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    Clinical Trial Results:
    A randomised, double blind, placebo controlled, parallel group efficacy and safety study of oral administration of empagliflozin twice daily versus once daily in two different daily doses over 16 weeks as add-on therapy to a twice daily dosing regimen of metformin in patients with type 2 diabetes mellitus and insufficient glycaemic control

    Summary
    EudraCT number
    		 2012-000905-53
    Trial protocol
    		 EE   LV   DE   LT   ES   PL   IT  
    Global end of trial date
    03 Dec 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Jun 2016
    First version publication date
    16 Jul 2015
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    1276.10
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01649297
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasee 173, Ingelheim am Rhein, Germany,
    Public contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim Pharma GmbH & Co KG, +49 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim Pharma GmbH & Co KG, +49 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
    11 Dec 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Nov 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Dec 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the efficacy and safety of different dosage regimens of empagliflozin, 5mg twice daily compared to 10 mg once daily versus placebo and 12.5 mg twice daily compared to 25 mg once daily versus placebo, administered orally as add-on therapy to metformin in patients with T2DM and insufficient glycaemic control. The study is designed to show non-inferiority of empagliflozin 5 mg bid and 12.5 mg bid treatment versus reference therapy with empagliflozin 10 mg qd and 25 mg qd respectively.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all patients as required. The safety of the patients was ensured by monitoring the patients for adverse events, both clinically and by laboratory testing. Symptoms that could be attributed to hypo- or hyperglycaemia were to be closely monitored in this trial. Furthermore, due to the expected effect of empagliflozin on blood pressure, symptoms that could be attributed to hypo- or hypertension were to be closely monitored in this trial.
    Background therapy
    		 All patients in this trial were on a metformin background medication and therefore received a medication approved for treatment of their disease.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Oct 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 80
    Country: Number of subjects enrolled
    Spain: 69
    Country: Number of subjects enrolled
    Estonia: 68
    Country: Number of subjects enrolled
    France: 66
    Country: Number of subjects enrolled
    Germany: 122
    Country: Number of subjects enrolled
    Italy: 88
    Country: Number of subjects enrolled
    Latvia: 83
    Country: Number of subjects enrolled
    Lithuania: 31
    Country: Number of subjects enrolled
    Canada: 128
    Country: Number of subjects enrolled
    Georgia: 100
    Country: Number of subjects enrolled
    Guatemala: 119
    Country: Number of subjects enrolled
    Australia: 8
    Country: Number of subjects enrolled
    Mexico: 63
    Country: Number of subjects enrolled
    New Zealand: 17
    Country: Number of subjects enrolled
    Russian Federation: 62
    Country: Number of subjects enrolled
    South Africa: 70
    Country: Number of subjects enrolled
    Ukraine: 54
    Country: Number of subjects enrolled
    United States: 398
    Worldwide total number of subjects
    1626
    EEA total number of subjects
    607
    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)
    1140
    From 65 to 84 years
    484
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 All subjects were screened for eligibility to participate in the trial. Subjects attended specialist sites which would then ensure that they (the subject) met all strictly implemented inclusion/exclusion criteria. Subjects were not randomised to trial treatment if any one of the specific entry criteria were violated.

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Empa 12.5mg BID
    Arm description
    		 Oral administration of Empagliflozin (Empa) 12.5 mg twice daily (BID) (Randomised set (RS) are the subjects who were randomised to receive the trial medication; this population is used for the Subject disposition and Baseline characteristics)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Empagliflozin 12.5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration of Empagliflozin (Empa) 12.5 mg twice daily (BID)

    Arm title
    		 Empa 25mg QD
    Arm description
    		 Oral administration of Empagliflozin (Empa) 25 mg once daily (QD) (RS is the population used for Subject disposition and Baseline characteristics)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Empagliflozin 25mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration of Empagliflozin (Empa) 25 mg once daily (QD)

    Arm title
    		 Empa 5mg BID
    Arm description
    		 Oral administration of Empagliflozin (Empa) 5 mg twice daily (BID). RS is the population used for Subject disposition and Baseline characteristics.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Empagliflozin 5mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration of Empagliflozin (Empa) 5 mg twice daily (BID)

