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    Clinical Trial Results:
    A Phase 2b, Randomised, Double-Blind, Active-Controlled, Multi-Centre Study to Evaluate the Efficacy, Safety and Tolerability of Oral AZD9977 and Dapagliflozin Treatment in Patients with Heart Failure and Chronic Kidney Disease

    Summary
    EudraCT number
    		 2020-003126-23
    Trial protocol
    		 BE   LT   HU   DK   SE   CZ   SK   BG   PL   DE   IT   ES  
    Global end of trial date
    22 Sep 2023

    Results information
    Results version number
    		 v2(current)
    This version publication date
    14 Dec 2024
    First version publication date
    06 Oct 2024
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    D6402C00001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04595370
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Södertälje, Södertälje, Sweden, 151 85
    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
    20 Oct 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Sep 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to evaluate the effect of AZD9977 in combination with dapagliflozin compared with dapagliflozin alone 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 International Council for Harmonisation (ICH)-Good Clinical Practice (GCP), applicable regulatory requirements and the AstraZeneca policy on Bioethics.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Jan 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 38
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Czechia: 7
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Japan: 14
    Country: Number of subjects enrolled
    Poland: 13
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 1
    Country: Number of subjects enrolled
    Russian Federation: 10
    Country: Number of subjects enrolled
    Slovakia: 15
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    Taiwan: 1
    Country: Number of subjects enrolled
    Ukraine: 3
    Country: Number of subjects enrolled
    United States: 21
    Worldwide total number of subjects
    144
    EEA total number of subjects
    91
    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)
    21
    From 65 to 84 years
    114
    85 years and over
    9

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted between 26-January-2021 (first subject first visit) to 22-September-2023 (last subject last visit). Study had 6 arms, however, AZD9977 monotherapy and placebo arms closed early due to change in Heart Failure (HF) treatment guidelines.

    Pre-assignment
    Screening details
    		 Subjects were enrolled after signing the Informed Consent Form (ICF). The study had an optional pre-screening visit. Study enrolled 153 subjects across 6 arms. Due to ERF limitations, subject disposition and baseline data were presented for only 144 subjects. Nine subjects were excluded from analysis due to site misconduct and GCP non-compliance.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AZD9977 15 mg + Dapagliflozin 10 mg
    Arm description
    		 Subjects received AZD9977 15 mg and dapagliflozin 10 mg orally once daily for 12 weeks.
    Arm type
    		 Experimental

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

    Investigational medicinal product name
    AZD9977
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received AZD9977 once daily for 12 weeks.

    Arm title
    		 AZD9977 50 mg + Dapagliflozin 10 mg
    Arm description
    		 Subjects received AZD9977 50 mg and dapagliflozin 10 mg orally once daily for 12 weeks.
    Arm type
    		 Experimental

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

    Investigational medicinal product name
    AZD9977
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received AZD9977 once daily for 12 weeks.

    Arm title
    		 AZD9977 150 mg + Dapagliflozin 10 mg
    Arm description
    		 Subjects received AZD9977 150 mg and dapagliflozin 10 mg orally once daily for 12 weeks.
    Arm type
    		 Experimental

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

    Investigational medicinal product name
    AZD9977
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received AZD9977 once daily for 12 weeks.

    Arm title
    		 AZD9977 150 mg
    Arm description
    		 Subjects received AZD9977 150 mg orally once daily for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received matching placebo to Dapagliflozin once daily for 12 weeks.

    Investigational medicinal product name
    AZD9977
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received AZD9977 once daily for 12 weeks.

    Arm title
    		 Dapagliflozin 10 mg
    Arm description
    		 Subjects received dapagliflozin 10 mg orally once daily for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received matching placebo to AZD9977 once daily for 12 weeks.

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

    Arm title
    		 Placebo
    Arm description
    		 Placebo subjects received placebo matching to AZD9977 and dapagliflozin orally once daily for 12 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received matching placebo to dapagliflozin once daily 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
    Subjects received matching placebo to AZD9977 once daily for 12 weeks.

