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    Clinical Trial Results:
    A 26-week Randomized, Double-blind, Controlled, Parallel-group, Multicenter Study to Evaluate the Efficacy and Safety of Sotagliflozin compared to Empagliflozin, and Placebo in Patients with Type 2 Diabetes Who Have Inadequate Glycemic Control on Dipeptidyl Peptidase 4 Inhibitor (DPP4(i)) With or Without Metformin

    Summary
    EudraCT number
    		 2016-001803-22
    Trial protocol
    		 GB   CZ   ES   LV   SK   BG   FR   IT  
    Global end of trial date
    16 May 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Jun 2020
    First version publication date
    01 Jun 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    EFC14867
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03351478
    WHO universal trial number (UTN)
    		 U1111-1190-7607
    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
    16 May 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 May 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the superiority of sotagliflozin versus placebo on hemoglobin A1c (HbA1c) reduction in subjects with type 2 diabetes (T2D) who have inadequate glycemic control on a Dipeptidyl Peptidase 4 Inhibitor (DPP4(i)) with or without metformin.
    Protection of trial subjects
    All study subjects were required to read and sign an informed consent form (ICF).
    Background therapy
    		 Subjects were enrolled with a background therapy consisting of their existing dipeptidyl peptidase 4 inhibitor (DPP4[i]) treatment and metformin treatment.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Nov 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: 73
    Country: Number of subjects enrolled
    Spain: 29
    Country: Number of subjects enrolled
    United Kingdom: 16
    Country: Number of subjects enrolled
    Bulgaria: 59
    Country: Number of subjects enrolled
    Czech Republic: 126
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Latvia: 42
    Country: Number of subjects enrolled
    Canada: 59
    Country: Number of subjects enrolled
    Italy: 20
    Country: Number of subjects enrolled
    Mexico: 87
    Country: Number of subjects enrolled
    Russian Federation: 104
    Country: Number of subjects enrolled
    United States: 148
    Worldwide total number of subjects
    770
    EEA total number of subjects
    372
    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)
    539
    From 65 to 84 years
    230
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects took part in the study at 160 investigative sites in Bulgaria, Canada, Czechia, France, Italy, Latvia, Mexico, Russian Federation, Slovakia, Spain, United Kingdom and the United States from 27 November 2017 to 16 May 2019

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

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sotagliflozin 400 mg
    Arm description
    		 Following a 2-week run-in period, sotagliflozin 400 mg (milligrams) administered as two 200 mg tablets and one placebo capsule (identical to empagliflozin capsule in appearance), once daily before the first meal of the day for up to 26 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sotagliflozin
    Investigational medicinal product code
    Other name
    SAR439954
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sotagliflozin 400 mg was administered as two 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
    Placebo was administered as one capsule (identical to the empagliflozin capsule in appearance), once daily before the first meal of the day.

    Arm title
    		 Empagliflozin 25 mg
    Arm description
    		 Following a 2-week run-in period, placebo matching sotagliflozin administered as two tablets (identical to sotagliglozin in appearance) and one capsule of empagliflozin 25 mg, once daily before the first meal of the day for up to 26 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Empagliflozin 25 mg capsule was administered, 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 two tablets (identical to sotagliflozin in appearance), once daily before the first meal of the day.

    Arm title
    		 Placebo
    Arm description
    		 Following a 2-week run-in period, placebo given as two placebo tablets (identical to sotagliflozin) and one placebo capsule (identical to empagliflozin) once daily before the first meal of the day for up to 26 weeks.
    Arm type
    		 Placebo comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was administered as one capsule (identical to the empagliflozin capsule in appearance), 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 two tablets (identical to sotagliflozin in appearance), once daily before the first meal of the day.

