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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo-controlled, 3-arm, Parallel group 52-week Multicenter Study to Evaluate the Efficacy and Safety of Sotagliflozin in Patients with Type 2 Diabetes Mellitus and Severe Renal Impairment who have Inadequate Glycemic Control

    Summary
    EudraCT number
    		 2016-004906-32
    Trial protocol
    		 DE   ES   HU   IT   RO  
    Global end of trial date
    11 Dec 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Sep 2020
    First version publication date
    20 Sep 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    EFC15166
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03242018
    WHO universal trial number (UTN)
    		 U1111-1190-7589
    Sponsors
    Sponsor organisation name
    Lexicon Pharmaceuticals, Inc.
    Sponsor organisation address
    8800 Technology Forest Place, The Woodlands, United States, TX 77381
    Public contact
    Medical Affairs, Lexicon Pharmaceuticals, Inc., medical-information@lexpharma.com
    Scientific contact
    Medical Affairs, Lexicon Pharmaceuticals, Inc., medical-information@lexpharma.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Dec 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Dec 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the superiority of sotagliflozin 400 milligram (mg) versus placebo with respect to hemoglobin A1c (HbA1c) reduction at week 26 in subjects with Type 2 diabetes who have inadequate glycemic control and severe renal impairment.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Aug 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: 21
    Country: Number of subjects enrolled
    Spain: 28
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Argentina: 13
    Country: Number of subjects enrolled
    Colombia: 14
    Country: Number of subjects enrolled
    Israel: 17
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Mexico: 32
    Country: Number of subjects enrolled
    Romania: 12
    Country: Number of subjects enrolled
    Russian Federation: 26
    Country: Number of subjects enrolled
    South Africa: 9
    Country: Number of subjects enrolled
    Ukraine: 14
    Country: Number of subjects enrolled
    United States: 48
    Country: Number of subjects enrolled
    Brazil: 24
    Worldwide total number of subjects
    277
    EEA total number of subjects
    80
    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)
    102
    From 65 to 84 years
    170
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects took part in the study at 106 investigative sites in the United States, Argentina, Brazil, Colombia, Germany, Hungary, Israel, Italy, Mexico, Poland, Romania, Russian Federation, South Africa, Spain, Ukraine from 16 August 2017 to 11 December 2019.

    Pre-assignment
    Screening details
    		 A total of 277 subjects with a diagnosis of Type 2 Diabetes Mellitus were randomised 1:1:1 to 1 of the 3 treatment groups: Placebo, Sotagliflozin 200 milligrams (mg) or Sotagliflozin 400 mg.

    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 phase, subjects received two placebo tablets (identical to sotagliflozin 200 mg in appearance) orally once daily for up to 56.3 weeks.
    Arm type
    		 Placebo comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was administered as 2 tablets (identical to the sotagliflozin 200 mg tablet in appearance), orally once daily.

    Arm title
    		 Sotagliflozin 200 mg
    Arm description
    		 Following a 2-week run-in phase, subjects received two tablets, one sotagliflozin 200 mg tablet and one placebo tablet (identical to sotagliflozin 200 mg in appearance), orally once daily for up to 55.3 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was administered as one tablet (identical to the sotagliflozin 200 mg tablet in appearance), orally, once daily.

    Investigational medicinal product name
    Sotagliflozin
    Investigational medicinal product code
    Other name
    SAR439954
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sotagliflozin 200 mg was administered as one tablet, orally once daily.

    Arm title
    		 Sotagliflozin 400 mg
    Arm description
    		 Following a 2-week run-in phase, subjects received sotagliflozin 400 mg, administered as 2 sotagliflozin 200 mg tablets, orally once daily for up to 56.1 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, orally once daily.

    Number of subjects in period 1
    		Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Started
    93
    92
    92
    Entered Follow-up Period
    93
    92
    92
    Completed
    75
    78
    78
    Not completed
    18
    14
    14
         At the subject’s own request
    5
    1
    4
         Adverse event
    7
    7
    6
         Study terminated by sponsor
    1
    -
    1
         Lost to follow-up
    2
    2
    2
         Reason not specified
    3
    4
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Following a 2-week run-in phase, subjects received two placebo tablets (identical to sotagliflozin 200 mg in appearance) orally once daily for up to 56.3 weeks.