    Number of subjects in period 1
    		AZD9977 15 mg + Dapagliflozin 10 mg AZD9977 50 mg + Dapagliflozin 10 mg AZD9977 150 mg + Dapagliflozin 10 mg AZD9977 150 mg Dapagliflozin 10 mg Placebo
    Started
    34
    31
    35
    6
    33
    5
    Completed
    32
    23
    26
    5
    27
    4
    Not completed
    2
    8
    9
    1
    6
    1
         Withdrawal of Consent
    1
    1
    1
    -
    -
    -
         Adverse event, non-fatal
    -
    4
    3
    1
    1
    1
         Death
    -
    1
    -
    -
    1
    -
         Subjects not treated, Withdrawal by subject
    -
    -
    1
    -
    -
    -
         Subjects not treated, Protocol Deviation
    1
    -
    -
    -
    -
    -
         Withdrawal by Subject
    -
    -
    1
    -
    2
    -
         Protocol-Specified Withdrawal Criterion Met
    -
    -
    1
    -
    -
    -
         Lost to follow-up
    -
    -
    -
    -
    1
    -
         Discontinued treatment due to other reasons
    -
    2
    2
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AZD9977 15 mg + Dapagliflozin 10 mg
    Reporting group description
    		 Subjects received AZD9977 15 mg and dapagliflozin 10 mg orally once daily for 12 weeks.

    Reporting group title
    AZD9977 50 mg + Dapagliflozin 10 mg
    Reporting group description
    		 Subjects received AZD9977 50 mg and dapagliflozin 10 mg orally once daily for 12 weeks.

    Reporting group title
    AZD9977 150 mg + Dapagliflozin 10 mg
    Reporting group description
    		 Subjects received AZD9977 150 mg and dapagliflozin 10 mg orally once daily for 12 weeks.

    Reporting group title
    AZD9977 150 mg
    Reporting group description
    		 Subjects received AZD9977 150 mg orally once daily for 12 weeks.

    Reporting group title
    Dapagliflozin 10 mg
    Reporting group description
    		 Subjects received dapagliflozin 10 mg orally once daily for 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo subjects received placebo matching to AZD9977 and dapagliflozin orally once daily for 12 weeks.

    Reporting group values
    		 AZD9977 15 mg + Dapagliflozin 10 mg AZD9977 50 mg + Dapagliflozin 10 mg AZD9977 150 mg + Dapagliflozin 10 mg AZD9977 150 mg Dapagliflozin 10 mg Placebo Total
    Number of subjects
    		 34 31 35 6 33 5 144
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 6 6 4 0 5 0 21
        From 65-84 years
    		 27 23 30 5 25 4 114
        85 years and over
    		 1 2 1 1 3 1 9
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 70.9 ( 7.1 ) 72.4 ( 8.4 ) 73.7 ( 8.1 ) 77.0 ( 8.7 ) 72.2 ( 9.4 ) 77.2 ( 5.8 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 11 5 8 1 10 1 36
        Male
    		 23 26 27 5 23 4 108
    Race
    Units: Subjects
        Asian
    		 4 3 7 0 3 0 17
        Black or African American
    		 0 1 1 0 2 1 5
        White
    		 30 27 27 6 28 4 122

    End points

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    End points reporting groups
    Reporting group title
    AZD9977 15 mg + Dapagliflozin 10 mg
    Reporting group description
    		 Subjects received AZD9977 15 mg and dapagliflozin 10 mg orally once daily for 12 weeks.

    Reporting group title
    AZD9977 50 mg + Dapagliflozin 10 mg
    Reporting group description
    		 Subjects received AZD9977 50 mg and dapagliflozin 10 mg orally once daily for 12 weeks.

    Reporting group title
    AZD9977 150 mg + Dapagliflozin 10 mg
    Reporting group description
    		 Subjects received AZD9977 150 mg and dapagliflozin 10 mg orally once daily for 12 weeks.

    Reporting group title
    AZD9977 150 mg
    Reporting group description
    		 Subjects received AZD9977 150 mg orally once daily for 12 weeks.

