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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo-controlled, 3-arm, Parallel-group 52-week Multicenter Study to Evaluate the Efficacy and Safety of Sotagliflozin in Patients with Type 2 Diabetes Mellitus and Moderate Renal Impairment who have Inadequate Glycemic Control

    Summary
    EudraCT number
    		 2016-004889-26
    Trial protocol
    		 ES   DE   HU   IT   RO  
    Global end of trial date
    25 Oct 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Sep 2020
    First version publication date
    20 Sep 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    EFC14837
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03242252
    WHO universal trial number (UTN)
    		 U1111-1187-8662
    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
    25 Oct 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Oct 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the superiority of sotagliflozin 200 milligrams (mg) and sotagliflozin 400 mg versus placebo on hemoglobin A1c (HbA1c) reduction at Week 26 in subjects with Type 2 diabetes who have inadequate glycemic control and moderate renal impairment.
    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
    16 Aug 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 84
    Country: Number of subjects enrolled
    Spain: 34
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Hungary: 57
    Country: Number of subjects enrolled
    Argentina: 24
    Country: Number of subjects enrolled
    Brazil: 66
    Country: Number of subjects enrolled
    Canada: 41
    Country: Number of subjects enrolled
    Colombia: 32
    Country: Number of subjects enrolled
    Israel: 56
    Country: Number of subjects enrolled
    Italy: 19
    Country: Number of subjects enrolled
    Mexico: 34
    Country: Number of subjects enrolled
    Romania: 33
    Country: Number of subjects enrolled
    Russian Federation: 39
    Country: Number of subjects enrolled
    South Africa: 22
    Country: Number of subjects enrolled
    Ukraine: 39
    Country: Number of subjects enrolled
    United States: 200
    Worldwide total number of subjects
    787
    EEA total number of subjects
    234
    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)
    197
    From 65 to 84 years
    576
    85 years and over
    14

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects took part in the study at 166 investigative sites in the United States, Argentina, Brazil, Canada, Colombia, Germany, Hungary, Israel, Italy, Mexico, Poland, Romania, Russian Federation, South Africa, Spain, and Ukraine from 16 August 2017 to 25 October 2019.

    Pre-assignment
    Screening details
    		 Subjects with a diagnosis of Type 2 Diabetes Mellitus were enrolled in 1 of 3 treatment groups: Placebo or Sotagliflozin 200 mg or Sotagliflozin 400 mg. Subjects were randomly assigned in the ratio of 1:1:1 to these reporting groups.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Following a 2-week run-in phase, subjects received two placebo tablets (identical to sotagliflozin 200 mg in appearance), orally once daily for up to 54 weeks.
    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 two tablets (identical to sotagliflozin in appearance), once daily before the first meal of the day.

    Arm title
    		 Sotagliflozin 200 mg
    Arm description
    		 Following a 2-week run-in phase, subjects received two tablets, one sotagliflozin 200 mg tablet and one placebo tablet (identical to sotagliflozin 200 mg in appearance), orally once daily for up to 58 weeks.
    Arm type
    		 Experimental

    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 one tablet (identical to the sotagliflozin 200 mg tablet in appearance), orally, once daily before the first meal of the day.

    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 200 mg was administered as one tablet, orally once daily before the first meal of the day.

    Arm title
    		 Sotagliflozin 400 mg
    Arm description
    		 Following a 2-week run-in phase, subjects received sotagliflozin 400 mg, administered as two sotagliflozin 200 mg tablets, orally once daily for up to 60 weeks.
    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 400 mg was administered as two sotagliflozin 200 mg tablets, orally once daily before the first meal of the day.

    Number of subjects in period 1
    		Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Started
    260
    263
    264
    Completed
    224
    240
    232
    Not completed
    36
    23
    32
         At the subject’s own request
    18
    10
    15
         Adverse event
    8
    6
    9
         Study terminated by sponsor
    1
    -
    -
         Poor compliance to protocol
    -
    2
    3
         Lost to follow-up
    5
    1
    4
         Reason not specified
    4
    4
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Following a 2-week run-in phase, subjects received two placebo tablets (identical to sotagliflozin 200 mg in appearance), orally once daily for up to 54 weeks.

    Reporting group title
    Sotagliflozin 200 mg
    Reporting group description
    		 Following a 2-week run-in phase, subjects received two tablets, one sotagliflozin 200 mg tablet and one placebo tablet (identical to sotagliflozin 200 mg in appearance), orally once daily for up to 58 weeks.

