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    Clinical Trial Results:
    Phase IV, Double-blind, Placebo-controlled, Randomised Withdrawal Trial Evaluating Sodium Zirconium Cyclosilicate (SZC) for the Management of Hyperkalaemia in Patients with Symptomatic Heart Failure with Reduced Ejection Fraction and Receiving Spironolactone (REALIZE-K)

    Summary
    EudraCT number
    		 2020-003312-27
    Trial protocol
    		 HU   ES  
    Global end of trial date
    07 Aug 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Apr 2025
    First version publication date
    26 Apr 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D9480C00018
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    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 8772409479, 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
    07 Aug 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Aug 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the efficacy of SZC as compared with placebo in keeping potassium levels within the normal range (3.5-5.0 mEq/L) while on spironolactone ≥ 25 mg daily without assistance of rescue therapy for hyperkalaemia.
    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 International Council for Harmonisation/Good Clinical Practice, applicable regulatory requirements, and the AstraZeneca policy on Bioethics.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Mar 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Brazil: 50
    Country: Number of subjects enrolled
    Canada: 23
    Country: Number of subjects enrolled
    Czechia: 16
    Country: Number of subjects enrolled
    Spain: 59
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    Hungary: 10
    Country: Number of subjects enrolled
    Poland: 18
    Country: Number of subjects enrolled
    United States: 14
    Worldwide total number of subjects
    203
    EEA total number of subjects
    103
    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)
    50
    From 65 to 84 years
    142
    85 years and over
    11

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This study consisted of two phases, an open-label run-in phase and a placebo-controlled randomized-withdrawal phase (RWP). Of the 366 participants enrolled in the open-label run-in phase, 203 participants entered into the RWP (102 received SZC treatment and 101 received placebo).

    Period 1
    Period 1 title
    Randomized-withdrawal Phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 SZC group
    Arm description
    		 Participants continued on the SZC and spironolactone dose they were receiving at the end of the run-in phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SZC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    10 g three times daily; then titrate between 5 g every other day and 5 g daily to 15 g daily

    Arm title
    		 Placebo group
    Arm description
    		 Participants continued on the placebo and spironolactone dose they were receiving at the end of the run-in phase.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Titrate between 5 g every other day and 5 g daily to 15 g daily

    Number of subjects in period 1
    		SZC group Placebo group
    Started
    102
    101
    Completed
    88
    87
    Not completed
    14
    14
         Adverse event, serious fatal
    1
    2
         Consent withdrawn by subject
    2
    2
         Adverse event, non-fatal
    5
    5
         Withdrawn as randomized in error
    1
    -
         Withdrawn due to protocol deviation
    1
    -
         Withdrawn due to not enough medication
    -
    1
         Withdrawn due to stopping spironolactone
    1
    -
         Lost to follow-up
    1
    -
         Development of Study-specific Withdrawal Criteria
    2
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SZC group
    Reporting group description
    		 Participants continued on the SZC and spironolactone dose they were receiving at the end of the run-in phase.

    Reporting group title
    Placebo group
    Reporting group description
    		 Participants continued on the placebo and spironolactone dose they were receiving at the end of the run-in phase.

    Reporting group values
    		 SZC group Placebo group Total
    Number of subjects
    		 102 101 203
    Age Categorical
    Units: Participants
        18-64 years
    		 18 32 50
        65-84 years
    		 79 63 142
        >=85 years
    		 5 6 11
    Age Continuous
    Age at Screening
    Units: Years
        arithmetic mean (standard deviation)
    		 72.5 ( 7.88 ) 69.2 ( 10.46 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 26 26 52
        Male
    		 76 75 151
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 91 94 185
        Black or African American
    		 5 5 10
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        American Indian or Alaskan Native
    		 0 0 0
        Other
    		 6 2 8
        Not Reported
    		 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 40 27 67
        Not Hispanic or Latino
    		 62 74 136
        Unknown or Not Reported
    		 0 0 0
    Country
    Units: Subjects
        BRA
    		 31 19 50
        CAN
    		 7 16 23
        CZE
    		 3 13 16
        ESP
    		 33 26 59
        GBR
    		 9 4 13
        HUN
    		 5 5 10
        POL
    		 8 10 18
        USA
    		 6 8 14
    Type 2 diabetes at baseline
    Coded using baseline medical history
    Units: Subjects
        With type 2 diabetes at baseline
    		 27 25 52
        Without type 2 diabetes at baseline
    		 75 76 151

    End points

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    End points reporting groups
    Reporting group title
    SZC group
    Reporting group description
    		 Participants continued on the SZC and spironolactone dose they were receiving at the end of the run-in phase.

