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    Clinical Trial Results:
    An Open-Label, Randomised, Phase 4 Study of Continuing Sodium Zirconium Cyclosilicate (SZC) after Discharge in Participants with Chronic Kidney Disease treated for Hyperkalaemia

    Summary
    EudraCT number
    		 2021-003527-14
    Trial protocol
    		 IT   ES   FR   NL   BE  
    Global end of trial date
    10 Dec 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Oct 2025
    First version publication date
    31 Oct 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D9480C00023
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05347693
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    151 85, Södertälje, Sweden,
    Public contact
    Global Clinical Lead, AstraZeneca, +1 8772409479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca, +1 18772409479, information.center@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Jan 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Dec 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Dec 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of continuing SZC as part of the discharge medications, compared to standard of care (SoC), in maintaining normokalaemia (NK)
    Protection of trial subjects
    This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with ICH / GCP, applicable regulatory requirements and the AstraZeneca policy on Bioethics.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Mar 2022
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    Spain: 145
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    France: 12
    Worldwide total number of subjects
    186
    EEA total number of subjects
    180
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    38
    From 65 to 84 years
    126
    85 years and over
    22

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 186 participants were screened from 28 study sites across 6 countries.

    Pre-assignment
    Screening details
    		 Of 186 participants entering the inpatient phase, 137 were randomized 1:1 to Arm A or B for the outpatient phase; one did not receive treatment. The remaining 49 were not randomized due to consent withdrawal, eligibility issues, screening failure, death, or other reasons.

    Pre-assignment period milestones
    Number of subjects started
    		 186
    Number of subjects completed
    		 137

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Adverse event, non-fatal: 3
    Reason: Number of subjects
    		 Adverse event, serious fatal: 2
    Reason: Number of subjects
    		 Consent withdrawn by subject: 10
    Reason: Number of subjects
    		 Physician decision: 5
    Reason: Number of subjects
    		 Withdrawn in error: 1
    Reason: Number of subjects
    		 Participant was discharged from hospital: 1
    Reason: Number of subjects
    		 screening failure: 8
    Reason: Number of subjects
    		 Failure to meet inclusion/ exclusion criteria: 19
    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Outpatient Period - Arm A: SZC
    Arm description
    		 Participants discharged with SZC, as per local label, to manage hyperkalaemia (HK) until 7 days before the end of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sodium zirconium cyclosilicate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    As per local label

    Arm title
    		 Outpatient Period - Arm B: Standard of Care (SoC)
    Arm description
    		 SZC was withdrawn and participants discharged with SoC, as per local practice, to manage HK until the end of study.
    Arm type
    		 SoC

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1 [1]
    		Outpatient Period - Arm A: SZC Outpatient Period - Arm B: Standard of Care (SoC)
    Started
    68
    69
    Received at least 1 treatment
    68
    68
    Completed
    42
    56
    Not completed
    26
    13
         Adverse event, serious fatal
    6
    2
         Consent withdrawn by subject
    8
    5
         Development of withdrawal criteria: Severe HK
    -
    1
         Adverse event, non-fatal
    9
    -
         Compliance unmonitored; complex circumstances
    1
    -
         Start of dialysis
    -
    1
         Started dialysis on 16 Feb 2023
    1
    -
         Lost to follow-up
    -
    1
         The participant entered hemodialysis
    -
    1
         Scheduled hemodialysis
    1
    -
         Severe HK
    -
    1
         Relocated; unable to attend study visits
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Of 186 participants entering the inpatient phase, 137 were randomized 1:1 to Arm A or B for the outpatient phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    		 -