    Reporting group title
    Dapagliflozin 10 mg
    Reporting group description
    		 Subjects received dapagliflozin 10 mg orally once daily for 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo subjects received placebo matching to AZD9977 and dapagliflozin orally once daily for 12 weeks.

    Primary: Percent Change from Baseline in Urinary Albumin to Creatinine Ratio (UACR) at Week 12

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    End point title
    		 Percent Change from Baseline in Urinary Albumin to Creatinine Ratio (UACR) at Week 12
    End point description
    Change from baseline in UACR at the end of 12 weeks of study treatment was calculated as the average of the UACR values at Week 12 and was analyzed by a mixed-effects model for repeated measures (MMRM). Due to early removal of arms (AZD9977 150 mg monotherapy and Placebo), the study objectives were revised and the MMRM analysis included the 4 remaining arms (AZD9977 15/50/150 mg + Dapagliflozin, and Dapagliflozin 10 mg). Since 2 arms were removed from the study resulting in fewer subjects only descriptive statistics are shown for those two arms without formal comparison. Here, -999.999 and 999.999 indicates that the lower and upper limits of the 95% CI were not calculated due to insufficient number of participants enrolled in this arm. FAS included all subjects who were randomized and either received or did not receive any study intervention.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and Week 12
    End point values
    		 AZD9977 15 mg + Dapagliflozin 10 mg AZD9977 50 mg + Dapagliflozin 10 mg AZD9977 150 mg + Dapagliflozin 10 mg AZD9977 150 mg Dapagliflozin 10 mg Placebo
    Number of subjects analysed
    32
    23
    25
    5
    28
    3
    Units: Percent change from baseline
        least squares mean (confidence interval 95%)
    -56.391 (-71.528 to -33.207)
    -42.085 (-64.174 to -6.376)
    -58.047 (-73.560 to -33.430)
    -45.01 (-999.999 to 999.999)
    -34.318 (-58.204 to 3.220)
    230.32 (-999.999 to 999.999)
    Statistical analysis title
    		 AZD9977 + Dapagliflozin v/s Dapagliflozin
    Comparison groups
    AZD9977 15 mg + Dapagliflozin 10 mg v AZD9977 50 mg + Dapagliflozin 10 mg v AZD9977 150 mg + Dapagliflozin 10 mg v Dapagliflozin 10 mg
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 = 0.3645
    Method
    		 F-Test
    Parameter type
    		 F test statistic
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -999.999
         upper limit
    		 999.999
    Notes
    [1] - Here, -999.999 and 999.999 indicates that lower limit and upper limit of 95% CI was not calculated and only a descriptive statistic of mean percent change from baseline was shown while the estimates for the remaining 4 arms were from the mixed model for repeated measure.

    Secondary: Percent Change from Baseline in Urinary Albumin to Creatinine Ratio (UACR) at 12 weeks to Assess Dose-Response Relationship