    Reporting group title
    Placebo group
    Reporting group description
    		 Participants continued on the placebo and spironolactone dose they were receiving at the end of the run-in phase.

    Primary: Participants who achieved response, defined as serum potassium (sK+) within 3.5 to 5.0 mEq/L, spironolactone greater than or equal to 25 mg daily, no rescue therapy for hyperkalaemia

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    End point title
    		 Participants who achieved response, defined as serum potassium (sK+) within 3.5 to 5.0 mEq/L, spironolactone greater than or equal to 25 mg daily, no rescue therapy for hyperkalaemia
    End point description
    The median percentages of participants having a response are presented. Response means all three requirements were met. Non-response was indicated for participants lost to follow-up, including death. The treatment effect was analysed using a generalised estimating equation (GEE) model with a binomial family and a log link, a dependent variable of response per visit, fixed independent variables of randomised treatment, subject recruitment country, a per visit indicator variable and open-label period cohort. The common odds ratio was derived together with two-sided 95% confidence intervals.
    End point type
    Primary
    End point timeframe
    From Month 1 (Visit 9) to Month 6 (Visit 14), up to 6 months
    End point values
    		 SZC group Placebo group
    Number of subjects analysed
    102
    101
    Units: Percentage of response
        number (not applicable)
    72.1
    35.7
    Statistical analysis title
    		 SZC group vs Placebo group
    Comparison groups
    SZC group v Placebo group
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 GEE model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    4.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.89
         upper limit
    		 6.86

    Secondary: Response defined as sK+ within 3.5-5.0 mEq/L, on the same dose of spironolactone as randomisation, no rescue therapy for hyperkalaemia

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    End point title
    		 Response defined as sK+ within 3.5-5.0 mEq/L, on the same dose of spironolactone as randomisation, no rescue therapy for hyperkalaemia
    End point description
    The median percentages of participants who achieved a response are presented. Response means all three requirements were met. Non-response was indicated for participants lost to follow-up, including death. The analysis was performed using a GEE model with a binomial family and a log link, a dependent variable of response per visit, fixed independent variables of randomised treatment, subject recruitment country, a per visit indicator variable and open-label period cohort. The common odds ratio was derived together with two-sided 95% confidence intervals.
    End point type
    Secondary
    End point timeframe
    From Month 1 (Visit 9) to Month 6 (Visit 14), up to 6 months
    End point values
    		 SZC group Placebo group
    Number of subjects analysed
    102
    101
    Units: Percentage of responses
        number (not applicable)
    58.2
    22.9
    Statistical analysis title
    		 SZC group vs Placebo group
    Comparison groups
    SZC group v Placebo group
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 GEE model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    4.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.78
         upper limit
    		 7.55

    Secondary: Participant who achieved response, defined as spironolactone greater than or equal to 25 mg daily

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    End point title
    		 Participant who achieved response, defined as spironolactone greater than or equal to 25 mg daily
    End point description
    The median percentages of participants who achieved a response are presented. Response means that the requirement was met. Non-response was indicated for subjects lost to follow-up, including death. The analysis was performed using a GEE model with a binomial family and a log link, a dependent variable of response per visit, fixed independent variables of randomised treatment, subject recruitment country, a per visit indicator variable and open-label period cohort. The common odds ratio was derived together with two-sided 95% confidence intervals.
    End point type
    Secondary
    End point timeframe
    From Month 1 (Visit 9) to Month 6 (Visit 14), up to 6 months
    End point values
    		 SZC group Placebo group
    Number of subjects analysed
    102
    101
    Units: Percentage of responses
        number (not applicable)
    81.4
    49.5
    Statistical analysis title
    		 SZC group vs Placebo group
    Comparison groups
    SZC group v Placebo group
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 GEE model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    4.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.5
         upper limit
    		 7.52

