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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo-controlled, Parallel-group, 52-week Multicenter Study to Evaluate the Efficacy and Safety of Sotagliflozin in Patients with Type 2 Diabetes Who Have Inadequate Glycemic Control on Basal Insulin Alone or in Addition to Oral Antidiabetes Drugs (OADs)

    Summary
    EudraCT number
    		 2016-001804-43
    Trial protocol
    		 GB   HU   CZ   SK   BG  
    Global end of trial date
    27 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
    EFC14868
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03285594
    WHO universal trial number (UTN)
    		 U1111-1190-7567
    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
    27 Sep 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Sep 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the superiority of sotagliflozin 400 milligram (mg) versus placebo with respect to hemoglobin A1C (HbA1c) reduction at week 18 in subjects with type 2 diabetes mellitus (T2D) who had inadequate glycemic control on basal insulin alone or with oral antidiabetes drugs (OADs).
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 Subjects were taking up to any 2 OADs which may include metformin at a stable dosage >=1500 milligrams per day (mg/day) or the maximum tolerated dose (documented).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Sep 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
    Canada: 29
    Country: Number of subjects enrolled
    United States: 279
    Country: Number of subjects enrolled
    Slovakia: 77
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Bulgaria: 57
    Country: Number of subjects enrolled
    Czech Republic: 49
    Country: Number of subjects enrolled
    France: 30
    Country: Number of subjects enrolled
    Hungary: 46
    Worldwide total number of subjects
    571
    EEA total number of subjects
    263
    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)
    312
    From 65 to 84 years
    257
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects took part in the study at 101 investigative sites in the United States, Bulgaria, Canada, Czech Republic, France, Hungary, Slovakia, the United Kingdom from 15 September 2017 to 27 September 2019.

    Pre-assignment
    Screening details
    		 Subjects with a diagnosis of Type 2 Diabetes Mellitus were enrolled in 1 of 3 treatment groups, placebo, sotagliflozin 200 mg and sotagliflozin 400 mg. Subjects were randomised at a ratio of 1:1:2 respectively to 1 of 3 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
    		 Investigator, Monitor, Data analyst, Carer, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Following a 4-week run-in period, subjects were randomised to receive matching placebo to sotagliflozin 200 mg administered as 2 tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 55.7 weeks. Background therapy with insulin glargine (with or without OADs) continued throughout the study.
    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 2 tablets (identical to the sotagliflozin 200 mg tablet in appearance), once daily, before the first meal of the day.

    Investigational medicinal product name
    Insulin glargine
    Investigational medicinal product code
    Other name
    HOE901
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Insulin glargine was administered either in the morning or evening, following the Investigator’s advice.

    Arm title
    		 Sotagliflozin 200 mg
    Arm description
    		 Following a 4-week run-in period, subjects were randomised to sotagliflozin 200 mg administered as 1 tablet and matching placebo as 1 tablet, once daily, before the first meal of the day in the double-blind treatment period for up to 54.7 weeks. Background therapy with insulin glargine (with or without OADs) continued throughout the study.
    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 200 mg administered as 1 tablet, 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 was administered as 1 tablet (identical to the sotagliflozin 200 mg tablet in appearance), once daily, before the first meal of the day.

    Investigational medicinal product name
    Insulin glargine
    Investigational medicinal product code
    Other name
    HOE901
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Insulin glargine was administered either in the morning or evening, following the Investigator’s advice.

    Arm title
    		 Sotagliflozin 400 mg
    Arm description
    		 Following a 4-week run-in period, subjects were randomised to sotagliflozin 400 mg administered as 2 tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 54.6 weeks. Background therapy with insulin glargine (with or without OADs) continued throughout the study.
    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 200 mg administered as 2 tablets, once daily, before the first meal of the day.

    Investigational medicinal product name
    Insulin glargine
    Investigational medicinal product code
    Other name
    HOE901
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Insulin glargine was administered either in the morning or evening, following the Investigator’s advice.

