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    Clinical Trial Results:
    A Phase 2b Multicentre, Randomised, Double-Blind, Active-Controlled, Parallel Group Dose-Ranging Study to Assess the Efficacy, Safety and Tolerability of Zibotentan and Dapagliflozin in Patients with Chronic Kidney Disease with Estimated Glomerular Filtration Rate (eGFR) ≥ 20 mL/min/1.73 m2

    Summary
    EudraCT number
    		 2020-004101-32
    Trial protocol
    		 HU   NL   BG   DK   IT   ES   SK   HR  
    Global end of trial date
    01 Jun 2023

    Results information
    Results version number
    		 v1
    This version publication date
    06 Jun 2024
    First version publication date
    06 Jun 2024
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    D4325C00001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04724837
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca AB
    Sponsor organisation address
    Södertälje, Södertälje, Sweden, 15185
    Public contact
    Global Clinical Lead, 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
    06 Jul 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jun 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of zibotentan 1.5 mg/dapagliflozin 10 mg versus dapagliflozin 10 mg monotherapy on urinary albumin to creatinine ratio (UACR).
    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
    28 Apr 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
    Argentina: 29
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    Brazil: 32
    Country: Number of subjects enrolled
    Bulgaria: 13
    Country: Number of subjects enrolled
    Canada: 26
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    Georgia: 29
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Italy: 27
    Country: Number of subjects enrolled
    Japan: 54
    Country: Number of subjects enrolled
    Malaysia: 1
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Slovakia: 1
    Country: Number of subjects enrolled
    South Africa: 6
    Country: Number of subjects enrolled
    Spain: 39
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    Ukraine: 3
    Country: Number of subjects enrolled
    United States: 170
    Worldwide total number of subjects
    447
    EEA total number of subjects
    93
    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)
    210
    From 65 to 84 years
    233
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted in approximately 170 sites in North America, South America, Africa, Asia/Pacific, and European countries.

    Pre-assignment
    Screening details
    		 The screening period was of 4 weeks. All the study assessments were performed as per the schedule of assessments. Participants who met the eligibility criteria were randomised to study intervention in addition to receiving background local standard of care therapy.

    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
    		 Carer, Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Zibotentan 0.25 mg + Dapagliflozin
    Arm description
    		 Participants received once daily oral dose of 0.25 mg zibotentan and 10 mg dapagliflozin for 12 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dapagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered with once daily oral dose of 0.25 mg zibotentan with 10 mg dapagliflozin for 12 weeks.

    Investigational medicinal product name
    Zibotentan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered with once daily oral dose of 0.25 mg zibotentan with 10 mg dapagliflozin for 12 weeks.

    Arm title
    		 Zibotentan 1.5 mg + Dapagliflozin
    Arm description
    		 Participants received once daily oral dose of 1.5 mg zibotentan and 10 mg dapagliflozin for 12 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dapagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered with once daily oral dose of 1.5 mg zibotentan with 10 mg dapagliflozin for 12 weeks.

    Investigational medicinal product name
    Zibotentan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered with once daily oral dose of 1.5 mg zibotentan with 10 mg dapagliflozin for 12 weeks.

    Arm title
    		 Placebo + Dapagliflozin
    Arm description
    		 Participants received once daily oral dose of dapagliflozin 10 mg and matching placebo for 12 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Dapagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received once daily oral dose of dapagliflozin 10 mg with matching placebo for 12 weeks.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received once daily oral dose of dapagliflozin 10 mg with matching placebo for 12 weeks.

    Number of subjects in period 1
    		Zibotentan 0.25 mg + Dapagliflozin Zibotentan 1.5 mg + Dapagliflozin Placebo + Dapagliflozin
    Started
    91
    179
    177
    Completed
    82
    142
    157
    Not completed
    9
    37
    20
         Adverse event, serious fatal
    -
    -
    1
         Consent withdrawn by subject
    2
    9
    9
         Physician decision
    1
    2
    -
         Adverse event, non-fatal
    2
    7
    4
         Failure to Meet Randomization Criteria
    -
    1
    3
         Other
    4
    16
    -
         Study Terminated by Sponsor
    -
    1
    -
         Lost to follow-up
    -
    1
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Zibotentan 0.25 mg + Dapagliflozin
    Reporting group description
    		 Participants received once daily oral dose of 0.25 mg zibotentan and 10 mg dapagliflozin for 12 weeks.

