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    Clinical Trial Results:
    A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of LX4211 as Adjunct Therapy in Adult Patients with Type 1 Diabetes Mellitus Who Have Inadequate Glycemic Control with Insulin Therapy

    Summary
    EudraCT number
    		 2014-005153-39
    Trial protocol
    		 SK   AT   ES   LT   DE   GB   HU   BE   SE   NL   PL   BG   RO   IT  
    Global end of trial date
    23 Jun 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Jul 2018
    First version publication date
    09 Jul 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    LX4211.1-310-T1DM
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02421510
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Lexicon Pharmaceuticals, Inc.
    Sponsor organisation address
    8800 Technology Forest Place, The Woodlands, TX, United States, 77381-1160
    Public contact
    Sangeeta Sawhney, Executive Medical Director, Lexicon Pharmaceuticals, Inc., +01 832 702 6527, ssawhney@lexpharma.com
    Scientific contact
    Sangeeta Sawhney, Executive Medical Director, Lexicon Pharmaceuticals, Inc., +01 832 702 6527, ssawhney@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
    23 Jun 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to demonstrate superiority of either LX4211 400 mg or 200 mg versus placebo on glycosylated hemoglobin A1C (A1C) reduction at Week 24 when used as an adjunct therapy in adult subjects with type 1 diabetes mellitus (T1D) who have inadequate glycemic control with insulin therapy.
    Protection of trial subjects
    All subjects were required to sign an informed consent.
    Background therapy
    		 Insulin via pump or multiple daily injections.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 May 2015
    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
    Israel: 49
    Country: Number of subjects enrolled
    Switzerland: 7
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Poland: 156
    Country: Number of subjects enrolled
    Romania: 71
    Country: Number of subjects enrolled
    Slovakia: 35
    Country: Number of subjects enrolled
    Spain: 105
    Country: Number of subjects enrolled
    Sweden: 6
    Country: Number of subjects enrolled
    United Kingdom: 36
    Country: Number of subjects enrolled
    Austria: 25
    Country: Number of subjects enrolled
    Belgium: 30
    Country: Number of subjects enrolled
    Bulgaria: 45
    Country: Number of subjects enrolled
    France: 23
    Country: Number of subjects enrolled
    Germany: 79
    Country: Number of subjects enrolled
    Hungary: 69
    Country: Number of subjects enrolled
    Italy: 19
    Country: Number of subjects enrolled
    Lithuania: 25
    Worldwide total number of subjects
    782
    EEA total number of subjects
    726
    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)
    749
    From 65 to 84 years
    33
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects took part in the study at 96 investigative sites throughout 16 European countries and 1 non-European country from 21 May 2015 to 23 June 2017.

    Pre-assignment
    Screening details
    		 995 subjects were screened and 800 subjects entered in a single blind 6-week placebo run-in period. 782 subjects with a diagnosis of Type 1 diabetes mellitus were randomized equally in 1 of 3 treatment groups: sotagliflozin 400 milligrams (mg), sotagliflozin 200 mg or placebo.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Two placebo-matching sotagliflozin tablets, once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo-matching sotagliflozin (two tablets), once daily, while fasting (before the first meal of the day).

    Arm title
    		 Sotagliflozin 200 mg
    Arm description
    		 Sotagliflozin 200 mg (one 200 mg tablet and one placebo tablet), once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sotagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    sotagliflozin 200 mg (one 200 mg tablet and one placebo tablet) daily, while fasting (before the first meal of the day).

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo-matching sotagliflozin (one tablet), once daily with sotagliflozin 200 mg , while fasting (before the first meal of the day).

    Arm title
    		 Sotagliflozin 400 mg
    Arm description
    		 Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sotagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg (two 200 mg tablets), once daily, while fasting (before the first meal of the day).

    Number of subjects in period 1
    		Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Started
    258
    261
    263
    Completed the 24 Week Treatment Period
    236
    239
    240
    Completed
    225
    226
    227
    Not completed
    33
    35
    36
         Physician decision
    1
    1
    3
         Death
    1
    -
    -
         Pregnancy
    1
    1
    -
         Adverse event
    9
    10
    18
         Noncompliance with study drug
    1
    -
    -
         Lost to follow-up
    1
    1
    -
         Other - unspecified
    4
    2
    3
         Withdrawal by subject
    14
    18
    12
         Protocol deviation
    1
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Two placebo-matching sotagliflozin tablets, once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.

