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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo-Controlled, Parallel-group, Multicenter Study to Evaluate the Efficacy and Safety of Sotagliflozin Added to a Sulfonylurea Alone or in Combination with Metformin in Patients with Type 2 Diabetes Who Have Inadequate Glycemic Control on a Sulfonylurea Alone or with Metformin

    Summary
    EudraCT number
    		 2016-002826-35
    Trial protocol
    		 EE   SK   HU   GB   PL   BG  
    Global end of trial date
    30 Apr 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Jul 2020
    First version publication date
    31 Jul 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    EFC14835
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03066830
    WHO universal trial number (UTN)
    		 U1111-1186-2612
    Sponsors
    Sponsor organisation name
    Lexicon Pharmaceuticals, Inc.
    Sponsor organisation address
    8800 Technology Forest Place, The Woodlands, United States, TX 77381, Texas, United States,
    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
    30 Apr 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the superiority of Sotagliflozin 400 mg versus Placebo on Hemoglobin A1c (HbA1c) reduction at Week 26 in subjects with Type 2 Diabetes (T2D) who have inadequate glycemic control with a Sulfonylurea alone or in combination with Metformin.
    Protection of trial subjects
    All study subjects were required to read and sign an informed consent form (ICF).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Feb 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 57
    Country: Number of subjects enrolled
    Slovakia: 32
    Country: Number of subjects enrolled
    United Kingdom: 35
    Country: Number of subjects enrolled
    Bulgaria: 12
    Country: Number of subjects enrolled
    Estonia: 1
    Country: Number of subjects enrolled
    Hungary: 100
    Country: Number of subjects enrolled
    Korea, Republic of: 57
    Country: Number of subjects enrolled
    Romania: 3
    Country: Number of subjects enrolled
    Ukraine: 37
    Country: Number of subjects enrolled
    United States: 173
    Worldwide total number of subjects
    507
    EEA total number of subjects
    240
    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)
    283
    From 65 to 84 years
    221
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects took part in the study at 76 investigative sites in the United States, Bulgaria, Estonia, Hungary, Republic of Korea, Poland, Romania, Slovakia, Ukraine, United Kingdom from 24 February 2017 to 30 April 2019.

    Pre-assignment
    Screening details
    		 Subjects with a diagnosis of Diabetes Mellitus were enrolled equally in 1 of 2 treatment groups, Sotagliflozin 400 milligrams (mg) and 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, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Following a 2-week run-in period, subjects were randomised to matching placebo administered as 2 tablets, once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Eligible subjects continued treatment in the Extension Period which was planned for up to 79 weeks.
    Arm type
    		 Placebo

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

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin was administered orally as prescribed by the Principal Investigator.

    Investigational medicinal product name
    Sulfonylurea
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sulfonylurea was administered orally as prescribed by the Principal Investigator.

    Arm title
    		 Sotagliflozin 400 mg
    Arm description
    		 Following a 2-week run-in phase, subjects received two Sotagliflozin tablets of 200 mg, orally once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Eligible subjects continued treatment in the Extension Period which was planned for up to 79 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sotagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sotagliflozin 200 mg was administered as 2 tablets, once daily, before the first meal of the day.

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin was administered orally as prescribed by the Principal Investigator.

    Investigational medicinal product name
    Sulfonylurea
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sulfonylurea was administered orally as prescribed by the Principal Investigator.

    Number of subjects in period 1
    		Placebo Sotagliflozin 400 mg
    Started
    254
    253
    Completed
    221
    231
    Not completed
    33
    22
         Adverse Event
    2
    2
         Other
    3
    -
         At the Subject's Own Request
    16
    17
         Poor Compliance to Protocol
    1
    -
         Lost to follow-up
    11
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Following a 2-week run-in period, subjects were randomised to matching placebo administered as 2 tablets, once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Eligible subjects continued treatment in the Extension Period which was planned for up to 79 weeks.

    Reporting group title
    Sotagliflozin 400 mg
    Reporting group description
    		 Following a 2-week run-in phase, subjects received two Sotagliflozin tablets of 200 mg, orally once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Eligible subjects continued treatment in the Extension Period which was planned for up to 79 weeks.

    Reporting group values
    		 Placebo Sotagliflozin 400 mg Total
    Number of subjects
    		 254 253 507
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.0 ( 9.9 ) 63.3 ( 8.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 124 104 228
        Male
    		 130 149 279
    Race
    Units: Subjects
        White
    		 211 215 426
        Black or African American
    		 8 8 16
        Asian
    		 34 28 62
        American Indian or Alaska native
    		 0 0 0
        Native Hawaiian or other Pacific Islander
    		 0 1 1
        Multiple
    		 1 0 1
        Not Reported
    		 0 1 1
        Unknown
    		 0 0 0
    Ethinicity
    Units: Subjects
        Hispanic or Latino
    		 43 53 96
        Not Hispanic or Latino
    		 210 198 408
        Not Reported
    		 0 2 2
        Unknown
    		 1 0 1
    Hemoglobin A1c (HbA1c)
    Units: percentage of HbA1c
        arithmetic mean (standard deviation)
    		 8.18 ( 0.83 ) 8.20 ( 0.83 ) -
    Systolic Blood Pressure (SBP)
    Units: millimetre of mercury (mmHg)
        arithmetic mean (standard deviation)
    		 133.08 ( 14.21 ) 134.30 ( 13.01 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Following a 2-week run-in period, subjects were randomised to matching placebo administered as 2 tablets, once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Eligible subjects continued treatment in the Extension Period which was planned for up to 79 weeks.