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    End point title
    		 Percent Change from Baseline in Urinary Albumin to Creatinine Ratio (UACR) at 12 weeks to Assess Dose-Response Relationship
    End point description
    Change from baseline in UACR at the end of 12 weeks of study treatment was calculated as the average of the UACR values at Week 12 and was analyzed by a mixed-effects model for repeated measures (MMRM). Due to early removal of arms (AZD9977 150 mg monotherapy and placebo), the study objectives were revised and the MMRM analysis included the 4 remaining arms (AZD9977 15/50/150 mg + Dapagliflozin, and Dapagliflozin 10 mg). Since 2 arms were removed from the study resulting in fewer subjects, only descriptive statistics was shown for those two arms without formal comparison. Here, -999.999 and 999.999 indicates that the lower and upper limits of the 95% CI were not calculated due to insufficient number of participants enrolled in this arm. FAS included all subjects who were randomized and either received or did not receive any study intervention.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 12
    End point values
    		 AZD9977 15 mg + Dapagliflozin 10 mg AZD9977 50 mg + Dapagliflozin 10 mg AZD9977 150 mg + Dapagliflozin 10 mg AZD9977 150 mg Dapagliflozin 10 mg Placebo
    Number of subjects analysed
    32
    23
    25
    5
    28
    3
    Units: Percent change from baseline
        least squares mean (confidence interval 95%)
    -56.391 (-71.528 to -33.207)
    -42.085 (-64.174 to -6.376)
    -58.047 (-73.560 to -33.430)
    -45.01 (-999.999 to 999.999)
    -34.318 (-58.204 to 3.220)
    230.32 (-999.999 to 999.999)
    Statistical analysis title
    		 AZD9977 15mg + Dapagliflozin v/s Dapagliflozin
    Comparison groups
    AZD9977 15 mg + Dapagliflozin 10 mg v Dapagliflozin 10 mg
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1588
    Method
    		 Mixed models analysis
    Parameter type
    		 Percent difference between treatment
    Point estimate
    -33.606
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -62.53
         upper limit
    		 17.644
    Statistical analysis title
    		 AZD9977 150mg + Dapagliflozin v/s Dapagliflozin
    Comparison groups
    AZD9977 150 mg + Dapagliflozin 10 mg v Dapagliflozin 10 mg
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1398
    Method
    		 Mixed models analysis
    Parameter type
    		 Percent difference between treatment
    Point estimate
    -36.127
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -64.85
         upper limit
    		 16.066
    Statistical analysis title
    		 AZD9977 50mg + Dapagliflozin v/s Dapagliflozin
    Comparison groups
    AZD9977 50 mg + Dapagliflozin 10 mg v Dapagliflozin 10 mg
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6846
    Method
    		 Mixed models analysis
    Parameter type
    		 Percent difference between treatment
    Point estimate
    -11.826
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -52.195
         upper limit
    		 62.634

    Secondary: Number of Subjects with Adverse Events (AEs)

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    End point title
    		 Number of Subjects with Adverse Events (AEs)
    End point description
    The safety and tolerability of AZD9977 combined with dapagliflozin 10 mg, AZD9977 monotherapy, dapagliflozin 10 mg monotherapy and placebo was assessed. Safety analysis set included all subjects who were randomized and received any study intervention.
    End point type
    Secondary
    End point timeframe
    From baseline (Day 1) until Day 113
    End point values
    		 AZD9977 15 mg + Dapagliflozin 10 mg AZD9977 50 mg + Dapagliflozin 10 mg AZD9977 150 mg + Dapagliflozin 10 mg AZD9977 150 mg Dapagliflozin 10 mg Placebo
    Number of subjects analysed
    33
    31
    34
    6
    33
    5
    Units: Subjects
        Any AE
    9
    12
    18
    5
    14
    3
        Any SAE
    1
    3
    2
    0
    4
    2
        Any SAE with outcome death
    0
    2
    0
    0
    1
    0
        Any AE leading to discontinuation of IP
    0
    4
    3
    1
    1
    1
        Any AE leading to withdrawal from study
    0
    5
    2
    0
    1
    0
        Any AE leading to dose interruption
    1
    1
    1
    0
    3
    1
    No statistical analyses for this end point

    Secondary: Change from Baseline in Serum Potassium (K+)

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    End point title
    		 Change from Baseline in Serum Potassium (K+)
    End point description
    Effect of AZD9977 combined with dapagliflozin 10 mg, AZD9977 monotherapy, dapagliflozin 10 mg monotherapy and placebo on serum K+ was assessed. Here, -999.999 and 999.999 indicates that the lower and upper limits of the 95% CI were not calculated due to insufficient number of participants enrolled in this arm. Safety analysis set included all subjects who were randomized and received any study intervention.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 12
    End point values
    		 AZD9977 15 mg + Dapagliflozin 10 mg AZD9977 50 mg + Dapagliflozin 10 mg AZD9977 150 mg + Dapagliflozin 10 mg AZD9977 150 mg Dapagliflozin 10 mg Placebo
    Number of subjects analysed
    27
    21
    25
    4
    25
    3
    Units: millimoles per liter (mmol/L)
        least squares mean (confidence interval 95%)
    0.056 (-0.106 to 0.219)
    0.003 (-0.184 to 0.190)
    0.109 (-0.061 to 0.279)
    0.55 (-999.999 to 999.999)
    0.040 (-0.129 to 0.209)
    0.03 (-999.999 to 999.999)
    No statistical analyses for this end point

