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    Clinical Trial Results:
    A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the Net Clinical Benefit of Sotagliflozin as Adjunct to Insulin Therapy in Type 1 Diabetes

    Summary
    EudraCT number
    		 2015-001709-15
    Trial protocol
    		 DE   HU   CZ   BE   SK   GB   ES   BG   PL   IT  
    Global end of trial date
    18 Apr 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 May 2018
    First version publication date
    02 May 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LX4211.1-312-T1DM
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02531035
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Lexicon Pharmaceuticals, Inc.
    Sponsor organisation address
    8800 Technology Forest Place, The Woodlands, United States, 77381-1160
    Public contact
    Sangeeta Sawhney, Executive Medical Director, Lexicon Pharmaceuticals, Inc., +01 832 702 6527, ssawhney@lexpharma.com
    Scientific contact
    Sangeeta Sawhney, Executive Medical Director, Lexicon Pharmaceuticals, Inc., +01 832 702 6527, ssawhney@lexpharma.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Apr 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Apr 2017
    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 in the proportion of patients with glycosylated A1C <7.0% at Week 24 and no episode of severe hypoglycemia and no episode of diabetic ketoacidosis (DKA) after randomization.
    Protection of trial subjects
    All subjects were required to read and sign an informed consent.
    Background therapy
    		 All subjects received insulin therapy adjusted consistent with standard of care.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Sep 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 88
    Country: Number of subjects enrolled
    Slovakia: 26
    Country: Number of subjects enrolled
    Spain: 46
    Country: Number of subjects enrolled
    United Kingdom: 29
    Country: Number of subjects enrolled
    Belgium: 24
    Country: Number of subjects enrolled
    Bulgaria: 61
    Country: Number of subjects enrolled
    Czech Republic: 70
    Country: Number of subjects enrolled
    France: 29
    Country: Number of subjects enrolled
    Germany: 33
    Country: Number of subjects enrolled
    Hungary: 62
    Country: Number of subjects enrolled
    Italy: 31
    Country: Number of subjects enrolled
    Argentina: 23
    Country: Number of subjects enrolled
    Australia: 79
    Country: Number of subjects enrolled
    Canada: 172
    Country: Number of subjects enrolled
    Colombia: 33
    Country: Number of subjects enrolled
    Israel: 39
    Country: Number of subjects enrolled
    New Zealand: 53
    Country: Number of subjects enrolled
    South Africa: 98
    Country: Number of subjects enrolled
    United States: 409
    Worldwide total number of subjects
    1405
    EEA total number of subjects
    499
    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)
    1304
    From 65 to 84 years
    101
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects took part in the study at 133 investigative sites in Poland, Slovakia, Spain, United Kingdom, Belgium, Bulgaria, Czech Republic, France, Germany, Hungary, Italy, Argentina, Australia, Canada, Colombia, Israel, New Zealand, South Africa and United States from 18 September 2015 to 18 April 2017.

    Pre-assignment
    Screening details
    		 1755 subjects were screened and 1490 entered the Single-blind Placebo run-in Period. 1405 subjects with a diagnosis of Type 1 Diabetes were enrolled equally in 1 of 2 treatment groups: placebo or sotagliflozin 400 mg.

    Pre-assignment period milestones
    Number of subjects started
    		 1405
    Number of subjects completed
    		 1402

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Lost to follow up: 1
    Reason: Number of subjects
    		 Withdrawal by subject: 2
    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Two placebo-matching sotagliflozin tablets daily, orally, before the first meal of the day for 24 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Two tablets daily, by mouth, before the first meal of the day for 24 weeks.

    Arm title
    		 Sotagliflozin 400 mg
    Arm description
    		 Sotagliflozin 400 mg (two 200 mg tablets) once daily, orally, before the first meal of the day for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sotagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Two 200 mg tablets once daily, by mouth, before the first meal of the day for 24 weeks

    Number of subjects in period 1 [1]
    		Placebo Sotagliflozin 400 mg
    Started
    703
    699
    Completed
    624
    605
    Not completed
    79
    94
         Physician decision
    1
    -
         Adverse event, non-fatal
    16
    45
         Other, unspecified
    3
    2
         Death
    -
    1
         Noncompliance with study drug
    8
    3
         Lost to follow-up
    8
    10
         Protocol deviation
    1
    1
         Withdrawal by subject
    42
    32
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Three participants did not receive study drug and are not included in the modified Intent-to-treat (mITT) population that is used for the Baseline Period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Two placebo-matching sotagliflozin tablets daily, orally, before the first meal of the day for 24 weeks.