    Reporting group title
    Sotagliflozin 200 mg
    Reporting group description
    		 Following a 2-week run-in phase, subjects received two tablets, one sotagliflozin 200 mg tablet and one placebo tablet (identical to sotagliflozin 200 mg in appearance), orally once daily for up to 55.3 weeks.

    Reporting group title
    Sotagliflozin 400 mg
    Reporting group description
    		 Following a 2-week run-in phase, subjects received sotagliflozin 400 mg, administered as 2 sotagliflozin 200 mg tablets, orally once daily for up to 56.1 weeks.

    Reporting group values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg Total
    Number of subjects
    		 93 92 92 277
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 68.0 ( 8.3 ) 66.8 ( 10.0 ) 67.3 ( 9.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 51 48 43 142
        Male
    		 42 44 49 135
    Race
    Units: Subjects
        White
    		 76 73 78 227
        Black or African American
    		 6 7 3 16
        Asian
    		 1 2 2 5
        American Indian or Alaska Native
    		 7 8 7 22
        Native Hawaiian or Other Pacific Islander
    		 0 1 0 1
        Multiple
    		 3 1 2 6
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 41 33 33 107
        Not Hispanic or Latino
    		 52 59 59 170
    HbA1c
    Units: percentage of HbA1c
        arithmetic mean (standard deviation)
    		 8.38 ( 1.06 ) 8.28 ( 1.03 ) 8.25 ( 0.87 ) -
    Systolic Blood Pressure (SBP)
    Units: millimetre of mercury (mmHg)
        arithmetic mean (standard deviation)
    		 144.72 ( 15.56 ) 143.10 ( 14.98 ) 144.20 ( 15.10 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Following a 2-week run-in phase, subjects received two placebo tablets (identical to sotagliflozin 200 mg in appearance) orally once daily for up to 56.3 weeks.

    Reporting group title
    Sotagliflozin 200 mg
    Reporting group description
    		 Following a 2-week run-in phase, subjects received two tablets, one sotagliflozin 200 mg tablet and one placebo tablet (identical to sotagliflozin 200 mg in appearance), orally once daily for up to 55.3 weeks.

    Reporting group title
    Sotagliflozin 400 mg
    Reporting group description
    		 Following a 2-week run-in phase, subjects received sotagliflozin 400 mg, administered as 2 sotagliflozin 200 mg tablets, orally once daily for up to 56.1 weeks.

    Subject analysis set title
    Sotagliflozin 200 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Following a 2-week run-in phase, subjects received two tablets, one sotagliflozin 200 mg tablet and one placebo tablet (identical to sotagliflozin 200 mg in appearance), orally once daily for up to 55.3 weeks. There were 2 subjects randomised to sotagliflozin 400 mg who were dosed with both sotagliflozin 200 mg and sotagliflozin 400 mg treatments during the study. The data for these subjects were summarised in the sotagliflozin 200 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 sotagliflozin 400 mg, administered as 2 sotagliflozin 200 mg tablets, orally once daily for up to 56.1 weeks. There were 2 subjects randomised to sotagliflozin 400 mg who were dosed with both sotagliflozin 200 mg and sotagliflozin 400 mg treatments during the study. The data for these subjects were summarized in the sotagliflozin 200 mg arm in the safety population.

