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    Clinical Trial Results:
    An Exploratory, Randomized, Double-blind, Placebo-controlled, Parallel Arm Trial of the Safety and Pharmacodynamic Activity of Sotagliflozin in Hemodynamically Stable Patients with Worsening Heart Failure

    Summary
    EudraCT number
    		 2017-002774-39
    Trial protocol
    		 NL   IT  
    Global end of trial date
    17 Aug 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Oct 2020
    First version publication date
    04 Oct 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    PDY15079
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03292653
    WHO universal trial number (UTN)
    		 U1111-1190-7962
    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
    17 Aug 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Aug 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is the assessment of safety and tolerability of Sotagliflozin, added to the standard of care treatment, in hemodynamically stable subjects hospitalized for worsening of heart failure, compared to placebo.
    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
    04 Dec 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
    United States: 29
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Netherlands: 2
    Worldwide total number of subjects
    32
    EEA total number of subjects
    2
    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)
    20
    From 65 to 84 years
    11
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects took part in the study at 6 investigative sites in the United States, Canada, and the Netherlands from 04 December 2017 to 17 August 2019.

    Pre-assignment
    Screening details
    		 Subjects with a diagnosis of Congestive Heart Failure (CHF), were enrolled in 1 of 3 treatment groups, Placebo, Sotagliflozin 200 milligrams (mg) and 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
    		 Subjects were randomised to matching placebo to Sotagliflozin administered as two tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.
    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 two tablets (identical to Sotagliflozin in appearance), once daily before the first meal of the day.

    Arm title
    		 Sotagliflozin 200 mg
    Arm description
    		 Subjects were randomised to one Sotagliflozin 200 mg tablet administered and one matching placebo tablet, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.
    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 200 mg
    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
    		 Subjects were randomised to Sotagliflozin 400 mg administered as two tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sotagliflozin 400 mg
    Investigational medicinal product code
    Other name
    SAR439954
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sotagliflozin 400 mg was administered as two Sotagliflozin 200 mg tablets, orally once daily.

    Number of subjects in period 1 [1]
    		Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Started
    10
    10
    11
    Completed
    10
    10
    10
    Not completed
    0
    0
    1
         Adverse event
    -
    -
    1
    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: Number of subjects reported in the baseline period is for treated population. The number of subjects in the worldwide is for randomised population.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were randomised to matching placebo to Sotagliflozin administered as two tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.

    Reporting group title
    Sotagliflozin 200 mg
    Reporting group description
    		 Subjects were randomised to one Sotagliflozin 200 mg tablet administered and one matching placebo tablet, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.

    Reporting group title
    Sotagliflozin 400 mg
    Reporting group description
    		 Subjects were randomised to Sotagliflozin 400 mg administered as two tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.

    Reporting group values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg Total
    Number of subjects
    		 10 10 11 31
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.8 ( 13.05 ) 55.1 ( 12.84 ) 65.1 ( 13.41 ) -
    Gender categorical
    Units: Subjects
        Female
    		 3 0 4 7
        Male
    		 7 10 7 24
    Race
    Units: Subjects
        White
    		 4 5 6 15
        Black or African American
    		 6 5 4 15
        Not Reported
    		 0 0 1 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 0 1 1
        Not Hispanic or Latino
    		 10 10 10 30

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were randomised to matching placebo to Sotagliflozin administered as two tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.

    Reporting group title
    Sotagliflozin 200 mg
    Reporting group description
    		 Subjects were randomised to one Sotagliflozin 200 mg tablet administered and one matching placebo tablet, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.

    Reporting group title
    Sotagliflozin 400 mg
    Reporting group description
    		 Subjects were randomised to Sotagliflozin 400 mg administered as two tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.