    Number of subjects in period 1
    		Sotagliflozin 400 mg Empagliflozin 25 mg Placebo
    Started
    307
    309
    154
    Completed
    293
    292
    147
    Not completed
    14
    17
    7
         At the subject's own request
    11
    12
    5
         Adverse event
    1
    2
    1
         Poor compliance to protocol
    1
    -
    -
         Lost to follow-up
    -
    -
    1
         Reason not Specified
    1
    3
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sotagliflozin 400 mg
    Reporting group description
    		 Following a 2-week run-in period, sotagliflozin 400 mg (milligrams) administered as two 200 mg tablets and one placebo capsule (identical to empagliflozin capsule in appearance), once daily before the first meal of the day for up to 26 weeks.

    Reporting group title
    Empagliflozin 25 mg
    Reporting group description
    		 Following a 2-week run-in period, placebo matching sotagliflozin administered as two tablets (identical to sotagliglozin in appearance) and one capsule of empagliflozin 25 mg, once daily before the first meal of the day for up to 26 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Following a 2-week run-in period, placebo given as two placebo tablets (identical to sotagliflozin) and one placebo capsule (identical to empagliflozin) once daily before the first meal of the day for up to 26 weeks.

    Reporting group values
    		 Sotagliflozin 400 mg Empagliflozin 25 mg Placebo Total
    Number of subjects
    		 307 309 154 770
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.9 ± 9.7 59.7 ± 9.6 59.8 ± 9.6 -
    Gender categorical
    Units: Subjects
        Female
    		 141 158 75 374
        Male
    		 166 151 79 396
    Race
    Units: Subjects
        White
    		 256 257 137 650
        Black or African American
    		 13 13 5 31
        Asian
    		 17 11 4 32
        American Indian or Alaska Native
    		 18 21 8 47
        Native Hawaiian or other Pacific Islander
    		 2 0 0 2
        Multiple
    		 0 1 0 1
        Not Reported
    		 1 6 0 7
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 56 66 33 155
        Not Hispanic or Latino
    		 251 243 121 615
    Hemoglobin A1c (HbA1c)
    Units: percentage of HBA1c
        arithmetic mean (standard deviation)
    		 8.23 ± 0.84 8.21 ± 0.93 8.21 ± 0.93 -
    Systolic Blood Pressure (SBP)
    Units: Millimetre of Mercury (mmHg)
        arithmetic mean (standard deviation)
    		 134.55 ± 13.56 131.64 ± 12.18 133.19 ± 12.53 -

    End points

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    End points reporting groups
    Reporting group title
    Sotagliflozin 400 mg
    Reporting group description
    		 Following a 2-week run-in period, sotagliflozin 400 mg (milligrams) administered as two 200 mg tablets and one placebo capsule (identical to empagliflozin capsule in appearance), once daily before the first meal of the day for up to 26 weeks.

    Reporting group title
    Empagliflozin 25 mg
    Reporting group description
    		 Following a 2-week run-in period, placebo matching sotagliflozin administered as two tablets (identical to sotagliglozin in appearance) and one capsule of empagliflozin 25 mg, once daily before the first meal of the day for up to 26 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Following a 2-week run-in period, placebo given as two placebo tablets (identical to sotagliflozin) and one placebo capsule (identical to empagliflozin) once daily before the first meal of the day for up to 26 weeks.

