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    Clinical Trial Results:
    A 52-week Randomized, Double-blind, Double-dummy, Active and Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the Efficacy and Safety of Sotagliflozin compared to Glimepiride or Placebo Added to Metformin in Patients with Type 2 Diabetes who have Inadequate Glycemic Control with Metformin Monotherapy

    Summary
    EudraCT number
    		 2016-001801-17
    Trial protocol
    		 SK   BG   HU  
    Global end of trial date
    06 Sep 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

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    Trial identification
    Sponsor protocol code
    EFC14838
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03332771
    WHO universal trial number (UTN)
    		 U1111-1190-7596
    Sponsors
    Sponsor organisation name
    Lexicon Pharmaceuticals, Inc.
    Sponsor organisation address
    8800 Technology Forest Place, The Woodlands, TX, United States, United States, 77381
    Public contact
    Medical Affairs, Lexicon Pharmaceuticals, Inc., 510 338-6064, medical-information@lexpharma.com
    Scientific contact
    Medical Affairs, Lexicon Pharmaceuticals, Inc., 510 338-6064, 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
    06 Sep 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Sep 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the non-inferiority of Sotagliflozin 400 milligrams (mg) compared to glimepiride on HbA1c (glycosylated A1c) reduction at Week 52 in subjects with Type 2 Diabetes (T2D) who have inadequate glycemic control with metformin.
    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
    01 Dec 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
    Slovakia: 80
    Country: Number of subjects enrolled
    Bulgaria: 45
    Country: Number of subjects enrolled
    Hungary: 136
    Country: Number of subjects enrolled
    United States: 693
    Worldwide total number of subjects
    954
    EEA total number of subjects
    261
    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)
    635
    From 65 to 84 years
    315
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects took part in the study at 138 investigative sites in United States, Bulgaria, Hungary, and Slovakia from 01 December 2017 to 06 September 2019.

    Pre-assignment
    Screening details
    		 Subjects with a diagnosis of T2D Mellitus were enrolled in 1 of 4 treatment groups: Placebo or Sotagliflozin 200 mg or Sotagliflozin 400 mg or Glimepiride. Subjects were randomly assigned in the ratio of 1:1:2:2 to these reporting groups. Total of 954 subjects were enrolled in the study, from which 952 were randomised and treated.

    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
    		 Placebo
    Arm description
    		 Following a 2-week run-in period, two Sotagliflozin-matching placebo tablets and two Glimepiride-matching placebo capsules, taken orally once daily before the first meal of the day in the double-blind treatment period up to 52 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo administered as 2 tablets, 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 was administered as 2 tablets, once daily before the first meal of the day.

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Glimepiride was administered as 2 capsules, once daily before the first meal of the day.

    Arm title
    		 Sotagliflozin 400 mg
    Arm description
    		 Following a 2-week run-in period, two Sotagliflozin 200 mg, tablets, and two Glimepiride-matching placebo capsules, taken orally once daily before the first meal of the day in the double-blind treatment period up to 52 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 was administered as 2 tablets, once daily before the first meal of the day.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Glimepiride-matching placebo administered as 2 capsules, orally once daily before the first meal of the day.

    Arm title
    		 Sotagliflozin 200 mg
    Arm description
    		 Following a 2-week run-in period, one Sotagliflozin 200 mg, tablet and one Sotagliflozin-matching placebo tablet, and two Glimepiride-matching placebo capsules, taken orally once daily before the first meal of the day in the double-blind treatment period up to 52 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 administered as 2 tablets, orally once daily before the first meal of the day.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo administered as 2 tablets, orally once daily before the first meal of the day.

    Arm title
    		 Glimepiride
    Arm description
    		 Following a 2-week run-in period, two Sotagliflozin-matching placebo tablets, and combination of two Glimepiride capsules with adequate dose strengths per dose titration (titrated up to 6mg), taken orally once daily before the first meal of the day in the double-blind treatment period up to 52 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 administered as 2 tablets, orally once daily before the first meal of the day

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Glimepiride was administered as 2 capsules, once daily before the first meal of the day.