    Reporting group values
    		 Overall Study Total
    Number of subjects
    		 137 137
    Age Categorical
    Age at Screening
    Units: Participants
        18-64 years
    		 27 27
        65-84 years
    		 93 93
        >=85 years
    		 17 17
    Age Continuous
    Age at Screening
    Units: Years
        arithmetic mean (standard deviation)
    		 72.5 ( 10.56 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 41 41
        Male
    		 96 96
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    		 31 31
        Not Hispanic or Latino
    		 100 100
        Other category
    		 6 6
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 129 129
        Black or African American
    		 0 0
        Asian
    		 1 1
        Native Hawaiian or Other Pacific Islander
    		 0 0
        American Indian or Alaskan Native
    		 0 0
        Other
    		 0 0
        Multiple
    		 0 0
        Not reported
    		 7 7
    Country
    Units: Subjects
        Belgium
    		 2 2
        Spain
    		 117 117
        France
    		 6 6
        United Kingdom
    		 2 2
        Italy
    		 9 9
        Netherlands
    		 1 1
    Subject analysis sets

    Subject analysis set title
    Outpatient Period - Arm A: SZC (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants were randomized and discharged with SZC, as per local label, to manage HK until 7 days before the end of the study.

    Subject analysis set title
    Outpatient Period - Arm B: SoC (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants were randomized and had SZC withdrawn and were discharged with SoC, as per local practice, to manage HK until the end of study.

    Subject analysis set title
    Outpatient Period - Arm A: SZC (SSR)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Set Randomized (SSR) includes all randomized participants who received at least 1 dose of SZC post-discharge. Participants in this arm were discharged with SZC, as per local label, to manage HK until 7 days before the end of the study.

    Subject analysis set title
    Outpatient Period - Arm B: SoC (SSR)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Includes all randomised participants who had SZC withdrawn and was discharged with SoC, as per local practice, to manage HK until the end of study.

    Subject analysis sets values
    		 Outpatient Period - Arm A: SZC (FAS) Outpatient Period - Arm B: SoC (FAS) Outpatient Period - Arm A: SZC (SSR) Outpatient Period - Arm B: SoC (SSR)
    Number of subjects
    68
    69
    68
    68
    Age Categorical
    Age at Screening
    Units: Participants
        18-64 years
    14
    13
    14
    13
        65-84 years
    45
    48
    45
    47
        >=85 years
    9
    8
    9
    8
    Age Continuous
    Age at Screening
    Units: Years
        arithmetic mean (standard deviation)
    72.8 ( 10.25 )
    72.2 ( 10.92 )
    72.8 ( 10.25 )
    72.1 ( 10.99 )
    Sex: Female, Male
    Units: Participants
        Female
    25
    16
    25
    16
        Male
    43
    53
    43
    52
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    21
    10
    21
    10
        Not Hispanic or Latino
    43
    57
    43
    56
        Other category
    4
    2
    4
    2
    Race/Ethnicity, Customized
    Units: Subjects
        White
    64
    65
    64
    64
        Black or African American
    0
    0
    0
    0
        Asian
    0
    1
    0
    1
        Native Hawaiian or Other Pacific Islander
    0
    0
    0
    0
        American Indian or Alaskan Native
    0
    0
    0
    0
        Other
    0
    0
    0
    0
        Multiple
    0
    0
    0
    0
        Not reported
    4
    3
    4
    3
    Country
    Units: Subjects
        Belgium
    0
    2
    0
    2
        Spain
    57
    60
    57
    59
        France
    4
    2
    4
    2
        United Kingdom
    0
    2
    0
    2
        Italy
    6
    3
    6
    3
        Netherlands
    1
    0
    1
    0

    End points

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    End points reporting groups
    Reporting group title
    Outpatient Period - Arm A: SZC
    Reporting group description
    		 Participants discharged with SZC, as per local label, to manage hyperkalaemia (HK) until 7 days before the end of the study.

    Reporting group title
    Outpatient Period - Arm B: Standard of Care (SoC)
    Reporting group description
    		 SZC was withdrawn and participants discharged with SoC, as per local practice, to manage HK until the end of study.

    Subject analysis set title
    Outpatient Period - Arm A: SZC (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants were randomized and discharged with SZC, as per local label, to manage HK until 7 days before the end of the study.

    Subject analysis set title
    Outpatient Period - Arm B: SoC (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants were randomized and had SZC withdrawn and were discharged with SoC, as per local practice, to manage HK until the end of study.