    Reporting group title
    Sotagliflozin 400 mg
    Reporting group description
    		 Following a 2-week run-in phase, subjects received sotagliflozin 400 mg, administered as two sotagliflozin 200 mg tablets, orally once daily for up to 60 weeks.

    Reporting group values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg Total
    Number of subjects
    		 260 263 264 787
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 69.3 ( 8.1 ) 69.6 ( 7.5 ) 69.5 ( 8.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 111 120 112 343
        Male
    		 149 143 152 444
    Race
    Units: Subjects
        White
    		 220 231 215 666
        Black or African American
    		 12 14 15 41
        Asian
    		 5 7 8 20
        American Indian or Alaska Native
    		 15 9 20 44
        Native Hawaiian or Other Pacific Islander
    		 1 1 0 2
        Multiple
    		 3 0 3 6
        Not Reported
    		 2 0 3 5
        Unknown
    		 2 1 0 3
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 67 67 64 198
        Not Hispanic or Latino
    		 193 196 200 589
    HbA1c
    Units: percentage of HbA1c
        arithmetic mean (standard deviation)
    		 8.33 ( 1.00 ) 8.33 ( 0.90 ) 8.31 ( 0.94 ) -
    Systolic Blood Pressure (SBP)
    Units: millimetre of mercury (mmHg)
        arithmetic mean (standard deviation)
    		 140.59 ( 14.59 ) 140.31 ( 15.15 ) 141.71 ( 15.01 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Following a 2-week run-in phase, subjects received two placebo tablets (identical to sotagliflozin 200 mg in appearance), orally once daily for up to 54 weeks.

    Reporting group title
    Sotagliflozin 200 mg
    Reporting group description
    		 Following a 2-week run-in phase, subjects received two tablets, one sotagliflozin 200 mg tablet and one placebo tablet (identical to sotagliflozin 200 mg in appearance), orally once daily for up to 58 weeks.

    Reporting group title
    Sotagliflozin 400 mg
    Reporting group description
    		 Following a 2-week run-in phase, subjects received sotagliflozin 400 mg, administered as two sotagliflozin 200 mg tablets, orally once daily for up to 60 weeks.

    Subject analysis set title
    Sotagliflozin 200 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Following a 2-week run-in phase, subjects received two tablets, one sotagliflozin 200 mg tablet and one placebo tablet (identical to sotagliflozin 200 mg in appearance), orally once daily for up to 58 weeks. Four subjects randomised to sotagliflozin 400 mg were dosed with both sotagliflozin 200 mg and sotagliflozin 400 mg were included in the sotagliflozin 200 mg arm in the safety population.

    Subject analysis set title
    Sotagliflozin 400 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Following a 2-week run-in phase, subjects received sotagliflozin 400 mg, administered as two sotagliflozin 200 mg tablets, orally once daily for up to 60 weeks. Four subjects randomised to sotagliflozin 400 mg were dosed with both sotagliflozin 200 mg and sotagliflozin 400 mg were included in the sotagliflozin 200 mg arm in the safety population.

    Primary: Change From Baseline in HbA1c % at Week 26

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    End point title
    		 Change From Baseline in HbA1c % at Week 26
    End point description
    An Analysis of covariance (ANCOVA) model was used for analysis. Intent-to-treat (ITT) population included all randomised subjects or subjects analysed according to their randomised treatment. Missing data was imputed using control-based copy reference multiple imputation under the missing not at random framework.
    End point type
    Primary
    End point timeframe
    Baseline to Week 26
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    260
    263
    264
    Units: percentage of HbA1c
        least squares mean (standard error)
    -0.22 ( 0.061 )
    -0.32 ( 0.060 )
    -0.46 ( 0.060 )
    Statistical analysis title
    		 Sotagliflozin 200 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 26 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤ 8.5, > 8.5%) at screening, randomisation strata of mean SBP (< 130, ≥ 130 mmHg) at screening, randomisation stratum of Chronic Kidney Disease (CKD) stage (3A, 3B) at screening, and country as fixed effects, and baseline HbA1c as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 200 mg
    Number of subjects included in analysis
    523
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2095
    Method
    		 ANCOVA
    Parameter type
    		 Difference in Least Square (LS) Means
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.245
         upper limit
    		 0.054
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.076
    Statistical analysis title
    		 Sotagliflozin 400 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 26 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤ 8.5, > 8.5%) at screening, randomisation strata of mean SBP (< 130, ≥ 130 mmHg) at screening, randomisation stratum of CKD stage (3A, 3B) at screening, and country as fixed effects, and baseline HbA1c as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    524
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0021
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.386
         upper limit
    		 -0.085
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.077