    Reporting group title
    Sotagliflozin 200 mg
    Reporting group description
    		 Sotagliflozin 200 mg (one 200 mg tablet and one placebo tablet), once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.

    Reporting group title
    Sotagliflozin 400 mg
    Reporting group description
    		 Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.

    Reporting group values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg Total
    Number of subjects
    		 258 261 263 782
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 244 252 253 749
        From 65-84 years
    		 14 9 10 33
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 39.7 ± 13.42 42.3 ± 13.59 41.7 ± 13.23 -
    Gender categorical
    Units: Subjects
        Female
    		 124 122 130 376
        Male
    		 134 139 133 406
    Insulin Delivery Method
    Units: Subjects
        Continuous Subcutaneous Insulin Infusion (CSII)
    		 66 68 67 201
        Multiple Daily Injections (MDI)
    		 192 193 196 581
    Hemoglobin A1C
    Units: Subjects
        ≤8.5%
    		 200 203 204 607
        >8.5%
    		 58 58 59 175
    Hemoglobin A1C Value at Actual Week -2 Value
    Some sites entered the wrong Week -2 A1C stratum for some subjects at randomization. This value is based on the stratum subjects should have been categorized based on their actual Week -2 A1C value.
    Units: Subjects
        ≤8.5%
    		 202 205 208 615
        >8.5%
    		 56 56 55 167
    Body Weight
    Units: kilograms (kg)
        arithmetic mean (standard deviation)
    		 81.08 ± 16.857 81.93 ± 17.386 81.97 ± 17.963 -
    Duration of Diabetes
    Units: years
        arithmetic mean (standard deviation)
    		 18.1 ± 10.72 18.2 ± 10.82 18.9 ± 11.18 -
    Daily Total Insulin Dose
    Units: International units per kilogram (IU/kg)
        arithmetic mean (standard deviation)
    		 0.75 ± 0.295 0.73 ± 0.277 0.74 ± 0.267 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Two placebo-matching sotagliflozin tablets, once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.

    Reporting group title
    Sotagliflozin 200 mg
    Reporting group description
    		 Sotagliflozin 200 mg (one 200 mg tablet and one placebo tablet), once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.

    Reporting group title
    Sotagliflozin 400 mg
    Reporting group description
    		 Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.

    Primary: Change from Baseline in A1C at Week 24

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    End point title
    		 Change from Baseline in A1C at Week 24
    End point description
    Baseline value was defined as the last value collected prior to the first dose of double-blind study medication. Least square (LS) means were obtained from a mixed-effects model for repeated measures (MMRM) that included fixed, categorical effects of treatment, randomization strata of insulin delivery method (MDI, CSII), randomization strata of Week -2 A1C (≤8.5%, >8.5%), time (study week), a treatment-by-time interaction, and Baseline A1C-by-time interaction as a covariate. A negative change from Baseline (a lower A1C value at Week 24) indicates an improvement. Analyses included subjects from the modified intent to treat (mITT) population, all randomly assigned subjects who had taken at least 1 dose of study drug, analyzed according to their randomized treatment.
    End point type
    Primary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    239
    239
    241
    Units: percentage of A1C
        least squares mean (standard error)
    -0.02 ± 0.044
    -0.39 ± 0.044
    -0.37 ± 0.043
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    LS means and p-values were obtained from MMRM model with treatment, randomization strata of insulin delivery (MDI, CSII) and Week -2 A1C (≤8.5%, >8.5%), time (study week), and a treatment-by-time interaction as fixed categorical effects, and Baseline A1C-by-time interaction as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 200 mg
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.001 [2]
    Method
    		 MMRM
    Parameter type
    		 Least squares mean difference
    Point estimate
    -0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.48
         upper limit
    		 -0.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.058
    Notes
    [1] - Sotagliflozin 200 mg versus Placebo.
    [2] - Threshold for significance ≤0.05
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    LS means and p-values were obtained from Mixed effect Model Repeat Measurement (MMRM) model with treatment, randomization strata of insulin delivery (MDI, CSII) and Week -2 A1C (≤8.5%, >8.5%), time (study week), and a treatment-by-time interaction as fixed categorical effects, and Baseline A1C-by-time interaction as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    480
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.001 [4]
    Method
    		 MMRM
    Parameter type
    		 Least squares mean difference
    Point estimate
    -0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.47
         upper limit
    		 -0.24
    Notes
    [3] - Sotagliflozin 400 mg versus Placebo.
    [4] - Threshold for significance ≤0.05

