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    Clinical Trial Results:
    A Phase III, randomised, double blind, placebo-controlled, parallel group, efficacy, safety and tolerability trial of once daily, oral doses of Empagliflozin as Adjunctive to inSulin thErapy over 26 weeks in patients with Type 1 Diabetes Mellitus (EASE-3)

    Summary
    EudraCT number
    		 2014-005256-26
    Trial protocol
    		 DE   SE   GB   FI   IE   LV   NL   HU   PT   GR   FR   CZ   IT  
    Global end of trial date
    20 Sep 2017

    Results information
    Results version number
    		 v1
    This version publication date
    06 Oct 2018
    First version publication date
    06 Oct 2018
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    1245.72
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02580591
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    Boehringer Ingelheim, QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, 011 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    Boehringer Ingelheim, QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, 011 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Feb 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Sep 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Sep 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this study was to assess the efficacy, safety, tolerability and pharmacokinetics (PK) of once daily oral doses of Empagliflozin 2.5 milligram (mg), 10 mg and 25 mg compared with placebo in patients with type 1 diabetes mellitus (T1DM) as adjunctive to optimized insulin therapy.
    Protection of trial subjects
    Only patients that met all the study inclusion and none of the exclusion criteria were to be randomized in the study. All patients were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all patients was adhered to throughout the trial conduct.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Oct 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
    Australia: 39
    Country: Number of subjects enrolled
    Canada: 111
    Country: Number of subjects enrolled
    Czech Republic: 78
    Country: Number of subjects enrolled
    Finland: 30
    Country: Number of subjects enrolled
    France: 35
    Country: Number of subjects enrolled
    Germany: 159
    Country: Number of subjects enrolled
    Greece: 25
    Country: Number of subjects enrolled
    Hungary: 112
    Country: Number of subjects enrolled
    Ireland: 3
    Country: Number of subjects enrolled
    Italy: 46
    Country: Number of subjects enrolled
    Latvia: 56
    Country: Number of subjects enrolled
    Mexico: 90
    Country: Number of subjects enrolled
    Netherlands: 50
    Country: Number of subjects enrolled
    New Zealand: 27
    Country: Number of subjects enrolled
    Norway: 39
    Country: Number of subjects enrolled
    Poland: 108
    Country: Number of subjects enrolled
    Portugal: 49
    Country: Number of subjects enrolled
    Romania: 57
    Country: Number of subjects enrolled
    Russian Federation: 60
    Country: Number of subjects enrolled
    South Africa: 59
    Country: Number of subjects enrolled
    Spain: 59
    Country: Number of subjects enrolled
    Sweden: 17
    Country: Number of subjects enrolled
    United Kingdom: 72
    Country: Number of subjects enrolled
    United States: 370
    Worldwide total number of subjects
    1751
    EEA total number of subjects
    995
    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)
    1642
    From 65 to 84 years
    109
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A randomized, placebo-controlled, double-blind, parallel-group study compared 3 doses of Empagliflozin (2.5 milligram (mg), 10 mg, and 25 mg) with placebo in patients with type 1 diabetes mellitus (T1DM) as adjunctive to optimized insulin therapy. A total of 1751 subjects were screened, 977 were entered/randomized and 975 were treated.

    Pre-assignment
    Screening details
    		 6-Week T1DM therapy (insulin) optimisation period followed by a 2-Week placebo run-in period before randomization. Patients who successfully completed both of the periods were randomized into the 26-Week double-blind treatment period. All treatments were administered in addition to optimized insulin therapy.

    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
    Blinding implementation details
    This was a Double-blind trial. This is Randomized and controlled trial.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo matching Empagliflozin
    Arm description
    		 Patients administered Placebo matching Empagliflozin film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo matching Empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients administered Placebo matching Empagliflozin film-coated tablet orally once daily in addition to optimized insulin therapy for 26 weeks.

    Arm title
    		 Empagliflozin 2.5 milligram (mg)
    Arm description
    		 Patients administered Empagliflozin 2.5 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients administered Empagliflozin 2.5 mg film-coated tablet orally once daily in addition to optimized insulin therapy for 26 weeks.

    Arm title
    		 Empagliflozin 10 mg
    Arm description
    		 Patients administered Empagliflozin 10 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients administered Empagliflozin 10 mg film-coated tablet orally once daily in addition to optimized insulin therapy for 26 weeks.