    Secondary: Time to first hyperkalaemia (sK+ greater than 5.0mEq/L) episode

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    End point title
    		 Time to first hyperkalaemia (sK+ greater than 5.0mEq/L) episode
    End point description
    The time to first hyperkalaemia episode for participants on SZC compared to placebo during the randomised-withdrawal period, with hyperkalaemia defined as sK+ greater than 5.0 mEq/L as assessed by central laboratory, is presented in median time (days). The analysis was performed using a Cox regression model including randomised treatment group and subject recruitment country, adjusted for the stratification factor (hyperkalaemia vs normokalaemia at study entry). Placebo group used as reference level in Cox model.
    End point type
    Secondary
    End point timeframe
    From randomisation to the end of treatment (EOT) visit, up to 6 months
    End point values
    		 SZC group Placebo group
    Number of subjects analysed
    102
    101
    Units: Days
        median (confidence interval 95%)
    65.0 (35.00 to 98.00)
    9.0 (8.00 to 13.00)
    Statistical analysis title
    		 SZC group vs Placebo group
    Comparison groups
    SZC group v Placebo group
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 0.71

    Secondary: Time to first instance of decrease or discontinuation of spironolactone dose due to hyperkalaemia

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    End point title
    		 Time to first instance of decrease or discontinuation of spironolactone dose due to hyperkalaemia
    End point description
    The time to first instance of decrease or discontinuation of spironolactone dose due to hyperkalaemia was determined. The analysis was performed using a Cox regression model, adjusted for the stratification factor (hyperkalaemia vs normokalaemia at study entry). 000 = not applicable. Median time to first event could not be calculated due to the low number of events.
    End point type
    Secondary
    End point timeframe
    From randomisation to the EOT visit, up to 6 months
    End point values
    		 SZC group Placebo group
    Number of subjects analysed
    102
    101
    Units: Days
        median (confidence interval 95%)
    000 (000 to 000)
    000 (000 to 000)
    Statistical analysis title
    		 SZC group vs Placebo group
    Comparison groups
    SZC group v Placebo group
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.17
         upper limit
    		 0.73

    Secondary: Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) at EOT

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    End point title
    		 Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) at EOT
    End point description
    The KCCQ is a 23-item instrument measuring, from the patients’ perspectives, their heart failure-related symptoms, physical limitations, social limitations, self-efficacy, and health-related quality of life over the prior 2 weeks. All items are measured on a Likert scale with 5-7 response options. The KCCQ is scored by assigning each response an ordinal value, beginning with 1 for the response that implies the lowest level of functioning and 5-7 for the highest level of functioning. To calculate a score, the responses are summed within each domain and the average is taken. Scale scores are transformed to a 0 to 100 range by subtracting the lowest possible scale score, dividing by the range of the scale and multiplying by 100. The CSS was calculated as the average of Physical Limitation Score and Total Symptom Score (TSS) and the TSS was calculated as the average of Symptom Frequency and Symptom Burden Scores.
    End point type
    Secondary
    End point timeframe
    At EOT visit (approximately 6 months post-randomisation)
    End point values
    		 SZC group Placebo group
    Number of subjects analysed
    72
    59
    Units: Score on a scale
        least squares mean (standard error)
    71.27 ( 2.57 )
    72.27 ( 2.36 )
    Statistical analysis title
    		 SZC group vs Placebo group
    Comparison groups
    SZC group v Placebo group
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.724
    Method
    		 t-test, 2-sided
    Parameter type
    		 Least-squares Mean Difference
    Point estimate
    -1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.64
         upper limit
    		 4.63
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.84