    Reporting group title
    Zibotentan 1.5 mg + Dapagliflozin
    Reporting group description
    		 Participants received once daily oral dose of 1.5 mg zibotentan and 10 mg dapagliflozin for 12 weeks.

    Reporting group title
    Placebo + Dapagliflozin
    Reporting group description
    		 Participants received once daily oral dose of dapagliflozin 10 mg and matching placebo for 12 weeks.

    Reporting group values
    		 Zibotentan 0.25 mg + Dapagliflozin Zibotentan 1.5 mg + Dapagliflozin Placebo + Dapagliflozin Total
    Number of subjects
    		 91 179 177 447
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 45 87 78 210
        From 65-84 years
    		 45 91 97 233
        85 years and over
    		 1 1 2 4
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.3 ( 12.72 ) 62.7 ( 12.33 ) 63.6 ( 11.60 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 28 55 55 138
        Male
    		 63 124 122 309
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 18 26 26 70
        Native Hawaiian or Other Pacific Islander
    		 0 2 0 2
        Black or African American
    		 7 17 22 46
        White
    		 56 124 125 305
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 10 10 4 24
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 23 58 46 127
        Not Hispanic or Latino
    		 68 121 131 320
        Unknown or Not Reported
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Zibotentan 0.25 mg + Dapagliflozin
    Reporting group description
    		 Participants received once daily oral dose of 0.25 mg zibotentan and 10 mg dapagliflozin for 12 weeks.

    Reporting group title
    Zibotentan 1.5 mg + Dapagliflozin
    Reporting group description
    		 Participants received once daily oral dose of 1.5 mg zibotentan and 10 mg dapagliflozin for 12 weeks.

    Reporting group title
    Placebo + Dapagliflozin
    Reporting group description
    		 Participants received once daily oral dose of dapagliflozin 10 mg and matching placebo for 12 weeks.

    Primary: Change in UACR from baseline to Week 12

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    End point title
    		 Change in UACR from baseline to Week 12 [1]
    End point description
    The effect of zibotentan 1.5/dapagliflozin 10 mg versus dapagliflozin 10 mg on UACR was assessed in the full analysis set. The full analysis set included all participants who were randomised and received any study intervention.
    End point type
    Primary
    End point timeframe
    From baseline (Week 0 [Day 1]) until Week 12 (Day 84)
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint description is specific to the arms which are presented. Separate outcome measures for Change in UACR are presented according to arm specificity. Hence, only the arms which are referenced in the description are presented per outcome measure.
    End point values
    		 Zibotentan 1.5 mg + Dapagliflozin Placebo + Dapagliflozin
    Number of subjects analysed
    105
    132
    Units: milligram/gram (mg/g)
        geometric mean (standard error)
    0.48 ( 1.094 )
    0.72 ( 1.090 )
    Statistical analysis title
    		 Change in UACR
    Statistical analysis description
    Comparison between Zibotentan 1.5 mg + Dapagliflozin and Dapagliflozin 10 mg + Placebo (PBO)
    Comparison groups
    Zibotentan 1.5 mg + Dapagliflozin v Placebo + Dapagliflozin
    Number of subjects included in analysis
    237
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted % mean change from baseline
    Point estimate
    -33.7
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -42.5
         upper limit
    		 -23.5
    Notes
    [2] - Two-sided p-value is presented. A p-value <0.10 indicates statistical significance, which is consistent with a one-sided test at the 5% level.

    Secondary: Change in UACR from baseline to Week 12

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    End point title
    		 Change in UACR from baseline to Week 12 [3]
    End point description
    The effect of zibotentan 0.25 mg/dapagliflozin 10 mg versus dapagliflozin 10 mg monotherapy on UACR was assessed in the full analysis set. The full analysis set included all participants who were randomised and received any study intervention.
    End point type
    Secondary
    End point timeframe
    From baseline (Week 0 [Day 1]) until Week 12
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint description is specific to the arms which are presented. Separate outcome measures for Change in UACR are presented according to arm specificity. Hence, only the arms which are referenced in the description are presented per outcome measure.
    End point values
    		 Zibotentan 0.25 mg + Dapagliflozin Placebo + Dapagliflozin
    Number of subjects analysed
    62
    132
    Units: mg/g
        geometric mean (standard error)
    0.52 ( 1.106 )
    0.72 ( 1.090 )
    Statistical analysis title
    		 Change in UACR
    Statistical analysis description
    Comparison between Zibotentan 0.25 mg + Dapagliflozin and Dapagliflozin 10 mg + PBO
    Comparison groups
    Zibotentan 0.25 mg + Dapagliflozin v Placebo + Dapagliflozin
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.002
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted % mean change from baseline
    Point estimate
    -27
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -38.4
         upper limit
    		 -13.6
    Notes
    [4] - Two-sided p-value is presented. A p-value <0.10 indicates statistical significance, which is consistent with a one-sided test at the 5% level.

