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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the Effects of Sotagliflozin on Clinical Outcomes in Hemodynamically Stable Patients with Type 2 Diabetes POST Worsening Heart Failure

    Summary
    EudraCT number
    2017-003510-16
    Trial protocol
    SE   NL   ES   LV   LT   GB   BE   DK   FR   AT   CZ   DE   SK   HU   FI   PT   GR   PL   IE   IT   RO  
    Global end of trial date
    05 Jun 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    20 Jun 2021
    First version publication date
    20 Jun 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC15156
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03521934
    WHO universal trial number (UTN)
    U1111-1190-7891
    Sponsors
    Sponsor organisation name
    Lexicon Pharmaceuticals, Inc.
    Sponsor organisation address
    8800 Technology Forest Place, The Woodlands, United States, TX 77381
    Public contact
    Medical Affairs, Lexicon Pharmaceuticals, Inc., medical-information@lexpharma.com
    Scientific contact
    Medical Affairs, Lexicon Pharmaceuticals, Inc., medical-information@lexpharma.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
    05 Jun 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jun 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To compare the effect of sotagliflozin to placebo on the total occurrences of cardiovascular (CV) death, hospitalization for heart failure (HHF), and urgent visit for heart failure (HF) in hemodynamically stable subjects after admission for worsening heart failure (WHF).
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    15 Jun 2018
    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
    Russian Federation: 168
    Country: Number of subjects enrolled
    Switzerland: 6
    Country: Number of subjects enrolled
    Turkey: 65
    Country: Number of subjects enrolled
    Israel: 49
    Country: Number of subjects enrolled
    Australia: 3
    Country: Number of subjects enrolled
    Romania: 14
    Country: Number of subjects enrolled
    New Zealand: 11
    Country: Number of subjects enrolled
    Korea, Republic of: 13
    Country: Number of subjects enrolled
    Netherlands: 13
    Country: Number of subjects enrolled
    Poland: 52
    Country: Number of subjects enrolled
    Portugal: 16
    Country: Number of subjects enrolled
    Slovakia: 18
    Country: Number of subjects enrolled
    Spain: 87
    Country: Number of subjects enrolled
    Sweden: 14
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    Austria: 18
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Czechia: 26
    Country: Number of subjects enrolled
    Denmark: 25
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Germany: 27
    Country: Number of subjects enrolled
    Greece: 29
    Country: Number of subjects enrolled
    Hungary: 81
    Country: Number of subjects enrolled
    Italy: 33
    Country: Number of subjects enrolled
    Latvia: 30
    Country: Number of subjects enrolled
    Lithuania: 36
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    United States: 72
    Country: Number of subjects enrolled
    Argentina: 166
    Country: Number of subjects enrolled
    Brazil: 59
    Country: Number of subjects enrolled
    Chile: 41
    Worldwide total number of subjects
    1222
    EEA total number of subjects
    549
    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)
    364
    From 65 to 84 years
    843
    85 years and over
    15

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects took part in the study at 306 investigative sites in North America, Latin America, Western Europe, Eastern Europe, and the Rest of the World from 15 June 2018 to 05 June 2020.

    Pre-assignment
    Screening details
    Subjects with a diagnosis of Type 2 Diabetes post Worsening Heart Failure were enrolled equally in 1 of 2 treatment groups, sotagliflozin or placebo.

    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, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sotagliflozin
    Arm description
    Sotagliflozin 200 mg tablet once daily, with possible up-titration in the first 8 months to 400 mg, for up to 21.2 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Sotagliflozin
    Investigational medicinal product code
    Other name
    SAR439954
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sotagliflozin was administered as a tablet(s), orally once daily.

    Arm title
    Placebo
    Arm description
    Matching placebo to sotagliflozin 200 mg once daily, with possible up-titration in the first 8 months to matching placebo to sotagliflozin 400 mg, for up to 21.6 months.
    Arm type
    Placebo comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was administered as a tablet(s) (identical to the sotagliflozin tablet in appearance), orally once daily.

    Number of subjects in period 1
    Sotagliflozin Placebo
    Started
    608
    614
    Randomized and Treated
    605
    611
    Completed
    0
    0
    Not completed
    608
    614
         Death
    65
    73
         Site terminated by sponsor
    39
    35
         Study terminated by sponsor
    483
    477
         Reason not specified
    3
    6
         Withdrawal by subject
    18
    23

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sotagliflozin
    Reporting group description
    Sotagliflozin 200 mg tablet once daily, with possible up-titration in the first 8 months to 400 mg, for up to 21.2 months.