    Primary: Percentage of Subjects with Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Special Interest (AESIs), AEs Leading to Discontinuation From the Investigational Medicinal Product (IMP) and Deaths

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    End point title
    		 Percentage of Subjects with Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Special Interest (AESIs), AEs Leading to Discontinuation From the Investigational Medicinal Product (IMP) and Deaths [1]
    End point description
    AE is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. SAEs: an event that results in death; an event that, in the view of the investigator, places the subjects at immediate risk of death (a life-threatening event); an outcome that results in a congenital anomaly/birth defect diagnosed in a child of a subject; an event that requires or prolongs inpatient hospitalization; an event that results in persistent or significant disability/incapacity. AESI: is an adverse event (serious or nonserious) of scientific and medical concern, specific to the IMP or program, for which ongoing monitoring and rapid communication by the Investigator to the Sponsor may be appropriate. Safety population included all randomised subjects who had exposure to any amount of IMP.
    End point type
    Primary
    End point timeframe
    Baseline up to Day 14
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistical analysis was planned to be reported for this endpoint.
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    10
    10
    11
    Units: percentage of subjects
    number (not applicable)
        AEs
    40
    30
    45.5
        SAEs
    10
    0
    0
        AESIs
    0
    0
    0
        AEs Leading to Discontinuation From the IMP
    0
    0
    9.1
        Deaths
    0
    0
    0
    No statistical analyses for this end point

    Primary: Change From Baseline in Hemoconcentration as Assessed by Changes in Albumin to Day 14

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    End point title
    		 Change From Baseline in Hemoconcentration as Assessed by Changes in Albumin to Day 14
    End point description
    Pharmacodynamic (PD) population included all randomised and treated subjects who had valid values of the main PD parameters at baseline and Day 14 End of Treatment (EOT).
    End point type
    Primary
    End point timeframe
    Baseline to Day 14
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    7 [2]
    6 [3]
    9 [4]
    Units: grams per litre (g/L)
        least squares mean (standard error)
    1.17 ( 2.71 )
    2.44 ( 2.40 )
    0.15 ( 2.14 )
    Notes
    [2] - The number of subjects analysed is the number of subjects with available data.
    [3] - The number of subjects analysed is the number of subjects with available data.
    [4] - The number of subjects analysed is the number of subjects with available data.
    Statistical analysis title
    		 Sotagliflozin 200 mg Vs Placebo
    Statistical analysis description
    Analysis of Covariance (ANCOVA) model with fixed effects for treatment and stratification factors of baseline subject status (diabetic/non-diabetic, ejection fraction status (reduced/preserved) with baseline plasma volume as the covariate.
    Comparison groups
    Sotagliflozin 200 mg v Placebo
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.736
    Method
    		 ANCOVA
    Parameter type
    		 Difference in Least Square (LS) Means
    Point estimate
    1.26
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -5.4
         upper limit
    		 7.93
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.64
    Statistical analysis title
    		 Sotagliflozin 400 mg Vs Placebo
    Statistical analysis description
    ANCOVA model with fixed effects for treatment and stratification factors of baseline subject status (diabetic/non-diabetic), ejection fraction status (reduced/preserved) with baseline plasma volume as the covariate.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7694
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.02
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -7.22
         upper limit
    		 5.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.38

    Primary: Change From Baseline in Hemoconcentration as Assessed by Changes in Hematocrit to Day 14

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    End point title
    		 Change From Baseline in Hemoconcentration as Assessed by Changes in Hematocrit to Day 14
    End point description
    PD population included all randomised and treated subjects who had valid values of the main PD parameters at baseline and Day 14 (EOT).
    End point type
    Primary
    End point timeframe
    Baseline to Day 14
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    10
    9 [5]
    10 [6]
    Units: ratio
        least squares mean (standard error)
    0.02 ( 0.02 )
    -0.02 ( 0.02 )
    -0.01 ( 0.02 )
    Notes
    [5] - The number of subjects analysed is the number of subjects with available data.
    [6] - The number of subjects analysed is the number of subjects with available data.
    Statistical analysis title
    		 Sotagliflozin 200 mg Vs Placebo
    Statistical analysis description
    ANCOVA model with fixed effects for treatment and stratification factors of baseline subject status (diabetic/non-diabetic), ejection fraction status (reduced/preserved) with baseline plasma volume as the covariate.
    Comparison groups
    Sotagliflozin 200 mg v Placebo
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.184
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.04
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.09
         upper limit
    		 0.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.03
    Statistical analysis title
    		 Sotagliflozin 400 mg Vs Placebo
    Statistical analysis description
    ANCOVA model with fixed effects for treatment and stratification factors of baseline subject status (diabetic/non-diabetic), ejection fraction status (reduced/preserved) with baseline plasma volume as the covariate.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3397
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.03
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.07
         upper limit
    		 0.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.03