    Secondary: Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26

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    End point title
    		 Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26
    End point description
    An ANCOVA model was used for analysis. ITT population included all randomised subjects or subjects analysed according to their randomised treatment. Missing data was imputed using the retrieved dropouts & washout imputation method.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 26
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    260
    263
    264
    Units: millimole per litre (mmol/L)
        least squares mean (standard error)
    -0.374 ( 0.1949 )
    -0.961 ( 0.1715 )
    -0.852 ( 0.1668 )
    Statistical analysis title
    		 Sotagliflozin 200 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 26 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤ 8.5, > 8.5%) at screening, randomisation strata of mean SBP (< 130, ≥ 130 mmHg) at screening, randomisation stratum of CKD stage (3A, 3B) at screening, and country as fixed effects, and baseline FPG as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 200 mg
    Number of subjects included in analysis
    523
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0144
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.587
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.0564
         upper limit
    		 -0.1169
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2397
    Statistical analysis title
    		 Sotagliflozin 400 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 26 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤ 8.5, > 8.5%) at screening, randomisation strata of mean SBP (< 130, ≥ 130 mmHg) at screening, randomisation stratum of CKD stage (3A, 3B) at screening, and country as fixed effects, and baseline FPG as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    524
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0436
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.478
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.942
         upper limit
    		 -0.0136
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2368

    Secondary: Change From Baseline in SBP for Subjects With Baseline SBP ≥130 mmHg at Week 12

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    End point title
    		 Change From Baseline in SBP for Subjects With Baseline SBP ≥130 mmHg at Week 12
    End point description
    An ANCOVA model was used for analysis. Analysis population included subjects with baseline SBP ≥ 130 mmHg in ITT population where, ITT population included all randomised subjects or subjects analysed according to their randomised treatment. Missing data was imputed using the retrieved dropouts & washout imputation method.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    175
    162
    182
    Units: millimetre of mercury (mmHg)
        least squares mean (standard error)
    -5.18 ( 1.462 )
    -7.46 ( 1.597 )
    -7.71 ( 1.247 )
    Statistical analysis title
    		 Sotagliflozin 200 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 12 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤ 8.5, > 8.5%) at screening, randomisation stratum of CKD stage (3A, 3B) at screening, and country as fixed effects, and baseline SBP as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 200 mg
    Number of subjects included in analysis
    337
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2627
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -2.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.265
         upper limit
    		 1.709
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.034
    Statistical analysis title
    		 Sotagliflozin 400 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 12 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤ 8.5, > 8.5%) at screening, randomisation stratum of CKD stage (3A, 3B) at screening, and country as fixed effects, and baseline SBP as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    357
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1602
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -2.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.052
         upper limit
    		 1
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.799

    Secondary: Change From Baseline in SBP at Week 12 for All Subjects

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    End point title
    		 Change From Baseline in SBP at Week 12 for All Subjects
    End point description
    An ANCOVA model was used for analysis. ITT population included all randomised subjects or subjects analysed according to their randomised treatment. Missing data was imputed using the retrieved dropouts & washout imputation method.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    260
    263
    264
    Units: mmHg
        least squares mean (standard error)
    -3.31 ( 1.037 )
    -4.91 ( 1.010 )
    -4.94 ( 0.983 )
    Statistical analysis title
    		 Sotagliflozin 200 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 12 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤ 8.5, > 8.5%) at screening, randomisation strata of mean SBP (< 130, ≥ 130 mmHg) at screening, randomisation stratum of CKD stage (3A, 3B) at screening, country as fixed effects, and baseline SBP as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 200 mg
    Number of subjects included in analysis
    523
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2212
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.142
         upper limit
    		 0.958
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.301
    Statistical analysis title
    		 Sotagliflozin 400 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 12 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤ 8.5, > 8.5%) at screening, randomisation strata of mean SBP (< 130, ≥ 130 mmHg) at screening, randomisation stratum of CKD stage (3A, 3B) at screening, country as fixed effects, and baseline SBP as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    524
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2089
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.171
         upper limit
    		 0.912
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.297