    Reporting group title
    Placebo
    Reporting group description
    Matching placebo to sotagliflozin 200 mg once daily, with possible up-titration in the first 8 months to matching placebo to sotagliflozin 400 mg, for up to 21.6 months.

    Reporting group values
    Sotagliflozin Placebo Total
    Number of subjects
    608 614 1222
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    68.6 ± 9.5 69.3 ± 8.8 -
    Gender categorical
    Units: Subjects
        Female
    198 214 412
        Male
    410 400 810
    Race
    Units: Subjects
        White
    567 572 1139
        Black or African American
    25 25 50
        Asian
    8 7 15
        Native Hawaiian or other Pacific Islander
    1 3 4
        Multiple
    1 1 2
        Not Reported
    6 5 11
        Unknown
    0 1 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    163 157 320
        Not Hispanic or Latino
    438 455 893
        Not Reported
    7 2 9

    End points

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    End points reporting groups
    Reporting group title
    Sotagliflozin
    Reporting group description
    Sotagliflozin 200 mg tablet once daily, with possible up-titration in the first 8 months to 400 mg, for up to 21.2 months.

    Reporting group title
    Placebo
    Reporting group description
    Matching placebo to sotagliflozin 200 mg once daily, with possible up-titration in the first 8 months to matching placebo to sotagliflozin 400 mg, for up to 21.6 months.

    Primary: Number of Total Occurrences of Cardiovascular (CV) Death, Hospitalizations for Heart Failure (HHF) and Urgent Visits for Heart Failure (HF)

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    End point title
    Number of Total Occurrences of Cardiovascular (CV) Death, Hospitalizations for Heart Failure (HHF) and Urgent Visits for Heart Failure (HF)
    End point description
    Combined endpoint of the total number of occurrences (first and potentially subsequent) of CV death, HHF, and urgent HF visits after randomisation. Events that occurred during the study were calculated as the total number of events per 100 person-years of follow-up. Intent-to-treat (ITT) population includes all randomised subjects.
    End point type
    Primary
    End point timeframe
    Up to 21.9 months
    End point values
    Sotagliflozin Placebo
    Number of subjects analysed
    608
    614
    Units: events per 100-person years
        number (not applicable)
    51
    76.3
    Statistical analysis title
    Sotagliflozin vs Placebo
    Statistical analysis description
    The estimates of the hazard ratio (HR) and corresponding 2-sided 95% confidence interval (CI) was to be provided by a marginal Cox proportional hazard model stratified by region and ejection fraction, with non-cardiovascular (non-CV) death treated as a competing event.
    Comparison groups
    Sotagliflozin v Placebo
    Number of subjects included in analysis
    1222
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Cox proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.52
         upper limit
    0.85

    Secondary: Total Number of Occurrences of HHF and Urgent HF Visits

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    End point title
    Total Number of Occurrences of HHF and Urgent HF Visits
    End point description
    Combined endpoint of the total occurrences (first and potentially subsequent) of HHF and urgent HF visits after randomization. Events that occurred during the study were calculated as the total number of events per 100 person-years of follow-up. ITT population includes all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Up to 21.9 months
    End point values
    Sotagliflozin Placebo
    Number of subjects analysed
    608
    614
    Units: events per 100-person years
        number (not applicable)
    40.4
    63.9
    Statistical analysis title
    Sotagliflozin vs Placebo
    Statistical analysis description
    The estimates of the HR and corresponding 2-sided 95% CI was to be provided by a marginal Cox proportional hazard model stratified by region and ejection fraction, with non-CV death treated as a competing event.
    Comparison groups
    Sotagliflozin v Placebo
    Number of subjects included in analysis
    1222
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Cox proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.49
         upper limit
    0.83

    Secondary: Total Number of Deaths from Cardiovascular Causes

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    End point title
    Total Number of Deaths from Cardiovascular Causes
    End point description
    Number of events that occurred during the study were calculated as the total number of events per 100 person-years of follow-up. ITT population includes all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Up to 21.9 months
    End point values
    Sotagliflozin Placebo
    Number of subjects analysed
    608
    614
    Units: events per 100-person years
        number (not applicable)
    10.6
    12.5
    Statistical analysis title
    Sotagliflozin vs Placebo
    Statistical analysis description
    The estimates of the HR and corresponding 2-sided 95% CI was to be provided by a marginal Cox proportional hazard model stratified by region and ejection fraction, with non-CV death treated as a competing event.
    Comparison groups
    Sotagliflozin v Placebo
    Number of subjects included in analysis
    1222
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.36
    Method
    Cox proportional hazards model
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.58
         upper limit
    1.22

