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    Clinical Trial Results:
    An International, Multicentre, Parallel-group, Randomised, Double-blind, Placebo-controlled, Phase III Study Evaluating the effect of Dapagliflozin on Exercise Capacity in Heart Failure Patients with Reduced Ejection Fraction (HFrEF)

    Summary
    EudraCT number
    		 2018-003442-16
    Trial protocol
    		 SE   DK  
    Global end of trial date
    07 Mar 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    20 Jun 2021
    First version publication date
    20 Mar 2021
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    D169EC00002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03877237
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Forskargatan 18, 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 Sep 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Mar 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Mar 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine whether dapagliflozin is superior to placebo in patients with chronic HF NYHA Functional Class II-IV and reduced ejection fraction (LVEF≤40%) [HFrEF] in: • reducing patient-reported HF symptoms • reducing patient-reported physical limitation • improving exercise capacity
    Protection of trial subjects
    This study will be conducted in accordance with the protocol and with the following: 1) Consensus ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 2) Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines 3) Applicable laws and regulations. The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and approved by the IRB/IEC before the study is initiated. Any amendments to the protocol will require IRB/IEC approval before implementation of changes made to the study design, except for changes necessary to eliminate an immediate hazard to study subjects.
    Background therapy
    		 All HFrEF patients were treated according to locally recognised guidelines on standard of care treatment with both drugs and devices, as appropriate. Guideline-recommended medications were used at recommended doses unless contraindicated or not tolerated. Therapy have been individually optimised and stable for ≥ 4 weeks (this does not apply to diuretics) before Visit 1 and include (unless contraindicated or not tolerated): • an ACE inhibitor, or ARB or sacubitril/valsartan and • a beta-blocker and • if considered appropriate by the patient’s treating physician; a mineralocorticoid receptor antagonist
    Evidence for comparator
    		 Comparator was placebo
    Actual start date of recruitment
    08 Apr 2019
    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
    Brazil: 22
    Country: Number of subjects enrolled
    Canada: 50
    Country: Number of subjects enrolled
    Denmark: 37
    Country: Number of subjects enrolled
    Japan: 30
    Country: Number of subjects enrolled
    Korea, Republic of: 15
    Country: Number of subjects enrolled
    Slovakia: 19
    Country: Number of subjects enrolled
    South Africa: 29
    Country: Number of subjects enrolled
    Sweden: 22
    Country: Number of subjects enrolled
    United States: 89
    Worldwide total number of subjects
    313
    EEA total number of subjects
    78
    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)
    116
    From 65 to 84 years
    187
    85 years and over
    10

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 313 patients were randomised in this international, multi-center study which was conducted at 77 centers in 9 countries between 09 April 2019 and 07 March 2020.

    Pre-assignment
    Screening details
    		 In DETERMINE-reduced, at the first visit, i.e. the enrollment visit 1, patients were evaluated regarding the protocol mandated inclusion and exclusion criteria.

    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, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dapa 10mg
    Arm description
    		 Dapagliflozin 10 mg, given once daily per oral use.
    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
    Dapagliflozin 10 mg tablets administered orally once daily

    Arm title
    		 Placebo
    Arm description
    		 Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use.
    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
    Matching placebo for dapagliflozin 10 mg administered orally once daily

    Number of subjects in period 1
    		Dapa 10mg Placebo
    Started
    156
    157
    Completed
    151
    151
    Not completed
    5
    6
         Adverse event, serious fatal
    3
    2
         Physician decision
    1
    -
         Adverse event, non-fatal
    1
    2
         Withdrawal by subject
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dapa 10mg
    Reporting group description
    		 Dapagliflozin 10 mg, given once daily per oral use.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use.

    Reporting group values
    		 Dapa 10mg Placebo Total
    Number of subjects
    		 156 157 313
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    		 56 60 116
        Elderly (From 65-84 years)
    		 95 92 187
        Elderly 85 years and over
    		 5 5 10
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 68.4 ( 9.84 ) 67.3 ( 10.95 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 45 35 80
        Male
    		 111 122 233
    Ethnicity (NH/OMB)
    Units: Subjects
        Hispanic/Latino
    		 18 21 39
        Not Hispanic/Not Latino
    		 138 136 274
    Race/Ethnicity customized
    Units: Subjects
        White
    		 100 98 198
        Black or Africian American
    		 25 22 47
        Native Hawaiian or other Pacific Islander
    		 0 0 0
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 19 27 46
        Other
    		 12 10 22
    Subject analysis sets

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients that were randomised, regardless of whether treated or not.