    Primary: Change From Baseline in Hemoconcentration as Assessed by Changes in Hemoglobin to Day 14

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    End point title
    		 Change From Baseline in Hemoconcentration as Assessed by Changes in Hemoglobin to Day 14
    End point description
    PD population included all randomised and treated subjects who had valid values of the main PD parameters at baseline and Day 14 (EOT).
    End point type
    Primary
    End point timeframe
    Baseline to Day 14
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    10
    9 [7]
    10 [8]
    Units: g/L
        least squares mean (standard error)
    8.16 ( 6.80 )
    -8.91 ( 6.02 )
    -3.94 ( 5.37 )
    Notes
    [7] - The number of subjects analysed is the number of subjects with available data.
    [8] - The number of subjects analysed is the number of subjects with available data.
    Statistical analysis title
    		 Sotagliflozin 200 mg Vs Placebo
    Statistical analysis description
    ANCOVA model with fixed effects for treatment and stratification factors of baseline subject status (diabetic/non-diabetic), ejection fraction status (reduced/preserved) with baseline plasma volume as the covariate.
    Comparison groups
    Placebo v Sotagliflozin 200 mg
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.094
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -17.07
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -33.79
         upper limit
    		 -0.35
    Variability estimate
    Standard error of the mean
    Dispersion value
    9.12
    Statistical analysis title
    		 Sotagliflozin 400 mg Vs Placebo
    Statistical analysis description
    ANCOVA model with fixed effects for treatment and stratification factors of baseline subject status (diabetic/non-diabetic), ejection fraction status (reduced/preserved) with baseline plasma volume as the covariate.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1878
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -12.09
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -27.65
         upper limit
    		 3.46
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.49

    Primary: Change From Baseline in Hemoconcentration as Assessed by Changes in Total Protein to Day 14

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    End point title
    		 Change From Baseline in Hemoconcentration as Assessed by Changes in Total Protein to Day 14
    End point description
    PD population included all randomised and treated subjects who had valid values of the main PD parameters at baseline and Day 14 (EOT).
    End point type
    Primary
    End point timeframe
    Baseline to Day 14
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    7 [9]
    6 [10]
    9 [11]
    Units: g/L
        least squares mean (standard error)
    5.31 ( 4.32 )
    0.49 ( 3.83 )
    -1.05 ( 3.41 )
    Notes
    [9] - The number of subjects analysed is the number of subjects with available data.
    [10] - The number of subjects analysed is the number of subjects with available data.
    [11] - The number of subjects analysed is the number of subjects with available data.
    Statistical analysis title
    		 Sotagliflozin 200 mg Vs Placebo
    Statistical analysis description
    ANCOVA model with fixed effects for treatment and stratification factors of baseline subject status (diabetic/non-diabetic), ejection fraction status (reduced/preserved) with baseline plasma volume as the covariate.
    Comparison groups
    Placebo v Sotagliflozin 200 mg
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4269
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -4.82
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -15.45
         upper limit
    		 5.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.8
    Statistical analysis title
    		 Sotagliflozin 400 mg Vs Placebo
    Statistical analysis description
    ANCOVA model with fixed effects for treatment and stratification factors of baseline subject status (diabetic/non-diabetic), ejection fraction status (reduced/preserved) with baseline plasma volume as the covariate.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2684
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -6.36
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -16.24
         upper limit
    		 3.52
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.39