    Secondary: Total Number of Occurrences of CV Death, HHF, Non-fatal Myocardial Infarction and Non-fatal Stroke

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    End point title
    Total Number of Occurrences of CV Death, HHF, Non-fatal Myocardial Infarction and Non-fatal Stroke
    End point description
    Combined endpoint of the total number of occurrences (first and potentially subsequent) of CV death, HHF, non-fatal stroke, and non-fatal myocardial infarction after randomisation. Events that occurred during the study were calculated as the total number of events per 100 person-years of follow-up. ITT population includes all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Up to 21.9 months
    End point values
    Sotagliflozin Placebo
    Number of subjects analysed
    608
    614
    Units: events per 100-person years
        number (not applicable)
    51.4
    71.0
    Statistical analysis title
    Sotagliflozin vs Placebo
    Statistical analysis description
    The estimates of the HR and corresponding 2-sided 95% CI was to be provided by a marginal Cox proportional hazard model stratified by region and ejection fraction, with non-CV death treated as a competing event.
    Comparison groups
    Sotagliflozin v Placebo
    Number of subjects included in analysis
    1222
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.56
         upper limit
    0.92

    Secondary: Total Number of Occurrences of HHF, Urgent HF Visit, CV Death, and HF While Hospitalized

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    End point title
    Total Number of Occurrences of HHF, Urgent HF Visit, CV Death, and HF While Hospitalized
    End point description
    Combined endpoint of the total number of occurrences (first and potentially subsequent) after randomisation of HHF, urgent HF visits, CV Death and HF while hospitalised. Events that occurred during the study were calculated as the total number of events per 100 person-years of follow-up. ITT population includes all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Up to 21.9 months
    End point values
    Sotagliflozin Placebo
    Number of subjects analysed
    608
    614
    Units: events per 100-person years
        number (not applicable)
    54.7
    80.6
    Statistical analysis title
    Sotagliflozin vs Placebo
    Statistical analysis description
    The estimates of the HR and corresponding 2-sided 95% CI was to be provided by a marginal Cox proportional hazard model stratified by region and ejection fraction, with non-CV death treated as a competing event.
    Comparison groups
    Sotagliflozin v Placebo
    Number of subjects included in analysis
    1222
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.54
         upper limit
    0.86

    Secondary: Total Number of Deaths from Any Cause

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    End point title
    Total Number of Deaths from Any Cause
    End point description
    Number of events that occurred during the study were calculated as the total number of events per 100 person-years of follow-up. ITT population includes all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Up to 21.9 months
    End point values
    Sotagliflozin Placebo
    Number of subjects analysed
    608
    614
    Units: events per 100-person years
        number (not applicable)
    13.5
    16.3
    Statistical analysis title
    Sotagliflozin vs Placebo
    Statistical analysis description
    The estimates of the HR and corresponding 2-sided 95% CI was to be provided by a marginal Cox proportional hazard model stratified by region and ejection fraction, with non-CV death treated as a competing event.
    Comparison groups
    Sotagliflozin v Placebo
    Number of subjects included in analysis
    1222
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.59
         upper limit
    1.14

    Secondary: Change from Baseline in Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) Scores at Month 4

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    End point title
    Change from Baseline in Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) Scores at Month 4
    End point description
    KCCQ-12 is a 12 question, subject completed questionnaire about how heart failure affected their life over the past 2 weeks. The scale has 4 domains: symptom frequency, physical limitation, social limitations and quality of life for a total possible transformed score of 0 to 100 where 100 denotes the highest health status. A positive change from baseline indicates improvement. An analysis of covariance (ANCOVA) model was used for analysis. ITT population includes all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 4
    End point values
    Sotagliflozin Placebo
    Number of subjects analysed
    608
    614
    Units: score on a scale
        least squares mean (standard error)
    17.7 ± 0.41
    13.6 ± 0.41
    Statistical analysis title
    Sotagliflozin vs Placebo
    Statistical analysis description
    The change from baseline to Month 4 was analysed using an ANCOVA model with treatment groups as factor and baseline KCCQ-12 score and randomisation stratification factors as covariates.
    Comparison groups
    Sotagliflozin v Placebo
    Number of subjects included in analysis
    1222
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    4.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.3
         upper limit
    7