    Subject analysis sets values
    		 Full analysis set
    Number of subjects
    313
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    116
        Elderly (From 65-84 years)
    187
        Elderly 85 years and over
    10
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    Gender Categorical
    Units: Subjects
        Female
        Male
    Ethnicity (NH/OMB)
    Units: Subjects
        Hispanic/Latino
        Not Hispanic/Not Latino
    Race/Ethnicity customized
    Units: Subjects
        White
        Black or Africian American
        Native Hawaiian or other Pacific Islander
        American Indian or Alaska Native
        Asian
        Other

    End points

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    End points reporting groups
    Reporting group title
    Dapa 10mg
    Reporting group description
    		 Dapagliflozin 10 mg, given once daily per oral use.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use.

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients that were randomised, regardless of whether treated or not.

    Primary: Change from baseline in Kansas-City Cardiomyopathy Questionnaire-Total Symptom Score (KCCQ-TSS) at week 16 (higher scores represent less HF symptom frequency and burden).

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    End point title
    		 Change from baseline in Kansas-City Cardiomyopathy Questionnaire-Total Symptom Score (KCCQ-TSS) at week 16 (higher scores represent less HF symptom frequency and burden).
    End point description
    Change from baseline in KCCQ-TSS was defined as the endpoint value at week 16 minus the baseline value. KCCQ is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. The KCCQ-TSS incorporates the symptom frequency (4 items) and symptom burden (3 items) domains into a single summary score. The score is transformed to a range of 0-100, in which a higher score reflects better health status. Baseline value is the last value on or prior to the randomisation visit. Deaths are treated as the worst outcome and ordering among deaths is based on last value while alive. In rank ANCOVA and HL estimation, multiple imputation was performed on missing values for patients who were alive at the visit at week 16 but did not have KCCQ-TSS values.
    End point type
    Primary
    End point timeframe
    At baseline and at week 16 or death before week 16
    End point values
    		 Dapa 10mg Placebo
    Number of subjects analysed
    156
    157
    Units: Scores on a scale
    median (inter-quartile range (Q1-Q3))
        Change from baseline at week 16
    2.08 (-4.17 to 14.58)
    0.00 (-10.42 to 9.38)
    Statistical analysis title
    		 HL estimate of treatment diff. and rank ANCOVA
    Statistical analysis description
    Rank ANCOVA model is used to analyse ranked data based on the hierarchical composite rank-based endpoint. The model includes baseline rank of outcome variable as a covariate, treatment group as a factor, and is stratified by T2DM status at randomisation.
    Comparison groups
    Placebo v Dapa 10mg
    Number of subjects included in analysis
    313
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.02164 [2]
    Method
    		 rank ANCOVA
    Parameter type
    		 Hodges-Lehmann median diff. vs placebo
    Point estimate
    4.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 8.22
    Notes
    [1] - For the primary efficacy endpoint KCCQ-TSS, the following hypothesis was tested using the significance level 0.04990 • H0: m(r(A)) = m(r(C)) versus • H1: m(r(A)) ≠ m(r(C)) Where H0 and H1 are the null and alternative hypotheses, respectively, and m(r(A)) and m(r(C)) represent the median of the ranked changes in the primary efficacy endpoint, KCCQ-TSS, from baseline to week 16, among patients receiving dapagliflozin (Active) and placebo (Control) treatment, respectively.
    [2] - To account for multiplicity, a pre-specified testing strategy was followed to control the overall type I error rate.

    Primary: Change from baseline in Kansas-City Cardiomyopathy Questionnaire-Physical Limitation Score (KCCQ-PLS) at week 16 (higher scores represent less physical limitation due to HF)

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    End point title
    		 Change from baseline in Kansas-City Cardiomyopathy Questionnaire-Physical Limitation Score (KCCQ-PLS) at week 16 (higher scores represent less physical limitation due to HF)
    End point description
    Change from baseline in KCCQ-PLS was defined as the endpoint value at week 16 minus the baseline value. KCCQ is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. The KCCQ-PLS incorporates the 6 physical limitation items into a single score. The score is transformed to a range of 0-100, in which a higher score reflects better health status. Baseline value is the last value on or prior to the randomisation visit. Deaths are treated as the worst outcome and ordering among deaths is based on last value while alive. In rank ANCOVA and HL estimation, multiple imputation was performed on missing values for patients who were alive at the visit at week 16 but did not have KCCQ-PLS values.
    End point type
    Primary
    End point timeframe
    At baseline and at week 16 or death before week 16
    End point values
    		 Dapa 10mg Placebo
    Number of subjects analysed
    153
    156
    Units: Score on the scale
        median (inter-quartile range (Q1-Q3))
    4.17 (-4.17 to 12.50)
    0.00 (-8.33 to 8.33)
    Statistical analysis title
    		 HL estimate of treatment diff. and rank ANCOVA
    Statistical analysis description
    Rank ANCOVA model is used to analyse ranked data based on the hierarchical composite rank-based endpoint. Model includes baseline rank of outcome variable as a covariate, treatment group as a factor, and is stratified by T2DM status at randomisation.
    Comparison groups
    Dapa 10mg v Placebo
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.05842 [4]
    Method
    		 Rank ANCOVA
    Parameter type
    		 Hodges-Lehmann median diff. vs placebo
    Point estimate
    4.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.03
         upper limit
    		 8.33
    Notes
    [3] - For the primary efficacy endpoint KCCQ-PLS, the following hypothesis was tested at significant level of 0.04990 • H0: m(r(A)) = m(r(C)) versus • H1: m(r(A)) ≠ m(r(C)) Where H0 and H1 are the null and alternative hypotheses, respectively, and m(r(A)) and m(r(C)) represent the median of the ranked changes in the primary efficacy endpoint, KCCQ-PLS, from baseline to week 16, among patients receiving dapagliflozin (Active) and placebo (Control) treatment, respectively.
    [4] - KCCQ-PLS was tested at the alpha level of 0.04990 because KCCQ-TSS had a statistically significant p-value, in accordance with the pre-specified testing strategy.