    Primary: Change from Baseline in HbA1c at Week 26 Comparing Sotagliflozin 400 mg Versus Placebo

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    End point title
    		 Change from Baseline in HbA1c at Week 26 Comparing Sotagliflozin 400 mg Versus Placebo [1]
    End point description
    Intent-to-treat (ITT) population included all randomised subjects, irrespective of compliance with the study protocol and procedures. Missing data was imputed using the retrieved dropouts & washout imputation method. An analysis of covariance (ANCOVA) model was used for the analysis.
    End point type
    Primary
    End point timeframe
    Baseline to Week 26
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for the following reporting arms Placebo and Sotagliflozin 400 mg only.
    End point values
    		 Placebo Sotagliflozin 400 mg
    Number of subjects analysed
    93
    92
    Units: percentage of HbA1c
        least squares mean (standard error)
    -0.11 ( 0.151 )
    -0.40 ( 0.131 )
    Statistical analysis title
    		 Sotagliflozin 400 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 26 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) 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
    185
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0962
    Method
    		 ANCOVA
    Parameter type
    		 Difference in Least Square (LS) Means
    Point estimate
    -0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.628
         upper limit
    		 0.051
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.173

    Secondary: Change from Baseline in HbA1c at Week 26 Comparing Sotagliflozin 200 mg Versus Placebo

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    End point title
    		 Change from Baseline in HbA1c at Week 26 Comparing Sotagliflozin 200 mg Versus Placebo [2]
    End point description
    ITT population included all randomised subjects, irrespective of compliance with the study protocol and procedures. Missing data was imputed using the retrieved dropouts & washout imputation method. An ANCOVA model was used for the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 26
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for the following reporting arms Placebo and Sotagliflozin 200 mg only.
    End point values
    		 Placebo Sotagliflozin 200 mg
    Number of subjects analysed
    93
    92
    Units: percentage of HbA1c
        least squares mean (standard error)
    -0.11 ( 0.151 )
    -0.07 ( 0.162 )
    Statistical analysis title
    		 Sotagliflozin 200 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 26 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) 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 200 mg
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8124
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.338
         upper limit
    		 0.431
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.196

    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, irrespective of compliance with the study protocol and procedures. Missing data was imputed using the retrieved dropouts & washout 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 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    93
    92
    92
    Units: millimole per liter (mmol/L)
        least squares mean (standard error)
    0.069 ( 0.4482 )
    -0.291 ( 0.5056 )
    -0.644 ( 0.4348 )
    Statistical analysis title
    		 Sotagliflozin 200 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 26 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of mean SBP (<130, ≥130 mmHg) at screening, and country as fixed effects, and baseline FPG as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 200 mg
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5501
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.361
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5431
         upper limit
    		 0.822
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.6033
    Statistical analysis title
    		 Sotagliflozin 400 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 26 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of mean SBP (<130, ≥130 mmHg) at screening, and country as fixed effects, and baseline FPG as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1779
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.714
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.7524
         upper limit
    		 0.3246
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.5298

    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, irrespective of compliance with the study protocol and procedures. Missing data was imputed using the retrieved dropouts & washout 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 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    93
    92
    92
    Units: kilogram (kg)
        least squares mean (standard error)
    0.39 ( 0.615 )
    -0.43 ( 0.480 )
    -1.02 ( 0.490 )
    Statistical analysis title
    		 Sotagliflozin 200 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 26 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of mean SBP (<130, ≥130 mmHg) at screening, and country as fixed effects, and baseline body weight as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 200 mg
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2432
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.197
         upper limit
    		 0.557
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.703
    Statistical analysis title
    		 Sotagliflozin 400 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 26 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of mean SBP (<130, ≥130 mmHg) at screening, and country as fixed effects, and baseline body weight as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0487
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.81
         upper limit
    		 -0.008
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.715

    Secondary: Change from Baseline in SBP at Week 12 in Subjects with Baseline SBP ≥130 mmHg

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    End point title
    		 Change from Baseline in SBP at Week 12 in Subjects with Baseline SBP ≥130 mmHg
    End point description
    Analysis population included all subjects with baseline SBP ≥130 mmHg in ITT population where, ITT population included all randomised subjects, irrespective of compliance with the study protocol and procedures. Missing data are imputed using control-based copy reference multiple imputation under the missing not at random framework. An ANCOVA model was used for the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    73
    68
    73
    Units: mmHg
        least squares mean (standard error)
    -2.70 ( 1.815 )
    -4.84 ( 1.882 )
    -7.10 ( 1.842 )
    Statistical analysis title
    		 Sotagliflozin 200 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 12 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at screening, and country as fixed effects, and baseline SBP as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 200 mg
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3954
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -2.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.066
         upper limit
    		 2.792
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.515
    Statistical analysis title
    		 Sotagliflozin 400 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 12 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at 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
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0716
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -4.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.185
         upper limit
    		 0.386
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.442