    Secondary: Percentage of Subjects with A1C <7.0% at Week 24 and No Episode of Severe Hypoglycemia, and No Episode of Diabetic Ketoacidosis (DKA) from Randomization to Week 24

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    End point title
    		 Percentage of Subjects with A1C <7.0% at Week 24 and No Episode of Severe Hypoglycemia, and No Episode of Diabetic Ketoacidosis (DKA) from Randomization to Week 24
    End point description
    The composite endpoint included fasting blood samples for the assessment of Hemoglobin A1C to determine the subjects with a value <7.0% and a central blinded adjudication process to determine whether subjects experienced either DKA or Severe Hypoglycemia. Only positively adjudicated severe hypoglycemia and diabetic ketoacidosis were included in the analysis. Analyses included subjects from the mITT population.
    End point type
    Secondary
    End point timeframe
    Randomization to Week 24
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    258
    261
    263
    Units: percentage of subjects
        number (not applicable)
    15.1
    31.4
    32.3
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    P-values were obtained from a CMH test stratified by the different levels of the randomization stratification factors of insulin delivery method (MDI, CSII) and Week -2 A1C (≤8.5%, >8.5%). The 95% CL were calculated using asymptotic Wald method. Only positively adjudicated severe hypoglycemia and diabetic ketoacidosis were included in the analysis.
    Comparison groups
    Placebo v Sotagliflozin 200 mg
    Number of subjects included in analysis
    519
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.001 [6]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage difference
    Point estimate
    16.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 9.17
         upper limit
    		 23.43
    Notes
    [5] - Sotagliflozin 200 mg versus Placebo. A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.
    [6] - Threshold for significance ≤0.05
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    P-values were obtained from a CMH test stratified by the different levels of the randomization stratification factors of insulin delivery method (MDI, CSII) and Week -2 A1C (≤8.5%, >8.5%). The 95% CL were calculated using asymptotic Wald method.
    Comparison groups
    Sotagliflozin 400 mg v Placebo
    Number of subjects included in analysis
    521
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 < 0.001 [8]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage difference
    Point estimate
    17.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 10.06
         upper limit
    		 24.35
    Notes
    [7] - Sotagliflozin 400 mg versus Placebo. A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.
    [8] - Threshold for significance ≤0.05

    Secondary: Change from Baseline in Body Weight at Week 24

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    End point title
    		 Change from Baseline in Body Weight at Week 24
    End point description
    Baseline value was defined as the last value collected prior to the first dose of double-blind study medication. LS means were obtained from MMRM model. A negative change from Baseline indicates a loss in body weight from Baseline to Week 24. Analyses included subjects from the mITT population, including all available post baseline values.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    240
    240
    241
    Units: kg
        least squares mean (standard error)
    0.11 ± 0.201
    -1.88 ± 0.200
    -2.47 ± 0.199
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    LS means and p-values were obtained from MMRM model with treatment, randomization strata of insulin delivery (MDI, CSII) and Week -2 A1C (≤8.5%, >8.5%), time (study week), and a treatment-by-time interaction as fixed categorical effects.
    Comparison groups
    Placebo v Sotagliflozin 200 mg
    Number of subjects included in analysis
    480
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 < 0.001 [10]
    Method
    		 MMRM
    Parameter type
    		 Least squares mean difference
    Point estimate
    -1.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.53
         upper limit
    		 -1.44
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.276
    Notes
    [9] - Sotagliflozin 200 mg versus Placebo. A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.
    [10] - Threshold for significance ≤0.05
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    LS means and p-values were obtained from MMRM model with treatment, randomization strata of insulin delivery (MDI, CSII) and Week -2 A1C (≤8.5%, >8.5%), time (study week), and a treatment-by-time interaction as fixed categorical effects.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    481
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 < 0.001 [12]
    Method
    		 MMRM
    Parameter type
    		 Least squares mean difference
    Point estimate
    -2.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.12
         upper limit
    		 -2.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.276
    Notes
    [11] - Sotagliflozin 400 mg versus Placebo. A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.
    [12] - Threshold for significance ≤0.05

