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    Clinical Trial Results:
    A phase 3b, multicenter, prospective, randomized, double blind, placebocontrolled study to reduce incidence of pre-dialysis hyperkalemia with Sodium Zirconium Cyclosilicate (DIALIZE)

    Summary
    EudraCT number
    2017-003029-14
    Trial protocol
    GB  
    Global end of trial date
    07 Nov 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Nov 2019
    First version publication date
    27 Nov 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D9480C00006
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03303521
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca AB
    Sponsor organisation address
    151 85, Södertälje, Sweden,
    Public contact
    AstraZeneca Clinical, AstraZeneca, +1 877-240-9479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca, +1 877-240-9479, 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 Nov 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Nov 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Nov 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of SZC in the treatment of hyperkalaemia in patients on haemodialysis.
    Protection of trial subjects
    Patients given full and adequate oral and written information about the nature, purpose, possible risk and benefit of the study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    17 Dec 2017
    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
    United Kingdom: 30
    Country: Number of subjects enrolled
    Japan: 56
    Country: Number of subjects enrolled
    Russian Federation: 66
    Country: Number of subjects enrolled
    United States: 44
    Worldwide total number of subjects
    196
    EEA total number of subjects
    30
    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)
    118
    From 65 to 84 years
    77
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The screening period ran for one week, beginning on a hemodialysis day following the Long Inter-Dialytic Interval (D -7) until the treatment period started on study day 1 (D1). Informed consent was obtained on study day -7 and patients were assessed to ensure they met the eligibility criteria during the screening period.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sodium Zirconium Cyclosilicate (SZC)
    Arm description
    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.
    Arm type
    Experimental

    Investigational medicinal product name
    Sodium zirconium cyclosilicate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral powder, Oral powder in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    Powder for oral suspension in a sachet (5 g). Single dose contains 1 to 3 sachets that should be suspended in 45 mL of water by patient and administered on non-dialysis days

    Arm title
    Placebo
    Arm description
    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.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral powder in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    Powder for oral suspension in a sachet. Single dose contains 1 to 3 sachets that should be suspended in 45 mL of water by patient and administered on non-dialysis days.

    Number of subjects in period 1
    Sodium Zirconium Cyclosilicate (SZC) Placebo
    Started
    97
    99
    Completed
    92
    96
    Not completed
    5
    3
         Investigational product discontinuation
    -
    1
         Transferred to non-study dialysis center
    1
    -
         Adverse event, serious fatal
    1
    -
         Adverse event, non-fatal
    1
    -
         Consent withdrawn by subject
    2
    -
         Non-comliance to study protocol
    -
    1
         Kidney transplantation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sodium Zirconium Cyclosilicate (SZC)
    Reporting group description
    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.

    Reporting group title
    Placebo
    Reporting group description
    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.

    Reporting group values
    Sodium Zirconium Cyclosilicate (SZC) Placebo Total
    Number of subjects
    97 99 196
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    65 53 118
        From 65-84 years
    32 45 77
        85 years and over
    0 1 1
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    55.7 ± 13.84 60.4 ± 13.2 -
    Sex: Female, Male
    Units: Subjects
        Female
    40 41 81
        Male
    57 58 115
    Race/Ethnicity, Customized
    Units: Subjects
        White
    50 52 102
        Black Or African American
    11 8 19
        Asian
    33 33 66
        American Indian Or Alaska Native
    1 2 3
        Other
    2 4 6

    End points

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    End points reporting groups
    Reporting group title
    Sodium Zirconium Cyclosilicate (SZC)
    Reporting group description
    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.

    Reporting group title
    Placebo
    Reporting group description
    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.

    Primary: Proportion of responders

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    End point title
    Proportion of responders
    End point description
    A subject was considered to be a responder if, during the evaluation period, they maintained a pre-dialysis serum potassium (S-K) between 4.0 and 5.0 mmol/L on at least 3 out of 4 dialysis treatments following the long inter-dialytic interval and did not receive rescue therapy. The S-K levels used for this analysis were based on the measurements obtained by the central laboratory.
    End point type
    Primary
    End point timeframe
    Evaluation period runs over the last 4 weeks of the treatment period, starting after visit 11 and ending on visit 15, thus it comprises post-long inter-dialytic interval visits 12, 13, 14 and 15.
    End point values
    Sodium Zirconium Cyclosilicate (SZC) Placebo
    Number of subjects analysed
    97
    99
    Units: Percentage of participants
        number (not applicable)
    41.2
    1.0
    Statistical analysis title
    Primary Analysis
    Statistical analysis description
    Proportion of responders
    Comparison groups
    Sodium Zirconium Cyclosilicate (SZC) v Placebo
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    68.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    10.85
         upper limit
    2810.85