    Primary: Change from Baseline in Hemoglobin A1c (HbA1c) % at Week 26

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    End point title
    		 Change from Baseline in Hemoglobin A1c (HbA1c) % at Week 26
    End point description
    Intent-to-treat (ITT) population included all randomised subjects. Missing data are imputed using the retrieved dropouts imputation method. An analysis of covariance (ANCOVA) model was used for the analysis.
    End point type
    Primary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Sotagliflozin 400 mg Empagliflozin 25 mg Placebo
    Number of subjects analysed
    307
    309
    154
    Units: percentage of HbA1c
        least squares mean (standard error)
    -0.7 ± 0.1
    -0.8 ± 0.1
    -0.3 ± 0.1
    Statistical analysis title
    		 Sotagliflozin vs Placebo
    Statistical analysis description
    The change from baseline to Week 26 is analysed using an ANCOVA model using multiple imputations to fill in missing data and is parameterised with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of metformin use at screening (Yes, No), randomisation strata of mean SBP (<130, ≥130 mmHg) at screening, and country as fixed effects, and baseline HbA1c as a covariate.
    Comparison groups
    Sotagliflozin 400 mg v Placebo
    Number of subjects included in analysis
    461
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in Least Square (LS) Means
    Point estimate
    -0.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.62
         upper limit
    		 -0.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.09
    Statistical analysis title
    		 Sotagliflozin vs Empagliflozin
    Statistical analysis description
    The change from baseline to Week 26 is analysed using an ANCOVA model using multiple imputations to fill in missing data and is parameterised with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of metformin use at screening (Yes, No), randomisation strata of mean SBP (<130, ≥130 mmHg) at screening, and country as fixed effects, and baseline HbA1c as a covariate.
    Comparison groups
    Sotagliflozin 400 mg v Empagliflozin 25 mg
    Number of subjects included in analysis
    616
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.145
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.28
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.08

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

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    End point title
    		 Change from Baseline in Sitting Systolic Blood Pressure (SBP) at Week 12 in Subjects with Baseline SBP ≥ 130 Millimeter of Mercury (mmHg)
    End point description
    Subjects from the ITT population, all randomised subjects with data available at the given time point for analysis. Missing data are imputed using washout imputation method. An ANCOVA model was used for the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Sotagliflozin 400 mg Empagliflozin 25 mg Placebo
    Number of subjects analysed
    146 [1]
    151 [2]
    84 [3]
    Units: mmHg
        least squares mean (standard error)
    -5.6 ± 1.3
    -6.7 ± 1.3
    -3.5 ± 1.5
    Notes
    [1] - Number analysed is the number of subjects evaluated for the endpoint.
    [2] - Number analysed is the number of subjects evaluated for the endpoint.
    [3] - Number analysed is the number of subjects evaluated for the endpoint.
    Statistical analysis title
    		 Sotagliflozin vs Placebo
    Statistical analysis description
    The change from baseline to Week 12 is analysed using an ANCOVA model using multiple imputations to fill in missing data and is parameterised with treatment groups, randomisation strata of HbA1c (≤ 8.5, >8.5%) at screening, randomisation strata of metformin use at screening (Yes, No) and country as fixed effects, and baseline SBP as a covariate.
    Comparison groups
    Sotagliflozin 400 mg v Placebo
    Number of subjects included in analysis
    230
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1529
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -2.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.87
         upper limit
    		 0.76
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.43
    Statistical analysis title
    		 Sotagliflozin vs Empagliflozin
    Statistical analysis description
    The change from baseline to Week 12 is analysed using an ANCOVA model using multiple imputations to fill in missing data and is parameterised with treatment groups, randomisation strata of HbA1c (≤ 8.5, >8.5%) at screening, randomisation strata of metformin use at screening (Yes, No) and country as fixed effects, and baseline SBP as a covariate.
    Comparison groups
    Empagliflozin 25 mg v Sotagliflozin 400 mg
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3377
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    1.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.21
         upper limit
    		 3.55
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.21

    Secondary: Change from Baseline in 2-hour Postprandial Glucose (PPG) following a Mixed Meal at Week 26