    Primary: Changes From Baseline in Plasma Volume to Day 14

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    End point title
    		 Changes From Baseline in Plasma Volume to Day 14
    End point description
    Change in plasma volume in millilitres (ml) was assessed by the indicator dilution method using 131I-labelled human albumin. PD population included all randomised and treated subjects who had valid values of the main PD parameters at baseline and Day 14 (EOT).
    End point type
    Primary
    End point timeframe
    Baseline to 14 Days
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    4 [12]
    6 [13]
    5 [14]
    Units: ml
        least squares mean (standard error)
    -525.00 ( 433.19 )
    322.20 ( 359.23 )
    -35.67 ( 392.43 )
    Notes
    [12] - The number of subjects analysed is the number of subjects with available data.
    [13] - The number of subjects analysed is the number of subjects with available data.
    [14] - The number of subjects analysed is the number of subjects with available data.
    Statistical analysis title
    		 Sotagliflozin 200 mg Vs Placebo
    Statistical analysis description
    ANCOVA model with fixed effects for treatment and stratification factors of baseline subject status (diabetic/non-diabetic), ejection fraction status (reduced/preserved) with baseline plasma volume as the covariate.
    Comparison groups
    Placebo v Sotagliflozin 200 mg
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1761
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    847.2
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -210.46
         upper limit
    		 1904.86
    Variability estimate
    Standard error of the mean
    Dispersion value
    576.98
    Statistical analysis title
    		 Sotagliflozin 400 mg Vs Placebo
    Statistical analysis description
    ANCOVA model with fixed effects for treatment and stratification factors of baseline subject status (diabetic/non-diabetic), ejection fraction status (reduced/preserved) with baseline plasma volume as the covariate.
    Comparison groups
    Placebo v Sotagliflozin 400 mg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4202
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    489.33
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -572.68
         upper limit
    		 1551.34
    Variability estimate
    Standard error of the mean
    Dispersion value
    579.35

    Secondary: Change From Baseline in Erythropoietin to Day 14

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    End point title
    		 Change From Baseline in Erythropoietin to Day 14
    End point description
    Change in erythropoietin international units per litre (IU/L) was measured by chemiluminescent enzyme-labelled immunometric assay. PD population included all randomised and treated subjects who had valid values of the main PD parameters at baseline and Day 14 (EOT).
    End point type
    Secondary
    End point timeframe
    Baseline to Day 14
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    7 [15]
    7 [16]
    10 [17]
    Units: international units per litre (IU/L)
        least squares mean (standard error)
    0.03 ( 5.92 )
    13.78 ( 6.26 )
    -0.07 ( 5.04 )
    Notes
    [15] - The number of subjects analysed is the number of subjects with available data.
    [16] - The number of subjects analysed is the number of subjects with available data.
    [17] - The number of subjects analysed is the number of subjects with available data.
    Statistical analysis title
    		 Sotagliflozin 200 mg Vs Placebo
    Statistical analysis description
    ANCOVA model with fixed effects for treatment and stratification factors of baseline subject status (diabetic/non-diabetic), ejection fraction status (reduced/preserved) with baseline erythropoietin as the covariate.
    Comparison groups
    Placebo v Sotagliflozin 200 mg
    Number of subjects included in analysis
    14
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1242
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    13.75
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1.03
         upper limit
    		 28.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.53
    Statistical analysis title
    		 Sotagliflozin 400 mg Vs Placebo
    Statistical analysis description
    ANCOVA model with fixed effects for treatment and stratification factors of baseline subject status (diabetic/non-diabetic), ejection fraction status (reduced/preserved) with baseline erythropoietin as the covariate.
    Comparison groups
    Sotagliflozin 400 mg v Placebo
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9903
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.1
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -13.49
         upper limit
    		 13.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.73