    Arm title
    		 Empa 10mg QD
    Arm description
    		 Oral administration of Empagliflozin (Empa) 10 mg once daily (QD). RS is the population used for Subject disposition and Baseline characteristics.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Empagliflozin 10mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration of Empagliflozin (Empa) 10 mg once daily (QD)

    Arm title
    		 Placebo
    Arm description
    		 Oral administration of Placebo tablets matching empagliflozin 25 mg, 10 mg, 5 mg, and 2.5 mg. RS is the population used for Subject disposition and Baseline characteristics.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration of Placebo tablets matching empagliflozin 25 mg, 10 mg, 5 mg, and 2.5 mg Unit strength: Not applicable

    Number of subjects in period 1 [1]
    		Empa 12.5mg BID Empa 25mg QD Empa 5mg BID Empa 10mg QD Placebo
    Started
    219
    218
    219
    220
    107
    Completed
    205
    205
    202
    201
    103
    Not completed
    14
    13
    17
    19
    4
         For other reason
    4
    1
    2
    -
    -
         Patient withdrawal (not due to AE)
    3
    6
    4
    1
    1
         Adverse event, non-fatal
    5
    5
    4
    13
    1
         Non compliant with Protocol
    1
    -
    3
    2
    1
         Lost to follow-up
    1
    1
    4
    3
    -
         Lack of efficacy
    -
    -
    -
    -
    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 randomised after successfully completing the screening period and received at least one of the trial medication.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Empa 12.5mg BID
    Reporting group description
    		 Oral administration of Empagliflozin (Empa) 12.5 mg twice daily (BID) (Randomised set (RS) are the subjects who were randomised to receive the trial medication; this population is used for the Subject disposition and Baseline characteristics)

    Reporting group title
    Empa 25mg QD
    Reporting group description
    		 Oral administration of Empagliflozin (Empa) 25 mg once daily (QD) (RS is the population used for Subject disposition and Baseline characteristics)

    Reporting group title
    Empa 5mg BID
    Reporting group description
    		 Oral administration of Empagliflozin (Empa) 5 mg twice daily (BID). RS is the population used for Subject disposition and Baseline characteristics.

    Reporting group title
    Empa 10mg QD
    Reporting group description
    		 Oral administration of Empagliflozin (Empa) 10 mg once daily (QD). RS is the population used for Subject disposition and Baseline characteristics.

    Reporting group title
    Placebo
    Reporting group description
    		 Oral administration of Placebo tablets matching empagliflozin 25 mg, 10 mg, 5 mg, and 2.5 mg. RS is the population used for Subject disposition and Baseline characteristics.

    Reporting group values
    		 Empa 12.5mg BID Empa 25mg QD Empa 5mg BID Empa 10mg QD Placebo Total
    Number of subjects
    		 219 218 219 220 107 983
    Age categorical
    Units: Subjects
    Age continuous
    Randomised set (RS) includes subjects who were randomised to receive the trial medication; this population is used for the Subject disposition and Baseline characteristics
    Units: years
        arithmetic mean (standard deviation)
    		 57.6 ± 9.9 58.1 ± 10.3 58.9 ± 10.1 58.4 ± 10.9 57.9 ± 11.2 -
    Gender categorical
    Units: Subjects
        Female
    		 93 100 96 109 52 450
        Male
    		 126 118 123 111 55 533

    End points

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    End points reporting groups
    Reporting group title
    Empa 12.5mg BID
    Reporting group description
    		 Oral administration of Empagliflozin (Empa) 12.5 mg twice daily (BID) (Randomised set (RS) are the subjects who were randomised to receive the trial medication; this population is used for the Subject disposition and Baseline characteristics)

    Reporting group title
    Empa 25mg QD
    Reporting group description
    		 Oral administration of Empagliflozin (Empa) 25 mg once daily (QD) (RS is the population used for Subject disposition and Baseline characteristics)

    Reporting group title
    Empa 5mg BID
    Reporting group description
    		 Oral administration of Empagliflozin (Empa) 5 mg twice daily (BID). RS is the population used for Subject disposition and Baseline characteristics.

    Reporting group title
    Empa 10mg QD
    Reporting group description
    		 Oral administration of Empagliflozin (Empa) 10 mg once daily (QD). RS is the population used for Subject disposition and Baseline characteristics.

    Reporting group title
    Placebo
    Reporting group description
    		 Oral administration of Placebo tablets matching empagliflozin 25 mg, 10 mg, 5 mg, and 2.5 mg. RS is the population used for Subject disposition and Baseline characteristics.