    Number of subjects in period 1
    		Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Started
    144
    141
    286
    Treated
    144
    141
    285
    Completed
    129
    130
    249
    Not completed
    15
    11
    37
         At the subject's own request
    10
    5
    21
         Adverse event
    2
    2
    6
         Poor compliance to protocol
    -
    -
    1
         Reason not specified
    3
    4
    8
         Lost to follow-up
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Following a 4-week run-in period, subjects were randomised to receive matching placebo to sotagliflozin 200 mg administered as 2 tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 55.7 weeks. Background therapy with insulin glargine (with or without OADs) continued throughout the study.

    Reporting group title
    Sotagliflozin 200 mg
    Reporting group description
    		 Following a 4-week run-in period, subjects were randomised to sotagliflozin 200 mg administered as 1 tablet and matching placebo as 1 tablet, once daily, before the first meal of the day in the double-blind treatment period for up to 54.7 weeks. Background therapy with insulin glargine (with or without OADs) continued throughout the study.

    Reporting group title
    Sotagliflozin 400 mg
    Reporting group description
    		 Following a 4-week run-in period, subjects were randomised to sotagliflozin 400 mg administered as 2 tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 54.6 weeks. Background therapy with insulin glargine (with or without OADs) continued throughout the study.

    Reporting group values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg Total
    Number of subjects
    		 144 141 286 571
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.2 ( 8.9 ) 62.1 ( 10.2 ) 62.7 ( 9.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 58 65 132 255
        Male
    		 86 76 154 316
    Race
    Units: Subjects
        White
    		 117 124 234 475
        Black or African American
    		 10 10 27 47
        Asian
    		 9 1 6 16
        American Indian or Alaska Native
    		 2 1 2 5
        Native Hawaiian or Other Pacific Islander
    		 0 0 3 3
        Multiple
    		 1 0 1 2
        Not reported
    		 5 4 12 21
        Unknown
    		 0 1 1 2
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 12 25 42 79
        Not Hispanic or Latino
    		 129 113 239 481
        Not reported
    		 2 2 4 8
        Unknown
    		 1 1 1 3
    Hemoglobin A1c (HbA1c)
    Units: percentage of HbA1c
        arithmetic mean (standard deviation)
    		 8.76 ( 0.79 ) 8.76 ( 0.83 ) 8.69 ( 0.80 ) -
    Systolic Blood Pressure (SBP)
    Units: millimetre of Mercury (mmHg)
        arithmetic mean (standard deviation)
    		 137.59 ( 14.12 ) 136.40 ( 15.54 ) 135.84 ( 14.95 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Following a 4-week run-in period, subjects were randomised to receive matching placebo to sotagliflozin 200 mg administered as 2 tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 55.7 weeks. Background therapy with insulin glargine (with or without OADs) continued throughout the study.

    Reporting group title
    Sotagliflozin 200 mg
    Reporting group description
    		 Following a 4-week run-in period, subjects were randomised to sotagliflozin 200 mg administered as 1 tablet and matching placebo as 1 tablet, once daily, before the first meal of the day in the double-blind treatment period for up to 54.7 weeks. Background therapy with insulin glargine (with or without OADs) continued throughout the study.

    Reporting group title
    Sotagliflozin 400 mg
    Reporting group description
    		 Following a 4-week run-in period, subjects were randomised to sotagliflozin 400 mg administered as 2 tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 54.6 weeks. Background therapy with insulin glargine (with or without OADs) continued throughout the study.

    Primary: Change from Baseline in Hemoglobin A1c (HbA1c) at Week 18

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    End point title
    		 Change from Baseline in Hemoglobin A1c (HbA1c) at Week 18
    End point description
    Intent-to-treat (ITT) population included all randomised subjects irrespective of compliance with the study protocol and procedures. Missing data was imputed using washout multiple imputation under the missing not at random framework. An analysis of covariance (ANCOVA) model was used for the analysis.
    End point type
    Primary
    End point timeframe
    Baseline and Week 18
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    144
    141
    286
    Units: percentage of HbA1c
        least squares mean (standard error)
    -0.27 ( 0.073 )
    -0.72 ( 0.073 )
    -0.81 ( 0.056 )
    Statistical analysis title
    		 Sotagliflozin 200 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 18 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at Week -1, randomisation strata of mean SBP (<130, ≥130 mmHg) at Week -1, randomisation strata of sulfonylureas use (yes, no) at Week -1, and country as fixed effects, and baseline HbA1c as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 200 mg
    Number of subjects included in analysis
    285
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in Least Square (LS) Means
    Point estimate
    -0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.638
         upper limit
    		 -0.271
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.094
    Statistical analysis title
    		 Sotagliflozin 400 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 18 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at Week -1, randomisation strata of mean SBP (<130, ≥130 mmHg) at Week -1, randomisation strata of sulfonylureas use (yes, no) at Week -1, and country as fixed effects, and baseline HbA1c as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    430
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.706
         upper limit
    		 -0.387
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.081