    Primary: Sensitivity analysis of the proportion of responders

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    End point title
    Sensitivity analysis of the proportion of responders
    End point description
    The sensitivity analysis assessed the impact of subjects classified as non-responders due to missing serum potassium (S-K) data. Missing values were imputed using available i-STAT measurements and last value carried forward approach. The Primary endpoint analysis was repeated on the imputed data.
    End point type
    Primary
    End point timeframe
    Evaluation period runs over the last 4 weeks of the treatment period, comprising post-long inter-dialytic interval visits 12, 13, 14 and 15.
    End point values
    Sodium Zirconium Cyclosilicate (SZC) Placebo
    Number of subjects analysed
    97
    99
    Units: Percentage of participants
        number (not applicable)
    42.3
    2.0
    Statistical analysis title
    Primary analysis
    Statistical analysis description
    Sensitivity analysis of the proportion of responders
    Comparison groups
    Sodium Zirconium Cyclosilicate (SZC) v Placebo
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.001
    Method
    Fisher exact
    Parameter type
    Odds ratio (OR)
    Point estimate
    35.51
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    8.53
         upper limit
    309.48

    Secondary: Proportion of patients needing rescue therapy

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    End point title
    Proportion of patients needing rescue therapy
    End point description
    Patients requiring any urgent intervention consistent with local practice patterns to reduce serum potassium (S-K) including insulin/glucose, beta-adrenergic agonists, sodium bicarbonate, K binders or any form of renal replacement therapy.
    End point type
    Secondary
    End point timeframe
    An 8 week overall treatment period (a 4 week adjustment phase plus a 4 week evaluation phase).
    End point values
    Sodium Zirconium Cyclosilicate (SZC) Placebo
    Number of subjects analysed
    97
    99
    Units: Percentage of participants
        number (not applicable)
    2.1
    5.1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events will be collected from time of randomization throughout the treatment period and including the follow-up period (until Visit 16 or the last patient visit in the study). SAEs will be recorded from the time of informed consent.
    Adverse event reporting additional description
    Safety Analysis Set (All randomized subjects who received at least 1 dose of investigational product, SZC or placebo. N=96 for SZC, N=99 for Placebo). Subjects excluded from the Safety Analysis Set (n=1 for SZC, n=0 Placebo) did not receive treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    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.

    Reporting group title
    Sodium Zirconium Cyclosilicate (SZC)
    Reporting group description
    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.

    Serious adverse events
    Placebo Sodium Zirconium Cyclosilicate (SZC)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 99 (8.08%)
    7 / 96 (7.29%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Injury, poisoning and procedural complications
    Arteriovenous fistula occlusion
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous fistula site complication
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 99 (0.00%)
    2 / 96 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Fluid overload
         subjects affected / exposed
    2 / 99 (2.02%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    3 / 99 (3.03%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 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
    Placebo Sodium Zirconium Cyclosilicate (SZC)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 99 (11.11%)
    7 / 96 (7.29%)
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    6 / 99 (6.06%)
    4 / 96 (4.17%)
         occurrences all number
    6
    5
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    5 / 99 (5.05%)
    3 / 96 (3.13%)
         occurrences all number
    5
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Jul 2017
    Stratification changed from site to country
    11 Sep 2017
    Cardiac monitoring/arrhythmia endpoint and related wording removed. Visit schedule updated (Visit 14 and 16 removed). Medications restrictions updated to reflect new information.
    05 Feb 2018
    Visit schedule updated (additional potassium sampling visits after Short InterDialytic Interval). EOT/EOS requirements updated for premature treatment discontinuation. Contraception and pregnancy restrictions updated to reflect EU guidelines. Outcome measure for primary objective updated. IDMC related wording added. Eligibility criteria updated (EC #2 removed; IC #9 added; IC #7 and EC #6 clarified). Patient dietary counseling and compliance with diet restrictions added. Dialysis adequacy and Interdialytic Weight Gain assessment clarified. Dosing instruction for Investigational Product updated. The list of pH-dependent drugs updated. EOS visit window updated. Study requirements for safety assessments and rescue treatment clarified.

    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
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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