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    End point title
    		 Change from Baseline in 2-hour Postprandial Glucose (PPG) following a Mixed Meal at Week 26
    End point description
    ITT population included all randomised subjects. Missing data are imputed using washout 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, Week 26
    End point values
    		 Sotagliflozin 400 mg Empagliflozin 25 mg Placebo
    Number of subjects analysed
    307
    309
    154
    Units: millimole per litre (mmol/L)
        least squares mean (standard error)
    -1.3 ± 0.2
    -1.2 ± 0.9
    -0.4 ± 0.2
    Statistical analysis title
    		 Sotagliflozin vs Placebo
    Statistical analysis description
    The change from baseline to Week 26 is analysed using an ANCOVA model using multiple imputations to fill in missing data and is parameterized with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of metformin use at screening (Yes, No), randomisation strata of mean SBP (<130, ≥130 mmHg) at screening, and country as fixed effects, and baseline 2-hour postprandial glucose as a covariate.
    Comparison groups
    Sotagliflozin 400 mg v Placebo
    Number of subjects included in analysis
    461
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.33
         upper limit
    		 -0.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.21
    Statistical analysis title
    		 Sotagliflozin vs Empagliflozin
    Statistical analysis description
    The change from baseline to Week 26 is analysed using an ANCOVA model using multiple imputations to fill in missing data and is parameterised with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of metformin use at screening (Yes, No), randomisation strata of mean SBP (<130, ≥ 130 mmHg) at screening, and country as fixed effects, and baseline 2-hour postprandial glucose as a covariate.
    Comparison groups
    Empagliflozin 25 mg v Sotagliflozin 400 mg
    Number of subjects included in analysis
    616
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8397
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.37
         upper limit
    		 0.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.17

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

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    End point title
    		 Change from Baseline in Fasting Plasma Glucose (FPG) at Week 26
    End point description
    ITT population included all randomised subjects. Missing data are imputed using the retrieved dropouts imputation method. An ANCOVA model was used for the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Sotagliflozin 400 mg Empagliflozin 25 mg Placebo
    Number of subjects analysed
    307
    309
    154
    Units: mmol/L
        least squares mean (standard error)
    -1.3 ± 0.2
    -1.6 ± 0.2
    -0.5 ± 0.2
    Statistical analysis title
    		 Sotagliflozin vs Placebo
    Statistical analysis description
    The change from baseline to Week 26 is analysed using an ANCOVA model using multiple imputations to fill in missing data and is parameterized with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of metformin use at screening (Yes, No), randomisation strata of mean SBP (<130, ≥130 mmHg) at screening, and country as fixed effects, and baseline fasting plasma glucose as a covariate.
    Comparison groups
    Sotagliflozin 400 mg v Placebo
    Number of subjects included in analysis
    461
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0005
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.25
         upper limit
    		 -0.35
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.23
    Statistical analysis title
    		 Sotagliflozin vs Empagliflozin
    Statistical analysis description
    The change from baseline to Week 26 is analysed using an ANCOVA model using multiple imputations to fill in missing data and is parameterized with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of metformin use at screening (Yes, No), randomisation strata of mean SBP (<130, ≥130 mmHg) at screening, and country as fixed effects, and baseline fasting plasma glucose as a covariate.
    Comparison groups
    Empagliflozin 25 mg v Sotagliflozin 400 mg
    Number of subjects included in analysis
    616
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1339
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.09
         upper limit
    		 0.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2

    Secondary: Change from Baseline in Body Weight at Week 26

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    End point title
    		 Change from Baseline in Body Weight at Week 26
    End point description
    ITT population included all randomised subjects. Missing data are imputed using the retrieved dropouts imputation method. An ANCOVA model was used for the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Sotagliflozin 400 mg Empagliflozin 25 mg Placebo
    Number of subjects analysed
    307
    309
    154
    Units: kilogram (kg)
        least squares mean (standard error)
    -2.7 ± 0.3
    -3.2 ± 0.3
    -0.5 ± 0.3
    Statistical analysis title
    		 Sotagliflozin vs Placebo
    Statistical analysis description
    The change from baseline to Week 26 is analysed using an ANCOVA model using multiple imputations to fill in missing data and is parameterised with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of metformin use at screening (Yes, No), randomisation strata of mean SBP (<130, ≥130 mmHg) at screening, and country as fixed effects, and baseline weight as a covariate.
    Comparison groups
    Sotagliflozin 400 mg v Placebo
    Number of subjects included in analysis
    461
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -2.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.95
         upper limit
    		 -1.54
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.36
    Statistical analysis title
    		 Sotagliflozin vs Empagliflozin
    Statistical analysis description
    The change from baseline to Week 26 is analysed using an ANCOVA model using multiple imputations to fill in missing data and is parameterised with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of metformin use at screening (Yes, No), randomisation strata of mean SBP (<130, ≥130 mmHg) at screening, and country as fixed effects, and baseline weight as a covariate.
    Comparison groups
    Sotagliflozin 400 mg v Empagliflozin 25 mg
    Number of subjects included in analysis
    616
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1407
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.17
         upper limit
    		 1.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.34