    Subject analysis set title
    Outpatient Period - Arm A: SZC (SSR)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Set Randomized (SSR) includes all randomized participants who received at least 1 dose of SZC post-discharge. Participants in this arm were discharged with SZC, as per local label, to manage HK until 7 days before the end of the study.

    Subject analysis set title
    Outpatient Period - Arm B: SoC (SSR)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Includes all randomised participants who had SZC withdrawn and was discharged with SoC, as per local practice, to manage HK until the end of study.

    Primary: Occurrence (Yes/No) of NK (K+ between 3.5 and 5.0 mmol/L, inclusive) at 180 Days Post-discharge

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    End point title
    		 Occurrence (Yes/No) of NK (K+ between 3.5 and 5.0 mmol/L, inclusive) at 180 Days Post-discharge
    End point description
    A response was defined as a participant having serum K+ within 3.5 and 5.0 mmol/L at 180 days post-discharge. No response was defined as a participant who: 1) used rescue therapy for hyperkalaemia (HK) during the outpatient period; 1) died prior to 180 days post-discharge; 3) were missing an assessment at visit 10; 4) were lost to follow-up prior to 180 days post-discharge; 5) down-titrated (or discontinued) RAASi. The number of participants who had a response/no response is presented.
    End point type
    Primary
    End point timeframe
    At 180 days post-discharge (Visit 10)
    End point values
    		 Outpatient Period - Arm A: SZC (FAS) Outpatient Period - Arm B: SoC (FAS)
    Number of subjects analysed
    68
    69
    Units: Number of participants
        Response
    21
    25
        No response
    47
    44
    Statistical analysis title
    		 Equivalence test
    Comparison groups
    Outpatient Period - Arm A: SZC (FAS) v Outpatient Period - Arm B: SoC (FAS)
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    P-value
    		 = 0.558
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 1.66
    Notes
    [1] - Equivalence margin is 0.29. Sample size estimate: • Two group χ² test • Significance level: 5% (2-sided) • Power: 80% • Proportions with NK (K+ between 3.5 and 5.0 mmol/L, inclusive) at 180 days post-discharge: - Arm A (SZC): 0.88 - Arm B (SoC): 0.59

    Secondary: Time to First Occurrence of Any Component of All-cause Hospital Admissions or ED Visits with HK as a Contributing Factor, or All-cause Death, or Use of Rescue Therapy for HK at Any Time Post-discharge up to 180 Days

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    End point title
    		 Time to First Occurrence of Any Component of All-cause Hospital Admissions or ED Visits with HK as a Contributing Factor, or All-cause Death, or Use of Rescue Therapy for HK at Any Time Post-discharge up to 180 Days
    End point description
    The time to first occurrence of all-cause hospital admission, emergency department (ED) visits with HK as a contributing factor, all-cause death or use of rescue therapy for HK was calculated as date of first occurrence of (all-cause hospital admission, ED visits with HK as a contributing factor, all-cause death, use of rescue therapy for HK, date of loss to follow-up) – date of randomization + 1. The median time to event (days) is presented. '9999' means 'Not Applicable' as no median time or confidence interval could be calculated due to fewer than 50% of participants experienced an event or there were too few events to estimate the confidence interval for the median, respectively.
    End point type
    Secondary
    End point timeframe
    At any time post-discharge (from Visits 4 to 10), up to 180 days
    End point values
    		 Outpatient Period - Arm A: SZC (FAS) Outpatient Period - Arm B: SoC (FAS)
    Number of subjects analysed
    68
    69
    Units: Days
        median (confidence interval 95%)
    136 (60.00 to 9999)
    9999 (63.00 to 9999)
    Statistical analysis title
    		 Equivalence test
    Comparison groups
    Outpatient Period - Arm A: SZC (FAS) v Outpatient Period - Arm B: SoC (FAS)
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [2]
    P-value
    		 = 0.743
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 1.51
    Notes
    [2] - Equivalence margin is 0.262. Sample size estimate: • Log-Rank Test for Equality of Survival Curves • Significance level: 5% • Power: 80% • Hazard ratio (HR; SZC/SoC): 0.329 • Proportions without the main secondary composite outcome (event-free) at 180 days post-discharge: - Arm A (SZC): 83% (17% with the outcome/event of interest) - Arm B (SoC): 56.8% (43.2% with the outcome/event of interest)