    Number of subjects in period 1
    		Placebo Sotagliflozin 400 mg Sotagliflozin 200 mg Glimepiride
    Started
    159
    317
    160
    318
    Completed
    125
    266
    128
    270
    Not completed
    34
    51
    32
    48
         Adverse Event
    6
    4
    1
    3
         Lost to Follow-up
    2
    2
    1
    2
         Poor compliance to protocol
    -
    1
    -
    1
         Reason not specified
    6
    18
    16
    19
         At the Subject’s Own Request
    20
    26
    14
    23

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Following a 2-week run-in period, two Sotagliflozin-matching placebo tablets and two Glimepiride-matching placebo capsules, taken orally once daily before the first meal of the day in the double-blind treatment period up to 52 weeks.

    Reporting group title
    Sotagliflozin 400 mg
    Reporting group description
    		 Following a 2-week run-in period, two Sotagliflozin 200 mg, tablets, and two Glimepiride-matching placebo capsules, taken orally once daily before the first meal of the day in the double-blind treatment period up to 52 weeks.

    Reporting group title
    Sotagliflozin 200 mg
    Reporting group description
    		 Following a 2-week run-in period, one Sotagliflozin 200 mg, tablet and one Sotagliflozin-matching placebo tablet, and two Glimepiride-matching placebo capsules, taken orally once daily before the first meal of the day in the double-blind treatment period up to 52 weeks.

    Reporting group title
    Glimepiride
    Reporting group description
    		 Following a 2-week run-in period, two Sotagliflozin-matching placebo tablets, and combination of two Glimepiride capsules with adequate dose strengths per dose titration (titrated up to 6mg), taken orally once daily before the first meal of the day in the double-blind treatment period up to 52 weeks.

    Reporting group values
    		 Placebo Sotagliflozin 400 mg Sotagliflozin 200 mg Glimepiride Total
    Number of subjects
    		 159 317 160 318 954
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.8 ± 11.2 59.7 ± 10.4 58.6 ± 9.9 59.8 ± 9.6 -
    Gender categorical
    Units: Subjects
        Female
    		 77 157 75 143 452
        Male
    		 82 160 85 175 502
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 48 85 53 111 297
        Not Hispanic or Latino
    		 110 230 106 207 653
        Unknown or Not Reported
    		 1 2 1 0 4
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 0 1 2
        Asian
    		 3 5 3 4 15
        Native Hawaiian or Other Pacific Islander
    		 1 1 2 0 4
        Black or African American
    		 13 34 19 36 102
        White
    		 141 269 136 277 823
        More than one race
    		 1 3 0 0 4
        Unknown or Not Reported
    		 0 4 0 0 4
    Hemoglobin A1c (HbA1c)
    Units: percentage of HbA1c
        arithmetic mean (standard deviation)
    		 8.12 ± 0.73 8.09 ± 0.78 8.11 ± 0.86 8.07 ± 0.79 -
    Systolic Blood Pressure (SBP)
    Units: millimetre of mercury (mmHg)
        arithmetic mean (standard deviation)
    		 133.23 ± 14.90 133.17 ± 14.37 132.78 ± 13.29 134.66 ± 14.43 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Following a 2-week run-in period, two Sotagliflozin-matching placebo tablets and two Glimepiride-matching placebo capsules, taken orally once daily before the first meal of the day in the double-blind treatment period up to 52 weeks.

    Reporting group title
    Sotagliflozin 400 mg
    Reporting group description
    		 Following a 2-week run-in period, two Sotagliflozin 200 mg, tablets, and two Glimepiride-matching placebo capsules, taken orally once daily before the first meal of the day in the double-blind treatment period up to 52 weeks.

    Reporting group title
    Sotagliflozin 200 mg
    Reporting group description
    		 Following a 2-week run-in period, one Sotagliflozin 200 mg, tablet and one Sotagliflozin-matching placebo tablet, and two Glimepiride-matching placebo capsules, taken orally once daily before the first meal of the day in the double-blind treatment period up to 52 weeks.

    Reporting group title
    Glimepiride
    Reporting group description
    		 Following a 2-week run-in period, two Sotagliflozin-matching placebo tablets, and combination of two Glimepiride capsules with adequate dose strengths per dose titration (titrated up to 6mg), taken orally once daily before the first meal of the day in the double-blind treatment period up to 52 weeks.