    Secondary: Change from Baseline in Sitting SBP at Week 12 for all Subjects

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    End point title
    		 Change from Baseline in Sitting SBP at Week 12 for all Subjects
    End point description
    ITT population included all randomised subjects. Missing data are imputed using the retrieved dropouts imputation method. An ANCOVA model was used for the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Sotagliflozin 400 mg Empagliflozin 25 mg Placebo
    Number of subjects analysed
    307
    309
    154
    Units: mmHg
        least squares mean (standard error)
    -1.7 ± 0.8
    -2.8 ± 0.8
    0.4 ± 1.0
    Statistical analysis title
    		 Sotagliflozin vs Placebo
    Statistical analysis description
    The change from baseline to Week 26 is analysed using an ANCOVA model using multiple imputations to fill in missing data and is parameterised with treatment groups, randomisation strata of HbA1c (≤ 8.5, >8.5%) at screening, randomisation strata of metformin use at screening (Yes, No) and country as fixed effects, and baseline SBP as a covariate.
    Comparison groups
    Sotagliflozin 400 mg v Placebo
    Number of subjects included in analysis
    461
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0325
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -2.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.89
         upper limit
    		 -0.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.95
    Statistical analysis title
    		 Sotagliflozin vs Empagliflozin
    Statistical analysis description
    The change from baseline to Week 26 is analysed using an ANCOVA model using multiple imputations to fill in missing data and is parameterised with treatment groups, randomisation strata of HbA1c (≤ 8.5, >8.5%) at screening, randomisation strata of metformin use at screening (Yes, No) and country as fixed effects, and baseline SBP as a covariate.
    Comparison groups
    Empagliflozin 25 mg v Sotagliflozin 400 mg
    Number of subjects included in analysis
    616
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1565
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.42
         upper limit
    		 2.63
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.78

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

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    End point title
    		 Percentage of Subjects with HbA1c <6.5% at Week 26
    End point description
    ITT population included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 Sotagliflozin 400 mg Empagliflozin 25 mg Placebo
    Number of subjects analysed
    307
    309
    154
    Units: percentage of subjects
        number (not applicable)
    12.1
    11.7
    3.9
    Statistical analysis title
    		 Sotagliflozin vs Placebo
    Statistical analysis description
    Percentage difference between treatment groups using the Cochran-Mantel-Haenszel test stratified by the randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of metformin use at screening (Yes, No), and the randomisation strata of mean SBP (<130, ≥130 mmHg) at screening. Missing data at Week 26 were assigned a status of nonresponder in the analysis.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    461
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0048
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    8.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.36
         upper limit
    		 12.89

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

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    End point title
    		 Percentage of Subjects with HbA1c <7.0% at Week 26
    End point description
    ITT population included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 Sotagliflozin 400 mg Empagliflozin 25 mg Placebo
    Number of subjects analysed
    307
    309
    154
    Units: percentage of subjects
        number (not applicable)
    32.6
    35.6
    15.6
    Statistical analysis title
    		 Sotagliflozin Vs Placebo
    Statistical analysis description
    Percentage difference between treatment groups using the Cochran-Mantel-Haenszel test stratified by the randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of metformin use at screening (Yes, No), and the randomisation strata of mean SBP (<130, ≥130 mmHg) at screening. Missing data at Week 26 were assigned a status of nonresponder in the analysis.
    Comparison groups
    Sotagliflozin 400 mg v Placebo
    Number of subjects included in analysis
    461
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    16.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 9.26
         upper limit
    		 24.52

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose of study drug to last dose of study drug (up to 26 weeks) + 4 weeks (Approximately 30 weeks)
    Adverse event reporting additional description
    Safety population included all randomised subjects who received at least one dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Sotagliflozin
    Reporting group description
    		 Following a 2-week run-in period, sotagliflozin administered as two tablets and one placebo capsule (identical to empagliflozin capsule in appearance), once daily before the first meal of the day for up to 26 weeks.