    Secondary: Time to First Occurrence of Any Component of All-cause Hospital Admission or ED Visit with HK as a Contributing Factor at Any Time Post-discharge up to 180 Days

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    End point title
    		 Time to First Occurrence of Any Component of All-cause Hospital Admission or ED Visit with HK as a Contributing Factor at Any Time Post-discharge up to 180 Days
    End point description
    The time to first occurrence of any component of all-cause hospital admission or ED visit with HK as a contributing factor at any time post-discharge up to 180 days was calculated as the earliest date of (all-cause hospital admission, ED visits with HK as a contributing factor, all-cause death, use of rescue therapy for HK, date of loss to follow-up, date of 180 days post-discharge) – date of randomization + 1. The median time to event (days) is presented. '9999' means 'Not Applicable' as no median time or confidence interval could be calculated due to fewer than 50% of participants experienced an event or there were too few events to estimate the confidence interval for the median, respectively.
    End point type
    Secondary
    End point timeframe
    At any time post-discharge (from Visits 4 to 10), up to 180 days
    End point values
    		 Outpatient Period - Arm A: SZC (FAS) Outpatient Period - Arm B: SoC (FAS)
    Number of subjects analysed
    68
    69
    Units: Days
        median (confidence interval 95%)
    9999 (116.00 to 9999)
    9999 (123.00 to 9999)
    Statistical analysis title
    		 Equivalence test
    Comparison groups
    Outpatient Period - Arm A: SZC (FAS) v Outpatient Period - Arm B: SoC (FAS)
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    P-value
    		 = 0.951
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 1.79
    Notes
    [3] - This outcome is unpowered.

    Secondary: Number of All-cause Hospital Admissions or ED Visits with HK as a Contributing Factor at Any Time Post-discharge up to 180 Days

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    End point title
    		 Number of All-cause Hospital Admissions or ED Visits with HK as a Contributing Factor at Any Time Post-discharge up to 180 Days
    End point description
    The number of all-cause hospital admissions or ED visits with HK as a contributing factor at any time post-discharge up to 180 days is presented. Participants who discontinued treatment, used rescue therapy for HK, experienced all-cause death or loss to follow-up prior to 180 days post-discharge or who down-titrated (including discontinued) RAASi were to have all available hospital admission data used irrespective of the intercurrent event (treatment policy strategy).
    End point type
    Secondary
    End point timeframe
    At any time post-discharge (from Visits 4 to 10), up to 180 days
    End point values
    		 Outpatient Period - Arm A: SZC (FAS) Outpatient Period - Arm B: SoC (FAS)
    Number of subjects analysed
    68
    69
    Units: Number of hospital admissions/ ED visits
        arithmetic mean (standard deviation)
    0.7 ( 0.92 )
    0.6 ( 0.83 )
    Statistical analysis title
    		 Equivalence test
    Comparison groups
    Outpatient Period - Arm A: SZC (FAS) v Outpatient Period - Arm B: SoC (FAS)
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [4]
    P-value
    		 = 0.152
    Method
    		 Negative binomial regression model
    Parameter type
    		 Incidence rate ratio
    Point estimate
    1.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 2.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4
    Notes
    [4] - This outcome is unpowered.