    Arm title
    		 Empagliflozin 25 mg
    Arm description
    		 Patients administered Empagliflozin 25 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients administered Empagliflozin 25 mg film-coated tablet orally once daily in addition to optimized insulin therapy for 26 weeks.

    Number of subjects in period 1 [1]
    		Placebo matching Empagliflozin Empagliflozin 2.5 milligram (mg) Empagliflozin 10 mg Empagliflozin 25 mg
    Started
    242
    242
    248
    245
    Completed
    224
    232
    235
    233
    Not completed
    18
    10
    13
    12
         Consent withdrawn by subject
    6
    1
    2
    3
         Adverse event, non-fatal
    -
    1
    2
    5
         Other than specified
    3
    2
    5
    2
         Lost to follow-up
    5
    3
    3
    1
         Protocol deviation
    3
    2
    1
    1
         Not treated
    1
    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: Baseline characteristics are based on patients who were randomized after successfully completing the screening period and received at least one dose of the trial medication.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo matching Empagliflozin
    Reporting group description
    		 Patients administered Placebo matching Empagliflozin film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.

    Reporting group title
    Empagliflozin 2.5 milligram (mg)
    Reporting group description
    		 Patients administered Empagliflozin 2.5 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.

    Reporting group title
    Empagliflozin 10 mg
    Reporting group description
    		 Patients administered Empagliflozin 10 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.

    Reporting group title
    Empagliflozin 25 mg
    Reporting group description
    		 Patients administered Empagliflozin 25 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.

    Reporting group values
    		 Placebo matching Empagliflozin Empagliflozin 2.5 milligram (mg) Empagliflozin 10 mg Empagliflozin 25 mg Total
    Number of subjects
    		 242 242 248 245 977
    Age categorical
    Units: Subjects
    Age Continuous
    Randomised set (RS): All patients from the Screened set (SCR) who were randomised to trial medication, regardless of whether any trial medication was taken.
    Units: years
        arithmetic mean (standard deviation)
    		 42.3 ± 13.2 43.4 ± 14.3 42.3 ± 13.2 44.4 ± 13.6 -
    Sex: Female, Male
    Randomised set (RS): All patients from the Screened set (SCR) who were randomised to trial medication, regardless of whether any trial medication was taken.
    Units: Subjects
        Female
    		 126 120 132 121 499
        Male
    		 116 122 116 124 478
    Race (NIH/OMB)
    Randomised set (RS): All patients from the Screened set (SCR) who were randomised to trial medication, regardless of whether any trial medication was taken.
    Units: Subjects
        American Indian or Alaska Native
    		 7 0 1 5 13
        Asian
    		 2 2 2 5 11
        Native Hawaiian or Other Pacific Islander
    		 1 0 0 0 1
        Black or African American
    		 5 3 10 4 22
        White
    		 227 234 234 231 926
        More than one race
    		 0 3 1 0 4
        Unknown or Not Reported
    		 0 0 0 0 0
    Ethnicity (NIH/OMB)
    Randomised set (RS): All patients from the Screened set (SCR) who were randomised to trial medication, regardless of whether any trial medication was taken.
    Units: Subjects
        Hispanic or Latino
    		 215 220 233 224 892
        Not Hispanic or Latino
    		 27 22 15 21 85
        Unknown or Not Reported
    		 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Placebo matching Empagliflozin
    Reporting group description
    		 Patients administered Placebo matching Empagliflozin film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.

    Reporting group title
    Empagliflozin 2.5 milligram (mg)
    Reporting group description
    		 Patients administered Empagliflozin 2.5 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.

    Reporting group title
    Empagliflozin 10 mg
    Reporting group description
    		 Patients administered Empagliflozin 10 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.

    Reporting group title
    Empagliflozin 25 mg
    Reporting group description
    		 Patients administered Empagliflozin 25 mg film-coated tablet orally once daily in addition as adjunctive to optimized insulin therapy for 26 weeks.