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

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    End point title
    		 Change from Baseline in SBP at Week 12 for All Subjects
    End point description
    ITT population included all randomised subjects, irrespective of compliance with the study protocol and procedures. Missing data are imputed using control-based copy reference multiple imputation under the missing not at random framework. An ANCOVA model was used for the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    93
    92
    92
    Units: mmHg
        least squares mean (standard error)
    -2.50 ( 1.762 )
    -5.74 ( 1.752 )
    -7.86 ( 1.794 )
    Statistical analysis title
    		 Sotagliflozin 200 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 12 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation 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 200 mg
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1232
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -3.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.365
         upper limit
    		 0.881
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.103
    Statistical analysis title
    		 Sotagliflozin 400 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 12 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation 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
    185
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0098
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -5.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.433
         upper limit
    		 -1.292
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.077

    Secondary: Percentage Change from Baseline in the Urine Albumin: Creatinine Ratio (UACR) at Week 26 in Subjects with Baseline UACR >30 milligrams per gram (mg/g)

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    End point title
    		 Percentage Change from Baseline in the Urine Albumin: Creatinine Ratio (UACR) at Week 26 in Subjects with Baseline UACR >30 milligrams per gram (mg/g)
    End point description
    Analysis population included all subjects with baseline UACR > 30 mg/g in ITT population where, ITT population included all randomised subjects, irrespective of compliance with the study protocol and procedures. Missing data was imputed using the retrieved dropouts & washout 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 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    66
    71
    75
    Units: percent change
        number (not applicable)
    -4.56
    -26.99
    -30.66
    Statistical analysis title
    		 Sotagliflozin 200 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 26 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of mean SBP (<130, ≥130 mmHg) at screening, and country as fixed effects, and log-transformed baseline UACR as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 200 mg
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.222
    Method
    		 ANCOVA
    Parameter type
    		 Percent Difference
    Point estimate
    -20.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -44.75
         upper limit
    		 14.77
    Statistical analysis title
    		 Sotagliflozin 400 mg Vs Placebo
    Statistical analysis description
    The change from baseline to Week 26 was analysed using an ANCOVA model with treatment groups, randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of mean SBP (<130, ≥130 mmHg) at screening, and country as fixed effects, and log-transformed baseline UACR as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1965
    Method
    		 ANCOVA
    Parameter type
    		 Percent Difference
    Point estimate
    -21.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -45.05
         upper limit
    		 13.1

    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, irrespective of compliance with the study protocol and procedures.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    93
    92
    92
    Units: percentage of subjects
        number (not applicable)
    2.2
    5.4
    8.7
    Statistical analysis title
    		 Sotagliflozin 200 mg Vs Placebo
    Statistical analysis description
    Percentage difference between treatment groups using the Cochran-Mantel-Haenszel test stratified by the randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of metformin use at screening (Yes, No), and the randomisation strata of mean SBP (<130, ≥130 mmHg) at screening.
    Comparison groups
    Sotagliflozin 200 mg v Placebo
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.242
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.17
         upper limit
    		 8.66
    Statistical analysis title
    		 Sotagliflozin 400 mg Vs Placebo
    Statistical analysis description
    Percentage difference between treatment groups using the Cochran-Mantel-Haenszel test stratified by the randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of metformin use at screening (Yes, No), and the randomisation strata of mean SBP (<130, ≥130 mmHg) at screening.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0513
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    6.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.04
         upper limit
    		 12.93