    Secondary: Change from Baseline in Fasting Plasma Glucose (FPG) at Week 18

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    End point title
    		 Change from Baseline in Fasting Plasma Glucose (FPG) at Week 18
    End point description
    FPG was performed in fasting state, that is, without any food intake (except for water) for at least 8 hours. ITT population included all randomised subjects irrespective of compliance with the study protocol and procedures. Missing data was imputed using washout multiple imputation method under the missing not at random framework. An ANCOVA model was used for the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 18
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    144
    141
    286
    Units: milligram per decilitre (mg/dL)
        least squares mean (standard error)
    12.882 ( 3.6045 )
    -2.975 ( 3.6083 )
    -8.949 ( 2.7550 )
    Statistical analysis title
    		 Sotagliflozin 200 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 18 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at Week -1, randomisation strata of mean SBP (<130, ≥130 mmHg) at Week -1, randomisation strata of sulfonylureas use (yes, no) at Week -1, and country as fixed effects, and baseline FPG as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 200 mg
    Number of subjects included in analysis
    285
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0006
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -15.858
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.8845
         upper limit
    		 -6.8309
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.6056
    Statistical analysis title
    		 Sotagliflozin 400 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 18 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at Week -1, randomisation strata of mean SBP (<130, ≥130 mmHg) at Week -1, randomisation strata of sulfonylureas use (yes, no) at Week -1, and country as fixed effects, and baseline FPG as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    430
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -21.832
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -29.7725
         upper limit
    		 -13.8911
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.0514

    Secondary: Change from Baseline in Body Weight at Week 18

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    End point title
    		 Change from Baseline in Body Weight at Week 18
    End point description
    ITT population included all randomised subjects irrespective of compliance with the study protocol and procedures. Missing data was imputed using washout multiple imputation under the missing not at random framework. An ANCOVA model was used for the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 18
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    144
    141
    286
    Units: kilogram (kg)
        least squares mean (standard error)
    0.36 ( 0.249 )
    -0.73 ( 0.250 )
    -1.37 ( 0.190 )
    Statistical analysis title
    		 Sotagliflozin 200 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 18 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at Week -1, randomisation strata of mean SBP (<130, ≥130 mmHg) at Week -1, randomisation strata of sulfonylureas use (yes, no) at Week -1, and country as fixed effects, and baseline body weight as a covariate.
    Comparison groups
    Sotagliflozin 200 mg v Placebo
    Number of subjects included in analysis
    285
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0007
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.716
         upper limit
    		 -0.462
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.32
    Statistical analysis title
    		 Sotagliflozin 400 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 18 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at Week -1, randomisation strata of mean SBP (<130, ≥130 mmHg) at Week -1, randomisation strata of sulfonylureas use (yes, no) at Week -1, 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
    430
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.274
         upper limit
    		 -1.183
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.278

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

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    End point title
    		 Change from Baseline in Systolic Blood Pressure (SBP) for Subjects with Baseline SBP ≥130 mmHg at Week 12
    End point description
    Analysis population included subjects with baseline SBP ≥ 130 mmHg in ITT population where, ITT population included all randomized subjects irrespective of compliance with the study protocol and procedures. Missing data was imputed using washout multiple imputation under the missing not at random framework. An ANCOVA model was used for the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    88
    92
    171
    Units: mmHg
        least squares mean (standard error)
    -4.67 ( 1.470 )
    -8.58 ( 1.447 )
    -8.50 ( 1.103 )
    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 Week -1, randomisation strata of sulfonylureas use (yes, no) at Week -1, and country as fixed effects, and baseline SBP as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 200 mg
    Number of subjects included in analysis
    180
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.04
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -3.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.642
         upper limit
    		 -0.178
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.904
    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 Week -1, randomisation strata of sulfonylureas use (yes, no) at Week -1, and country as fixed effects, and baseline SBP as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    259
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0239
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -3.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.161
         upper limit
    		 -0.507
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.697