    Reporting group title
    Empagliflozin
    Reporting group description
    		 Following a 2-week run-in period, empagliflozin administered as two placebo tablets (identical to sotagliflozin in appearance) and one capsule of empagliflozin, once daily before the first meal of the day for up to 26 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Following a 2-week run-in period, placebo given as two placebo tablets (identical to sotagliflozin) and one placebo capsule (identical to empagliflozin) once daily before the first meal of the day for up to 26 weeks.

    Serious adverse events
    		 Sotagliflozin Empagliflozin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 307 (3.26%)
    13 / 309 (4.21%)
    9 / 154 (5.84%)
         number of deaths (all causes)
    0
    1
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Intraductal proliferative breast lesion
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 309 (0.00%)
    0 / 154 (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
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 309 (0.00%)
    0 / 154 (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
    Meningioma
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 309 (0.32%)
    0 / 154 (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
    Laryngeal cancer
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 309 (0.32%)
    0 / 154 (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
    Nasal cavity cancer
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 309 (0.00%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 309 (0.00%)
    0 / 154 (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
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 309 (0.00%)
    0 / 154 (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
    Hypertensive crisis
         subjects affected / exposed
    0 / 307 (0.00%)
    0 / 309 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 309 (0.32%)
    0 / 154 (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
    Sinus node dysfunction
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 309 (0.00%)
    0 / 154 (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
    Right ventricular failure
         subjects affected / exposed
    0 / 307 (0.00%)
    0 / 309 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial fibrosis
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 309 (0.32%)
    0 / 154 (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
    Nervous system disorders
    Cerebral haematoma
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 309 (0.00%)
    0 / 154 (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
    Cerebral ischaemia
         subjects affected / exposed
    0 / 307 (0.00%)
    0 / 309 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 307 (0.00%)
    2 / 309 (0.65%)
    0 / 154 (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
    Ischaemic stroke
         subjects affected / exposed
    0 / 307 (0.00%)
    0 / 309 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 309 (0.00%)
    0 / 154 (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
    Blood and lymphatic system disorders
    Abdominal lymphadenopathy
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 309 (0.00%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Umbilical hernia
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 309 (0.32%)
    0 / 154 (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
    Diverticulum intestinal
         subjects affected / exposed
    0 / 307 (0.00%)
    2 / 309 (0.65%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 307 (0.00%)
    0 / 309 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 307 (0.00%)
    0 / 309 (0.00%)
    1 / 154 (0.65%)
         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, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 307 (0.00%)
    0 / 309 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 309 (0.32%)
    0 / 154 (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
    Pulmonary infarction
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 309 (0.32%)
    0 / 154 (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
    Pulmonary mass
         subjects affected / exposed
    0 / 307 (0.00%)
    0 / 309 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 309 (0.32%)
    0 / 154 (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
    Gallbladder polyp
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 309 (0.00%)
    0 / 154 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 307 (0.00%)
    0 / 309 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 309 (0.32%)
    0 / 154 (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