    Primary: Change From Baseline in Hemoglobin A1c % at Week 52

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    End point title
    		 Change From Baseline in Hemoglobin A1c % at Week 52
    End point description
    Missing data are imputed using the retrieved dropouts imputation method. An analysis of covariance (ANCOVA) model was used for the analysis. Intend to treat (ITT) population included all randomised subjects.
    End point type
    Primary
    End point timeframe
    Baseline, Week 52
    End point values
    		 Placebo Sotagliflozin 400 mg Sotagliflozin 200 mg Glimepiride
    Number of subjects analysed
    159
    317
    160
    318
    Units: percentage of HbA1c
        least squares mean (standard error)
    -0.40 ± 0.187
    -0.65 ± 0.101
    -0.49 ± 0.114
    -0.61 ± 0.093
    Statistical analysis title
    		 Sotagliflozin 400 mg, Glimepiride
    Statistical analysis description
    The change from baseline to Week 52 is analysed using ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of SBP (<130, ≥130 mmHg) at screening, and country as fixed effects, and baseline HbA1c as a covariate.
    Comparison groups
    Sotagliflozin 400 mg v Glimepiride
    Number of subjects included in analysis
    635
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.3306
    Method
    		 ANCOVA
    Parameter type
    		 Difference in Least Squares (LS) Mean
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.12
         upper limit
    		 0.357
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.122
    Statistical analysis title
    		 Sotagliflozin 200 mg, Glimepiride
    Statistical analysis description
    The change from baseline to Week 52 is analysed using ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of SBP (<130, ≥130 mmHg) at screening, and country as fixed effects, and baseline HbA1c as a covariate.
    Comparison groups
    Sotagliflozin 200 mg v Glimepiride
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.7112
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.265
         upper limit
    		 0.181
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.114

    Secondary: Change From Baseline in Hemoglobin A1c % at Week 26

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    End point title
    		 Change From Baseline in Hemoglobin A1c % at Week 26
    End point description
    Missing data are imputed using the washout imputation method. An ANCOVA model was used for the analysis. ITT population included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Placebo Sotagliflozin 400 mg Sotagliflozin 200 mg Glimepiride
    Number of subjects analysed
    159
    317
    160
    318
    Units: percentage of HbA1c
        least squares mean (standard error)
    -0.41 ± 0.097
    -0.77 ± 0.076
    -0.61 ± 0.098
    -1.02 ± 0.075
    Statistical analysis title
    		 Sotagliflozin 400 mg, Glimepiride
    Statistical analysis description
    The change from baseline to Week 26 is analysed using ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of SBP (<130, ≥130 mmHg) at screening, and country as fixed effects, and baseline HbA1c as a covariate.
    Comparison groups
    Sotagliflozin 400 mg v Glimepiride
    Number of subjects included in analysis
    635
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0827
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.44
         upper limit
    		 0.027
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.119
    Statistical analysis title
    		 Sotagliflozin 200 mg, Glimepiride
    Statistical analysis description
    The change from baseline to Week 26 is analysed using ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of SBP (<130, ≥130 mmHg) at screening, and country as fixed effects, and baseline HbA1c as a covariate.
    Comparison groups
    Glimepiride v Sotagliflozin 200 mg
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.571
         upper limit
    		 -0.167
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.103