    Reporting group title
    Sotagliflozin 400 mg
    Reporting group description
    		 Sotagliflozin 400 mg (two 200 mg tablets) once daily, orally, before the first meal of the day for 24 weeks.

    Reporting group values
    		 Placebo Sotagliflozin 400 mg Total
    Number of subjects
    		 703 699 1402
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 42.4 ± 14.04 43.3 ± 14.17 -
    Gender categorical
    Units: Subjects
        Female
    		 364 341 705
        Male
    		 339 358 697
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 5 1 6
        Asian
    		 5 7 12
        Black or African American
    		 22 24 46
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        White
    		 621 619 1240
        Other
    		 37 31 68
        Not Applicable
    		 13 16 29
    Body weight
    Units: kg (kilograms)
        arithmetic mean (standard deviation)
    		 81.55 ± 17.032 82.40 ± 17.131 -
    A1C
    A1C is the measurement of hemoglobin A1C. Data is available for 701 participants in the Placebo arm and 699 participants in the Sotagliflozin arm.
    Units: percent of A1C
        arithmetic mean (standard deviation)
    		 8.21 ± 0.921 8.26 ± 0.965 -
    Body Mass Index
    Units: kg/m^2 (kilogram(s)/square meter)
        arithmetic mean (standard deviation)
    		 28.1 ± 5.183 28.29 ± 5.128 -
    Duration of Diabetes
    Units: years
        arithmetic mean (standard deviation)
    		 19.6 ± 12.07 20.5 ± 12.37 -
    Baseline Total Daily Insulin
    Units: International Units/kilogram (IU/kg)
        arithmetic mean (standard deviation)
    		 0.71 ± 0.291 0.69 ± 0.276 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Two placebo-matching sotagliflozin tablets daily, orally, before the first meal of the day for 24 weeks.

    Reporting group title
    Sotagliflozin 400 mg
    Reporting group description
    		 Sotagliflozin 400 mg (two 200 mg tablets) once daily, orally, before the first meal of the day for 24 weeks.

    Subject analysis set title
    Placebo (Baseline SBP >=130 mm Hg)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Two placebo-matching sotagliflozin tablets daily, orally, before the first meal of the day for 24 weeks. Includes participants with Baseline Systolic Blood Pressure (SBP) >=130 mm Hg.

    Subject analysis set title
    Sotagliflozin 400 mg (Baseline SBP >=130 mm Hg)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Sotagliflozin 400 mg (two 200 mg tablets) once daily, orally, before the first meal of the day for 24 weeks. Includes participants with SBP >= 130 mm Hg.

    Primary: Percentage of Participants with A1C <7.0% at Week 24 and No Episode of Severe Hypoglycemia and No Episode of DKA after Randomization

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    End point title
    		 Percentage of Participants with A1C <7.0% at Week 24 and No Episode of Severe Hypoglycemia and No Episode of DKA after Randomization
    End point description
    The Primary composite endpoint included fasting blood samples for the assessment of Hemoglobin A1C to determine the participants with a value <7.0%. A central blinded adjudication process determined whether participants experienced either DKA or Severe Hypoglycemia. The primary efficacy analyses were based on the modified Intent-to-Treat (mITT) population, defined as all randomly assigned patients who had taken at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Baseline to end of treatment (Week 24)
    End point values
    		 Placebo Sotagliflozin 400 mg
    Number of subjects analysed
    703
    699
    Units: percentage of participants
        number (not applicable)
    15.2
    28.6
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    1402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [1]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage difference
    Point estimate
    13.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.97
         upper limit
    		 17.81
    Notes
    [1] - P-values from a CMH test stratified by the different levels of the stratification factors of BMI at Screening (<25 kg/m^2, ≥25 kg/m^2), Week -2 A1C (≤9.0%, >9.0%), and use of continuous subcutaneous insulin infusion (CSII) at Screening (yes, no).