    Primary: HbA1c (Glycosylated Haemoglobin) Change From Baseline at Week 16

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    End point title
    		 HbA1c (Glycosylated Haemoglobin) Change From Baseline at Week 16
    End point description
    Change from baseline in HbA1c (%) after 16 weeks of treatment. The term 'baseline' refers to the last observation prior to the first intake of any randomised study medication. Means provided are the adjusted means. Full Analysis Set (FAS): All randomised patients who were treated with at least 1 dose of the trial medication,had a baseline and at least 1 on treatment HbA1c assessment. FAS is the basis for the intention-to-treat analysis. FAS with last observation carried forward (LOCF) imputation is used as the primary method of accounting for missing data. Values after the patient started rescue medication were excluded from analysis (and imputed with an LOCF procedure).
    End point type
    Primary
    End point timeframe
    Baseline and 16 weeks
    End point values
    		 Empa 12.5mg BID Empa 25mg QD Empa 5mg BID Empa 10mg QD Placebo
    Number of subjects analysed
    215 [1]
    214 [2]
    215 [3]
    213 [4]
    107 [5]
    Units: percentage of HbA1c
        arithmetic mean (standard error)
    -0.83 ± 0.05
    -0.72 ± 0.05
    -0.66 ± 0.05
    -0.64 ± 0.05
    -0.22 ± 0.07
    Notes
    [1] - FAS with LOCF has been used for HbA1c analyses
    [2] - FAS with LOCF has been used for HbA1c analyses
    [3] - FAS with LOCF has been used for HbA1c analyses
    [4] - FAS with LOCF has been used for HbA1c analyses
    [5] - FAS with LOCF has been used for HbA1c analyses
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The primary objective was to test the non-inferiority of empagliflozin 5 mg BID versus empagliflozin 10 mg QD, and non-inferiority of empagliflozin 12.5 mg BID versus empagliflozin 25 mg QD, assuming a non-inferiority margin of 0.35% ANCOVA: Treatment, geographical region, renal function (screening eGFR [MDRD] value)- fixed effects and baseline HbA1c- linear covariate. (Empa 5mg BID - Empa 10mg QD)
    Comparison groups
    Empa 5mg BID v Empa 10mg QD
    Number of subjects included in analysis
    428
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [6]
    P-value
    		 < 0.0001 [7]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.16
         upper limit
    		 0.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.07
    Notes
    [6] - Null hypotheses for non-inferiority: H10: Mean change from baseline in HbA1c (%) after 16 weeks of treatment with empagliflozin 5 mg twice daily ≥ mean change from baseline in HbA1c (%) after 16 weeks of treatment with empagliflozin 10 mg once daily + 0.35% H20: Mean change from baseline in HbA1c (%) after 16 weeks of treatment with empagliflozin 12.5 mg twice daily ≥ mean change from baseline in HbA1c (%) after 16 weeks of treatment with empagliflozin 25 mg once daily + 0. 35%
    [7] - The two non-inferiority hypotheses H10 and H20 were tested using the Hochberg procedure in order to control the family-wise type I error at 0.025 (one-sided).
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    The primary objective was to test the non-inferiority of empagliflozin 5 mg BID versus empagliflozin 10 mg QD, and non-inferiority of empagliflozin 12.5 mg BID versus empagliflozin 25 mg QD, assuming a non-inferiority margin of 0.35% ANCOVA: Treatment, geographical region, renal function (screening eGFR [MDRD] value)- fixed effects and baseline HbA1c- linear covariate. (Empa 12.5 mg BID - Empa 25 mg QD)
    Comparison groups
    Empa 12.5mg BID v Empa 25mg QD
    Number of subjects included in analysis
    429
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [8]
    P-value
    		 < 0.0001 [9]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.26