    Secondary: Change From Baseline in Body Weight at Week 26

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    End point title
    		 Change From Baseline in Body Weight at Week 26
    End point description
    An ANCOVA model was used for analysis. ITT population included all randomised subjects or subjects analysed according to their randomised treatment. Missing data was imputed using the retrieved dropouts & washout imputation method.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 26
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    260
    263
    264
    Units: kilogram (kg)
        least squares mean (standard error)
    -0.38 ( 0.262 )
    -1.66 ( 0.246 )
    -1.20 ( 0.257 )
    Statistical analysis title
    		 Sotagliflozin 200 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 26 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤ 8.5, > 8.5%) at screening, randomisation strata of mean SBP (< 130, ≥ 130 mmHg) at screening, randomisation stratum of CKD stage (3A, 3B) at screening, country as fixed effects, and baseline body weight as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 200 mg
    Number of subjects included in analysis
    523
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.92
         upper limit
    		 -0.644
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.326
    Statistical analysis title
    		 Sotagliflozin 400 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 26 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤ 8.5, > 8.5%) at screening, randomisation strata of mean SBP (< 130, ≥ 130 mmHg) at screening, randomisation stratum of CKD stage (3A, 3B) at screening, country as fixed effects, and baseline body weight as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    524
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0155
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.487
         upper limit
    		 -0.156
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.339

    Secondary: Percentage Change from Baseline in the Urine Albumin: Creatinine Ratio (UACR) at Week 26 in Subjects with Baseline UACR >30 milligrams per gram (mg/g)

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    End point title
    		 Percentage Change from Baseline in the Urine Albumin: Creatinine Ratio (UACR) at Week 26 in Subjects with Baseline UACR >30 milligrams per gram (mg/g)
    End point description
    An ANCOVA model was used for analysis. Analysis population included subjects with baseline UACR > 30 mg/g in ITT population where, ITT population included all randomised subjects or subjects analysed according to their randomised treatment. Missing data was imputed using control-based copy reference multiple imputation under the missing not at random framework.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 26
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    260
    263
    264
    Units: percent change
        number (not applicable)
    -18.71
    -43.68
    -48.12
    Statistical analysis title
    		 Sotagliflozin 200 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 26 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤ 8.5, > 8.5%) at screening, randomisation strata of mean SBP (< 130, ≥ 130 mmHg) at screening, randomisation stratum of CKD stage (3A, 3B) at screening, country as fixed effects, and and log-transformed baseline UACR as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 200 mg
    Number of subjects included in analysis
    523
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0015
    Method
    		 ANCOVA
    Parameter type
    		 Percent Difference
    Point estimate
    -30.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -44.78
         upper limit
    		 -13.07
    Statistical analysis title
    		 Sotagliflozin 400 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 26 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤ 8.5, > 8.5%) at screening, randomisation strata of mean SBP (< 130, ≥ 130 mmHg) at screening, randomisation stratum of CKD stage (3A, 3B) at screening, country as fixed effects, and and log-transformed baseline UACR as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    524
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003
    Method
    		 ANCOVA
    Parameter type
    		 Percent Difference
    Point estimate
    -36.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -49.91
         upper limit
    		 -18.68

    Secondary: Percentage of Subjects With HbA1c < 6.5% at Week 26

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    End point title
    		 Percentage of Subjects With HbA1c < 6.5% at Week 26
    End point description
    ITT population included all randomised subjects or subjects analysed according to their randomised treatment.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    260
    263
    264
    Units: percentage of subjects
        number (not applicable)
    4.2
    5.7
    5.7
    Statistical analysis title
    		 Sotagliflozin 200 mg Vs Placebo
    Statistical analysis description
    Percentage difference between treatment groups using the Cochran-Mantel-Haenszel test stratified by the randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of mean SBP (<130, ≥130 mmHg) at screening and randomisation strata of CKD stage (3A, 3B) at screening.
    Comparison groups
    Placebo v Sotagliflozin 200 mg
    Number of subjects included in analysis
    523
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4328
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.23
         upper limit
    		 5.21
    Statistical analysis title
    		 Sotagliflozin 400 mg Vs Placebo
    Statistical analysis description
    Percentage difference between treatment groups using the Cochran-Mantel-Haenszel test stratified by the randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of mean SBP (<130, ≥130 mmHg) at screening and randomisation strata of CKD stage (3A, 3B) at screening.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    524
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4328
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.2
         upper limit
    		 5.17