    Secondary: Change From Baseline in NT-proBNP to Day 14

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    End point title
    		 Change From Baseline in NT-proBNP to Day 14
    End point description
    Change in NT-proBNP picomoles per litre (pmol/L) was measured by standard electrochemiluminescence immunoassay. PD population included all randomised and treated subjects who had valid values of the main PD parameters at baseline and Day 14 (EOT).
    End point type
    Secondary
    End point timeframe
    Baseline to Day 14
    End point values
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Number of subjects analysed
    7 [18]
    6 [19]
    9 [20]
    Units: picomoles per litre (pmol/L)
        least squares mean (standard error)
    91.36 ( 78.04 )
    -59.53 ( 81.28 )
    86.10 ( 65.87 )
    Notes
    [18] - The number of subjects analysed is the number of subjects with available data.
    [19] - The number of subjects analysed is the number of subjects with available data.
    [20] - The number of subjects analysed is the number of subjects with available data.
    Statistical analysis title
    		 Sotagliflozin 200 mg Vs Placebo
    Statistical analysis description
    ANCOVA model with fixed effects for treatment and stratification factors of baseline subject status (diabetic/non-diabetic), ejection fraction status (reduced/preserved) with baseline NT-proBNP as the covariate.
    Comparison groups
    Placebo v Sotagliflozin 200 mg
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2121
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -150.89
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -353.57
         upper limit
    		 51.78
    Variability estimate
    Standard error of the mean
    Dispersion value
    116.09
    Statistical analysis title
    		 Sotagliflozin 400 mg Vs Placebo
    Statistical analysis description
    ANCOVA model with fixed effects for treatment and stratification factors of baseline subject status (diabetic/non-diabetic), ejection fraction status (reduced/preserved) with baseline NT-proBNP as the covariate.
    Comparison groups
    Sotagliflozin 400 mg v Placebo
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9574
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -5.26
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -174.4
         upper limit
    		 163.87
    Variability estimate
    Standard error of the mean
    Dispersion value
    96.88

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose of study drug to last dose of study drug (up to Day 14) + 2 weeks
    Adverse event reporting additional description
    Safety population included all randomised subjects who had exposure to any amount of IMP.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were randomised to matching placebo to Sotagliflozin administered as two tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.

    Reporting group title
    Sotagliflozin 200 mg
    Reporting group description
    		 Subjects were randomised to one Sotagliflozin 200 mg tablet administered and one matching placebo tablet, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.

    Reporting group title
    Sotagliflozin 400 mg
    Reporting group description
    		 Subjects were randomised to Sotagliflozin 400 mg administered as two tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.

    Serious adverse events
    		 Placebo Sotagliflozin 200 mg Sotagliflozin 400 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 11 (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
    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
    4 / 10 (40.00%)
    3 / 10 (30.00%)
    5 / 11 (45.45%)
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Myocardial infarction
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 10 (10.00%)
    1 / 11 (9.09%)
         occurrences all number
    2
    1
    1
    Nausea
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    1
    Rectal haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    Hypoxia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    Wheezing
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Stress
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Fluid intake reduced
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Hypoglycaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Jan 2018
    Amendment 1: 1. Added EudraCT and World Health Organization (WHO) Universal Trial numbers. 2. Added exclusion of History of Type 1 Diabetes Mellitus. 3. Removed the exclusion of high dose thiazide diuretic. 4. Added exclusion of lower extremity diabetic complications requiring treatment. 5. Screening duration was updated. 6. Guidance for stopping rules were updated. 7. Appendices for sample collection were removed.
    14 Mar 2018
    Amendment 2: 1. Added that exploratory analysis may be performed for safety reasons as requested by the Data Monitoring Committee (DMC) or Ethics committee that would not result in changes to the protocol. 2. Clarified procedures for subjects who were not discharged.
    01 Aug 2019
    Amendment 3: 1. Removed 200 mg arm from cohort 3 without replacing subjects. 2. Reduce the burden off the subjects-traveling to the site by reducing the visit. 3. Removed pharmacokinetic (PK) assessments from the cohort 3. 4. Clarified that tachycardia >130 at screening is grounds for exclusion. 5. Removed reference to the interim analysis. 6. Removed the requirement to eat 15 minutes after investigational medicinal product (IMP) administration in cohort 3.

    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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