    Primary: Change from baseline in Glycated hemoglobin (HbA1c) at Week 26 for full analysis set (FAS) (observed cases [OC])

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    End point title
    		 Change from baseline in Glycated hemoglobin (HbA1c) at Week 26 for full analysis set (FAS) (observed cases [OC])
    End point description
    Change from baseline in Glycated hemoglobin (HbA1c) for full analysis set (FAS) (observed cases [OC]) is presented. With regards to efficacy and safety endpoints, the term ‘baseline’ referred to the last observed measurement prior to administration of any randomized trial medication. Least squares mean is adjusted mean change from baseline.
    End point type
    Primary
    End point timeframe
    Baseline to week 26
    End point values
    		 Placebo matching Empagliflozin Empagliflozin 2.5 milligram (mg) Empagliflozin 10 mg Empagliflozin 25 mg
    Number of subjects analysed
    238
    237
    244
    242
    Units: Percentage (%)
        least squares mean (standard error)
    0.20 ± 0.05
    -0.09 ± 0.05
    -0.25 ± 0.05
    -0.33 ± 0.05
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Model includes baseline HbA1c, baseline Estimated glomerular filtration rate (eGFR) as linear covariates and baseline pre−existing insulin therapy, treatment, visit, visit by treatment interaction, baseline HbA1c by visit interaction as fixed effects. Patient is included as random effect. An unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 2.5 milligram (mg)
    Number of subjects included in analysis
    475
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed effect Model Repeat Measurement
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.28
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 -0.46
         upper limit
    		 -0.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.07
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Model includes baseline HbA1c, baseline eGFR as linear covariates and baseline pre−existing insulin therapy, treatment, visit, visit by treatment interaction, baseline HbA1c by visit interaction as fixed effects. Patient is included as random effect. An unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 10 mg
    Number of subjects included in analysis
    482
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed effect Model Repeat Measurement
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.45
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 -0.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.07
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Model includes baseline HbA1c, baseline eGFR as linear covariates and baseline pre−existing insulin therapy, treatment, visit, visit by treatment interaction, baseline HbA1c by visit interaction as fixed effects. Patient is included as random effect. An unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 25 mg
    Number of subjects included in analysis
    480
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed effect Model Repeat Measurement
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.52
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -0.68
         upper limit
    		 -0.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.07

    Primary: Change from baseline in Glycated hemoglobin (HbA1c) at Week 26 for modified intention-to-treat population set (mITT) (observed case – all data [OC-AD])

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    End point title
    		 Change from baseline in Glycated hemoglobin (HbA1c) at Week 26 for modified intention-to-treat population set (mITT) (observed case – all data [OC-AD])
    End point description
    Change from baseline in Glycated hemoglobin (HbA1c) for modified intention-to-treat population set (mITT) (observed case – all data [OC-AD]) is presented. With regards to efficacy and safety endpoints, the term ‘baseline’ referred to the last observed measurement prior to administration of any randomized trial medication. Least squares mean is adjusted mean change from baseline.
    End point type
    Primary
    End point timeframe
    Baseline to week 26
    End point values
    		 Placebo matching Empagliflozin Empagliflozin 2.5 milligram (mg) Empagliflozin 10 mg Empagliflozin 25 mg
    Number of subjects analysed
    239
    239
    246
    245
    Units: Percentage (%)
        least squares mean (standard error)
    0.21 ± 0.05
    -0.06 ± 0.05
    -0.23 ± 0.05
    -0.30 ± 0.05
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Model includes baseline HbA1c, baseline eGFR as linear covariates and baseline pre−existing insulin therapy, treatment, visit, visit by treatment interaction, baseline HbA1c by visit interaction as fixed effects. Patient is included as random effect. An unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 2.5 milligram (mg)
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed effect Model Repeat Measurement
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 -0.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.07
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Model includes baseline HbA1c, baseline eGFR as linear covariates and baseline pre−existing insulin therapy, treatment, visit, visit by treatment interaction, baseline HbA1c by visit interaction as fixed effects. Patient is included as random effect. An unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 10 mg
    Number of subjects included in analysis
    485
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed effect Model Repeat Measurement
    Parameter type
    		 Median difference (final values)
    Point estimate
    -0.44
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -0.59
         upper limit
    		 -0.28
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.07
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Model includes baseline HbA1c, baseline eGFR as linear covariates and baseline pre−existing insulin therapy, treatment, visit, visit by treatment interaction, baseline HbA1c by visit interaction as fixed effects. Patient is included as random effect. An unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 25 mg
    Number of subjects included in analysis
    484
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed effect Model Repeat Measurement
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.5
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -0.66
         upper limit
    		 -0.35
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.07