    Secondary: Percentage of Subjects with HbA1c < 7.0% at Week 26

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    End point title
    		 Percentage of Subjects with HbA1c < 7.0% at Week 26
    End point description
    ITT population included all randomised subjects or subjects analysed according to their randomised treatment.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    260
    263
    264
    Units: percentage of subjects
        number (not applicable)
    13.5
    19.4
    20.8
    Statistical analysis title
    		 Sotagliflozin 200 mg Vs Placebo
    Statistical analysis description
    Percentage difference between treatment groups using the Cochran-Mantel-Haenszel test stratified by the randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of mean SBP (<130, ≥130 mmHg) at screening and randomisation strata of CKD stage (3A, 3B) at screening.
    Comparison groups
    Placebo v Sotagliflozin 200 mg
    Number of subjects included in analysis
    523
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0614
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 12.21
    Statistical analysis title
    		 Sotagliflozin 400 mg Vs Placebo
    Statistical analysis description
    Percentage difference between treatment groups using the Cochran-Mantel-Haenszel test stratified by the randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of mean SBP (<130, ≥130 mmHg) at screening and randomisation strata of CKD stage (3A, 3B) at screening.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    524
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.023
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    7.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.08
         upper limit
    		 13.65

    Secondary: Percentage of Subjects With Treatment-emergent Adverse Events (TEAEs)

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    End point title
    		 Percentage of Subjects With Treatment-emergent Adverse Events (TEAEs) [1]
    End point description
    Safety population included all subjects who received at least 1 dose of study drug analysed according to the treatment actually received.
    End point type
    Secondary
    End point timeframe
    Up to 60 weeks
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for the following reporting arms Placebo and subject analysis sets Sotagliflozin 200 mg and Sotagliflozin 400 mg.
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    260
    267
    260
    Units: percentage of subjects
        number (not applicable)
    78.1
    76.8
    74.2
    No statistical analyses for this end point

    Other pre-specified: Percentage of Subjects with Hypoglycemic Events

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    End point title
    		 Percentage of Subjects with Hypoglycemic Events [2]
    End point description
    Percentage of subjects with hypoglycemic events are reported for the following 3 categories: Any hypoglycemia (as reported in the Electronic Case Report Form); Documented symptomatic hypoglycemia [typical symptoms of hypoglycemia (increased sweating, nervousness, asthenia/weakness, tremor, dizziness, increased appetite, palpitations, headache, sleep disorder, confusion, seizures, unconsciousness, and/or coma) and plasma glucose ≤ 70 mg/dL (3.9 mmol/L)]; Severe [an event requiring assistance of another person to actively administer carbohydrate, glucagon, intravenous glucose or other resuscitative actions] or documented symptomatic hypoglycemia [typical symptoms of hypoglycemia and plasma glucose ≤ 70 mg/dL]. Safety population included all subjects who received at least 1 dose of study drug analysed according to the treatment actually received.
    End point type
    Other pre-specified
    End point timeframe
    Up to 60 weeks
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for the following reporting arms Placebo and subject analysis sets Sotagliflozin 200 mg and Sotagliflozin 400 mg.
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    260
    267
    260
    Units: percentage of subjects
    number (not applicable)
        Any hypoglycemia
    38.1
    41.9
    35.4
        Documented symptomatic hypoglycemia
    26.9
    29.6
    22.3
        Severe or documented symptomatic hypoglycemia
    26.9
    29.6
    22.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 60 weeks
    Adverse event reporting additional description
    Safety population included all subjects who received at least 1 dose of study drug analysed according to the treatment actually received. Hypoglycemia was captured and handled separately from other adverse events and is reported in the endpoint section.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Following a 2-week run-in phase, subjects received two placebo tablets (identical to sotagliflozin 200 mg in appearance) orally once daily for up to 54 weeks.

    Reporting group title
    Sotagliflozin 200 mg
    Reporting group description
    		 Following a 2-week run-in phase, subjects received two tablets, one sotagliflozin 200 mg tablet and one placebo tablet (identical to sotagliflozin 200 mg in appearance), orally once daily for up to 58 weeks. Four subjects randomised to sotagliflozin 400 mg were dosed with both sotagliflozin 200 mg and sotagliflozin 400 mg were included in the sotagliflozin 200 mg arm in the safety population.

    Reporting group title
    Sotagliflozin 400 mg
    Reporting group description
    		 Following a 2-week run-in phase, subjects received sotagliflozin 400 mg, administered as two sotagliflozin 200 mg tablets, orally once daily for up to 60 weeks.