    Secondary: Change in office systolic blood pressure from baseline to Week 12

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    End point title
    		 Change in office systolic blood pressure from baseline to Week 12
    End point description
    The change in office systolic blood pressure for doses of zibotentan combined with dapagliflozin 10 mg versus dapagliflozin 10 mg monotherapy was assessed in the full analysis set. The full analysis set included all participants who were randomised and received any study intervention.
    End point type
    Secondary
    End point timeframe
    From baseline (Week 0 [Day 1]) until Week 12 (Day 84)
    End point values
    		 Zibotentan 0.25 mg + Dapagliflozin Zibotentan 1.5 mg + Dapagliflozin Placebo + Dapagliflozin
    Number of subjects analysed
    65
    108
    137
    Units: Millimeters of mercury (mmHg)
        arithmetic mean (confidence interval 90%)
    -7.1 (-10.0 to -4.1)
    -11.0 (-13.5 to -8.4)
    -3.4 (-5.8 to -1.0)
    Statistical analysis title
    		 Change in office systolic blood pressure
    Statistical analysis description
    Comparison between Zibotentan 0.25 mg + Dapagliflozin and Dapagliflozin 10 mg + PBO
    Comparison groups
    Zibotentan 0.25 mg + Dapagliflozin v Placebo + Dapagliflozin
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Adjusted Least Square (LS) mean CFB
    Point estimate
    -3.6
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -6.8
         upper limit
    		 -0.5
    Statistical analysis title
    		 Change in office systolic blood pressure
    Statistical analysis description
    Comparison between Zibotentan 1.5 mg + Dapagliflozin and Dapagliflozin 10 mg + PBO
    Comparison groups
    Zibotentan 1.5 mg + Dapagliflozin v Placebo + Dapagliflozin
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Adjusted LS mean CFB
    Point estimate
    -7.6
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -10.3
         upper limit
    		 -4.9

    Secondary: Change in office diastolic blood pressure from baseline to Week 12

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    End point title
    		 Change in office diastolic blood pressure from baseline to Week 12
    End point description
    The change in office diastolic blood pressure for doses of zibotentan combined with dapagliflozin 10 mg versus dapagliflozin 10 mg monotherapy was assessed in the full analysis set. The full analysis set included all participants who were randomised and received any study intervention.
    End point type
    Secondary
    End point timeframe
    From baseline (Week 0 [Day 1]) until Week 12 (Day 84)
    End point values
    		 Zibotentan 0.25 mg + Dapagliflozin Zibotentan 1.5 mg + Dapagliflozin Placebo + Dapagliflozin
    Number of subjects analysed
    65
    108
    137
    Units: mmHg
        arithmetic mean (confidence interval 90%)
    -4.3 (-6.2 to -2.5)
    -6.8 (-8.4 to -5.2)
    -1.4 (-2.9 to 0.1)
    Statistical analysis title
    		 Change in office diastolic blood pressure
    Statistical analysis description
    Comparison between Zibotentan 1.5 mg + Dapagliflozin and Dapagliflozin 10 mg + PBO
    Comparison groups
    Zibotentan 1.5 mg + Dapagliflozin v Placebo + Dapagliflozin
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Adjusted LS Mean CFB
    Point estimate
    -5.4
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -7.1
         upper limit
    		 -3.7
    Statistical analysis title
    		 Change in office diastolic blood pressure
    Statistical analysis description
    Comparison between Zibotentan 0.25 mg + Dapagliflozin and Dapagliflozin 10 mg + PBO
    Comparison groups
    Zibotentan 0.25 mg + Dapagliflozin v Placebo + Dapagliflozin
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Adjusted LS Mean CFB
    Point estimate
    -3
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -5
         upper limit
    		 -1

    Secondary: Change in UACR from baseline to Week 12 (all arms)

