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    Clinical Trial Results:
    A 24-week phase III randomized, double-blind, parallel group study to evaluate the efficacy and safety of twice daily oral administration of empagliflozin + metformin compared with the individual components of empagliflozin or metformin in drug naïve patients with type 2 diabetes mellitus.

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    		 2010-021375-92
    Trial protocol
    		 GB   DE   ES   CZ  
    Global end of trial date
    01 Dec 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Jul 2016
    First version publication date
    01 Jul 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    1276.1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01719003
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 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
    18 Dec 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Nov 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study was to investigate the efficacy, safety, and tolerability of the combinations of empagliflozin (12.5 mg bid or 5 mg bid) and metformin (1000 mg bid or 500 mg bid) compared with the corresponding individual components (empagliflozin 25 mg qd, empagliflozin 10 mg qd, metformin 1000 mg bid, and metformin 500 mg bid) after 24 weeks of treatment in patients with type 2 diabetes mellitus and insufficient glycaemic control, despite diet and exercise. An additional objective of the study was to investigate the non-inferiority and subsequent superiority of the efficacy of empagliflozin 25 mg qd and empagliflozin 10 mg qd vs. metformin 1000 mg bid, measured by the change from baseline in HbA1c (Glycosylated Haemoglobin) after 24 weeks of treatment in this population.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be 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.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Nov 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
    Brazil: 252
    Country: Number of subjects enrolled
    Canada: 106
    Country: Number of subjects enrolled
    Czech Republic: 63
    Country: Number of subjects enrolled
    Egypt: 52
    Country: Number of subjects enrolled
    France: 63
    Country: Number of subjects enrolled
    Germany: 59
    Country: Number of subjects enrolled
    Guatemala: 191
    Country: Number of subjects enrolled
    Korea, Republic of: 88
    Country: Number of subjects enrolled
    Lebanon: 68
    Country: Number of subjects enrolled
    Malaysia: 52
    Country: Number of subjects enrolled
    Mexico: 134
    Country: Number of subjects enrolled
    Peru: 90
    Country: Number of subjects enrolled
    Philippines: 190
    Country: Number of subjects enrolled
    Russian Federation: 140
    Country: Number of subjects enrolled
    Serbia: 101
    Country: Number of subjects enrolled
    Spain: 82
    Country: Number of subjects enrolled
    Taiwan: 49
    Country: Number of subjects enrolled
    Thailand: 35
    Country: Number of subjects enrolled
    Turkey: 51
    Country: Number of subjects enrolled
    United Kingdom: 96
    Country: Number of subjects enrolled
    United States: 520
    Worldwide total number of subjects
    2482
    EEA total number of subjects
    363
    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)
    2070
    From 65 to 84 years
    403
    85 years and over
    9

    Subject disposition

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    Recruitment
    Recruitment details
    		 With the first global protocol amendment (13-Dec-2012), the HbA1c inclusion criterion changed and further enrolment in the open label (OL) group was stopped, but the patients already entered in the OL group could continue until their scheduled end of the study.

    Pre-assignment
    Screening details
    		 All subjects were screened for eligibility to participate in the trial. Subjects were not to be randomised to trial treatment if any one of the trial specific entry criteria were violated. Patients with HbA1c >10.0% at screening and meeting all other inclusion criteria were initially directly included in an OL treatment group.

    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
    		 Empagliflozin 12.5 mg bid+ Metformin 1000 mg bid
    Arm description
    		 Oral administration of Empagliflozin 12.5 mg and Metformin 1000 mg twice daily (bid)
    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
    12.5 mg (two tables: 10mg + 2.5 mg) of Empagliflozin administered orally twice daily

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000 mg of Metformin administered orally twice daily

    Arm title
    		 Empagliflozin 12.5 mg bid+ Metformin 500 mg bid
    Arm description
    		 Oral administration of Empagliflozin 12.5 mg and Metformin 500 mg bid
    Arm type
    		 Experimental

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500 mg of Metformin administered orally twice daily