    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, irrespective of compliance with the study protocol and procedures.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    93
    92
    92
    Units: percentage of subjects
        number (not applicable)
    4.3
    16.3
    17.4
    Statistical analysis title
    		 Sotagliflozin 200 mg Vs Placebo
    Statistical analysis description
    Percentage difference between treatment groups using the Cochran-Mantel-Haenszel test stratified by the randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of metformin use at screening (Yes, No), and the randomisation strata of mean SBP (<130, ≥130 mmHg) at screening.
    Comparison groups
    Placebo v Sotagliflozin 200 mg
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0066
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.48
         upper limit
    		 20.61
    Statistical analysis title
    		 Sotagliflozin 400 mg Vs Placebo
    Statistical analysis description
    Percentage difference between treatment groups using the Cochran-Mantel-Haenszel test stratified by the randomisation strata of HbA1c (≤8.5, >8.5%) at screening, randomisation strata of metformin use at screening (Yes, No), and the randomisation strata of mean SBP (<130, ≥130 mmHg) at screening.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0043
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.28
         upper limit
    		 21.75

    Secondary: Percentage of Subjects with Treatment-emergent Adverse Events (TEAEs)

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    End point title
    		 Percentage of Subjects with Treatment-emergent Adverse Events (TEAEs) [3]
    End point description
    An AE is any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the investigational medicinal product (IMP). Safety population included all randomised subjects who received at least one dose of double-blind IMP (regardless of the amount of treatment administered).
    End point type
    Secondary
    End point timeframe
    First dose of study drug to last dose of study drug (up to 56.3 weeks) + 4 weeks
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for the following reporting arms Placebo and subject analysis sets Sotagliflozin 200 mg and Sotagliflozin 400 mg.
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    93
    94
    90
    Units: percentage of subjects
        number (not applicable)
    82.8
    86.2
    81.1
    No statistical analyses for this end point

    Other pre-specified: Percentage of Subjects with Hypoglycemic Events

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    End point title
    		 Percentage of Subjects with Hypoglycemic Events [4]
    End point description
    Percentage of subjects with hypoglycemic events are reported for the following 3 categories: Any hypoglycemia (as reported in the Electronic Case Report Form); Documented symptomatic hypoglycemia [typical symptoms of hypoglycemia (increased sweating, nervousness, asthenia/weakness, tremor, dizziness, increased appetite, palpitations, headache, sleep disorder, confusion, seizures, unconsciousness, and/or coma) and plasma glucose ≤ 70 mg/dL (3.9 mmol/L)]; Severe [an event requiring assistance of another person to actively administer carbohydrate, glucagon, intravenous glucose or other resuscitative actions] or documented symptomatic hypoglycemia [typical symptoms of hypoglycemia and plasma glucose ≤ 70 mg/dL]. Safety population included all randomised subjects who received at least 1 dose of double-blind investigational medicinal product (IMP) (regardless of the amount of treatment administered).
    End point type
    Other pre-specified
    End point timeframe
    up to 56.3 weeks
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for the following reporting arms Placebo and subject analysis sets Sotagliflozin 200 mg and Sotagliflozin 400 mg.
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    93
    94
    90
    Units: percentage of subjects
    number (not applicable)
        Any hypoglycemia
    40.9
    40.4
    38.9
        Documented symptomatic hypoglycemia
    35.5
    28.7
    27.8
        Severe or documented symptomatic hypoglycemia
    35.5
    30.9
    27.8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Deaths: Up to approximately 60 weeks; Adverse Events: First dose of study drug to last dose of study drug (up to 56.3 weeks) + 4 weeks
    Adverse event reporting additional description
    Safety population included all randomised subjects who had received at least one dose of double-blind IMP. Hypoglycemia was captured and handled separately from other adverse events and is reported in the endpoint section.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Following a 2-week run-in phase, subjects received two placebo tablets (identical to sotagliflozin 200 mg in appearance) orally once daily for up to 56.3 weeks.

    Reporting group title
    Sotagliflozin 200 mg
    Reporting group description
    		 Following a 2-week run-in phase, subjects received two tablets, one sotagliflozin 200 mg tablet and one placebo tablet (identical to sotagliflozin 200 mg in appearance), orally once daily for up to 55.3 weeks. There were 2 subjects randomised to sotagliflozin 400 mg who were dosed with both sotagliflozin 200 mg and sotagliflozin 400 mg treatments during the study. The data for these subjects were summarised in the sotagliflozin 200 mg arm in the safety population.