    Secondary: Change from Baseline in Mean Daily Bolus Insulin Dose at Week 24

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    End point title
    		 Change from Baseline in Mean Daily Bolus Insulin Dose at Week 24
    End point description
    The mean bolus insulin dose in international units/day (IU/day) for Week 24 was the average over the 3 to 5 days prior to the Week 24 visit. The Baseline value was defined as the last value collected prior to the first dose of double-blind study medication. LS means were obtained from MMRM model including all available post Baseline values. A negative change from Baseline indicated a reduction in the amount of bolus insulin used and a positive change from Baseline indicated an increase in the amount of bolus insulin used between Baseline and Week 24. Analyses included subjects from the mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    238
    237
    239
    Units: IU/day
        least squares mean (standard error)
    -1.19 ± 0.635
    -4.38 ± 0.636
    -4.78 ± 0.634
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    LS means and p-values were obtained from MMRM model with treatment, randomization strata of insulin delivery (MDI, CSII) and Week -2 A1C (≤8.5%, >8.5%), time (study week), and a treatment-by-time interaction as fixed categorical effects, and Baseline mean daily bolus insulin dose-by-time interaction as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 200 mg
    Number of subjects included in analysis
    475
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 < 0.001 [14]
    Method
    		 MMRM
    Parameter type
    		 Least squares mean difference
    Point estimate
    -3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.86
         upper limit
    		 -1.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.847
    Notes
    [13] - Sotagliflozin 200 mg versus Placebo. A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.
    [14] - Threshold for significance ≤0.05
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    LS means and p-values were obtained from MMRM model with treatment, randomization strata of insulin delivery (MDI, CSII) and Week -2 A1C (≤8.5%, >8.5%), time (study week), and a treatment-by-time interaction as fixed categorical effects, and Baseline mean daily bolus insulin dose-by-time interaction as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    477
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 < 0.001 [16]
    Method
    		 MMRM
    Parameter type
    		 Least squares mean difference
    Point estimate
    -3.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.25
         upper limit
    		 -1.93
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.845
    Notes
    [15] - Sotagliflozin 400 mg versus Placebo. A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.
    [16] - Threshold for significance ≤0.05

    Secondary: Change from Baseline in Fasting Plasma Glucose (FPG) at Week 24

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    End point title
    		 Change from Baseline in Fasting Plasma Glucose (FPG) at Week 24
    End point description
    The Baseline value was defined as the last value collected prior to the first dose of double-blind study medication. LS means were obtained from MMRM model including all available post Baseline values. A negative change from Baseline indicates a lower glucose at Week 24 compared to Baseline and a positive change from Baseline indicates an increase in glucose at Week 24 compared to Baseline. Analyses included subjects from the mITT population, including all available post baseline values.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    239
    237
    239
    Units: milligram per deciliter (mg/dL)
        least squares mean (standard error)
    8.8 ± 3.95
    -12.8 ± 3.97
    -16.9 ± 3.96
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    LS means and p-values were obtained from MMRM model with treatment, randomization strata of insulin delivery (MDI, CSII) and Week -2 A1C (≤8.5%, >8.5%), time (study week), and a treatment-by-time interaction as fixed categorical effects, and Baseline Fasting Plasma Glucose-by-time interaction as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 200 mg
    Number of subjects included in analysis
    476
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 < 0.001 [18]
    Method
    		 MMRM
    Parameter type
    		 Least squares mean difference
    Point estimate
    -21.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -32.2
         upper limit
    		 -11
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.38
    Notes
    [17] - Sotagliflozin 200 mg versus Placebo. A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.
    [18] - Threshold for significance ≤0.05
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    LS means and p-values were obtained from MMRM model with treatment, randomization strata of insulin delivery (MDI, CSII) and Week -2 A1C (≤8.5%, >8.5%), time (study week), and a treatment-by-time interaction as fixed categorical effects, and Baseline Fasting Plasma Glucose-by-time interaction as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 < 0.001 [20]
    Method
    		 MMRM
    Parameter type
    		 Least squares mean difference
    Point estimate
    -25.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -36.2
         upper limit
    		 -15.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.37
    Notes
    [19] - Sotagliflozin 400 mg versus Placebo. A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.
    [20] - Threshold for significance ≤0.05