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    End point title
    		 Change in UACR from baseline to Week 12 (all arms)
    End point description
    The assessment of dose-response and relationship across different dose of zibotentan/dapagliflozin and dapagliflozin alone on UACR reduction in the full analysis set. The full analysis set included all participants who were randomised and received any study intervention.
    End point type
    Secondary
    End point timeframe
    From baseline (Week 0 [Day 1]) until Week 12 (Day 84)
    End point values
    		 Zibotentan 0.25 mg + Dapagliflozin Zibotentan 1.5 mg + Dapagliflozin Placebo + Dapagliflozin
    Number of subjects analysed
    62
    105
    132
    Units: mg/g
        geometric mean (standard error)
    0.52 ( 1.106 )
    0.48 ( 1.094 )
    0.72 ( 1.090 )
    Statistical analysis title
    		 Change in UACR
    Statistical analysis description
    Comparison between Zibotentan 1.5 mg + Dapagliflozin and Dapagliflozin 10 mg + PBO
    Comparison groups
    Zibotentan 1.5 mg + Dapagliflozin v Placebo + Dapagliflozin
    Number of subjects included in analysis
    237
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Adjusted % mean change from baseline
    Point estimate
    -33.7
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -42.5
         upper limit
    		 -23.5
    Statistical analysis title
    		 Change in UACR
    Statistical analysis description
    Comparison between Zibotentan 0.25 mg + Dapagliflozin and Dapagliflozin 10 mg + PBO
    Comparison groups
    Zibotentan 0.25 mg + Dapagliflozin v Placebo + Dapagliflozin
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Adjusted % mean change from baseline
    Point estimate
    -27
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -38.4
         upper limit
    		 -13.6

    Secondary: Change in eGFR from baseline to Week 1, Week 12, and Week 14

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    End point title
    		 Change in eGFR from baseline to Week 1, Week 12, and Week 14
    End point description
    The effect of different doses of zibotentan and dapagliflozin 10 mg in combination versus dapagliflozin 10 mg monotherapy on eGFR was assessed in the full analysis set. The full analysis set included all participants who were randomised and received any study intervention.
    End point type
    Secondary
    End point timeframe
    From baseline (Week 0 [Day 1]) until Week 1 (Day 8), Week 12 (Day 84), and Week 14 (Day 98)
    End point values
    		 Zibotentan 0.25 mg + Dapagliflozin Zibotentan 1.5 mg + Dapagliflozin Placebo + Dapagliflozin
    Number of subjects analysed
    83
    152
    151
    Units: milliliters/minutes/1.73 square metres
    arithmetic mean (confidence interval 90%)
        Week 1 (n= 83, 152, 151)
    -2.0 (-3.5 to -0.5)
    -3.9 (-5.2 to -2.6)
    -3.1 (-4.4 to -1.8)
        Week 12 (n= 64, 108, 135)
    -3.1 (-4.7 to -1.5)
    -3.0 (-4.4 to -1.6)
    -1.9 (-3.3 to -0.6)
        Week 14 (n= 63, 105, 131)
    0.2 (-1.4 to 1.8)
    -2.0 (-3.4 to -0.6)
    0.1 (-1.2 to 1.5)
    Statistical analysis title
    		 Change in eGFR
    Statistical analysis description
    Week 1 - Comparison between Zibotentan 0.25 mg + Dapagliflozin and Dapagliflozin 10 mg + PBO
    Comparison groups
    Zibotentan 0.25 mg + Dapagliflozin v Placebo + Dapagliflozin
    Number of subjects included in analysis
    234
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Adjusted LS mean CFB
    Point estimate
    1.1
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 2.6
    Statistical analysis title
    		 Change in eGFR
    Statistical analysis description
    Week 14 - Comparison between Zibotentan 1.5 mg + Dapagliflozin and Dapagliflozin 10 mg + PBO
    Comparison groups
    Zibotentan 1.5 mg + Dapagliflozin v Placebo + Dapagliflozin
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Adjusted LS mean CFB
    Point estimate
    -2.1
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -3.5
         upper limit
    		 -0.7
    Statistical analysis title
    		 Change in eGFR
    Statistical analysis description
    Week 12 - Comparison between Zibotentan 1.5 mg + Dapagliflozin and Dapagliflozin 10 mg + PBO
    Comparison groups
    Zibotentan 1.5 mg + Dapagliflozin v Placebo + Dapagliflozin
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Adjusted LS mean CFB
    Point estimate
    -1.1
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -2.5
         upper limit
    		 0.3
    Statistical analysis title
    		 Change in eGFR
    Statistical analysis description
    Week 14 - Comparison between Zibotentan 0.25 mg + Dapagliflozin and Dapagliflozin 10 mg + PBO
    Comparison groups
    Zibotentan 0.25 mg + Dapagliflozin v Placebo + Dapagliflozin
    Number of subjects included in analysis
    234
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Adjusted LS mean CFB
    Point estimate
    0.1
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 1.8
    Statistical analysis title
    		 Change in eGFR
    Statistical analysis description
    Week 1 - Comparison between Zibotentan 1.5 mg + Dapagliflozin and Dapagliflozin 10 mg + PBO
    Comparison groups
    Zibotentan 1.5 mg + Dapagliflozin v Placebo + Dapagliflozin
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Adjusted LS mean CFB
    Point estimate
    -0.8
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 0.5
    Statistical analysis title
    		 Change in eGFR
    Statistical analysis description
    Week 12 - Comparison between Zibotentan 0.25 mg + Dapagliflozin and Dapagliflozin 10 mg + PBO
    Comparison groups
    Zibotentan 0.25 mg + Dapagliflozin v Placebo + Dapagliflozin
    Number of subjects included in analysis
    234
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Adjusted LS mean CFB
    Point estimate
    -1.2
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -2.8
         upper limit
    		 0.5