    Secondary: Rate per patient-year of investigator-reported symptomatic hypoglycemic adverse events (AEs) with confirmed plasma glucose (PG)

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    End point title
    		 Rate per patient-year of investigator-reported symptomatic hypoglycemic adverse events (AEs) with confirmed plasma glucose (PG)
    End point description
    Rate per patient-year of investigator-reported symptomatic hypoglycemic adverse events (AEs) with confirmed plasma glucose (PG) <54 milligram per deciliter (mg/dL) (<3.0 millimoles per litre (mmol/L)) and/or severe hypoglycemic AEs (i.e. all investigator-reported AEs that had confirmed PG <54 mg/dL [<3.0 mmol/L] with symptoms reported and all severe hypoglycemic events that were confirmed by adjudication) is presented for (i) From week 5 to 26 and (ii) From week 1 to 26. Least squares mean is actually an adjusted event rate. This is key secondary endpoints.
    End point type
    Secondary
    End point timeframe
    Week 5 to Week 26, Week 1 to Week 26
    End point values
    		 Placebo matching Empagliflozin Empagliflozin 2.5 milligram (mg) Empagliflozin 10 mg Empagliflozin 25 mg
    Number of subjects analysed
    235
    237
    241
    237
    Units: Per patient year
    least squares mean (confidence interval 95%)
        Week 5 to 26|
    6.13 (4.83 to 7.78)
    5.77 (4.53 to 7.34)
    7.37 (5.83 to 9.31)
    6.25 (4.94 to 7.91)
        Week 1 to 26|
    6.62 (5.30 to 8.27)
    6.17 (4.93 to 7.73)
    8.33 (6.70 to 10.37)
    6.96 (5.58 to 8.67)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    For Week 5 to 26, negative binomial model includes baseline rate of hypoglycemia, baseline HbA1c, and baseline Estimated glomerular filtration rate (eGFR) as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects. Log (time at risk [days]) was used as offset.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 2.5 milligram (mg)
    Number of subjects included in analysis
    472
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Negative binomial model
    Parameter type
    		 Adjusted Rate Ratio (%)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.673
         upper limit
    		 1.314
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    For Week 5 to 26, negative binomial model includes baseline rate of hypoglycemia, baseline HbA1c, and baseline Estimated glomerular filtration rate (eGFR) as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects. Log (time at risk [days]) was used as offset.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 10 mg
    Number of subjects included in analysis
    476
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2752
    Method
    		 Negative binomial model
    Parameter type
    		 Adjusted Rate Ratio (%)
    Point estimate
    1.202
    Confidence interval
         level
    		 97.75%
         sides
    2-sided
         lower limit
    		 0.818
         upper limit
    		 1.766
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    For Week 5 to 26, negative binomial model includes baseline rate of hypoglycemia, baseline HbA1c, and baseline Estimated glomerular filtration rate (eGFR) as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects. Log (time at risk [days]) was used as offset.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 25 mg
    Number of subjects included in analysis
    472
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9077
    Method
    		 Negative binomial model
    Parameter type
    		 Adjusted Rate Ratio (%)
    Point estimate
    1.02
    Confidence interval
         level
    		 97.75%
         sides
    2-sided
         lower limit
    		 0.693
         upper limit
    		 1.501
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    For Week 1 to 26, negative binomial model includes baseline rate of hypoglycemia, baseline HbA1c, and baseline Estimated glomerular filtration rate (eGFR) as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects. Log (time at risk [days]) was used as offset.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 2.5 milligram (mg)
    Number of subjects included in analysis
    472
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Negative binomial model
    Parameter type
    		 Adjusted Rate Ratio (%)
    Point estimate
    0.932
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.682
         upper limit
    		 1.274
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    For Week 1 to 26, negative binomial model includes baseline rate of hypoglycemia, baseline HbA1c, and baseline Estimated glomerular filtration rate (eGFR) as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects. Log (time at risk [days]) was used as offset.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 10 mg
    Number of subjects included in analysis
    476
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1438 [1]
    Method
    		 Negative binomial model
    Parameter type
    		 Adjusted Rate Ratio (%)
    Point estimate
    1.258
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.925
         upper limit
    		 1.713
    Notes
    [1] - This is a nominal p-value.
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    For Week 1 to 26, negative binomial model includes baseline rate of hypoglycemia, baseline HbA1c, and baseline Estimated glomerular filtration rate (eGFR) as linear covariates and baseline pre-existing insulin therapy and treatment as fixed effects. Log (time at risk [days]) was used as offset.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 25 mg
    Number of subjects included in analysis
    472
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7543 [2]
    Method
    		 Negative binomial model
    Parameter type
    		 Adjusted Rate Ratio (%)
    Point estimate
    1.051
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.771
         upper limit
    		 1.433
    Notes
    [2] - This is a nominal p-value.