    Secondary: Change from Baseline in Diabetes Treatment Satisfaction Questionnaire (DTSQ) Score at Week 24

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    End point title
    		 Change from Baseline in Diabetes Treatment Satisfaction Questionnaire (DTSQ) Score at Week 24
    End point description
    The DTSQ instrument contains 8 items assessing overall treatment satisfaction, treatment convenience and flexibility, satisfaction with understanding of diabetes, willingness to continue present treatment and to recommend it to others, and frequency of unacceptably high and unacceptably low blood glucose levels. 6 items (excluding perceived hyperglycemia and hypoglycemia items) were scored using a 7-point scale where 0=very dissatisfied to 6= very satisfied for a total possible score of 0 to 36, where higher scores indicate higher satisfaction. The Baseline value was defined as the last value collected prior to the first dose of double-blind study medication. LS means were obtained from MMRM model including all available post Baseline values. A positive change from Baseline indicates improvement. Analyses included subjects from the mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    228
    229
    240
    Units: score on a scale
        least squares mean (standard error)
    -0.1 ± 0.28
    1.9 ± 0.28
    1.6 ± 0.28
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    LS means and p-values were obtained from MMRM model with treatment, randomization strata of insulin delivery (MDI, CSII) and Week -2 A1C (≤8.5%, >8.5%), time (study week), and a treatment-by-time interaction as fixed categorical effects, and Baseline DTSQs Total score-by-time interaction as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 200 mg
    Number of subjects included in analysis
    457
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 < 0.001 [22]
    Method
    		 MMRM
    Parameter type
    		 Least squares mean difference
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.3
         upper limit
    		 2.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.37
    Notes
    [21] - Sotagliflozin 200 mg versus Placebo. A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.
    [22] - Threshold for significance ≤0.05
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    LS means and p-values were obtained from MMRM model with treatment, randomization strata of insulin delivery (MDI, CSII) and Week -2 A1C (≤8.5%, >8.5%), time (study week), and a treatment-by-time interaction as fixed categorical effects, and Baseline DTSQs Total score-by-time interaction as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    468
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 < 0.001 [24]
    Method
    		 MMRM
    Parameter type
    		 Least squares mean difference
    Point estimate
    1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 2.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.36
    Notes
    [23] - Sotagliflozin 400 mg versus Placebo. A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.
    [24] - Threshold for significance ≤0.05

    Secondary: Change from Baseline in 2-Item Diabetes Distress Screen 2 (DDS2) Score at Week 24

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    End point title
    		 Change from Baseline in 2-Item Diabetes Distress Screen 2 (DDS2) Score at Week 24
    End point description
    DDS2 is a 2-item diabetes distress screening instrument where subjects rated the degree to which the following items caused distress: (1) feeling overwhelmed by the demands of living with diabetes, and (2) feeling that I am often failing with my diabetes regimen using a 6-point scale: where 1=no distress to 5=severe distress for a total possible score of 2 to 10. LS means were obtained from MMRM model including all available post Baseline values. A negative change from Baseline indicates improvement Analyses included subjects from the mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    232
    232
    243
    Units: score on a scale
        least squares mean (standard error)
    0.0 ± 0.12
    -0.3 ± 0.12
    -0.4 ± 0.11
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    LS means and p-values were obtained from MMRM model with treatment, randomization strata of insulin delivery (MDI, CSII) and Week -2 A1C (≤8.5%, >8.5%), time (study week), and a treatment-by-time interaction as fixed categorical effects, and Baseline DDS2 Total score-by-time interaction as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 200 mg
    Number of subjects included in analysis
    464
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 = 0.025 [26]
    Method
    		 MMRM
    Parameter type
    		 Least squares mean difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 0
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.15
    Notes
    [25] - Sotagliflozin 200 mg versus Placebo. A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.
    [26] - Threshold for significance ≤0.05
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    LS means and p-values were obtained from MMRM model with treatment, randomization strata of insulin delivery (MDI, CSII) and Week -2 A1C (≤8.5%, >8.5%), time (study week), and a treatment-by-time interaction as fixed categorical effects, and Baseline DDS2 Total score-by-time interaction as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    475
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 = 0.003 [28]
    Method
    		 MMRM
    Parameter type
    		 Least squares mean difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 -0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.15
    Notes
    [27] - Sotagliflozin 400 mg versus Placebo. A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.
    [28] - Threshold for significance ≤0.05