    Erysipelas
         subjects affected / exposed
    1 / 307 (0.33%)
    0 / 309 (0.00%)
    0 / 154 (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
    Diverticulitis
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 309 (0.32%)
    0 / 154 (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
    Infection
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 309 (0.32%)
    0 / 154 (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
    Pneumonia
         subjects affected / exposed
    0 / 307 (0.00%)
    0 / 309 (0.00%)
    2 / 154 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 309 (0.32%)
    0 / 154 (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
    Urosepsis
         subjects affected / exposed
    0 / 307 (0.00%)
    1 / 309 (0.32%)
    0 / 154 (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
    Vestibular neuronitis
         subjects affected / exposed
    0 / 307 (0.00%)
    0 / 309 (0.00%)
    1 / 154 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Sotagliflozin Empagliflozin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    58 / 307 (18.89%)
    68 / 309 (22.01%)
    39 / 154 (25.32%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 307 (2.28%)
    8 / 309 (2.59%)
    6 / 154 (3.90%)
         occurrences all number
    9
    11
    7
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    3 / 307 (0.98%)
    5 / 309 (1.62%)
    6 / 154 (3.90%)
         occurrences all number
    3
    5
    6
    Diarrhoea
         subjects affected / exposed
    10 / 307 (3.26%)
    8 / 309 (2.59%)
    5 / 154 (3.25%)
         occurrences all number
    10
    10
    6
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    6 / 307 (1.95%)
    3 / 309 (0.97%)
    4 / 154 (2.60%)
         occurrences all number
    6
    3
    5
    Infections and infestations
    Genital infection fungal
         subjects affected / exposed
    7 / 307 (2.28%)
    5 / 309 (1.62%)
    0 / 154 (0.00%)
         occurrences all number
    7
    6
    0
    Influenza
         subjects affected / exposed
    5 / 307 (1.63%)
    9 / 309 (2.91%)
    5 / 154 (3.25%)
         occurrences all number
    6
    9
    6
    Nasopharyngitis
         subjects affected / exposed
    12 / 307 (3.91%)
    20 / 309 (6.47%)
    5 / 154 (3.25%)
         occurrences all number
    12
    21
    6
    Urinary tract infection
         subjects affected / exposed
    11 / 307 (3.58%)
    8 / 309 (2.59%)
    2 / 154 (1.30%)
         occurrences all number
    13
    9
    3
    Vulvovaginal mycotic infection
         subjects affected / exposed
    5 / 307 (1.63%)
    10 / 309 (3.24%)
    1 / 154 (0.65%)
         occurrences all number
    5
    12
    1
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    6 / 307 (1.95%)
    6 / 309 (1.94%)
    9 / 154 (5.84%)
         occurrences all number
    6
    7
    11
    Any Hypoglycaemia
         subjects affected / exposed
    2 / 307 (0.65%)
    9 / 309 (2.91%)
    7 / 154 (4.55%)
         occurrences all number
    6
    17
    8
    Documented Symptomatic Hypoglycaemia
         subjects affected / exposed
    1 / 307 (0.33%)
    8 / 309 (2.59%)
    3 / 154 (1.95%)
         occurrences all number
    1
    15
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Sep 2017
    Amendment 1: 1. Change to the Exclusion criteria and temporary investigational medicinal product (IMP) discontinuation. 2. Change to the exclusion criteria and guidance on contraceptive methods. 3. Change to exclusion assessment. 4.Change to the general guidelines for reporting of adverse events. 5. Change to hepatitis serology test at screening and related exclusion. 6. Change to the definition of one event(s) of special interest (EOSI) “volume depletion”. 7. Change to urine laboratory test. 8. Change to instruction for blood pressure measurement. 9. Other minor changes for corrections of inconsistency or administration were listed.
    11 Apr 2018
    Amendment 2: 1. Addition of a new section to describe the independent safety assessments for drug-induced liver injuries (DILI) and amputation. 2. Change to exclusion criterion E20 regarding the use of a selective sodium-glucose cotransport type 2 (SGLT2) inhibitor. 3. Change to the definition of baseline for estimated glomerular filtration rate (eGFR). 4. Change to the description of the objectives and endpoints for the Ambulatory Blood Pressure Monitoring (ABPM) substudy. 5. Update to the statistical analysis for the primary and secondary study endpoints, compliance analysis, and multiplicity considerations. 6. 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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