    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
    eGFR is a test for renal function. A blood sample was collected and was sent to a central laboratory. eGFR was calculated by the Modification of Diet in Renal Disease (MDRD) equation reported as milliliters/minute/1.73 meter squared (mL/min/1.73 m^2). A mixed model for repeated measures (MMRM) was used for analysis. ITT population includes all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Baseline up to 21.9 months
    End point values
    Sotagliflozin Placebo
    Number of subjects analysed
    608
    614
    Units: mL/min/1.73 m^2
        least squares mean (standard error)
    -0.34 ± 1.33
    -0.18 ± 1.33
    Statistical analysis title
    Sotagliflozin vs Placebo
    Statistical analysis description
    Rate of decline in eGFR observed over time was analysed by MMRM with absolute change in eGFR from baseline as the outcome, a random effect for intercept, and fixed effects for treatment, baseline value, and time.
    Comparison groups
    Placebo v Sotagliflozin
    Number of subjects included in analysis
    1222
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Difference in Least Squares Means
    Point estimate
    -0.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.3
         upper limit
    0.98

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose of study drug up to 10 days after the last dose of study drug (Up to 21.9 months)
    Adverse event reporting additional description
    Number of Deaths (All causes) is based on all randomised subjects (n=608,614). Adverse Events are based on the Safety population that included all randomised subjects who received at least one dose of study drug (n=605,611).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Sotagliflozin
    Reporting group description
    Sotagliflozin 200 mg tablet once daily, with possible up-titration in the first 8 months to 400 mg, for up to 21.2 months.

    Reporting group title
    Placebo
    Reporting group description
    Matching placebo to sotagliflozin 200 mg once daily, once daily with possible up-titration in the first 8 months to matching placebo to sotagliflozin 400 mg, for up to 21.6 months.