    Secondary: Absolute Value of Serum Potassium Over Time

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    End point title
    		 Absolute Value of Serum Potassium Over Time
    End point description
    Effect of AZD9977 combined with dapagliflozin 10 mg, AZD9977 monotherapy, dapagliflozin 10 mg monotherapy and placebo on serum K+ was assessed. Safety analysis set included all subjects who were randomized and received any study intervention. Here, "n" specifies the number of subjects who were evaluated for this outcome measure at the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 12
    End point values
    		 AZD9977 15 mg + Dapagliflozin 10 mg AZD9977 50 mg + Dapagliflozin 10 mg AZD9977 150 mg + Dapagliflozin 10 mg AZD9977 150 mg Dapagliflozin 10 mg Placebo
    Number of subjects analysed
    30
    25
    29
    5
    33
    5
    Units: mmol/L
    arithmetic mean (standard deviation)
        Baseline (n=30, 25, 29, 5, 33, 5)
    4.60 ( 0.38 )
    4.44 ( 0.61 )
    4.46 ( 0.44 )
    4.50 ( 0.38 )
    4.60 ( 0.66 )
    4.50 ( 0.28 )
        Week 12 (n=27, 21, 25, 4, 25, 3)
    4.62 ( 0.50 )
    4.53 ( 0.43 )
    4.63 ( 0.43 )
    5.00 ( 0.61 )
    4.64 ( 0.40 )
    4.33 ( 0.32 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Estimated Glomerular Filtration Rate (eGFR)

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    End point title
    		 Change from Baseline in Estimated Glomerular Filtration Rate (eGFR)
    End point description
    Effect of AZD9977 combined with dapagliflozin 10 mg, AZD9977 monotherapy, dapagliflozin 10 mg monotherapy and placebo on eGFR was assessed. Here, -999.999 and 999.999 indicates that the lower and upper limits of the 95% CI were not calculated due to insufficient number of participants enrolled in this arm. Safety analysis set included all subjects who were randomized and received any study intervention.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 12
    End point values
    		 AZD9977 15 mg + Dapagliflozin 10 mg AZD9977 50 mg + Dapagliflozin 10 mg AZD9977 150 mg + Dapagliflozin 10 mg AZD9977 150 mg Dapagliflozin 10 mg Placebo
    Number of subjects analysed
    26
    21
    24
    4
    23
    3
    Units: mL/min/1.73 m^2
        least squares mean (confidence interval 95%)
    -1.432 (-4.305 to 1.441)
    -1.160 (-4.351 to 2.030)
    -5.307 (-8.295 to -2.320)
    -0.923 (-999.999 to 999.999)
    -3.498 (-6.528 to -0.469)
    6.880 (-999.999 to 999.999)
    No statistical analyses for this end point

    Secondary: Absolute Value of eGFR Over Time

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    End point title
    		 Absolute Value of eGFR Over Time
    End point description
    Effect of all doses of AZD9977 combined with dapagliflozin 10 mg, AZD9977 monotherapy, dapagliflozin 10 mg monotherapy and placebo on eGFR was assessed. Safety analysis set included all subjects who were randomized and received any study intervention. Here, "n" specifies the number of subjects who were evaluated for this outcome measure at the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 12
    End point values
    		 AZD9977 15 mg + Dapagliflozin 10 mg AZD9977 50 mg + Dapagliflozin 10 mg AZD9977 150 mg + Dapagliflozin 10 mg AZD9977 150 mg Dapagliflozin 10 mg Placebo
    Number of subjects analysed
    32
    31
    33
    5
    32
    5
    Units: mL/min/1.73 m^2
    arithmetic mean (standard deviation)
        Baseline (n=32, 31, 33, 5, 32, 5)
    41.341 ( 12.902 )
    38.586 ( 10.155 )
    43.663 ( 16.168 )
    36.874 ( 12.626 )
    41.895 ( 12.791 )
    40.288 ( 15.176 )
        Week 12 (n=26, 21, 24, 4, 23, 3)
    41.219 ( 15.112 )
    39.429 ( 8.998 )
    39.063 ( 13.819 )
    34.075 ( 21.071 )
    37.973 ( 11.571 )
    48.920 ( 21.111 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline (Day 1) until Day 113
    Adverse event reporting additional description
    Safety set included all subjects who were randomized and received any study intervention. All AEs that were reported with an onset date and time, or worsening, on or after date and time of first dose of IP up to and including 5 days after last dose of IP were included in the safety analysis.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    AZD9977 15 mg + Dapagliflozin 10 mg
    Reporting group description
    		 Subjects received AZD9977 15 mg and dapagliflozin 10 mg orally once daily for 12 weeks.