    Secondary: Change from Baseline in A1C

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    End point title
    		 Change from Baseline in A1C
    End point description
    Baseline value was defined as the last value collected prior to the first dose of double-blind study medication. LS means were obtained from a MMRM model including all available post baseline data. A negative change from Baseline (a lower AIC value at Week 24) indicates an improvement. Analyses included participants from the mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Placebo Sotagliflozin 400 mg
    Number of subjects analysed
    628
    627
    Units: percent change in A1C
        least squares mean (standard error)
    -0.33 ± 0.031
    -0.79 ± 0.032
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Testing according to hierarchical procedure. Post-Baseline LS means and p-values were obtained from MMRM model with treatment, randomization stratum of BMI at Screening (<25 kg/m^2, ≥25 kg/m^2), randomization stratum of Week -2 A1C (≤9.0%, >9.0%), randomization stratum of use of CSII at Screening (yes, no), time (study week), and a treatment-by-time interaction as fixed categorical effects, and Baseline A1C-by-time interaction as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    1255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.54
         upper limit
    		 -0.38

    Secondary: Absolute Change from Baseline in Body Weight

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    End point title
    		 Absolute Change from Baseline in Body Weight
    End point description
    Baseline value was defined as the last value collected prior to the first dose of double-blind study medication. LS means were obtained from MMRM model. A negative change from Baseline indicates a loss in body weight from Baseline to Week 24. Analyses included participants from the mITT population, including all available post baseline values.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Placebo Sotagliflozin 400 mg
    Number of subjects analysed
    633
    630
    Units: kg (kilograms)
        least squares mean (standard error)
    0.77 ± 0.122
    -2.21 ± 0.122
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Testing according to hierarchical procedure. Post-Baseline LS means and p-values were obtained from MMRM model with treatment, randomization stratum of BMI at Screening (<25 kg/m^2, >=25 kg/m^2), randomization stratum of Week -2 A1C (<=9%, >9%), randomization stratum of Use of CSII at Screening (Yes, No), time (study week), and a treatment-by-time interaction as fixed categorical effects, and Baseline weight-by-time interaction as a covariate.
    Comparison groups
    Sotagliflozin 400 mg v Placebo
    Number of subjects included in analysis
    1263
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -2.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.31
         upper limit
    		 -2.66

    Secondary: Change from Baseline in Systolic Blood Pressure (SBP) in the Subset of Participants with Baseline SBP >=130 mm Hg

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    End point title
    		 Change from Baseline in Systolic Blood Pressure (SBP) in the Subset of Participants with Baseline SBP >=130 mm Hg
    End point description
    An automatic sphygmomanometer was used with instructions on blood pressure measurements to allow for standardization. Week 16 was used because the protocol required Investigators to keep participant's hypertensive medications stable between Baseline and Week 16, unless a change was required for safety reasons. Baseline was defined as the last value collected prior to the first does of double-blind study medication. LS means were obtained from MMRM model including all available post baseline values. A negative change indicates a decrease in SBP between Baseline and Week 16. Participants from mITT population, all randomly assigned participants who had a Baseline SBP ≥130 mm Hg.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    		 Placebo (Baseline SBP >=130 mm Hg) Sotagliflozin 400 mg (Baseline SBP >=130 mm Hg)
    Number of subjects analysed
    192
    186
    Units: mm Hg
        least squares mean (standard error)
    -5.7 ± 0.90
    -9.2 ± 0.92
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Testing according to the hierarchical procedure. Post-Baseline LS means and p-values were obtained from MMRM model with treatment, randomization stratum of BMI at Screening (<25 kg/m2, ≥25 kg/m2), randomization stratum of Week -2 A1C (≤9.0%, >9.0%), randomization stratum of use of CSII at Screening (yes, no), time (study week), and a treatment-by- time interaction as fixed categorical effects, and Baseline SBP-by-time interaction as a covariate.
    Comparison groups
    Sotagliflozin 400 mg (Baseline SBP >=130 mm Hg) v Placebo (Baseline SBP >=130 mm Hg)
    Number of subjects included in analysis
    378
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -3.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.7
         upper limit
    		 -1.3

    Secondary: Percent Change from Baseline in Mean Daily Bolus Insulin Dose

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    End point title
    		 Percent Change from Baseline in Mean Daily Bolus Insulin Dose
    End point description
    The mean bolus insulin dose in international units/day (IU/day) for Week 24 was the average over the 3 to 5 days prior to the Week 24 visit. The Baseline value was defined as the last value collected prior to the first dose of double-blind study medication. LS means were obtained from MMRM model including all available post Baseline values. A negative percent change from Baseline indicated a reduction in the amount of bolus insulin used and a positive percent change from Baseline indicated an increase in the amount of bolus insulin used between Baseline and Week 24. Analyses included participants from the mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Placebo Sotagliflozin 400 mg
    Number of subjects analysed
    623
    617
    Units: percent change in IU/day
        least squares mean (standard error)
    6.62 ± 2.272
    -5.71 ± 2.289
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Testing according to hierarchical procedure. Post-Baseline LS means and p-values were obtained from MMRM model with treatment, randomization stratum of BMI at Screening (<25 kg/m2, ≥25 kg/m2), randomization stratum of Week -2 A1C (≤9.0%, >9.0%), randomization stratum of use of CSII at Screening (yes, no), time (study week), a treatment-by-time interaction as fixed categorical effects, and Baseline mean daily bolus insulin dose-by-time interaction as a covariate.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    1240
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 MMRM
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -12.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18.17
         upper limit
    		 -6.48