    Primary: Change from baseline in 6-minute walk distance (6MWD) at week 16 (larger distances represent better functional capacity).

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    End point title
    		 Change from baseline in 6-minute walk distance (6MWD) at week 16 (larger distances represent better functional capacity).
    End point description
    Change from baseline in 6-minute walk distance (6MWD) (exercise capacity) at week 16 was defined as the distance walked in 6 minutes at week 16 minus the baseline value. Baseline value is the last value on or prior to the randomisation visit. Deaths are treated as the worst outcome and ordering among deaths is based on last value while alive. In rank ANCOVA and HL estimation, multiple imputation was performed on missing values for patients who were alive at the visit at week 16 but did not have 6MWD values.
    End point type
    Primary
    End point timeframe
    At baseline and at week 16 or death prior to week 16
    End point values
    		 Dapa 10mg Placebo
    Number of subjects analysed
    156
    157
    Units: meters
        median (inter-quartile range (Q1-Q3))
    20.0 (-2.0 to 42.0)
    13.5 (-12.5 to 46.5)
    Statistical analysis title
    		 HL estimate of treatment diff. and rank ANCOVA
    Statistical analysis description
    Rank ANCOVA model is used to analyse ranked data based on the hierarchical composite rank-based endpoint. The model includes baseline rank of outcome variable as a covariate, treatment group as a factor, and is stratified by T2DM status at randomisation.
    Comparison groups
    Dapa 10mg v Placebo
    Number of subjects included in analysis
    313
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.68626 [6]
    Method
    		 rank ANCOVA
    Parameter type
    		 Hodges-Lehmann median diff. vs placebo
    Point estimate
    3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.5
         upper limit
    		 13
    Notes
    [5] - For the primary efficacy endpoint 6MWD, the following hypothesis was tested using the significance level 0.00010: H0: m(r(A)) = m(r(C)) versus H1: m(r(A)) ≠ m(r(C)) Where H0 and H1 are the null and alternative hypotheses, respectively, and m(r(A)) and m(r(C)) represent the median of the ranked changes in the primary efficacy endpoint, 6MWD, from baseline to week 16, among patients receiving dapagliflozin (Active) and placebo (Control) treatment, respectively.
    [6] - To account for multiplicity, a pre-specified testing strategy was followed to control the overall type I error rate.

    Secondary: Change from baseline at the end of the study in the total time spent in light to vigorous physical activity, as assessed using a wearable activity monitor (accelerometer).