    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
    Change from baseline in body weight is presented With regards to efficacy and safety endpoints, the term ‘baseline’ referred to the last observed measurement prior to administration of any randomized trial medication. Least squares mean is adjusted mean change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline to week 26
    End point values
    		 Placebo matching Empagliflozin Empagliflozin 2.5 milligram (mg) Empagliflozin 10 mg Empagliflozin 25 mg
    Number of subjects analysed
    238
    237
    243
    240
    Units: Kilogram (kg)
        least squares mean (standard error)
    0.21 ± 0.20
    -1.55 ± 0.20
    -2.83 ± 0.20
    -3.22 ± 0.20
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Model includes baseline weight, baseline Estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre−existing insulin therapy, treatment, visit, visit by treatment interaction, baseline weight by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 2.5 milligram (mg)
    Number of subjects included in analysis
    475
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed effect Model Repeat Measurement
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.32
         upper limit
    		 -1.2
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Model includes baseline weight, baseline Estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre−existing insulin therapy, treatment, visit, visit by treatment interaction, baseline weight by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 10 mg
    Number of subjects included in analysis
    481
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed effect Model Repeat Measurement
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.04
    Confidence interval
         level
    		 99.75%
         sides
    2-sided
         lower limit
    		 -3.91
         upper limit
    		 -2.18
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Model includes baseline weight, baseline Estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre−existing insulin therapy, treatment, visit, visit by treatment interaction, baseline weight by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 25 mg
    Number of subjects included in analysis
    478
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed effect Model Repeat Measurement
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.43
    Confidence interval
         level
    		 99.75%
         sides
    2-sided
         lower limit
    		 -4.3
         upper limit
    		 -2.57

    Secondary: Change from baseline in Total daily insulin dose (TDID) at Week 26

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    End point title
    		 Change from baseline in Total daily insulin dose (TDID) at Week 26
    End point description
    Change from baseline in Total daily insulin dose (TDID) is presented. With regards to efficacy and safety endpoints, the term ‘baseline’ referred to the last observed measurement prior to administration of any randomized trial medication. Least squares mean is adjusted mean change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline to week 26
    End point values
    		 Placebo matching Empagliflozin Empagliflozin 2.5 milligram (mg) Empagliflozin 10 mg Empagliflozin 25 mg
    Number of subjects analysed
    217
    223
    217
    220
    Units: Unit/kilogram (U/kg)
        least squares mean (standard error)
    -0.011 ± 0.007
    -0.060 ± 0.007
    -0.080 ± 0.007
    -0.102 ± 0.007
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Model includes baseline total daily insulin dose, baseline estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre−existing insulin therapy, treatment, visit, visit by treatment interaction, baseline total daily insulin dose by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 2.5 milligram (mg)
    Number of subjects included in analysis
    440
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed effect Model Repeat Measurement
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.049
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.069
         upper limit
    		 -0.03
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Model includes baseline total daily insulin dose, baseline estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre−existing insulin therapy, treatment, visit, visit by treatment interaction, baseline total daily insulin dose by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 10 mg
    Number of subjects included in analysis
    434
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed effect Model Repeat Measurement
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.07
    Confidence interval
         level
    		 99.75%
         sides
    2-sided
         lower limit
    		 -0.101
         upper limit
    		 -0.039
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Model includes baseline total daily insulin dose, baseline estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre−existing insulin therapy, treatment, visit, visit by treatment interaction, baseline total daily insulin dose by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 25 mg
    Number of subjects included in analysis
    437
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed effect Model Repeat Measurement
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.091
    Confidence interval
         level
    		 99.75%
         sides
    2-sided
         lower limit
    		 -0.122
         upper limit
    		 -0.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.01