    Secondary: Change From Baseline in Body Weight at Week 26 and 52

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    End point title
    		 Change From Baseline in Body Weight at Week 26 and 52
    End point description
    Missing data are imputed using the retrieved dropouts & washout imputation method. An ANCOVA model was used for the analysis. ITT population included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26 and 52
    End point values
    		 Placebo Sotagliflozin 400 mg Sotagliflozin 200 mg Glimepiride
    Number of subjects analysed
    159
    317
    160
    318
    Units: kilogram (kg)
    least squares mean (standard error)
        Week 26
    -1.26 ± 0.329
    -2.75 ± 0.257
    -2.24 ± 0.336
    0.70 ± 0.256
        Week 52
    -0.47 ± 1.406
    -2.64 ± 0.503
    -1.74 ± 0.707
    0.94 ± 0.452
    Statistical analysis title
    		 Placebo, Sotagliflozin 400 mg (Week 26)
    Statistical analysis description
    The change from baseline to Week 26 is analysed using ANCOVA model with treatment groups, randomisation strata of HbA1c (≤ 8.5, >8.5%) at screening, randomisation strata of SBP (<130,≥ 130 mmHg) at screening, and country as fixed effects, and baseline body weight as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    476
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -1.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.173
         upper limit
    		 -0.803
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.349
    Statistical analysis title
    		 Sotagliflozin 400 mg, Glimepiride (Week 52)
    Statistical analysis description
    The change from baseline to Week 52 is analysed using analysis of ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of SBP (<130, ≥130 mmHg) at screening, and country as fixed effects and baseline body weight as a covariate.
    Comparison groups
    Sotagliflozin 400 mg v Glimepiride
    Number of subjects included in analysis
    635
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -3.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.651
         upper limit
    		 -2.517
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.544

    Secondary: Change From Baseline in Systolic Blood Pressure (SBP) for Subjects With SBP ≥130 mmHg at Week 12

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    End point title
    		 Change From Baseline in Systolic Blood Pressure (SBP) for Subjects With SBP ≥130 mmHg at Week 12
    End point description
    Missing data are imputed using washout imputation method. An ANCOVA model was used for the analysis. Analysis was performed on ITT population in subjects with baseline SBP ≥130 mmHg.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo Sotagliflozin 400 mg Sotagliflozin 200 mg Glimepiride
    Number of subjects analysed
    79
    161
    81
    175
    Units: mmHg
        least squares mean (standard error)
    -5.34 ± 1.451
    -8.03 ± 1.064
    -9.12 ± 1.466
    -3.86 ± 1.081
    Statistical analysis title
    		 Sotagliflozin 400 mg, Glimepiride
    Statistical analysis description
    The change from baseline to Week 12 is analysed using ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at screening, and country as fixed effects, and baseline SBP as a covariate.
    Comparison groups
    Sotagliflozin 400 mg v Glimepiride
    Number of subjects included in analysis
    336
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0012
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -4.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.701
         upper limit
    		 -1.65
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.288
    Statistical analysis title
    		 Placebo, Sotagliflozin 400 mg
    Statistical analysis description
    The change from baseline to Week 12 is analysed using ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) 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
    240
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0973
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.89
         upper limit
    		 0.491
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0973

    Secondary: Change From Baseline in Systolic Blood Pressure (SBP) for All Subjects at Week 12

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    End point title
    		 Change From Baseline in Systolic Blood Pressure (SBP) for All Subjects at Week 12
    End point description
    Missing data are imputed using washout imputation method under the missing not at random framework. An ANCOVA model was used for the analysis. ITT population included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo Sotagliflozin 400 mg Sotagliflozin 200 mg Glimepiride
    Number of subjects analysed
    159
    317
    160
    318
    Units: mmHg
        least squares mean (standard error)
    -2.64 ± 1.013
    -4.70 ± 0.791
    -4.77 ± 1.033
    -0.68 ± 0.795
    Statistical analysis title
    		 Sotagliflozin 400 mg, Glimepiride
    Statistical analysis description
    The change from baseline to Week 12 is analysed using ANCOVA model with treatment groups, randomisation strata of HbA1c (≤ 8.5, >8.5%) at screening, and country as fixed effects, and baseline SBP as a covariate.
    Comparison groups
    Sotagliflozin 400 mg v Glimepiride
    Number of subjects included in analysis
    635
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -4.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.73
         upper limit
    		 -2.319
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.87

    Secondary: Percentage of Subjects With At Least One Documented Symptomatic Hypoglycemic Event (≤70 milligrams per decilitre [mg/dL])