    Reporting group title
    AZD9977 50 mg + Dapagliflozin 10 mg
    Reporting group description
    		 Subjects received AZD9977 50 mg and dapagliflozin 10 mg orally once daily for 12 weeks.

    Reporting group title
    AZD9977 150 mg
    Reporting group description
    		 Subjects received AZD9977 150 mg orally once daily for 12 weeks.

    Reporting group title
    Dapagliflozin 10 mg
    Reporting group description
    		 Subjects received dapagliflozin 10 mg orally once daily for 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo subjects received placebo matching to AZD9977 and dapagliflozin orally once daily for 12 weeks.

    Reporting group title
    AZD9977 150 mg + Dapagliflozin 10 mg
    Reporting group description
    		 Subjects received AZD9977 150 mg and dapagliflozin 10 mg orally once daily for 12 weeks.

    Serious adverse events
    		 AZD9977 15 mg + Dapagliflozin 10 mg AZD9977 50 mg + Dapagliflozin 10 mg AZD9977 150 mg Dapagliflozin 10 mg Placebo AZD9977 150 mg + Dapagliflozin 10 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 33 (3.03%)
    3 / 31 (9.68%)
    0 / 6 (0.00%)
    4 / 33 (12.12%)
    2 / 5 (40.00%)
    2 / 34 (5.88%)
         number of deaths (all causes)
    0
    2
    0
    1
    0
    0
         number of deaths resulting from adverse events
    0
    2
    0
    1
    0
    0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 31 (0.00%)
    0 / 6 (0.00%)
    0 / 33 (0.00%)
    0 / 5 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 31 (3.23%)
    0 / 6 (0.00%)
    0 / 33 (0.00%)
    1 / 5 (20.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 31 (0.00%)
    0 / 6 (0.00%)
    1 / 33 (3.03%)
    0 / 5 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 31 (3.23%)
    0 / 6 (0.00%)
    0 / 33 (0.00%)
    0 / 5 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 31 (0.00%)
    0 / 6 (0.00%)
    0 / 33 (0.00%)
    0 / 5 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Peripheral swelling
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 31 (0.00%)
    0 / 6 (0.00%)
    1 / 33 (3.03%)
    0 / 5 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 31 (0.00%)
    0 / 6 (0.00%)
    1 / 33 (3.03%)
    0 / 5 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 31 (0.00%)
    0 / 6 (0.00%)
    1 / 33 (3.03%)
    0 / 5 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 31 (3.23%)
    0 / 6 (0.00%)
    0 / 33 (0.00%)
    0 / 5 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 31 (3.23%)
    0 / 6 (0.00%)
    0 / 33 (0.00%)
    1 / 5 (20.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 AZD9977 15 mg + Dapagliflozin 10 mg AZD9977 50 mg + Dapagliflozin 10 mg AZD9977 150 mg Dapagliflozin 10 mg Placebo AZD9977 150 mg + Dapagliflozin 10 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 33 (3.03%)
    4 / 31 (12.90%)
    5 / 6 (83.33%)
    7 / 33 (21.21%)
    2 / 5 (40.00%)
    13 / 34 (38.24%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 31 (0.00%)
    0 / 6 (0.00%)
    2 / 33 (6.06%)
    0 / 5 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    0
    2
    0
    1
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 31 (0.00%)
    0 / 6 (0.00%)
    0 / 33 (0.00%)
    0 / 5 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Hypotension
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 31 (0.00%)
    1 / 6 (16.67%)
    0 / 33 (0.00%)
    0 / 5 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Syncope
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 31 (0.00%)
    0 / 6 (0.00%)
    0 / 33 (0.00%)
    1 / 5 (20.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 31 (0.00%)
    1 / 6 (16.67%)
    0 / 33 (0.00%)
    0 / 5 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 31 (0.00%)
    0 / 6 (0.00%)
    0 / 33 (0.00%)
    0 / 5 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Diarrhoea
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 31 (0.00%)
    0 / 6 (0.00%)
    0 / 33 (0.00%)
    1 / 5 (20.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    Colitis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 31 (0.00%)
    0 / 6 (0.00%)
    0 / 33 (0.00%)