    Secondary: Change from baseline in Systolic blood pressure (SBP) and Diastolic blood pressure (DBP) at Week 26

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    End point title
    		 Change from baseline in Systolic blood pressure (SBP) and Diastolic blood pressure (DBP) at Week 26
    End point description
    Change from baseline in Systolic blood pressure (SBP) and Diastolic blood pressure (DBP) is presented. With regards to efficacy and safety endpoints, the term ‘baseline’ referred to the last observed measurement prior to administration of any randomized trial medication. Least squares mean is adjusted mean change from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline to week 26
    End point values
    		 Placebo matching Empagliflozin Empagliflozin 2.5 milligram (mg) Empagliflozin 10 mg Empagliflozin 25 mg
    Number of subjects analysed
    237
    236
    240
    238
    Units: Millimeters of mercury (mmHg)
    least squares mean (standard error)
        SBP|
    0.4 ± 0.7
    -1.7 ± 0.7
    -3.5 ± 0.7
    -3.4 ± 0.7
        DBP|
    0.0 ± 0.4
    -0.4 ± 0.4
    -1.8 ± 0.4
    -1.5 ± 0.4
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    For SBP, the model includes baseline SBP seated, baseline Estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre−existing insulin therapy, treatment, visit, treatment by visit interaction, baseline SBP seated by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 2.5 milligram (mg)
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed effect Model Repeat MeasurementMix
    Parameter type
    		 Median difference (final values)
    Point estimate
    -2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.9
         upper limit
    		 -0.2
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    For SBP, the model includes baseline SBP seated, baseline Estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre−existing insulin therapy, treatment, visit, , treatment by visit interaction, baseline SBP seated by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 10 mg
    Number of subjects included in analysis
    477
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed effect Model Repeat Measurement
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.9
    Confidence interval
         level
    		 99.75%
         sides
    2-sided
         lower limit
    		 -6.8
         upper limit
    		 -1.1
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    For SBP, the model includes baseline SBP seated, baseline Estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre−existing insulin therapy, treatment, visit, treatment by visit interaction, baseline SBP seated by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 25 mg
    Number of subjects included in analysis
    475
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed effect Model Repeat Measurement
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.7
    Confidence interval
         level
    		 99.75%
         sides
    2-sided
         lower limit
    		 -6.6
         upper limit
    		 -0.9
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    For DBP, the model includes baseline DBP seated, baseline Estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre−existing insulin therapy, treatment, visit, treatment by visit interaction, baseline DBP seated by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 2.5 milligram (mg)
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed effect Model Repeat Measurement
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 0.9
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    For DBP, the model includes baseline DBP seated, baseline Estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre−existing insulin therapy, treatment, visit, ß, treatment by visit interaction, baseline DBP seated by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 10 mg
    Number of subjects included in analysis
    477
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0047
    Method
    		 Mixed effect Model Repeat Measurement
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.7
    Confidence interval
         level
    		 99.75%
         sides
    2-sided
         lower limit
    		 -3.6
         upper limit
    		 0.1
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    For DBP, the model includes baseline DBP seated, baseline Estimated glomerular filtration rate (eGFR), baseline HbA1c as linear covariate and baseline pre−existing insulin therapy, treatment, visit, ß, treatment by visit interaction, baseline DBP seated by visit interaction as fixed effect. An unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Placebo matching Empagliflozin v Empagliflozin 25 mg
    Number of subjects included in analysis
    475
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0202
    Method
    		 Mixed effect Model Repeat Measurement
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.4
    Confidence interval
         level
    		 99.75%
         sides
    2-sided
         lower limit
    		 -3.3
         upper limit
    		 0.4

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first drug administration until 7 days after the last drug administration.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Empa 2.5mg
    Reporting group description
    		 -