    Serious adverse events
    Sotagliflozin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    235 / 605 (38.84%)
    251 / 611 (41.08%)
         number of deaths (all causes)
    65
    76
         number of deaths resulting from adverse events
    51
    54
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    1 / 605 (0.17%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon adenoma
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kaposi's sarcoma
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    1 / 605 (0.17%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Papillary renal cell carcinoma
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    2 / 605 (0.33%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic rupture
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Arteriosclerosis
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 605 (0.00%)
    2 / 611 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 605 (0.00%)
    2 / 611 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    6 / 605 (0.99%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 605 (0.17%)
    5 / 611 (0.82%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    1 / 605 (0.17%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    2 / 605 (0.33%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Surgical and medical procedures
    Aortic valve replacement
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac pacemaker insertion
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac rehabilitation therapy
         subjects affected / exposed
    1 / 605 (0.17%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac resynchronisation therapy
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Percutaneous coronary intervention
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Therapeutic procedure
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac death
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Chest pain
         subjects affected / exposed
    3 / 605 (0.50%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 605 (0.33%)
    4 / 611 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 4
    Fatigue
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 605 (0.17%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Nodule
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 605 (0.17%)
    3 / 611 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 605 (0.00%)
    2 / 611 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyrexia
         subjects affected / exposed
    0 / 605 (0.00%)
    3 / 611 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    7 / 605 (1.16%)
    9 / 611 (1.47%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 9
         deaths causally related to treatment / all
    0 / 8
    0 / 9
    Sudden death
         subjects affected / exposed
    2 / 605 (0.33%)
    2 / 611 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Vascular stent thrombosis
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    2 / 605 (0.33%)
    3 / 611 (0.49%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 605 (0.17%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    3 / 605 (0.50%)
    4 / 611 (0.65%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 605 (0.33%)
    3 / 611 (0.49%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dyspnoea exertional
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    1 / 605 (0.17%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pleural effusion
         subjects affected / exposed
    3 / 605 (0.50%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 605 (0.00%)
    6 / 611 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    2 / 605 (0.33%)
    2 / 611 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Respiratory arrest
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    3 / 605 (0.50%)
    3 / 611 (0.49%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wheezing
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Acute psychosis
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 605 (0.00%)
    3 / 611 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug abuse
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device malfunction
         subjects affected / exposed
    1 / 605 (0.17%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lead dislodgement
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 605 (0.33%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biopsy prostate
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood glucose increased
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheterisation cardiac
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SARS-CoV-2 test positive
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transplant evaluation
         subjects affected / exposed
    1 / 605 (0.17%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Cardiac valve replacement complication
         subjects affected / exposed
    0 / 605 (0.00%)
    2 / 611 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    2 / 605 (0.33%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Fall
         subjects affected / exposed
    4 / 605 (0.66%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 605 (0.17%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foreign body in gastrointestinal tract
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 605 (0.17%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Humerus fracture
         subjects affected / exposed
    1 / 605 (0.17%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periprosthetic fracture
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 605 (0.17%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Phimosis
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute left ventricular failure
         subjects affected / exposed
    2 / 605 (0.33%)
    2 / 611 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    4 / 605 (0.66%)
    3 / 611 (0.49%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Angina pectoris
         subjects affected / exposed
    4 / 605 (0.66%)
    3 / 611 (0.49%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    8 / 605 (1.32%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia supraventricular
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    8 / 605 (1.32%)
    8 / 611 (1.31%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 605 (0.17%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 605 (0.17%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradyarrhythmia
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bundle branch block left
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    80 / 605 (13.22%)
    121 / 611 (19.80%)
         occurrences causally related to treatment / all
    0 / 114
    1 / 194
         deaths causally related to treatment / all
    0 / 11
    0 / 15
    Cardiac failure acute
         subjects affected / exposed
    12 / 605 (1.98%)
    11 / 611 (1.80%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 12
         deaths causally related to treatment / all
    0 / 4
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 605 (0.17%)
    8 / 611 (1.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Cardiac failure congestive
         subjects affected / exposed
    11 / 605 (1.82%)
    16 / 611 (2.62%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 29
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    2 / 605 (0.33%)
    2 / 611 (0.33%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Chronic left ventricular failure
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    2 / 605 (0.33%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 605 (0.17%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    6 / 605 (0.99%)
    9 / 611 (1.47%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Myocardial ischaemia
         subjects affected / exposed
    2 / 605 (0.33%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 605 (0.00%)
    2 / 611 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    2 / 605 (0.33%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinoatrial block
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 605 (0.17%)
    2 / 611 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 605 (0.17%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    4 / 605 (0.66%)
    4 / 611 (0.65%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haematoma
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral infarction
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral ischaemia
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    5 / 605 (0.83%)
    3 / 611 (0.49%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Cognitive disorder
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    9 / 605 (1.49%)
    9 / 611 (1.47%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 9
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Loss of consciousness
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelopathy
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postresuscitation encephalopathy
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal claudication
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord ischaemia
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 605 (0.33%)
    12 / 611 (1.96%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 605 (0.33%)
    0 / 611 (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
    Anaemia
         subjects affected / exposed
    5 / 605 (0.83%)
    2 / 611 (0.33%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Eye haemorrhage
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 605 (0.00%)
    3 / 611 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 605 (0.17%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 605 (0.17%)
    4 / 611 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    2 / 605 (0.33%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 605 (0.17%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    2 / 605 (0.33%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-abdominal haematoma
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    1 / 605 (0.17%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oesophageal perforation
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic artery aneurysm
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulcerative gastritis
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 605 (0.00%)
    3 / 611 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    1 / 605 (0.17%)
    2 / 611 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    2 / 605 (0.33%)
    2 / 611 (0.33%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    2 / 605 (0.33%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (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
    11 / 605 (1.82%)
    16 / 611 (2.62%)
         occurrences causally related to treatment / all
    3 / 14
    1 / 16
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Calculus urinary
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    3 / 605 (0.50%)
    6 / 611 (0.98%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 605 (0.17%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephritis
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephropathy toxic
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oliguria
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    3 / 605 (0.50%)
    6 / 611 (0.98%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal impairment
         subjects affected / exposed
    0 / 605 (0.00%)
    3 / 611 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gouty arthritis
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mobility decreased
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 605 (0.00%)
    2 / 611 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteitis
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    3 / 605 (0.50%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoporosis
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyarthritis
         subjects affected / exposed
    1 / 605 (0.17%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal sepsis
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 605 (0.33%)
    2 / 611 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis viral
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 605 (0.17%)
    2 / 611 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cellulitis
         subjects affected / exposed
    4 / 605 (0.66%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 605 (0.17%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Erysipelas
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    2 / 605 (0.33%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 605 (0.00%)
    2 / 611 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis clostridial
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    0 / 605 (0.00%)
    2 / 611 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective thrombosis
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 605 (0.17%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal abscess
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngotonsillitis
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    19 / 605 (3.14%)
    26 / 611 (4.26%)
         occurrences causally related to treatment / all
    0 / 21
    0 / 28
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Pneumonia bacterial
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyelonephritis
         subjects affected / exposed
    2 / 605 (0.33%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 605 (0.17%)
    2 / 611 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 605 (0.00%)
    4 / 611 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    2 / 605 (0.33%)
    4 / 611 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Skin infection
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 605 (0.33%)
    6 / 611 (0.98%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    3 / 605 (0.50%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    3 / 605 (0.50%)
    4 / 611 (0.65%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic complication
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic metabolic decompensation
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (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
    2 / 605 (0.33%)
    4 / 611 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemic hyperosmolar nonketotic syndrome
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperinsulinaemic hypoglycaemia
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 605 (0.17%)
    4 / 611 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    8 / 605 (1.32%)
    4 / 611 (0.65%)
         occurrences causally related to treatment / all
    4 / 8
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 605 (0.00%)
    1 / 611 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 605 (0.17%)
    4 / 611 (0.65%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic disorder
         subjects affected / exposed
    1 / 605 (0.17%)
    0 / 611 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Sotagliflozin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    101 / 605 (16.69%)
    90 / 611 (14.73%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    33 / 605 (5.45%)
    27 / 611 (4.42%)
         occurrences all number
    37
    29
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    41 / 605 (6.78%)
    57 / 611 (9.33%)
         occurrences all number
    54
    77
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    36 / 605 (5.95%)
    18 / 611 (2.95%)
         occurrences all number
    42
    19