         upper limit
    		 0.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.07
    Notes
    [8] - Null hypotheses for non-inferiority: H10: Mean change from baseline in HbA1c (%) after 16 weeks of treatment with empagliflozin 5 mg twice daily ≥ mean change from baseline in HbA1c (%) after 16 weeks of treatment with empagliflozin 10 mg once daily + 0.35% H20: Mean change from baseline in HbA1c (%) after 16 weeks of treatment with empagliflozin 12.5 mg twice daily ≥ mean change from baseline in HbA1c (%) after 16 weeks of treatment with empagliflozin 25 mg once daily + 0. 35%
    [9] - The two non-inferiority hypotheses H10 and H20 were tested using the Hochberg procedure in order to control the family-wise type I error at 0.025 (one-sided).
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Superiority of once daily dose of empagliflozin (10 mg and 25 mg) versus placebo and superiority of twice daily dose of empagliflozin (5 mg and 12.5 mg) versus placebo in reducing HbA1c after 16 weeks of treatment was tested in an exploratory manner, to demonstrate assay sensitivity against placebo at 0.05 level (two-sided). ANCOVA: Treatment, geographical region, renal function (screening eGFR [MDRD] value)- fixed effects and baseline HbA1c- linear covariate. (Empa 12.5 mg BID - Placebo)
    Comparison groups
    Empa 12.5mg BID v Placebo
    Number of subjects included in analysis
    322
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.79
         upper limit
    		 0.44
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.09
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Superiority of once daily dose of empagliflozin (10 mg and 25 mg) versus placebo and superiority of twice daily dose of empagliflozin (5 mg and 12.5 mg) versus placebo in reducing HbA1c after 16 weeks of treatment was tested in an exploratory manner, to demonstrate assay sensitivity against placebo at 0.05 level (two-sided). ANCOVA: Treatment, geographical region, renal function (screening eGFR [MDRD] value)- fixed effects and baseline HbA1c- linear covariate. (Empa 25 mg QD - Placebo)
    Comparison groups
    Placebo v Empa 25mg QD
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.68
         upper limit
    		 -0.32
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.09
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Superiority of once daily dose of empagliflozin (10 mg and 25 mg) versus placebo and superiority of twice daily dose of empagliflozin (5 mg and 12.5 mg) versus placebo in reducing HbA1c after 16 weeks of treatment was tested in an exploratory manner, to demonstrate assay sensitivity against placebo at 0.05 level (two-sided). ANCOVA: Treatment, geographical region, renal function (screening eGFR [MDRD] value)- fixed effects and baseline HbA1c- linear covariate. (Empa 5mg BID - Placebo)
    Comparison groups
    Placebo v Empa 5mg BID
    Number of subjects included in analysis
    322
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.62
         upper limit
    		 -0.27
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.09
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Superiority of once daily dose of empagliflozin (10 mg and 25 mg) versus placebo and superiority of twice daily dose of empagliflozin (5 mg and 12.5 mg) versus placebo in reducing HbA1c after 16 weeks of treatment was tested in an exploratory manner, to demonstrate assay sensitivity against placebo at 0.05 level (two-sided). ANCOVA: Treatment, geographical region, renal function (screening eGFR [MDRD] value)- fixed effects and baseline HbA1c- linear covariate. (Empa 10mg QD - Placebo)
    Comparison groups
    Placebo v Empa 10mg QD
    Number of subjects included in analysis
    320
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 -0.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.09

