
China
Participant flow
Recruitment details
The study has been completed and was conducted in 37 centres across China. 281 subjects were screened and 134 randomised subjects (67 per treatment group).
Pre-assignment details
Eligbile Chinese subjects with end-stage renal disease (ESRD) on stable haemodialysis were randomly assigned to either sodium zirconium cyclosilicate (SZC) or placebo in a 1:1 ratio.
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. | 67 |
| 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. | 67 |
| Total | 134 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
| Overall Study | Other | 1 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 1 |
Baseline characteristics
| Characteristic | Sodium Zirconium Cyclosilicate (SZC) | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 54.9 Years STANDARD_DEVIATION 11.32 | 54.5 Years STANDARD_DEVIATION 11.36 | 54.7 Years STANDARD_DEVIATION 11.3 |
| Age, Customized Age group (years) >=50 - <65 years | 33 Participants | 33 Participants | 66 Participants |
| Age, Customized Age group (years) <50 years | 20 Participants | 22 Participants | 42 Participants |
| Age, Customized Age group (years) >=65 -<85 years | 14 Participants | 11 Participants | 25 Participants |
| Age, Customized Age group (years) >=85 years | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 67 Participants | 67 Participants | 134 Participants |
| Sex: Female, Male Female | 34 Participants | 34 Participants | 68 Participants |
| Sex: Female, Male Male | 33 Participants | 33 Participants | 66 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 66 | 1 / 67 |
| other Total, other adverse events | 24 / 66 | 25 / 67 |
| serious Total, serious adverse events | 6 / 66 | 8 / 67 |
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 (LIDI) and did not receive rescue therapy. Subjects with no data during the evaluation period were classified as non-responders. 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.
Population: Full analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) | Percentage of Responders | 25 Participants |
| Placebo | Percentage of Responders | 7 Participants |
p-value: <0.00195% CI: [1.9, 15.12]Fisher Exact
Secondary
Expected Number of Normokalaemic (S-K 4.0-5.0 mmol/L) Instances
The expected number of normokalemic instances is the sum of the probabilities of normokalaemic instance at each visit during the evaluation period. Normokalaemic is defined as S-K between 4.0 and 5.0 mmol/L.
Time frame: Evaluation period runs over the last 4 weeks of the treatment period up to 8 weeks.
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) | Expected Number of Normokalaemic (S-K 4.0-5.0 mmol/L) Instances | 1.91 Sum of probabilities |
| Placebo | Expected Number of Normokalaemic (S-K 4.0-5.0 mmol/L) Instances | 0.70 Sum of probabilities |
95% CI: [0.77, 1.64]
Secondary
Instances of Potassium Gradient of < 3.0 mmol/L After LIDI During the Evaluation Period
The probability of maintaining instances of potassium gradient of \< 3.0 mmol/L was evaluated at each LIDI visit during the evaluation period, by categorisation of potassium gradient into \< 3.0 or \>=3.0 mmol/L. Values coinciding with rescue therapy or not true LIDI (i.e. records which do not occur \>= 55 hours after the previous dialysis starting time) were excluded.
Time frame: Evaluation period runs over the last 4 weeks of the treatment period up to 8 weeks.
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) | Instances of Potassium Gradient of < 3.0 mmol/L After LIDI During the Evaluation Period | 0.52 Probability |
| Placebo | Instances of Potassium Gradient of < 3.0 mmol/L After LIDI During the Evaluation Period | 0.16 Probability |
p-value: <0.00195% CI: [3.15, 10.73]Generalised linear mixed model (GLMM)
Secondary
Instances of Pre-dialysis S-K After LIDI Between 4.0 and 5.0 mmol/L During the Evaluation Period
The probability of maintaining instances of pre-dialysis S-K between 4.0 and 5.0 mmol/L (normokalaemia) was evaluated at each LIDI visit during the evaluation period, by categorisation of pre-dialysis S-K into values between 4.0 and 5.0 mmol/L or not. Values coinciding with rescue therapy or not true LIDI (i.e. records which do not occur \>= 55 hours after the previous dialysis starting time) were excluded.
Time frame: Evaluation period runs over the last 4 weeks of the treatment period up to 8 weeks.
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) | Instances of Pre-dialysis S-K After LIDI Between 4.0 and 5.0 mmol/L During the Evaluation Period | 0.48 Probability |
| Placebo | Instances of Pre-dialysis S-K After LIDI Between 4.0 and 5.0 mmol/L During the Evaluation Period | 0.17 Probability |
p-value: <0.00195% CI: [2.53, 7.67]Generalised linear mixed model (GLMM)
Secondary
Maximum Pre-dialysis S-K Values After SIDI and LIDI Below or Equal to 5.5 mmol/L During Evaluation Period
Probability of maintaining maximum S-K value \<= 5.5 mmol/L was evaluated. Each subject's maximum pre-dialysis S-K at long inter-dialytic interval (LIDI) and short inter-dialytic interval (SIDI) visits during the evaluation period were categorised into \<= 5.5 or \> 5.5 mmol/L. Missing S-K values including those omitted due to coinciding with rescue therapy use or records omitted that are not true LIDI (i.e. records which do not occur \>= 55 hours after the previous dialysis starting time) were imputed using multiple imputation (MI).
Time frame: Evaluation period runs over the last 4 weeks of the treatment period up to 8 weeks.
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) | Maximum Pre-dialysis S-K Values After SIDI and LIDI Below or Equal to 5.5 mmol/L During Evaluation Period | 0.54 Probability |
| Placebo | Maximum Pre-dialysis S-K Values After SIDI and LIDI Below or Equal to 5.5 mmol/L During Evaluation Period | 0.15 Probability |
p-value: <0.00195% CI: [2.64, 15.55]Regression, Logistic
Secondary
Pre-dialysis S-K After LIDI Between 3.5 and 5.5 mmol/L During the Evaluation Period
Probability of all S-K values between 3.5 and 5.5 mmol/L was evaluated. Subjects were categorised to either having all pre-dialysis LIDI values between 3.5 and 5.5 mmol/L during the evaluation period or not. Missing S-K values including those omitted due to coinciding with rescue therapy use or records omitted that are not true LIDI (i.e. records which do not occur \>= 55 hours after the previous dialysis starting time) were imputed using multiple imputation (MI).
Time frame: Evaluation period runs over the last 4 weeks of the treatment period up to 8 weeks.
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sodium Zirconium Cyclosilicate (SZC) | Pre-dialysis S-K After LIDI Between 3.5 and 5.5 mmol/L During the Evaluation Period | 0.58 Probability |
| Placebo | Pre-dialysis S-K After LIDI Between 3.5 and 5.5 mmol/L During the Evaluation Period | 0.17 Probability |
p-value: <0.00195% CI: [2.71, 15.12]Regression, Logistic