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline (Day 1) of the Double-blind Period to 30 days after end of treatment (Up to 28 Weeks)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Two placebo-matching sotagliflozin tablets daily, orally, before the first meal of the day for 24 weeks.

    Reporting group title
    Sotagliflozin 400 mg
    Reporting group description
    		 Sotagliflozin 400 mg (two 200 mg tablets) once daily, orally, before the first meal of the day for 24 weeks.

    Serious adverse events
    		 Placebo Sotagliflozin 400 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 703 (3.27%)
    48 / 699 (6.87%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 703 (0.14%)
    0 / 699 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 703 (0.14%)
    0 / 699 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 703 (0.00%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 703 (0.00%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 703 (0.14%)
    0 / 699 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 703 (0.14%)
    0 / 699 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    1 / 703 (0.14%)
    0 / 699 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcoholism
         subjects affected / exposed
    1 / 703 (0.14%)
    0 / 699 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 703 (0.00%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 703 (0.00%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Suicidal ideation
         subjects affected / exposed
    1 / 703 (0.14%)
    0 / 699 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood ketone body increased
         subjects affected / exposed
    0 / 703 (0.00%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urine ketone body present
         subjects affected / exposed
    1 / 703 (0.14%)
    0 / 699 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    0 / 703 (0.00%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 703 (0.00%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary artery disease
         subjects affected / exposed
    0 / 703 (0.00%)
    2 / 699 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 703 (0.00%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 703 (0.00%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 703 (0.00%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Hypoglycaemic unconsciousness
         subjects affected / exposed
    4 / 703 (0.57%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalomalacia
         subjects affected / exposed
    0 / 703 (0.00%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic coma
         subjects affected / exposed
    0 / 703 (0.00%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic seizure
         subjects affected / exposed
    0 / 703 (0.00%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 703 (0.00%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 703 (0.14%)
    0 / 699 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Aural polyp
         subjects affected / exposed
    0 / 703 (0.00%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Vitreous haemorrhage
         subjects affected / exposed
    1 / 703 (0.14%)
    0 / 699 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 703 (0.14%)
    0 / 699 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 703 (0.00%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 703 (0.00%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesenteric panniculitis
         subjects affected / exposed
    0 / 703 (0.00%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 703 (0.00%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 703 (0.00%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 703 (0.00%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 703 (0.00%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
         subjects affected / exposed
    0 / 703 (0.00%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 703 (0.14%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis infective
         subjects affected / exposed
    1 / 703 (0.14%)
    0 / 699 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 703 (0.14%)
    0 / 699 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 703 (0.00%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    0 / 703 (0.00%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    0 / 703 (0.00%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 703 (0.14%)
    0 / 699 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    1 / 703 (0.14%)
    0 / 699 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    0 / 703 (0.00%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    5 / 703 (0.71%)
    22 / 699 (3.15%)
         occurrences causally related to treatment / all
    3 / 5
    12 / 26
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 703 (0.14%)
    3 / 699 (0.43%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 703 (0.14%)
    0 / 699 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    0 / 703 (0.00%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 703 (0.00%)
    1 / 699 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    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
    70 / 703 (9.96%)
    70 / 699 (10.01%)
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    17 / 703 (2.42%)
    35 / 699 (5.01%)
         occurrences all number
    22
    41
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    55 / 703 (7.82%)
    41 / 699 (5.87%)
         occurrences all number
    62
    46

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Oct 2015
    Amendment 1: -Instruction that patients taking concomitant digoxin (or other P-gp substrates) should be evaluated for dose adjustments as necessary (based on data from LX4211.1- 114-NRM) -Inclusion of Beta-Hydroxybutyrate (BHB) meter to be distributed to patients -Text clarification for temporary study drug interruption in case of AEs -Inclusion of all cases of metabolic acidosis as events of special interest (EOSI) (as per FDA recommendation)

    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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