    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
    ITT population included all randomised subjects irrespective of compliance with the study protocol and procedures. Missing data was imputed using washout multiple imputation under the missing not at random framework. An ANCOVA model was used for the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    144
    141
    286
    Units: mmHg
        least squares mean (standard error)
    -0.21 ( 1.120 )
    -5.15 ( 1.117 )
    -4.10 ( 0.867 )
    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 Week -1, randomisation strata of mean SBP (<130, ≥130 mmHg) at Week -1, randomisation strata of sulfonylureas use (yes, no) at Week -1, and country as fixed effects, and baseline SBP as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 200 mg
    Number of subjects included in analysis
    285
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in LS Means
    Point estimate
    -4.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.73
         upper limit
    		 -2.142
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.425
    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 Week -1, randomisation strata of mean SBP (<130, ≥130 mmHg) at Week -1, randomisation strata of sulfonylureas use (yes, no) at Week -1, and country as fixed effects, and baseline SBP as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    430
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0018
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -3.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.333
         upper limit
    		 -1.448
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.246

    Secondary: Change from Baseline in HbA1c at Week 52

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    End point title
    		 Change from Baseline in HbA1c at Week 52
    End point description
    ITT population included all randomised subjects irrespective of compliance with the study protocol and procedures. Missing data was imputed using washout multiple imputation under the missing not at random framework. An ANCOVA model was used for the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    144
    141
    286
    Units: percentage of HbA1c
        least squares mean (standard error)
    0.00 ( 0.279 )
    -0.52 ( 0.152 )
    -0.57 ( 0.114 )
    Statistical analysis title
    		 Sotagliflozin 200 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 52 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at Week -1, randomisation strata of mean SBP (<130, ≥130 mmHg) at Week -1, randomisation strata of sulfonylureas use (yes, no) at Week -1, and country as fixed effects, and baseline HbA1c as a covariate.
    Comparison groups
    Sotagliflozin 200 mg v Placebo
    Number of subjects included in analysis
    285
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1265
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.185
         upper limit
    		 0.147
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.34
    Statistical analysis title
    		 Sotagliflozin 400 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 52 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at Week -1, randomisation strata of mean SBP (<130, ≥130 mmHg) at Week -1, randomisation strata of sulfonylureas use (yes, no) at Week -1, and country as fixed effects, and baseline HbA1c as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    430
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.074
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.199
         upper limit
    		 0.055
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.32

    Secondary: Change from Baseline in Body Weight at Week 52

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    End point title
    		 Change from Baseline in Body Weight at Week 52
    End point description
    ITT population included all randomised subjects irrespective of compliance with the study protocol and procedures. Missing data was imputed using washout multiple imputation under the missing not at random framework. An ANCOVA model was used for the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    144
    141
    286
    Units: kg
        least squares mean (standard error)
    -0.18 ( 0.579 )
    -1.19 ( 0.620 )
    -0.83 ( 0.374 )
    Statistical analysis title
    		 Sotagliflozin 200 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 52 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at Week -1, randomisation strata of mean SBP (<130, ≥130 mmHg) at Week -1, randomisation strata of sulfonylureas use (yes, no) at Week -1, and country as fixed effects, and baseline body weight as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 200 mg
    Number of subjects included in analysis
    285
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2466
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.707
         upper limit
    		 0.696
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.868
    Statistical analysis title
    		 Sotagliflozin 400 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 52 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at Week -1, randomisation strata of mean SBP (<130, ≥130 mmHg) at Week -1, randomisation strata of sulfonylureas use (yes, no) at Week -1, 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
    430
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.332
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.969
         upper limit
    		 0.665
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.672