    Reporting group title
    Sotagliflozin 400 mg
    Reporting group description
    		 Following a 2-week run-in phase, subjects received sotagliflozin 400 mg, administered as 2 sotagliflozin 200 mg tablets, orally once daily for up to 56.1 weeks. There were 2 subjects randomised to sotagliflozin 400 mg who were dosed with both sotagliflozin 200 mg and sotagliflozin 400 mg treatments during the study. The data for these subjects were summarized in the sotagliflozin 200 mg arm in the safety population.

    Serious adverse events
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 93 (22.58%)
    18 / 94 (19.15%)
    20 / 90 (22.22%)
         number of deaths (all causes)
    6
    6
    3
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 94 (0.00%)
    2 / 90 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder neoplasm
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 94 (0.00%)
    1 / 90 (1.11%)
         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 ductal breast carcinoma
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 94 (0.00%)
    0 / 90 (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
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 94 (1.06%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 94 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 94 (1.06%)
    0 / 90 (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
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 94 (1.06%)
    2 / 90 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 94 (1.06%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 94 (1.06%)
    0 / 90 (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
    Death
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 94 (0.00%)
    0 / 90 (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
    Sudden cardiac death
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 94 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 94 (1.06%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 94 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic respiratory failure
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 94 (0.00%)
    0 / 90 (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
    Painful respiration
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 94 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 94 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 94 (1.06%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 94 (0.00%)
    2 / 90 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheomalacia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 94 (0.00%)
    0 / 90 (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
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 94 (1.06%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Glomerular filtration rate decreased
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 94 (0.00%)
    0 / 90 (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
    Hepatitis C antibody positive
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 94 (0.00%)
    1 / 90 (1.11%)
         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
    Fall
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 94 (0.00%)
    0 / 90 (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
    Femoral neck fracture
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 94 (1.06%)
    0 / 90 (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
    Hip fracture
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 94 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 94 (0.00%)
    0 / 90 (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
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 94 (1.06%)
    0 / 90 (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
    Radius fracture
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 94 (0.00%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    2 / 93 (2.15%)
    0 / 94 (0.00%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    4 / 93 (4.30%)
    1 / 94 (1.06%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 94 (1.06%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 94 (1.06%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 93 (2.15%)
    1 / 94 (1.06%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    2 / 93 (2.15%)
    0 / 94 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    2 / 93 (2.15%)
    1 / 94 (1.06%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 94 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 94 (0.00%)
    0 / 90 (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
    Diastolic dysfunction
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 94 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 94 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 94 (0.00%)
    0 / 90 (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
    Peripheral sensorimotor neuropathy
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 94 (1.06%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 94 (0.00%)
    0 / 90 (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 / 93 (1.08%)
    0 / 94 (0.00%)
    0 / 90 (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
    1 / 93 (1.08%)
    0 / 94 (0.00%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 94 (0.00%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood loss anaemia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 94 (0.00%)
    0 / 90 (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
    Eye disorders
    Eye haemorrhage
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 94 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 94 (0.00%)
    0 / 90 (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
    Haemorrhoids
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 94 (1.06%)
    0 / 90 (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
    Inguinal hernia
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 94 (1.06%)