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Dec 2018
    Amendment 1: 1. Re-ordered secondary objectives and endpoints. 2. New endpoint was added which provides scientific and clinical leadership 3. Deleted other objective to compare sotagliflozin versus placebo on the occurrence of premature ventricular complexes. 4. Deleted information regarding mechanistic substudy. 5. Changed fixed sequence approach to an alpha passing concept. 6. Deleted sentence on open-ended questions within KCCQ-12 questionnaire. 7. Deleted renal adverse events from AEs waived from expedited reporting. 8. Revised to include additional tests on pregnancy. 9. Added the measurement of HbA1c to be performed at month 16. 10. Added the measurement of eGFR. 11. Added potential benefits of sotagliflozin outweigh potential risks for subjects with T1D and T2D. 12. Modified to include all diagnostic imaging to document historical LVEF at Screening. 13. Time point specified for changes from baseline in loop diuretics. 14. Modified to clarify urinalysis will be performed at the local laboratory at Visit 1 and subsequently at the central laboratory. If the urinalysis is positive for nitrite and leukocyte esterase or blood, reflexive testing will be performed at the local laboratory at Visit 1, and at the central laboratory for subsequent visits. 15. Clarified that blood samples for BNP or NT-proBNP collected at Screening to assess the subject’s eligibility would be analysed by the local laboratory. 16. Separated IMP accounting and compliance in the study flow chart and deleted the accountability of IMP at Visit 3, 4, and 5. 17. Minor editorial, typographical error corrections, and document formatting revisions have been made throughout the document.
    22 Aug 2019
    Amendment 2: 1. Updated protocol title, number and date. 2. Extended randomisation window after hospital discharge. 3. Added secondary endpoint, “CV death and HHF in subjects with LVEF <50% with and without T2D”. 4. Moved secondary endpoints to “Other” endpoints. 5. Updated a few Inclusion criteria. 6. Added stratification for subjects with T2D. 7. Added requirement for the same laboratory for consistency in testing results. 8. Updated Exclusion criteria. 9. Removed Serum potassium >5.5 mEq/L as laboratory finding exclusion criteria. 10. Added Type 1 diabetes to exclusion criteria. 11. Added exclusion criteria, Heart Failure with Preserved Ejection Fraction in subjects without T2D. 12. Reworded primary and secondary hypotheses and renumbering the hypotheses in the graph. Removed “final” from αFinal. Provided clearer language on the relationship between sotagliflozin and diabetic ketoacidosis. 13. Laboratory tests for chemistry clarified. 14. Delated asymptomatic overdose as a standard AE. 15. Deleted neutropenia, thrombocytopenia, and increased creatinine phosphokinase from the list of laboratory abnormalities. 16. Deleted Three decision trees in appendix D. 17. Removed redundant/unnecessary liver test analysis. 18. Minor editorial, typographical error corrections, and document formatting revisions were made throughout the document.

    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.
    The study was terminated prematurely due to financial reasons and Covid-19 pandemic.
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