    Secondary: Percent Change from Baseline in Body Weight at Week 24

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    End point title
    		 Percent Change from Baseline in Body Weight at Week 24
    End point description
    Baseline value was defined as the last value collected prior to the first dose of double-blind study medication. LS means were obtained from MMRM model. A negative percent change from Baseline indicates a loss in body weight from Baseline to Week 24. Analyses included subjects from the mITT population, including all available post baseline values.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    240
    240
    241
    Units: percent change in body weight
        least squares mean (standard error)
    0.10 ± 0.245
    -2.38 ± 0.245
    -2.99 ± 0.244
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose and up to 30 days after the last dose of double-blind study treatment. Some AEs may have been attributed to the long-term effects of study drug; included even if the onset was >30 days after the last dose of study drug (up to 393 days).
    Adverse event reporting additional description
    Safety Population consisted of all randomly assigned subjects treated with at least 1 dose of study drug, analyzed according to their actual treatment received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Two placebo-matching sotagliflozin tablets, once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.

    Reporting group title
    Sotagliflozin 200 mg
    Reporting group description
    		 Sotagliflozin 200 mg (one 200 mg tablet and one placebo tablet), once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.

    Reporting group title
    Sotagliflozin 400 mg
    Reporting group description
    		 Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.

    Serious adverse events
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 258 (6.59%)
    26 / 261 (9.96%)
    21 / 263 (7.98%)
         number of deaths (all causes)
    2
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine leiomyoma
         subjects affected / exposed
    1 / 258 (0.39%)
    1 / 261 (0.38%)
    0 / 263 (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
    Breast cancer metastatic
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 261 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 261 (0.38%)
    0 / 263 (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
    Clear cell renal cell carcinoma
         subjects affected / exposed
    0 / 258 (0.00%)
    0 / 261 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Invasive breast carcinoma
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 261 (0.38%)
    0 / 263 (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
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 261 (0.00%)
    0 / 263 (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
    Pregnancy, puerperium and perinatal conditions
    Abortion
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 261 (0.00%)
    0 / 263 (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
    General disorders and administration site conditions
    Impaired healing
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 261 (0.38%)
    0 / 263 (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
    Pyrexia
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 261 (0.38%)
    0 / 263 (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
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 261 (0.38%)
    0 / 263 (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
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 258 (0.00%)
    0 / 261 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 261 (0.00%)
    0 / 263 (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
    Ligament rupture
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 261 (0.38%)
    0 / 263 (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
    Patella fracture
         subjects affected / exposed
    0 / 258 (0.00%)
    0 / 261 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 258 (0.00%)
    0 / 261 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 261 (0.00%)
    0 / 263 (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
    Wrist fracture
         subjects affected / exposed
    0 / 258 (0.00%)
    0 / 261 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 258 (0.00%)
    0 / 261 (0.00%)
    2 / 263 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 258 (0.00%)
    0 / 261 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 261 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 258 (0.00%)
    0 / 261 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 261 (0.38%)
    0 / 263 (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
    Myocardial infarction
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 261 (0.38%)
    0 / 263 (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
    Nervous system disorders
    Hypoglycaemic unconsciousness
         subjects affected / exposed
    3 / 258 (1.16%)
    2 / 261 (0.77%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemic seizure
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 261 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 261 (0.00%)
    0 / 263 (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
    Sciatica
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 261 (0.00%)
    0 / 263 (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
    Syncope
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 261 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 258 (0.00%)
    0 / 261 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular headache
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 261 (0.38%)
    0 / 263 (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
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 258 (0.39%)
    1 / 261 (0.38%)
    0 / 263 (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
    Angle closure glaucoma
         subjects affected / exposed
    0 / 258 (0.00%)
    0 / 261 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 261 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 261 (0.38%)
    0 / 263 (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
    Oedematous pancreatitis
         subjects affected / exposed
    0 / 258 (0.00%)
    0 / 261 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prepyloric stenosis
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 261 (0.38%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 261 (0.38%)
    0 / 263 (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
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 261 (0.00%)
    0 / 263 (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
    Diabetic foot
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 261 (0.38%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Cystitis noninfective
         subjects affected / exposed
    0 / 258 (0.00%)
    0 / 261 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Goiter
         subjects affected / exposed
    0 / 258 (0.00%)
    0 / 261 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 261 (0.00%)
    0 / 263 (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
    Rhabdomyolysis
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 261 (0.00%)
    0 / 263 (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
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 258 (0.00%)
    2 / 261 (0.77%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 258 (0.39%)
    1 / 261 (0.38%)
    0 / 263 (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
    Cystitis
         subjects affected / exposed
    0 / 258 (0.00%)
    0 / 261 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ecthyma
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 261 (0.38%)
    0 / 263 (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 / 258 (0.39%)
    0 / 261 (0.00%)
    0 / 263 (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
    Gastroenteritis viral
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 261 (0.38%)
    0 / 263 (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
    Pilonidal cyst
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 261 (0.38%)
    0 / 263 (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
    Pyoderma
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 261 (0.38%)
    0 / 263 (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
    Rotavirus infection
         subjects affected / exposed
    0 / 258 (0.00%)
    1 / 261 (0.38%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 258 (0.00%)
    7 / 261 (2.68%)
    12 / 263 (4.56%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 7
    8 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 258 (0.00%)
    2 / 261 (0.77%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 258 (0.39%)
    0 / 261 (0.00%)
    0 / 263 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ketosis
         subjects affected / exposed
    0 / 258 (0.00%)
    0 / 261 (0.00%)
    1 / 263 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    46 / 258 (17.83%)
    52 / 261 (19.92%)
    64 / 263 (24.33%)
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    10 / 258 (3.88%)
    12 / 261 (4.60%)
    20 / 263 (7.60%)
         occurrences all number
    13
    18
    29
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    40 / 258 (15.50%)
    44 / 261 (16.86%)
    49 / 263 (18.63%)
         occurrences all number
    58
    60
    70