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    End point title
    		 Percentage of Subjects With At Least One Documented Symptomatic Hypoglycemic Event (≤70 milligrams per decilitre [mg/dL])
    End point description
    ITT population included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Placebo Sotagliflozin 400 mg Sotagliflozin 200 mg Glimepiride
    Number of subjects analysed
    159
    317
    160
    318
    Units: percentage of subjects
        number (not applicable)
    0.63
    1.26
    3.75
    16.67
    Statistical analysis title
    		 Sotagliflozin 400 mg, Glimepiride
    Statistical analysis description
    Weighted average of percentage difference between treatment groups from each stratum [randomization strata of HbA1c [≤8.5%, >8.5%] at screening, randomisation strata of mean SBP [<130, ≥130 mmHg] at screening using Cochran-Mantel-Haenszel weights.
    Comparison groups
    Glimepiride v Sotagliflozin 400 mg
    Number of subjects included in analysis
    635
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage difference
    Point estimate
    -15.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.67
         upper limit
    		 -11.12

    Secondary: Percentage of Subjects With Adverse Events (AEs)

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    End point title
    		 Percentage of Subjects With Adverse Events (AEs)
    End point description
    An AE is any untoward medical occurrence in a subjects or clinical investigation subject administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. Safety population defined as all randomised subjects who had received at least 1 dose of double-blind investigational medicinal product (IMP).
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Placebo Sotagliflozin 400 mg Sotagliflozin 200 mg Glimepiride
    Number of subjects analysed
    159
    317
    159
    317
    Units: percentage of subjects
        number (not applicable)
    57.2
    59.9
    56.6
    49.2
    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
    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 randomised subjects who received at least 1 dose of double-blind investigational medicinal product (IMP).
    End point type
    Other pre-specified
    End point timeframe
    Up to Week 52
    End point values
    		 Placebo Sotagliflozin 400 mg Sotagliflozin 200 mg Glimepiride
    Number of subjects analysed
    159
    317
    159
    317
    Units: percentage of subjects
    number (not applicable)
        Any hypoglycemia
    2.5
    4.1
    6.3
    25.9
        Documented symptomatic hypoglycemia
    0.6
    1.3
    3.8
    16.7
        Severe or documented symptomatic hypoglycemia
    0.6
    1.3
    3.8
    16.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose of study drug to the last dose of study drug (up to 52 weeks) + 2 weeks
    Adverse event reporting additional description
    Safety population defined as all randomised subjects who had received at least 1 dose of double-blind investigational medicinal product (IMP). 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 period, two Sotagliflozin-matching placebo tablets and two Glimepiride-matching placebo capsules, taken orally once daily before the first meal of the day in the double-blind treatment period up to 52 weeks.

    Reporting group title
    Sotagliflozin 400 mg
    Reporting group description
    		 Following a 2-week run-in period, two Sotagliflozin 200 mg, tablets, and two Glimepiride-matching placebo capsules, taken orally once daily before the first meal of the day in the double-blind treatment period up to 52 weeks.

    Reporting group title
    Sotagliflozin 200 mg
    Reporting group description
    		 Following a 2-week run-in period, one Sotagliflozin 200 mg, tablet and one Sotagliflozin-matching placebo tablet, and two Glimepiride-matching placebo capsules, taken orally once daily before the first meal of the day in the double-blind treatment period up to 52 weeks.

    Reporting group title
    Glimepiride
    Reporting group description
    		 Following a 2-week run-in period, two Sotagliflozin-matching placebo tablets, and combination of two Glimepiride capsules with adequate dose strengths per dose titration (titrated up to 6mg), taken orally once daily before the first meal of the day in the double-blind treatment period up to 52 weeks.