    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 subjects administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. Safety population included all randomised subjects who received at least 1 dose of double-blind investigational medicinal product (IMP) (regardless of the amount of treatment administered).
    End point type
    Secondary
    End point timeframe
    First dose of study drug to last dose of study drug (up to 55.7 weeks) + 2 weeks
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    144
    141
    285
    Units: percentage of subjects
        number (not applicable)
    64.6
    54.6
    59.3
    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) (regardless of the amount of treatment administered).
    End point type
    Other pre-specified
    End point timeframe
    Up to 55.7 weeks
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    144
    141
    285
    Units: percentage of subjects
    number (not applicable)
        Any hypoglycemia
    62.5
    56
    62.8
        Documented symptomatic hypoglycemia
    44.4
    41.8
    46
        Severe or documented symptomatic hypoglycemia
    44.4
    41.8
    46
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Deaths: Up to approximately 60 weeks; Adverse Events: First dose of study drug to last dose of study drug (up to 55.7 weeks) + 2 weeks
    Adverse event reporting additional description
    Safety population included all randomised subjects who had received at least 1 dose of double-blind investigational medicinal product (regardless of the amount of treatment administered). 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 4-week run-in period, subjects were randomised to receive matching placebo to sotagliflozin 200 mg administered as 2 tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 55.7 weeks. Background therapy with insulin glargine (with or without OADs) continued throughout the study.

    Reporting group title
    Sotagliflozin 200 mg
    Reporting group description
    		 Following a 4-week run-in period, subjects were randomised to sotagliflozin 200 mg administered as 1 tablet and matching placebo as 1 tablet, once daily, before the first meal of the day in the double-blind treatment period for up to 54.7 weeks. Background therapy with insulin glargine (with or without OADs) continued throughout the study.

    Reporting group title
    Sotagliflozin 400 mg
    Reporting group description
    		 Following a 4-week run-in period, subjects were randomised to sotagliflozin 400 mg administered as 2 tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 54.6 weeks. Background therapy with insulin glargine (with or without OADs) continued throughout the study.