    Secondary: Fasting Plasma Glucose (FPG) Change From Baseline at Week 16

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    End point title
    		 Fasting Plasma Glucose (FPG) Change From Baseline at Week 16
    End point description
    Change from baseline in FPG (mg/dL) after 16 weeks of treatment. The term 'baseline' refers to the last observation prior to the first intake of any randomised study medication. Means provided are the adjusted means.
    End point type
    Secondary
    End point timeframe
    Baseline and 16 weeks
    End point values
    		 Empa 12.5mg BID Empa 25mg QD Empa 5mg BID Empa 10mg QD Placebo
    Number of subjects analysed
    213 [10]
    214 [11]
    213 [12]
    213 [13]
    107 [14]
    Units: mg/dL
        arithmetic mean (standard error)
    -27.7 ± 2
    -22.7 ± 2
    -21.2 ± 2
    -17.6 ± 2
    -0.2 ± 2.8
    Notes
    [10] - FAS with LOCF has been used for FPG analyses
    [11] - FAS with LOCF has been used for FPG analyses
    [12] - FAS with LOCF has been used for FPG analyses
    [13] - FAS with LOCF has been used for FPG analyses
    [14] - FAS with LOCF has been used for FPG analyses
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    ANCOVA: Treatment, geographical region, renal function (screening (eGFR) [MDRD]value)-fixed effects and baseline HbA1c,baseline FPG-linear covariates Empa 5mg BID - Empa 10 mg QD
    Comparison groups
    Empa 5mg BID v Empa 10mg QD
    Number of subjects included in analysis
    426
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9
         upper limit
    		 1.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.8
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    ANCOVA: Treatment, geographical region, renal function (screening (eGFR) [MDRD]value)-fixed effects and baseline HbA1c and baseline FPG-linear covariates Empa 12.5mg BID - Empa 25mg QD
    Comparison groups
    Empa 12.5mg BID v Empa 25mg QD
    Number of subjects included in analysis
    427
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.4
         upper limit
    		 0.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.8
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Superiority of once daily dose of empagliflozin (10 mg and 25 mg) versus placebo and superiority of twice daily dose of empagliflozin (5 mg and 12.5 mg) versus placebo in reducing FPG after 16 weeks of treatment was tested in an exploratory manner, to demonstrate assay sensitivity against placebo at 0.05 level (two-sided) ANCOVA: Treatment, geographical region, renal function (screening (eGFR) [MDRD]value)-fixed effects and baseline HbA1c,baseline FPG-linear covariates Empa 12.5mg BID -Placebo
    Comparison groups
    Placebo v Empa 12.5mg BID
    Number of subjects included in analysis
    320
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -27.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -34.2
         upper limit
    		 -20.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.4
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Superiority of once daily dose of empagliflozin (10 mg and 25 mg) versus placebo and superiority of twice daily dose of empagliflozin (5 mg and 12.5 mg) versus placebo in reducing FPG after 16 weeks of treatment was tested in an exploratory manner, to demonstrate assay sensitivity against placebo at 0.05 level (two-sided) ANCOVA: Treatment, geographical region, renal function (screening (eGFR) [MDRD]value)-fixed effects and baseline HbA1c,baseline FPG-linear covariates Empa 25mg QD - Placebo
    Comparison groups
    Placebo v Empa 25mg QD
    Number of subjects included in analysis
    321
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -22.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -29.2
         upper limit
    		 -15.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.4
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Superiority of once daily dose of empagliflozin (10 mg and 25 mg) versus placebo and superiority of twice daily dose of empagliflozin (5 mg and 12.5 mg) versus placebo in reducing FPG after 16 weeks of treatment was tested in an exploratory manner, to demonstrate assay sensitivity against placebo at 0.05 level (two-sided) ANCOVA: Treatment, geographical region, renal function (screening (eGFR) [MDRD]value)-fixed effects and baseline HbA1c,baseline FPG-linear covariates Empa 5mg BID - Placebo
    Comparison groups
    Placebo v Empa 5mg BID
    Number of subjects included in analysis
    320
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -21.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -27.7
         upper limit
    		 -14.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.4
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Superiority of once daily dose of empagliflozin (10 mg and 25 mg) versus placebo and superiority of twice daily dose of empagliflozin (5 mg and 12.5 mg) versus placebo in reducing FPG after 16 weeks of treatment was tested in an exploratory manner, to demonstrate assay sensitivity against placebo at 0.05 level (two-sided) ANCOVA: Treatment, geographical region, renal function (screening (eGFR) [MDRD]value)-fixed effects and baseline HbA1c,baseline FPG-linear covariates Empa 10mg QD vs Placebo
    Comparison groups
    Placebo v Empa 10mg QD
    Number of subjects included in analysis
    320
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -17.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.1
         upper limit
    		 -10.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.4

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    16 weeks + 1 week follow-up
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Empa 12.5mg BID
    Reporting group description
    		 Oral administration of Empagliflozin (Empa) 12.5 mg twice daily (BID)

    Reporting group title
    Empa 25mg QD
    Reporting group description
    		 Oral administration of Empagliflozin (Empa) 25 mg once daily (QD)

    Reporting group title
    Empa 5mg BID
    Reporting group description
    		 Oral administration of Empagliflozin (Empa) 5 mg twice daily (BID)

    Reporting group title
    Empa 10mg QD
    Reporting group description
    		 Oral administration of Empagliflozin (Empa) 10 mg once daily (QD)

    Reporting group title
    Placebo
    Reporting group description
    		 Oral administration of Placebo tablets matching empagliflozin 25 mg, 10 mg, 5mg, and 2.5 mg