    Reporting group title
    Sotagliflozin 400 mg
    Reporting group description
    		 Following a 2-week run-in phase, subjects received two Sotagliflozin tablets of 200 mg, orally once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Eligible subjects continued treatment in the Extension Period which was planned for up to 79 weeks.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Following a 2-week run-in period, subjects were randomised to matching placebo administered as 2 tablets, once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Eligible subjects continued treatment in the Extension Period which was planned for up to 79 weeks. One subject randomised to Placebo who was dosed with Sotagliflozin 400 mg treatment during the study is included in the Sotagliflozin 400 mg arm in the safety population.

    Subject analysis set title
    Sotagliflozin 400 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Following a 2-week run-in phase, subjects received two Sotagliflozin tablets of 200 mg, orally once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Eligible subjects continued treatment in the Extension Period which was planned for up to 79 weeks. One subject randomised to Placebo who was dosed with Sotagliflozin 400 mg treatment during the study is included in the Sotagliflozin 400 mg arm in the safety population.

    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 to Week 26
    End point values
    		 Placebo Sotagliflozin 400 mg
    Number of subjects analysed
    254
    253
    Units: percentage of HbA1c
        least squares mean (standard error)
    0.06 ( 0.082 )
    -0.70 ( 0.068 )
    Statistical analysis title
    		 Sotagliflozin Vs Placebo
    Statistical analysis description
    The change from baseline to Week 26 is analysed using ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of metformin use at screening, randomisation strata of mean SBP (<130, ≥ 130 mmHg) at screening, and country as fixed effects, and baseline HbA1c as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    507
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in Least Square (LS) Mean
    Point estimate
    -0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.946
         upper limit
    		 -0.574
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.095

    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 to Week 26
    End point values
    		 Placebo Sotagliflozin 400 mg
    Number of subjects analysed
    254
    253
    Units: millimole per litre (mmol/L)
        least squares mean (standard error)
    0.277 ( 0.2691 )
    -1.331 ( 0.1844 )
    Statistical analysis title
    		 Sotagliflozin Vs Placebo
    Statistical analysis description
    The change from baseline to Week 26 is analysed using ANCOVA model with treatment groups randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of metformin use at screening, randomization 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
    507
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.608
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.1685
         upper limit
    		 -1.0471
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.286

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

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    End point title
    		 Change from Baseline in Systolic Blood Pressure (SBP) at Week 12 in Subjects with Baseline SBP ≥130 mmHg
    End point description
    Analysis was performed on ITT population in subjects with baseline SBP ≥130 mmHg. Missing data are imputed using the 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 to Week 12
    End point values
    		 Placebo Sotagliflozin 400 mg
    Number of subjects analysed
    144
    146
    Units: mmHg
        least squares mean (standard error)
    -3.58 ( 1.052 )
    -4.41 ( 1.061 )
    Statistical analysis title
    		 Sotagliflozin Vs Placebo
    Statistical analysis description
    The change from baseline to Week 12 is analysed using ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of metformin use at screening and country as fixed effects, and baseline SBP as a covariate.
    Comparison groups
    Sotagliflozin 400 mg v Placebo
    Number of subjects included in analysis
    290
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5172
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.316
         upper limit
    		 1.669
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.272

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

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    End point title
    		 Change from Baseline in SBP at Week 12 for All Subjects
    End point description
    ITT population included all randomised subjects. 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 to Week 12
    End point values
    		 Placebo Sotagliflozin 400 mg
    Number of subjects analysed
    254
    253
    Units: mmHg
        least squares mean (standard error)
    -0.69 ( 0.826 )
    -1.71 ( 0.830 )
    Statistical analysis title
    		 Sotagliflozin Vs Placebo
    Statistical analysis description
    The change from baseline to Week 12 is analysed using ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of metformin use at screening, randomization strata of mean SBP (< 130, ≥ 130 mmHg) at screening, and country as fixed effects, and baseline SBP as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    507
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2994
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.946
         upper limit
    		 0.907
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.983

    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 to Week 26
    End point values
    		 Placebo Sotagliflozin 400 mg
    Number of subjects analysed
    254
    253
    Units: kilogram (kg)
        least squares mean (standard error)
    -0.29 ( 0.206 )
    -1.70 ( 0.215 )
    Statistical analysis title
    		 Sotagliflozin Vs Placebo
    Statistical analysis description
    The change from baseline to Week 26 is analysed using ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of Metformin use at screening, 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
    507
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.932
         upper limit
    		 -0.884
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.267