    Secondary: Time to First Occurrence of RAASi Down-titration (or Discontinuation) at Any Time Post-discharge up to 180 Days

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    End point title
    		 Time to First Occurrence of RAASi Down-titration (or Discontinuation) at Any Time Post-discharge up to 180 Days
    End point description
    The time to first occurrence of RAASi down-titration (or discontinuation) was calculated as date of first occurrence of (RAASi down-titration, all-cause death, date of loss to follow-up) – date of randomization + 1. The median time to event (days) is presented. '9999' means 'Not Applicable' as no median time or confidence interval could be calculated due to fewer than 50% of participants experienced an event or there were too few events to estimate the confidence interval for the median, respectively.
    End point type
    Secondary
    End point timeframe
    At any time post-discharge (from Visits 4 to 10), up to 180 days
    End point values
    		 Outpatient Period - Arm A: SZC (FAS) Outpatient Period - Arm B: SoC (FAS)
    Number of subjects analysed
    68
    69
    Units: Days
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Statistical analysis title
    		 Equivalence test
    Comparison groups
    Outpatient Period - Arm A: SZC (FAS) v Outpatient Period - Arm B: SoC (FAS)
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [5]
    P-value
    		 = 0.515
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 4.35
    Notes
    [5] - This outcome is unpowered.

    Secondary: Time to First Occurrence of Hospital Admission or ED Visit, Both With HK as a Contributing Factor at Any Time Post-discharge up to 180 Days

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    End point title
    		 Time to First Occurrence of Hospital Admission or ED Visit, Both With HK as a Contributing Factor at Any Time Post-discharge up to 180 Days
    End point description
    The time to first occurrence of hospital admission or ED visit, both with HK as a contributing factor, was calculated as date of first occurrence of (Hospital admission or ED visit with HK as a contributing factor, all-cause death, use of rescue therapy for HK, date of loss to follow-up) – date of randomization + 1. The median time to event (days) is presented. '9999' means 'Not Applicable' as no median time or confidence interval could be calculated due to fewer than 50% of participants experienced an event or there were too few events to estimate the confidence interval for the median, respectively.
    End point type
    Secondary
    End point timeframe
    At any time post-discharge (from Visits 4 to 10), up to 180 days
    End point values
    		 Outpatient Period - Arm A: SZC (FAS) Outpatient Period - Arm B: SoC (FAS)
    Number of subjects analysed
    68
    69
    Units: Days
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Statistical analysis title
    		 Equivalence test
    Comparison groups
    Outpatient Period - Arm A: SZC (FAS) v Outpatient Period - Arm B: SoC (FAS)
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [6]
    P-value
    		 = 0.258
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.07
         upper limit
    		 1.83
    Notes
    [6] - This outcome is unpowered.

    Secondary: Number of Hospital Admissions or ED Visits with HK as a Contributing Factor, at Any Time Post-discharge up to 180 Days

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    End point title
    		 Number of Hospital Admissions or ED Visits with HK as a Contributing Factor, at Any Time Post-discharge up to 180 Days
    End point description
    The number of hospital admissions or ED visits with HK as a contributing factor, at any time post-discharge up to 180 days is presented. Participants who discontinued treatment, used rescue therapy for HK, experienced all-cause death or loss to follow-up prior to 180 days post-discharge or who downtitrated (including discontinued) RAASi were to have all available hospital admission data used irrespective of the intercurrent event (treatment policy strategy).
    End point type
    Secondary
    End point timeframe
    At any time post-discharge (from Visits 4 to 10), up to 180 days
    End point values
    		 Outpatient Period - Arm A: SZC (FAS) Outpatient Period - Arm B: SoC (FAS)
    Number of subjects analysed
    68
    69
    Units: Number of hospital admissions/ ED visits
        arithmetic mean (standard deviation)
    0.1 ( 0.24 )
    0.1 ( 0.26 )
    Statistical analysis title
    		 Equivalence test
    Comparison groups
    Outpatient Period - Arm A: SZC (FAS) v Outpatient Period - Arm B: SoC (FAS)
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [7]
    P-value
    		 = 0.239
    Method
    		 Negative binomial regression model
    Parameter type
    		 Incidence risk ratio
    Point estimate
    0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 1.81
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.31
    Notes
    [7] - This outcome is unpowered.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were collected from the start of the outpatient phase (OP) through 7 days post-last dose. AEs which occurred prior to first dose of investigational product that worsened after dosing during the OP were recorded; up to ~6 months
    Adverse event reporting additional description
    AEs for the SSR are presented. Of the 137 participants randomised into the 2 arms (68 in Arm A: SZC and 69 in Arm B: SoC), there was 1 participant in the SoC who did not receive treatment during the OP and was excluded from the safety analysis.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.1
    Reporting groups
    Reporting group title
    Outpatient Period - Arm B: SoC (SSR)
    Reporting group description
    		 -