    Serious adverse events
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 144 (11.11%)
    19 / 141 (13.48%)
    28 / 285 (9.82%)
         number of deaths (all causes)
    2
    1
    6
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma pancreas
         subjects affected / exposed
    0 / 144 (0.00%)
    1 / 141 (0.71%)
    0 / 285 (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
    B-cell lymphoma
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 141 (0.00%)
    0 / 285 (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
    Basal cell carcinoma
         subjects affected / exposed
    1 / 144 (0.69%)
    1 / 141 (0.71%)
    0 / 285 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Metastases to bone
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Prostate cancer
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         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
         subjects affected / exposed
    0 / 144 (0.00%)
    1 / 141 (0.71%)
    0 / 285 (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
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         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 / 144 (0.00%)
    1 / 141 (0.71%)
    0 / 285 (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
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         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 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 141 (0.00%)
    0 / 285 (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
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         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 oedema
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         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
    0 / 144 (0.00%)
    1 / 141 (0.71%)
    0 / 285 (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
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Jaw fracture
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative thrombosis
         subjects affected / exposed
    0 / 144 (0.00%)
    1 / 141 (0.71%)
    0 / 285 (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
    Subdural haematoma
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 141 (0.00%)
    0 / 285 (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
    Tendon injury
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 141 (0.00%)
    0 / 285 (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 / 144 (1.39%)
    0 / 141 (0.00%)
    2 / 285 (0.70%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 144 (0.69%)
    1 / 141 (0.71%)
    0 / 285 (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
    Atrial fibrillation
         subjects affected / exposed
    3 / 144 (2.08%)
    0 / 141 (0.00%)
    0 / 285 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 144 (0.00%)
    1 / 141 (0.71%)
    0 / 285 (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
    Cardiac arrest
         subjects affected / exposed
    0 / 144 (0.00%)
    1 / 141 (0.71%)
    0 / 285 (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
    Cardiac failure
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 141 (0.00%)
    0 / 285 (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
    0 / 144 (0.00%)
    1 / 141 (0.71%)
    0 / 285 (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
    Cardiac failure congestive
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    2 / 285 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    0 / 144 (0.00%)
    1 / 141 (0.71%)
    0 / 285 (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
    Left ventricular failure
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 141 (0.00%)
    0 / 285 (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
    Reperfusion arrhythmia
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         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
    Cervicobrachial syndrome
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 141 (0.00%)
    0 / 285 (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
    Hypoglycaemic unconsciousness
         subjects affected / exposed
    0 / 144 (0.00%)
    1 / 141 (0.71%)
    0 / 285 (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 / 144 (0.69%)
    1 / 141 (0.71%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         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
    Retinal artery thrombosis
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinopathy proliferative
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    0 / 144 (0.00%)
    1 / 141 (0.71%)
    0 / 285 (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
    Pancreatitis chronic
         subjects affected / exposed
    0 / 144 (0.00%)
    1 / 141 (0.71%)
    0 / 285 (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
    Enlarged uvula
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 141 (0.00%)
    0 / 285 (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
    Hepatobiliary disorders
    Biliary dyskinesia
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         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
    Nephrolithiasis
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal haematoma
         subjects affected / exposed
    0 / 144 (0.00%)
    1 / 141 (0.71%)
    0 / 285 (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
    Urethral stenosis
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 144 (0.00%)
    2 / 141 (1.42%)
    0 / 285 (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
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 141 (0.00%)
    0 / 285 (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
    Bursitis
         subjects affected / exposed
    0 / 144 (0.00%)
    1 / 141 (0.71%)
    0 / 285 (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
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 144 (0.00%)
    1 / 141 (0.71%)
    0 / 285 (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
    Infected bite
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis acute
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 141 (0.00%)
    0 / 285 (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
    Pyelonephritis chronic
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         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 abscess
         subjects affected / exposed
    0 / 144 (0.00%)
    1 / 141 (0.71%)
    0 / 285 (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
    Scrotal abscess
         subjects affected / exposed
    1 / 144 (0.69%)
    0 / 141 (0.00%)
    0 / 285 (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
    Urinary tract infection
         subjects affected / exposed
    0 / 144 (0.00%)
    1 / 141 (0.71%)
    0 / 285 (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
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 144 (0.00%)
    1 / 141 (0.71%)
    0 / 285 (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
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic metabolic decompensation
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 144 (0.00%)
    0 / 141 (0.00%)
    1 / 285 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 144 (0.00%)
    1 / 141 (0.71%)
    0 / 285 (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
    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
    30 / 144 (20.83%)
    18 / 141 (12.77%)
    45 / 285 (15.79%)
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 144 (4.86%)
    9 / 141 (6.38%)
    14 / 285 (4.91%)
         occurrences all number
    9
    9
    15
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 144 (5.56%)
    1 / 141 (0.71%)
    14 / 285 (4.91%)
         occurrences all number
    10
    1
    17
    Urinary tract infection
         subjects affected / exposed
    8 / 144 (5.56%)
    6 / 141 (4.26%)
    11 / 285 (3.86%)
         occurrences all number
    11
    6
    16
    Metabolism and nutrition disorders
    Vitamin D deficiency
         subjects affected / exposed
    9 / 144 (6.25%)
    4 / 141 (2.84%)
    10 / 285 (3.51%)
         occurrences all number
    9
    4
    10

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Sep 2017
    Amendment 2: 1. Change to the exclusion criteria and guidance on contraceptive methods. 2. Change to the exclusion criteria and temporary IMP discontinuation. 3. Change to exclusion assessment. 4. Change to the general guidelines for reporting of adverse events. 5. Change to the events for Clinical Endpoint Committee (CEC) adjudication. 6. Changes to the observation period for safety endpoints. 7. Change to hepatitis serology test at screening and related exclusion. 8. Change to code breaking related to pharmacokinetic (PK) laboratory. 9. Change to the definition of one events of special interest (EOSI) “volume depletion”. 10. Change to definition of baseline. 11. Change to instruction for blood pressure measurement. 12. Change to other study objectives and other endpoints. 13. Change to urine laboratory test. 14. Other minor changes for corrections of inconsistency or administration clarification.
    06 Mar 2018
    Amendment 3: 1. New secondary objectives are added to evaluate the long-term efficacy of sotagliflozin based on HbA1c reduction over 52 weeks of treatment. 2. Corresponding to the additional secondary objectives, new secondary endpoints are added to assess these objectives. 3. Addition of a new section to describe the independent safety assessments for drug-induced liver injuries (DILI) and amputation. 4. Change to the description of the continuous glucose monitoring (CGM) sub-study. 5. Change to exclusion criterion E15. 6. Change to the non-investigational medicinal product (NIMP) Lantus dosing regimen. 7. 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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