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Mar 2015
    Amendment 1: -Continuous glucose monitoring (CGM) measure deleted for Week 51 and Week 52 in main study periods; -Unscheduled visits added for subject follow-up as needed; -Investigators were not responsible for supplying insulin/analogs; subjects were to continue to use their own background insulin regimen; -Glycemic goals revised per 2015 American Diabetes Association (ADA) standards for medical care; -Investigator was expected to evaluate PPG after first dose of study drug and continue reduction in insulin-to-carbohydrate (I/C) ratio; -Deleted fasting status requirement to allow subjects to treat or avoid hypoglycemic episodes and collect laboratory samples in a nonfasting status; -Contraindications added for CGM device; -Prohibited medications added for CGM substudy; -New text for DKA recognition and management; -Insulin titration to start at Week -5.
    15 May 2015
    Amendment 2: -Frequency of bolus removed as efficacy endpoint; -Additional text to clarify vitamin D supplementation in study subjects; -Added text to clarify childbearing potential and acceptable methods of contraception.
    19 Oct 2015
    Amendment 3: -Number of sites increased to 110 to meet enrollment targets; -Clarification and flexibility added for target number of subjects in each substudy; -Inclusion of beta-hydroxybutyrate (BHB) meter distribution to all participating subjects; -Insulin adjustment clarified for subjects undergoing Mixed Meal on Day 1; -Phosphorus:creatinine ratio (PCR) added for subjects in the dual-energy X-ray absorptiometry (DEXA) substudy; -Included all events of metabolic acidosis for adjudication per FDA recommendation; -Added precautions to minimize risk of DKA in case of planned procedures/surgeries; -Addition of option for pooling data for substudies between 309 and 310; -Removed efficacy analysis of storage samples; -Data from completed digoxin drug-drug interaction study added; -Added ±5 minute time window in collection of 2-hour postprandial glucose (PPG).

    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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