    Serious adverse events
    		 Empa 12.5mg BID Empa 25mg QD Empa 5mg BID Empa 10mg QD Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 219 (2.28%)
    2 / 218 (0.92%)
    7 / 219 (3.20%)
    5 / 220 (2.27%)
    1 / 107 (0.93%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Biliary adenoma
         subjects affected / exposed
    0 / 219 (0.00%)
    0 / 218 (0.00%)
    0 / 219 (0.00%)
    1 / 220 (0.45%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 219 (0.00%)
    0 / 218 (0.00%)
    0 / 219 (0.00%)
    1 / 220 (0.45%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 219 (0.00%)
    0 / 218 (0.00%)
    1 / 219 (0.46%)
    0 / 220 (0.00%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 218 (0.00%)
    0 / 219 (0.00%)
    0 / 220 (0.00%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    0 / 219 (0.00%)
    0 / 218 (0.00%)
    1 / 219 (0.46%)
    0 / 220 (0.00%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 219 (0.00%)
    0 / 218 (0.00%)
    0 / 219 (0.00%)
    0 / 220 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 218 (0.00%)
    0 / 219 (0.00%)
    0 / 220 (0.00%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 218 (0.00%)
    0 / 219 (0.00%)
    0 / 220 (0.00%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Macular degeneration
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 218 (0.46%)
    0 / 219 (0.00%)
    0 / 220 (0.00%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    0 / 219 (0.00%)
    0 / 218 (0.00%)
    0 / 219 (0.00%)
    1 / 220 (0.45%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 219 (0.00%)
    0 / 218 (0.00%)
    1 / 219 (0.46%)
    1 / 220 (0.45%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parotid gland enlargement
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 218 (0.00%)
    0 / 219 (0.00%)
    0 / 220 (0.00%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 218 (0.00%)
    0 / 219 (0.00%)
    0 / 220 (0.00%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salivary gland pain
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 218 (0.00%)
    0 / 219 (0.00%)
    0 / 220 (0.00%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 219 (0.00%)
    0 / 218 (0.00%)
    0 / 219 (0.00%)
    1 / 220 (0.45%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 219 (0.00%)
    0 / 218 (0.00%)
    1 / 219 (0.46%)
    0 / 220 (0.00%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 219 (0.00%)
    0 / 218 (0.00%)
    0 / 219 (0.00%)
    1 / 220 (0.45%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 219 (0.00%)
    0 / 218 (0.00%)
    1 / 219 (0.46%)
    0 / 220 (0.00%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Psoriasis
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 218 (0.00%)
    0 / 219 (0.00%)
    0 / 220 (0.00%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    0 / 219 (0.00%)
    0 / 218 (0.00%)
    1 / 219 (0.46%)
    0 / 220 (0.00%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Exostosis of jaw
         subjects affected / exposed
    0 / 219 (0.00%)
    0 / 218 (0.00%)
    1 / 219 (0.46%)
    0 / 220 (0.00%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 219 (0.00%)
    0 / 218 (0.00%)
    0 / 219 (0.00%)
    1 / 220 (0.45%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Synovial cyst
         subjects affected / exposed
    0 / 219 (0.00%)
    0 / 218 (0.00%)
    1 / 219 (0.46%)
    0 / 220 (0.00%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 218 (0.46%)
    0 / 219 (0.00%)
    0 / 220 (0.00%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngotonsillitis
         subjects affected / exposed
    0 / 219 (0.00%)
    0 / 218 (0.00%)
    1 / 219 (0.46%)
    0 / 220 (0.00%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Empa 12.5mg BID Empa 25mg QD Empa 5mg BID Empa 10mg QD Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 219 (4.57%)
    10 / 218 (4.59%)
    8 / 219 (3.65%)
    15 / 220 (6.82%)
    4 / 107 (3.74%)
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    10 / 219 (4.57%)
    10 / 218 (4.59%)
    8 / 219 (3.65%)
    15 / 220 (6.82%)
    4 / 107 (3.74%)
         occurrences all number
    11
    10
    8
    16
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jun 2012
    Global amendments involved only logistical or administrative aspects and had no impact on trial conduct. These amendments were therefore implemented without IEC or Competent Authority approval.
    11 Oct 2012
    Global amendments involved only logistical or administrative aspects and had no impact on trial conduct. These amendments were therefore implemented without IEC or Competent Authority approval.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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