    Other pre-specified: Location and severity of peripheral oedema

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    End point title
    		 Location and severity of peripheral oedema
    End point description
    The location and severity of peripheral oedema that occurred during the randomised-withdrawal phase are presented. Participants with multiple peripheral oedema events were counted only once. The location of oedema is not mutually exclusive so multiple locations may apply for each participant.
    End point type
    Other pre-specified
    End point timeframe
    During the RWP and up to 14 days after discontinuation of SZC or placebo, up to 6.5 months
    End point values
    		 SZC group Placebo group
    Number of subjects analysed
    22
    16
    Units: Participants
        Location of oedema: pedal oedema
    13
    10
        Location of oedema: ankle oedema
    17
    13
        Location of oedema: pretibial oedema
    11
    5
        Location of oedema: thigh oedema
    1
    0
        Severity of pedal oedema - right side: trace
    4
    3
        Severity of pedal oedema - right side: mild
    1
    5
        Severity of pedal oedema - right side: moderate
    7
    1
        Severity of pedal oedema - right side: severe
    0
    0
        Severity of pedal oedema - left side: trace
    4
    5
        Severity of pedal oedema - left side: mild
    2
    4
        Severity of pedal oedema - left side: moderate
    7
    1
        Severity of pedal oedema - left side: severe
    0
    0
        Severity of ankle oedema - right side: trace
    4
    4
        Severity of ankle oedema - right side: mild
    5
    6
        Severity of ankle oedema - right side: moderate
    7
    1
        Severity of ankle oedema - right side: severe
    0
    0
        Severity of ankle oedema - left side: trace
    4
    6
        Severity of ankle oedema - left side: mild
    5
    6
        Severity of ankle oedema - left side: moderate
    8
    1
        Severity of ankle oedema - left side: severe
    0
    0
        Severity of pretibial edema - right side: trace
    2
    1
        Severity of pretibial edema - right side: mild
    4
    2
        Severity of pretibial edema - right side: moderate
    5
    1
        Severity of pretibial edema - right side: severe
    0
    0
        Severity of pretibial edema - left side: trace
    1
    2
        Severity of pretibial edema - left side: mild
    3
    2
        Severity of pretibial edema - left side: moderate
    7
    1
        Severity of pretibial edema - left side: severe
    0
    0
        Severity of thigh edema - right side: trace
    0
    0
        Severity of thigh edema - right side: mild
    0
    0
        Severity of thigh edema - right side: moderate
    1
    0
        Severity of thigh edema - right side: severe
    0
    0
        Severity of thigh edema - left side: trace
    0
    0
        Severity of thigh edema - left side: mild
    0
    0
        Severity of thigh edema - left side: moderate
    1
    0
        Severity of thigh edema - left side: severe
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) that occurred during the RWP and up to 14 days after discontinuation of SZC/placebo and all AEs which occurred prior to first dose which worsened in severity following dosing during the RWP, up to 6.5 months, were included.
    Adverse event reporting additional description
    Participants with multiple events in the same category were counted only once in that category. Participants with events in more than one category were counted once in each of those categories.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    SZC group
    Reporting group description
    		 -

    Reporting group title
    Placebo group
    Reporting group description
    		 -

    Serious adverse events
    		 SZC group Placebo group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 101 (22.77%)
    22 / 101 (21.78%)
         number of deaths (all causes)
    2
    2
         number of deaths resulting from adverse events
    2
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Toe amputation
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 101 (0.99%)
         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
    Sudden cardiac death
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Death
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Reproductive system and breast disorders
    Gynaecomastia
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 101 (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
    1 / 101 (0.99%)
    0 / 101 (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
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Systolic dysfunction
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    12 / 101 (11.88%)
    4 / 101 (3.96%)
         occurrences causally related to treatment / all
    1 / 14
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 101 (0.99%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 101 (0.99%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis ulcerative
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Ureterolithiasis
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 101 (0.00%)
    2 / 101 (1.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Fasciitis
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 101 (1.98%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 101 (0.99%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    1 / 101 (0.99%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    2 / 101 (1.98%)
    3 / 101 (2.97%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 SZC group Placebo group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 101 (19.80%)
    25 / 101 (24.75%)
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    6 / 101 (5.94%)
    2 / 101 (1.98%)
         occurrences all number
    6
    2
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    12 / 101 (11.88%)
    23 / 101 (22.77%)
         occurrences all number
    16
    34
    Hypokalaemia
         subjects affected / exposed
    6 / 101 (5.94%)
    0 / 101 (0.00%)
         occurrences all number
    6
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Jun 2021
    The overall rationale (one primary driver) for the changes implemented in the protocol amendment were minor clarifications and further descriptions (e.g., changes to individual inclusion/exclusion criteria).
    03 Aug 2022
    The overall rationale (one primary driver) for the changes implemented in protocol amendment 2 was the shortening of the randomised, double-blind, withdrawal phase from 8 to 6 months. Based on recent results from a similar study (DIAMOND study), shortening the duration by 2 months would not impact the results and may have alleviated the burden to the participants.
    09 Nov 2023
    Updates to the primary and secondary endpoint definitions with clarification and alignment updates on statistical analysis methods

    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.
    None reported
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    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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