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    End point title
    		 Change from baseline at the end of the study in the total time spent in light to vigorous physical activity, as assessed using a wearable activity monitor (accelerometer).
    End point description
    Change from baseline at the end of the study in total time spent in light to vigorous physical activity (LVPA), as assessed using a wearable activity monitor, was defined as the total time [per day] spent in LVPA at the end of the study minus the baseline value. Baseline is the 7 day period starting on the day of enrolment and ending before randomisation. End of study is defined as the period starting on the day of week 14 and prior to the week 16 visit. Deaths are treated as the worst outcome and ordering among deaths is based on last value while alive.
    End point type
    Secondary
    End point timeframe
    At baseline and at end of study or death before week 16.
    End point values
    		 Dapa 10mg Placebo
    Number of subjects analysed
    42 [7]
    34 [8]
    Units: hours
        median (inter-quartile range (Q1-Q3))
    -0.19 (-0.57 to 0.15)
    -0.15 (-0.68 to 0.53)
    Notes
    [7] - 92 patients from device-sites had wearable activity monitor data collected in Dapa 10mg group
    [8] - 83 patients from device-sites had wearable activity monitor data collected in Placebo group
    Statistical analysis title
    		 HL estimate of treatment diff. and rank ANCOVA
    Statistical analysis description
    Rank ANCOVA model is used to analyse ranked data based on the hierarchical composite rank-based endpoint. Model includes baseline rank of outcome variable as a covariate, treatment group as a factor, and is stratified by T2DM status at randomisation.
    Comparison groups
    Dapa 10mg v Placebo
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.19748 [10]
    Method
    		 rank ANCOVA
    Parameter type
    		 Hodges-Lehmann median diff. vs placebo
    Point estimate
    -0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.55
         upper limit
    		 0.22
    Notes
    [9] - For the secondary efficacy endpoint, total time spent in LVPA, the testing hypothesis is • H0: m(r(A)) = m(r(C)) versus • H1: m(r(A)) ≠ m(r(C)) Where H0 and H1 are the null and alternative hypotheses, respectively, and m(r(A)) and m(r(C)) represent the median of the ranked changes in secondary efficacy endpoint, total time spent in LVPA, from baseline to End of study among patients receiving dapagliflozin (Active) and placebo (Control) treatment, respectively.
    [10] - Total time spent in LVPA was not tested for statistical significance and the p-value is considered nominal because the test for 6MWD was not statistically significant.

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Includes data collected on or after date of first dose and up to (including) 30 days following last dose of randomized study drug, and no later than visit 5 (up to day 119). Deaths collected on or after first dose of randomized study drug,up to 119 days.
    Adverse event reporting additional description
    For analysis of Adverse Events Safety analysis set is used. Safety analysis set : All randomised participants who received at least one dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Dapa 10 mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: There was not any non-serious AEs occurring in greater than 5% of participants.
    Serious adverse events
    		 Dapa 10 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 156 (12.18%)
    23 / 157 (14.65%)
         number of deaths (all causes)
    3
    2
         number of deaths resulting from adverse events
    3
    2
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mediastinal haemorrhage
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Postoperative thoracic procedure complication
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 156 (0.64%)
    2 / 157 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 156 (0.64%)
    2 / 157 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    3 / 156 (1.92%)
    6 / 157 (3.82%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure acute
         subjects affected / exposed
    1 / 156 (0.64%)
    4 / 157 (2.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 156 (0.00%)
    2 / 157 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 156 (0.00%)
    2 / 157 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 156 (1.28%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 156 (0.00%)
    2 / 157 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer haemorrhage
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 156 (0.00%)
    2 / 157 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Chagas' cardiomyopathy
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 156 (0.64%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Dapa 10 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 157 (0.00%)

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Mar 2020
    The main purpose of this amendment was to add 2 primary objectives to the study (ie, reduction in HF symptoms and reduction in physical limitation). The primary objectives are now to determine whether dapagliflozin is superior to placebo in reducing heart failure symptoms, reducing physical limitation, or improving exercise capacity in patients with chronic heart failure. The family of primary endpoints are KCCQ-TSS, KCCQ-PLS, and 6MWD. Some secondary objectives became exploratory objectives and other exploratory endpoints were revised. Clarifications were also made to text unrelated to the endpoints. The following details the key changes: Section 1.2 (Synopsis): Updated to reflect changes in the CSP text, including the changes to the objectives/endpoints as detailed in Section 3. Section 2: (INTRODUCTION) Updated to reflect changes in the objectives/endpoints as detailed in Section 3. Section 3 (OBJECTIVES AND ENDPOINTS): Two additional primary efficacy objectives/endpoints were added (ie, KCCQ-TSS and KCCQ-PLS) to create a primary endpoint family. Some secondary objectives became exploratory and certain exploratory objectives/endpoints were reordered and rephrased. Section 4 (STUDY DESIGN): Updated to reflect changes in the objectives/endpoints as detailed in Section 3. Explanation/clarification was added for the choice of primary endpoints. Section 6.3.1.2 (Capping): Updated to allow it on a level lower than the whole study. Section 7.4 (Discontinuation of the study): Reasons for the early closure of the study site were added as per more recent protocol template. Section 8.1 (Efficacy assessments): Updated to reflect changes in the objectives/endpoints as detailed in Section 3. Section 9 (STATISTICAL CONSIDERATIONS): Updated to reflect changes in the objectives/endpoints as detailed in Section 3, including updated power calculations and methodology for type I error control. General:Minor editing corrections to improve clarity and consistency.

    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.
    Data collection from the wearable device worn by a subset of patients at home for 3 periods of 7 days was challenging and a substantial amount of data was missing. This limits the use of the data based on the wearable activity monitors.
    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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