    Serious adverse events
    		 Placebo Sotagliflozin 400 mg Sotagliflozin 200 mg Glimepiride
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 159 (6.92%)
    17 / 317 (5.36%)
    11 / 159 (6.92%)
    14 / 317 (4.42%)
         number of deaths (all causes)
    2
    1
    0
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-cell lymphoma
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    1 / 159 (0.63%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 317 (0.00%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 317 (0.32%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 159 (0.63%)
    1 / 317 (0.32%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal adenocarcinoma
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 317 (0.00%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    0 / 159 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 317 (0.00%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    1 / 159 (0.63%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 317 (0.00%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    1 / 159 (0.63%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 317 (0.00%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Incarcerated hernia
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 317 (0.32%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 317 (0.00%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 159 (1.26%)
    1 / 317 (0.32%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    0 / 159 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Reproductive system and breast disorders
    Adnexa uteri mass
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 317 (0.32%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    0 / 159 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 317 (0.00%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcohol withdrawal syndrome
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 317 (0.32%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    1 / 159 (0.63%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    1 / 159 (0.63%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 317 (0.32%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 317 (0.32%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    0 / 159 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    0 / 159 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    1 / 159 (0.63%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    1 / 159 (0.63%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    1 / 159 (0.63%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 317 (0.32%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 317 (0.32%)
    1 / 159 (0.63%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Tibia fracture
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    1 / 159 (0.63%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular graft stenosis
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 317 (0.32%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute left ventricular failure
         subjects affected / exposed
    1 / 159 (0.63%)
    1 / 317 (0.32%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 317 (0.32%)
    0 / 159 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 317 (0.00%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 317 (0.00%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    1 / 159 (0.63%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 317 (0.32%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    0 / 159 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 317 (0.00%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebellar stroke
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 317 (0.00%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    1 / 159 (0.63%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    1 / 159 (0.63%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 317 (0.00%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal haemorrhage
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 317 (0.32%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 317 (0.32%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    0 / 159 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 317 (0.32%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 317 (0.32%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    0 / 159 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis chronic
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 317 (0.32%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    1 / 159 (0.63%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Cervical spinal stenosis
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    0 / 159 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 317 (0.32%)
    0 / 159 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    1 / 159 (0.63%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    0 / 159 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertebral osteophyte
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    0 / 159 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cholecystitis infective
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 317 (0.32%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 317 (0.32%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    1 / 159 (0.63%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 317 (0.32%)
    0 / 159 (0.00%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    1 / 159 (0.63%)
    2 / 317 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia legionella
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    1 / 159 (0.63%)
    0 / 317 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis chronic
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    0 / 159 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 317 (0.32%)
    1 / 159 (0.63%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 317 (0.32%)
    0 / 159 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    0 / 159 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    0 / 159 (0.00%)
    0 / 317 (0.00%)
    0 / 159 (0.00%)
    1 / 317 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Sotagliflozin 400 mg Sotagliflozin 200 mg Glimepiride
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 159 (18.87%)
    49 / 317 (15.46%)
    21 / 159 (13.21%)
    22 / 317 (6.94%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    11 / 159 (6.92%)
    14 / 317 (4.42%)
    7 / 159 (4.40%)
    12 / 317 (3.79%)
         occurrences all number
    11
    15
    7
    19
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    11 / 159 (6.92%)
    14 / 317 (4.42%)
    8 / 159 (5.03%)
    7 / 317 (2.21%)
         occurrences all number
    13
    17
    8
    7
    Infections and infestations
    Vulvovaginal mycotic infection
         subjects affected / exposed
    2 / 159 (1.26%)
    19 / 317 (5.99%)
    6 / 159 (3.77%)
    2 / 317 (0.63%)
         occurrences all number
    2
    26
    9
    2
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    8 / 159 (5.03%)
    5 / 317 (1.58%)
    2 / 159 (1.26%)
    2 / 317 (0.63%)
         occurrences all number
    9
    5
    2
    3

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Sep 2017
    The overall reason for this amendment was to update •Changed the EudraCT number •Replaced another objective “Change in SBP for patients with baseline SBP <130 mmHg” with "Changed in SBP for all patients, the subset with baseline SBP <130 mmHg, and the subset with baseline SBP ≥130 mmHg" •Removed requirements for hepatitis serology tests at screening and the related exclusion criterion •Changes in exclusion assessment •Change to the exclusion criteria and guidance on contraceptive methods. Removed urgent coronary revascularizations from the events subject to the Clinical Endpoint Committees (CECs) review
    09 Apr 2018
    The overall reason for this amendment was to •Change to exclusion criterion E18 regarding the use of a selective sodium-glucose transporters (SGLT2) inhibitor •Change to guidance on contraceptive methods •Addition of a new section to describe the independent safety assessments for drug-induced liver injuries (DILI) and amputation •Change to a urine laboratory test.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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