    Secondary: Number of participants with Adverse Events (AE) and Serious Adverse Events (SAE)

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    End point title
    		 Number of participants with Adverse Events (AE) and Serious Adverse Events (SAE)
    End point description
    The safety and tolerability of all doses of zibotentan combined with dapagliflozin 10 mg and dapagliflozin 10 mg monotherapy was assessed in the safety analysis set. The safety analysis set included all participants that were randomised and received any study intervention.
    End point type
    Secondary
    End point timeframe
    From Screening (Day -28) until Follow-up visit (Day 98)
    End point values
    		 Zibotentan 0.25 mg + Dapagliflozin Zibotentan 1.5 mg + Dapagliflozin Placebo + Dapagliflozin
    Number of subjects analysed
    91
    179
    177
    Units: Participants
        Any AE
    45
    86
    66
        AE with outcome of death
    0
    0
    1
        Any SAE
    2
    10
    4
        Any AE leading to discontinuation of IP
    11
    22
    7
        Any AE leading to dose interruption
    3
    7
    10
        Any AE leading to withdrawal from study
    2
    7
    4
        Any AE related to IP
    14
    33
    16
    No statistical analyses for this end point

    Secondary: Change in eGFR from Week 1 to Week 12

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    End point title
    		 Change in eGFR from Week 1 to Week 12
    End point description
    The effect of different doses of zibotentan and dapagliflozin 10 mg in combination versus dapagliflozin 10 mg monotherapy on eGFR was assessed in the full analysis set. The full analysis set included all participants who were randomised and received any study intervention.
    End point type
    Secondary
    End point timeframe
    From Week 1 (Day 8) to Week 12 (Day 84)
    End point values
    		 Zibotentan 0.25 mg + Dapagliflozin Zibotentan 1.5 mg + Dapagliflozin Placebo + Dapagliflozin
    Number of subjects analysed
    64
    108
    135
    Units: milliliters/minutes/1.73 square metres
        arithmetic mean (confidence interval 90%)
    -1.1 (-2.5 to 0.4)
    0.9 (-0.2 to 2.0)
    1.2 (0.1 to 2.2)
    Statistical analysis title
    		 Change in eGFR
    Statistical analysis description
    Week 1 and 12 - Comparison between Zibotentan 1.5 mg + Dapagliflozin and Dapagliflozin 10 mg + PBO
    Comparison groups
    Zibotentan 1.5 mg + Dapagliflozin v Placebo + Dapagliflozin
    Number of subjects included in analysis
    243
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Adjusted LS mean change
    Point estimate
    -0.3
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 1.3
    Statistical analysis title
    		 Change in eGFR
    Statistical analysis description
    Week 1 and Week 12 - Comparison between Zibotentan 0.25 mg + Dapagliflozin and Dapagliflozin 10 mg + PBO
    Comparison groups
    Zibotentan 0.25 mg + Dapagliflozin v Placebo + Dapagliflozin
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Adjusted LS mean change
    Point estimate
    -2.2
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -4
         upper limit
    		 -0.4

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs: From screening (Day -28) to Final Follow-up (Day 98) AEs: From Day 1 to Final Follow-up (Day 98)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Zibotentan 0.25 mg + Dapagliflozin
    Reporting group description
    		 Participants received once daily oral dose of 0.25 mg zibotentan and 10 mg dapagliflozin for 12 weeks.