    Reporting group title
    Empa 10mg
    Reporting group description
    		 -

    Reporting group title
    Empa 25mg
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo Empa 2.5mg Empa 10mg Empa 25mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 241 (6.64%)
    13 / 241 (5.39%)
    21 / 248 (8.47%)
    16 / 245 (6.53%)
         number of deaths (all causes)
    0
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anogenital warts
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    2 / 241 (0.83%)
    1 / 241 (0.41%)
    0 / 248 (0.00%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vaginal cancer stage 0
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 241 (0.41%)
    0 / 248 (0.00%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 241 (0.00%)
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Endometriosis
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory arrest
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 241 (0.00%)
    0 / 248 (0.00%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 241 (0.00%)
    0 / 248 (0.00%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Anion gap increased
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bicarbonate increased
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood gases abnormal
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood glucose decreased
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood glucose increased
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood ketone body increased
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood potassium increased
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urine ketone body present
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hand fracture
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 241 (0.41%)
    0 / 248 (0.00%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 241 (0.00%)
    2 / 241 (0.83%)
    0 / 248 (0.00%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Nervous system disorders
    Demyelination
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disturbance in attention
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 241 (0.00%)
    0 / 248 (0.00%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vestibular disorder
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Eye haemorrhage
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 241 (0.00%)
    0 / 248 (0.00%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinopathy haemorrhagic
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 241 (0.00%)
    0 / 248 (0.00%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    2 / 248 (0.81%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatolithiasis
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 241 (0.00%)
    0 / 248 (0.00%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    2 / 248 (0.81%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc degeneration
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 241 (0.00%)
    0 / 248 (0.00%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 241 (0.41%)
    0 / 248 (0.00%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis viral
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 241 (0.00%)
    0 / 248 (0.00%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Acetonaemia
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 241 (0.41%)
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    2 / 241 (0.83%)
    2 / 241 (0.83%)
    6 / 248 (2.42%)
    5 / 245 (2.04%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
    4 / 6
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketosis
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Euglycaemic diabetic ketoacidosis
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    0 / 248 (0.00%)
    1 / 245 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    4 / 241 (1.66%)
    3 / 241 (1.24%)
    3 / 248 (1.21%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    2 / 3
    3 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ketoacidosis
         subjects affected / exposed
    1 / 241 (0.41%)
    1 / 241 (0.41%)
    3 / 248 (1.21%)
    2 / 245 (0.82%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    2 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ketosis
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 241 (0.41%)
    0 / 248 (0.00%)
    3 / 245 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic disorder
         subjects affected / exposed
    0 / 241 (0.00%)
    0 / 241 (0.00%)
    1 / 248 (0.40%)
    0 / 245 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Empa 2.5mg Empa 10mg Empa 25mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    153 / 241 (63.49%)
    146 / 241 (60.58%)
    172 / 248 (69.35%)
    162 / 245 (66.12%)
    Investigations
    Blood ketone body increased
         subjects affected / exposed
    3 / 241 (1.24%)
    4 / 241 (1.66%)
    15 / 248 (6.05%)
    10 / 245 (4.08%)
         occurrences all number
    3
    5
    24
    20
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    24 / 241 (9.96%)
    23 / 241 (9.54%)
    22 / 248 (8.87%)
    26 / 245 (10.61%)
         occurrences all number
    29
    27
    24
    31
    Urinary tract infection
         subjects affected / exposed
    12 / 241 (4.98%)
    12 / 241 (4.98%)
    9 / 248 (3.63%)
    16 / 245 (6.53%)
         occurrences all number
    14
    15
    10
    17
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    144 / 241 (59.75%)
    137 / 241 (56.85%)
    162 / 248 (65.32%)
    151 / 245 (61.63%)
         occurrences all number
    2047
    1610
    2232
    1956

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Oct 2016
    Added confirmatory testing step for the effectiveness for the primary endpoint, based on regulatory feedback and moved the exploratory efficacy endpoints based on Continuous glucose monitoring (CGM) from ‘secondary endpoints’ to ‘further exploratory efficacy endpoints’, to align with project standards. Events involving lower-limb amputation were added as an Adverse event of special interest (protocol-defined) (AESI) to meet new regulatory requirements. Insulin titration was clarified and optimized: in the original Clinical Trial Protocol investigators were advised to reduce the total insulin dose by 10% regardless of HbA1c values. In the amended protocol this advice was upheld for patients with HbA1c of 7.5 to <8%, whereas for patients with HbA1c of ≥8% investigators were advised to adjust the total insulin dose based on need. Changes to the inclusion and exclusion criteria for the purpose of safety and for clarification introduced. The removal of patients from the trial was modified with regard to concomitant medications.

    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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