    1 / 5 (20.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Gingival recession
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 31 (0.00%)
    1 / 6 (16.67%)
    0 / 33 (0.00%)
    0 / 5 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Renal and urinary disorders
    Chronic kidney disease
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 31 (3.23%)
    1 / 6 (16.67%)
    1 / 33 (3.03%)
    0 / 5 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    1
    1
    1
    1
    0
    2
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 31 (0.00%)
    0 / 6 (0.00%)
    0 / 33 (0.00%)
    1 / 5 (20.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Diabetes mellitus
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 31 (0.00%)
    0 / 6 (0.00%)
    0 / 33 (0.00%)
    1 / 5 (20.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Spinal pain
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 31 (0.00%)
    1 / 6 (16.67%)
    0 / 33 (0.00%)
    0 / 5 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 31 (0.00%)
    0 / 6 (0.00%)
    0 / 33 (0.00%)
    1 / 5 (20.00%)
    0 / 34 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Infections and infestations
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 31 (6.45%)
    0 / 6 (0.00%)
    0 / 33 (0.00%)
    0 / 5 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 31 (3.23%)
    0 / 6 (0.00%)
    3 / 33 (9.09%)
    0 / 5 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    0
    3
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 31 (0.00%)
    0 / 6 (0.00%)
    1 / 33 (3.03%)
    0 / 5 (0.00%)
    3 / 34 (8.82%)
         occurrences all number
    0
    0
    0
    1
    0
    3
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 31 (3.23%)
    1 / 6 (16.67%)
    3 / 33 (9.09%)
    0 / 5 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    1
    1
    3
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Oct 2020
    Protocol version 1.0 was updated to include modifications to the number of sites and countries and updates to laboratory parameters for clarity.
    26 Jan 2021
    Protocol version 2.0 was updated to clarify randomisation of subgroups; clarify the lower limit of eGFR; addition of text "to use of bioimpedance devices that was contraindicated for patients with pacemakers or other electronic implanted devices"; clarify regarding hypertension treatment; describe addition of new device for site-based ECG monitoring; to include findings from recent clinical trials with dapagliflozin and to further describe the risk and benefit in patients with chronic kidney disease; to clarify eligibility criteria and medication restrictions, time frames for procedures performed, availability of results and handling of health-related issues, overdose definition; addition of new section Clinical Study Medical Device/ Device Constituent Report Form included; and to describe statistical considerations of the study.
    15 Jul 2021
    Protocol version 4.0 was updated to implement patient-centric measures and improve recruitment.
    20 Dec 2021
    Protocol version 5.0 was updated to adjust the design to heart failure treatment guidelines (ESC Guidelines 2021), by dropping the placebo and AZD9977 monotherapy arms to ensure all patients receive SGLT2i (dapagliflozin) during the study, as well as to reduce the burden of study assessments on study patients.
    02 Feb 2022
    Protocol Version 6.0 was updated to correct the typo in Table 1, clarification of study procedures, provide the correct literature reference and to align with revised study design.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    26 Nov 2021
    Recruitment was paused while implementing the amended Protocol (Protocol amendment number 5)
    01 Mar 2022

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Enrolment stopped early because of slow recruitment. Therefore, pre-specified sample size of 500 and planned statistical power were not achieved. Nine subjects were excluded from analysis due to site misconduct and GCP non-compliance.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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