    Reporting group title
    Placebo + Dapagliflozin
    Reporting group description
    		 Participants received once daily oral dose of dapagliflozin 10 mg and matching placebo for 12 weeks.

    Reporting group title
    Zibotentan 1.5 mg + Dapagliflozin
    Reporting group description
    		 Participants received once daily oral dose of 1.5 mg zibotentan and 10 mg dapagliflozin for 12 weeks.

    Serious adverse events
    		 Zibotentan 0.25 mg + Dapagliflozin Placebo + Dapagliflozin Zibotentan 1.5 mg + Dapagliflozin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 91 (2.20%)
    4 / 177 (2.26%)
    10 / 179 (5.59%)
         number of deaths (all causes)
    0
    1
    0
         number of deaths resulting from adverse events
    0
    1
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 177 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 177 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 177 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 177 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic left ventricular failure
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 177 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 177 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Sudden cardiac death
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 177 (0.56%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 177 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Small intestinal obstruction
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 177 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 177 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 177 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 91 (1.10%)
    0 / 177 (0.00%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Restlessness
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 177 (0.56%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 177 (0.56%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 177 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 91 (0.00%)
    1 / 177 (0.56%)
    0 / 179 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 91 (0.00%)
    0 / 177 (0.00%)
    1 / 179 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Zibotentan 0.25 mg + Dapagliflozin Placebo + Dapagliflozin Zibotentan 1.5 mg + Dapagliflozin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 91 (15.38%)
    6 / 177 (3.39%)
    24 / 179 (13.41%)
    Investigations
    Brain natriuretic peptide increased
         subjects affected / exposed
    2 / 91 (2.20%)
    1 / 177 (0.56%)
    9 / 179 (5.03%)
         occurrences all number
    2
    1
    9
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 91 (5.49%)
    1 / 177 (0.56%)
    0 / 179 (0.00%)
         occurrences all number
    5
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 91 (6.59%)
    2 / 177 (1.13%)
    8 / 179 (4.47%)
         occurrences all number
    6
    2
    9
    Metabolism and nutrition disorders
    Metabolic acidosis
         subjects affected / exposed
    5 / 91 (5.49%)
    2 / 177 (1.13%)
    7 / 179 (3.91%)
         occurrences all number
    5
    2
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Dec 2021
    Lower eGFR limit decreased to eGFR ≥ 20 mL/min/1.73 m2, upper limit of ≤ 60 mL/min/1.73 m2 removed, and lower UACR limit decreased to ≥ 150 mg/g to align study population with target population in Phase 3; removed local B-type natriuretic peptide (BNP) testing after screening, added local N-terminal pro-BNP (NT-proBNP) as an option at the screening visit; removed home-based ambulatory blood pressure monitoring (ABPM); updated study schema to clarify that data contributing to interim analyses and data to be reviewed was combined from Part A and Part B; updated sample size determination to reduce number of Part B participants while maintaining statistical power for primary endpoint; updated inclusion criteria; updated exclusion criteria to allow for participants with epilepsy syndrome, add ejection fraction < 50% at screening exclusion, and clarify reproduction exclusion.
    05 Apr 2022
    Update of study design with randomisation of participants closed to zibotentan 5 mg monotherapy arm, zibotentan 5 mg/dapagliflozin 10 mg arm, and placebo arm, with dapagliflozin 10 mg used as primary active comparator instead of placebo: title page, study schema and schedule of activities updated to reflect new study design; end of treatment visit removed; updated mitigation strategy for potential fluid retention risk from zibotentan; updated number of study sites; added clarification of inclusion criteria; updated doses, dose range, and IP information for remaining treatment arms; added that participants on a stable dose of mineralocorticoid receptor antagonists (MRA) may be included in the study; added clarification of discontinuation criteria for study intervention; updated statistical hypothesis and sample size determination; updated populations for analyses; updated primary, secondary, and exploratory endpoints; updated number and timing of interim analyses to reflect new study design.

    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.
    No multiple testing correction was considered in this early phase study.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/37632201
    http://www.ncbi.nlm.nih.gov/pubmed/37931629
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