    0 / 90 (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
    Obstructive pancreatitis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 94 (1.06%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 94 (1.06%)
    0 / 90 (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
    Cholelithiasis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 94 (1.06%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    6 / 93 (6.45%)
    1 / 94 (1.06%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 94 (0.00%)
    0 / 90 (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
    End stage renal disease
         subjects affected / exposed
    1 / 93 (1.08%)
    2 / 94 (2.13%)
    3 / 90 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 94 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 94 (1.06%)
    0 / 90 (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 failure
         subjects affected / exposed
    0 / 93 (0.00%)
    2 / 94 (2.13%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 94 (0.00%)
    1 / 90 (1.11%)
         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
    Fistula
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 94 (0.00%)
    0 / 90 (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
    Metatarsalgia
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 94 (1.06%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 94 (1.06%)
    0 / 90 (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
    Cellulitis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 94 (1.06%)
    0 / 90 (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
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 94 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 94 (1.06%)
    0 / 90 (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
    Herpes zoster
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 94 (0.00%)
    0 / 90 (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
    Influenza
         subjects affected / exposed
    0 / 93 (0.00%)
    0 / 94 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 94 (1.06%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 94 (0.00%)
    4 / 90 (4.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 94 (1.06%)
    0 / 90 (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
    Sepsis
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 94 (0.00%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 93 (0.00%)
    2 / 94 (2.13%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Fluid overload
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 94 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 93 (0.00%)
    2 / 94 (2.13%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    44 / 93 (47.31%)
    44 / 94 (46.81%)
    29 / 90 (32.22%)
    Investigations
    Glomerular filtration rate decreased
         subjects affected / exposed
    3 / 93 (3.23%)
    10 / 94 (10.64%)
    8 / 90 (8.89%)
         occurrences all number
    3
    11
    8
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 93 (5.38%)
    1 / 94 (1.06%)
    3 / 90 (3.33%)
         occurrences all number
    5
    1
    4
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 93 (3.23%)
    5 / 94 (5.32%)
    5 / 90 (5.56%)
         occurrences all number
    3
    5
    8
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    7 / 93 (7.53%)
    5 / 94 (5.32%)
    3 / 90 (3.33%)
         occurrences all number
    7
    6
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 93 (5.38%)
    3 / 94 (3.19%)
    2 / 90 (2.22%)
         occurrences all number
    6
    4
    2
    Infections and infestations
    Influenza
         subjects affected / exposed
    5 / 93 (5.38%)
    5 / 94 (5.32%)
    2 / 90 (2.22%)
         occurrences all number
    5
    5
    2
    Nasopharyngitis
         subjects affected / exposed
    4 / 93 (4.30%)
    8 / 94 (8.51%)
    1 / 90 (1.11%)
         occurrences all number
    4
    9
    1
    Urinary tract infection
         subjects affected / exposed
    16 / 93 (17.20%)
    10 / 94 (10.64%)
    6 / 90 (6.67%)
         occurrences all number
    19
    12
    6
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    2 / 93 (2.15%)
    9 / 94 (9.57%)
    5 / 90 (5.56%)
         occurrences all number
    2
    12
    5
    Hyperuricaemia
         subjects affected / exposed
    6 / 93 (6.45%)
    2 / 94 (2.13%)
    1 / 90 (1.11%)
         occurrences all number
    6
    2
    1
    Vitamin D deficiency
         subjects affected / exposed
    6 / 93 (6.45%)
    9 / 94 (9.57%)
    3 / 90 (3.33%)
         occurrences all number
    6
    9
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Dec 2017
    Amendment 1: 1. Change to the exclusion criteria. 2. Changes to guidance on contraceptive methods. 3. Change to the temporary IMP discontinuation. 4. Change to hepatitis serology test at screening and the related exclusion criterion. 5. Change to the exclusion criterion requiring stability of insulin dose. 6. Change to the general guidelines for reporting of AEs. 7. Remove urgent coronary revascularizations from the events subject to the Clinical Endpoint Committees (CECs) review. 8. Addition of a new section to describe the independent safety assessments for drug-induced liver injuries (DILI) and amputation. 9. Changes to the observation period for safety endpoints. 10. Change to code breaking related to Pharmacokinetic laboratory. 11. Change to the definition of one Event of Special Interest (EOSI), “volume depletion”. 12. Change to definition of baseline for estimated glomerular filtration rate (eGFR). 13. Change to instruction for blood pressure measurement. 14. Change to rescue therapy. 15. Change to urine laboratory test. 16. Change in the order of secondary objectives and endpoints for the study. 17. Other minor changes for corrections of inconsistency, editorial changes, or administration clarification.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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