    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
    		 Placebo Sotagliflozin 400 mg
    Number of subjects analysed
    254
    253
    Units: percentage of subjects
        number (not applicable)
    1.6
    8.3
    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, randomization strata of mean SBP (< 130, ≥ 130 mmHg) at screening, randomization strata of metformin use at the 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
    507
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0004
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage difference
    Point estimate
    6.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.03
         upper limit
    		 10.47

    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
    		 Placebo Sotagliflozin 400 mg
    Number of subjects analysed
    254
    253
    Units: percentage of subjects
        number (not applicable)
    8.7
    26.1
    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 mean SBP (< 130, ≥ 130 mmHg) at screening, randomisation strata of metformin use 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
    507
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage difference
    Point estimate
    17.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 11.16
         upper limit
    		 23.73

    Other pre-specified: Percentage of Subjects with Hypoglycemic Events

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    End point title
    		 Percentage of Subjects with Hypoglycemic Events
    End point description
    Percentage of subjects with hypoglycemic events are reported for the following 3 categories: Any hypoglycemia (as reported in the Electronic Case Report Form); Documented symptomatic hypoglycemia [typical symptoms of hypoglycemia (increased sweating, nervousness, asthenia/weakness, tremor, dizziness, increased appetite, palpitations, headache, sleep disorder, confusion, seizures, unconsciousness, and/or coma) and plasma glucose ≤ 70 mg/dL (3.9 mmol/L)]; Severe [an event requiring assistance of another person to actively administer carbohydrate, glucagon, intravenous glucose or other resuscitative actions] or documented symptomatic hypoglycemia [typical symptoms of hypoglycemia and plasma glucose ≤ 70 mg/dL]. Subjects may be reported in more than one category. Safety population was defined as all randomised subjects who had received at least 1 dose of the double-blind investigational medicinal product.
    End point type
    Other pre-specified
    End point timeframe
    Up to 79 weeks in the treatment period
    End point values
    		 Placebo Sotagliflozin 400 mg
    Number of subjects analysed
    253
    254
    Units: percentage of subjects
    number (not applicable)
        Any hypoglycemia
    22.1
    19.7
        Documented symptomatic hypoglycemia
    13.0
    11.4
        Severe or documented symptomatic hypoglycemia
    13.0
    11.8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose of study drug to last dose of study drug (up to 82.9 weeks) + 2 weeks
    Adverse event reporting additional description
    Safety population included all randomised subjects who received at least one dose of double-blind IMP. One subject randomised to Placebo who was dosed with Sotagliflozin 400 mg treatment during the study is included in the Sotagliflozin 400 mg arm in the safety population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Following a 2-week run-in period, subjects were randomised to matching placebo administered as 2 tablets, once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Eligible subjects continued treatment in the Extension Period which was planned for up to 79 weeks. One subject randomised to Placebo who was dosed with Sotagliflozin 400 mg treatment during the study is included in the Sotagliflozin 400 mg arm in the safety population.

    Reporting group title
    Sotagliflozin 400 mg
    Reporting group description
    		 Following a 2-week run-in phase, subjects received two Sotagliflozin tablets of 200 mg, orally once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Eligible subjects continued treatment in the Extension Period which was planned for up to 79 weeks. One subject randomised to Placebo who was dosed with Sotagliflozin 400 mg treatment during the study is included in the Sotagliflozin 400 mg arm in the safety population.

    Serious adverse events
    		 Placebo Sotagliflozin 400 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    40 / 253 (15.81%)
    32 / 254 (12.60%)
         number of deaths (all causes)
    2
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    2 / 253 (0.79%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pituitary tumour benign
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer recurrent
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial hyperplasia
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine prolapse
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 253 (0.79%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anastomotic ulcer
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 253 (0.40%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    1 / 253 (0.40%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac disorders
    Acute left ventricular failure
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 253 (0.00%)
    2 / 254 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 253 (0.40%)
    2 / 254 (0.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 253 (0.40%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    3 / 253 (1.19%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nodal arrhythmia
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Silent myocardial infarction
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 253 (0.79%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 253 (0.40%)
    2 / 254 (0.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nerve compression
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial seizures with secondary generalisation
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post stroke epilepsy
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual impairment
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral hernia
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 253 (0.40%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    0 / 253 (0.00%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic metabolic decompensation
         subjects affected / exposed
    1 / 253 (0.40%)
    0 / 254 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    3 / 253 (1.19%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 253 (0.40%)
    1 / 254 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Sotagliflozin 400 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    90 / 253 (35.57%)
    71 / 254 (27.95%)
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    11 / 253 (4.35%)
    22 / 254 (8.66%)
         occurrences all number
    12
    48
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    23 / 253 (9.09%)
    21 / 254 (8.27%)
         occurrences all number
    27
    23
    Upper respiratory tract infection
         subjects affected / exposed
    19 / 253 (7.51%)
    9 / 254 (3.54%)
         occurrences all number
    23
    11
    Urinary tract infection
         subjects affected / exposed
    8 / 253 (3.16%)
    19 / 254 (7.48%)
         occurrences all number
    9
    26
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    48 / 253 (18.97%)
    14 / 254 (5.51%)
         occurrences all number
    61
    24

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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