    Reporting group title
    Outpatient Period - Arm A: SZC (SSR)
    Reporting group description
    		 -

    Serious adverse events
    		 Outpatient Period - Arm B: SoC (SSR) Outpatient Period - Arm A: SZC (SSR)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 68 (30.88%)
    29 / 68 (42.65%)
         number of deaths (all causes)
    2
    6
         number of deaths resulting from adverse events
    2
    6
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemia
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Male genital tract fistula
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 68 (0.00%)
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure chronic
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    2 / 68 (2.94%)
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pericarditis
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myasthenia gravis crisis
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ischaemic stroke
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    1 / 68 (1.47%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Chronic kidney disease
         subjects affected / exposed
    2 / 68 (2.94%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 68 (1.47%)
    3 / 68 (4.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 68 (1.47%)
    3 / 68 (4.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Penile abscess
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Subcutaneous abscess
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 68 (1.47%)
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Electrolyte imbalance
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic metabolic decompensation
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    2 / 68 (2.94%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Outpatient Period - Arm B: SoC (SSR) Outpatient Period - Arm A: SZC (SSR)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 68 (44.12%)
    22 / 68 (32.35%)
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    2 / 68 (2.94%)
    4 / 68 (5.88%)
         occurrences all number
    2
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 68 (11.76%)
    3 / 68 (4.41%)
         occurrences all number
    8
    3
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    4 / 68 (5.88%)
    5 / 68 (7.35%)
         occurrences all number
    4
    5
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    6 / 68 (8.82%)
    1 / 68 (1.47%)
         occurrences all number
    8
    1
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    17 / 68 (25.00%)
    12 / 68 (17.65%)
         occurrences all number
    19
    14
    Metabolic acidosis
         subjects affected / exposed
    4 / 68 (5.88%)
    3 / 68 (4.41%)
         occurrences all number
    4
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Aug 2021
    Study intervention dispensation was added at visit 4 to allow for study intervention dispensation if dose needed to be adjusted.
    07 Jul 2022
    RAASi down-titration (including discontinuation) is now defined as non-response and included in the primary composite outcome as treatment failure due to its potential to normalise K levels. Objective #2 now assesses SZC’s effect on reducing hospital admissions or ED visits with HK. Objective #3 focuses on SZC's effect on reducing hospital admissions or ED visits with HK. A new objective evaluates SZC’s role in lowering the risk of RAASi down-titration. Objectives #4 to 10 were reclassified as exploratory to simplify endpoints. Inclusion criterion #4 now defines HK per site practice, with K⁺ >5.0 to ≤6.5 mmol/L. Exclusion criteria #3 and #14 were merged to exclude all kidney transplant recipients. Sensitivity analyses were updated to reflect SZC’s benefit for mild versus moderate/severe HK. Re-screening was allowed (up to 2). Duration of inpatient stay was extended from 14 to 21 days post-baseline. Definition of overdose during SZC maintenance phase was modified from 15 g/day to 10 g/day.
    16 Oct 2023
    First secondary endpoint was revised to include all-cause hospital admissions or ED visits with HK as a contributing factor. The sample size was recalculated from 344 to 104 total evaluable participants. Inclusion criteria were expanded to allow participants with any stage of CKD or eGFR < 90 mL/min/1.73 m². Clarifications were made to inclusion criterion #4 regarding K levels at enrolment. Exclusion criteria were simplified to improve clarity and to exclude participants with a hospitalisation for an acute cardiovascular event within 12 weeks prior to screening. The planned interim analysis was cancelled due to the reduced sample size.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to high, imbalanced missing K⁺ data at Day 180 (51.5% SZC, 36.2% SoC), results are described with no conclusive statement and should be interpreted with caution.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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