    Serious adverse events
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    48 / 260 (18.46%)
    43 / 267 (16.10%)
    44 / 260 (16.92%)
         number of deaths (all causes)
    3
    2
    5
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-cell lymphoma
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    3 / 260 (1.15%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer female
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lipoma
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma of eyelid
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuroendocrine tumour
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine neoplasm
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Extremity necrosis
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral artery aneurysm
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 267 (0.75%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Cardiac death
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vocal cord polyp
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood pressure increased
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural shock
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    2 / 260 (0.77%)
    2 / 267 (0.75%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Angina pectoris
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 267 (0.37%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 260 (0.00%)
    4 / 267 (1.50%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    2 / 260 (0.77%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery insufficiency
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 267 (0.37%)
    3 / 260 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Basal ganglia infarction
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 260 (0.38%)
    3 / 267 (1.12%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic neuropathy
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemic unconsciousness
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 267 (0.75%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    2 / 260 (0.77%)
    2 / 267 (0.75%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Glaucoma
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Iris neovascularisation
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 267 (0.75%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mallory-Weiss syndrome
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ingrowing nail
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    End stage renal disease
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Foot deformity
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 260 (0.77%)
    1 / 267 (0.37%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tenosynovitis
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    2 / 260 (0.77%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 267 (0.75%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 267 (0.37%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Corneal abscess
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterococcal infection
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Funguria
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    2 / 260 (0.77%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infective periostitis
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 260 (0.38%)
    2 / 267 (0.75%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Sepsis pasteurella
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tick-borne viral encephalitis
         subjects affected / exposed
    0 / 260 (0.00%)
    0 / 267 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 260 (0.00%)
    3 / 267 (1.12%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic metabolic decompensation
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 267 (0.37%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 267 (0.37%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 267 (0.37%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 267 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    80 / 260 (30.77%)
    72 / 267 (26.97%)
    77 / 260 (29.62%)
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    13 / 260 (5.00%)
    15 / 267 (5.62%)
    22 / 260 (8.46%)
         occurrences all number
    14
    16
    28
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    13 / 260 (5.00%)
    7 / 267 (2.62%)
    12 / 260 (4.62%)
         occurrences all number
    15
    8
    13
    Upper respiratory tract infection
         subjects affected / exposed
    18 / 260 (6.92%)
    16 / 267 (5.99%)
    13 / 260 (5.00%)
         occurrences all number
    21
    22
    15
    Urinary tract infection
         subjects affected / exposed
    21 / 260 (8.08%)
    19 / 267 (7.12%)
    21 / 260 (8.08%)
         occurrences all number
    32
    21
    24
    Metabolism and nutrition disorders
    Vitamin D deficiency
         subjects affected / exposed
    30 / 260 (11.54%)
    24 / 267 (8.99%)
    24 / 260 (9.23%)
         occurrences all number
    31
    24
    25

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Dec 2017
    Amendment 1: 1. Change to exclusion criterion and guidance on contraceptive methods. 2. Change to exclusion criterion and temporary IMP discontinuation. 3. Change to exclusion criterion to clarify that subjects should not be enrolled in case of any concomitant condition or major systemic disorder that in investigator’s opinion could affect their safety during the study. 4. Change to hepatitis serology test at screening. 5. Change to exclusion criterion to clarify that subjects should not be enrolled if currently enrolled in other investigational studies. 6. Change to the exclusion criterion requiring stability of insulin dose. 7. Change to the general guidelines for reporting of AEs. 8. Remove urgent coronary revascularizations from the events subject to the Clinical Endpoint Committees (CECs) review. 9. Addition of a new section to describe the independent safety assessments for drug-induced liver injuries (DILI) and amputation. 10. Changes to the observation period for safety endpoints. 11. Change to code breaking related to pharmacokinetic (PK) laboratory. 12. Change to the definition of one Event of Special Interest (EOSI), “volume depletion”. 13. Change to definition of baseline for estimated glomerular filtration rate (eGFR). 14. Change to instruction for blood pressure measurement. 15. Change to rescue therapy. 16. Change to urine laboratory test. 17. Change in the order of secondary objectives and endpoints for the study. 18. Addition of femoral neck as a region for the bone mineral density (BMD) assessments. 19. Other minor changes for corrections of inconsistency, editorial changes, or administration clarification.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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