    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
    12.5 mg (two tables: 10mg + 2.5 mg) of Empagliflozin administered orally twice daily

    Arm title
    		 Empagliflozin 5 mg bid + Metformin 1000 mg bid
    Arm description
    		 Oral administration of Empagliflozin 5 mg and Metformin 1000 mg bid. Patient that was randomised to the Empagliflozin 5 mg bid + Metformin 1000 mg bid arm was not treated. Consequently, number of subjects that started is 172 but only 171 treated, thus reported.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000 mg of Metformin administered orally twice daily

    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
    5 mg of Empagliflozin administered orally twice daily

    Arm title
    		 Empagliflozin 5 mg bid + Metformin 500 mg bid
    Arm description
    		 Oral administration of Empagliflozin 5 mg and Metformin 500 mg bid. Patient that was randomised to the Empagliflozin 5 mg bid + Metformin 500 mg bid arm was not treated. Consequently, number of subjects that started is 170 but only 169 treated, thus reported.
    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
    5 mg of Empagliflozin administered orally twice daily

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500 mg of Metformin administered orally twice daily

    Arm title
    		 Empagliflozin 25 mg qd
    Arm description
    		 Oral administration of Empagliflozin 25 mg once daily (qd). Patient that was randomised to the Empagliflozin 25 mg qd arm was not treated. Consequently, number of subjects that started is 168 but only 167 treated, thus reported.
    Arm type
    		 Active comparator

    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
    25 mg of Empagliflozin administered orally once daily

    Arm title
    		 Empagliflozin 10 mg qd
    Arm description
    		 Oral administration of Empagliflozin 10 mg qd
    Arm type
    		 Active comparator

    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
    10 mg of Empagliflozin administered orally once daily

    Arm title
    		 Metformin 1000 mg bid
    Arm description
    		 Oral administration of Metformin 1000 mg bid. Patient that was randomised to the Metformin 1000 mg bid arm was not treated. Consequently, number of subjects that started is 171 but only 170 treated, thus reported.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000 mg of Metformin administered orally twice daily

    Arm title
    		 Metformin 500 mg bid
    Arm description
    		 Oral administration of Metformin 500 mg bid
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500 mg of Metformin administered orally twice daily

    Arm title
    		 Empagliflozin 12.5 mg bid + Metformin 1000 mg bid OL
    Arm description
    		 Oral administration of Empagliflozin 12.5 mg and Metformin 1000 mg bid in an open label (OL)
    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
    12.5 mg (two tables: 10mg + 2.5 mg) of Empagliflozin administered orally twice daily

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000 mg of Metformin administered orally twice daily

    Number of subjects in period 1 [1]
    		Empagliflozin 12.5 mg bid+ Metformin 1000 mg bid Empagliflozin 12.5 mg bid+ Metformin 500 mg bid Empagliflozin 5 mg bid + Metformin 1000 mg bid Empagliflozin 5 mg bid + Metformin 500 mg bid Empagliflozin 25 mg qd Empagliflozin 10 mg qd Metformin 1000 mg bid Metformin 500 mg bid Empagliflozin 12.5 mg bid + Metformin 1000 mg bid OL
    Started
    170
    170
    171
    169
    167
    172
    170
    171
    53
    Completed
    161
    153
    154
    156
    150
    160
    150
    151
    49
    Not completed
    9
    17
    17
    13
    17
    12
    20
    20
    4
         Non compliant with protocol
    1
    1
    -
    1
    2
    1
    2
    3
    -
         Adverse event, non-fatal
    6
    5
    4
    3
    4
    3
    6
    5
    -
         Refusal to continue, not due to AE
    2
    5
    4
    4
    4
    3
    8
    7
    1
         Lost to follow-up
    -
    6
    7
    2
    3
    4
    3
    2
    2
         Reason other than those specified
    -
    -
    2
    3
    4
    1
    -
    3
    1
         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 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
    Empagliflozin 12.5 mg bid+ Metformin 1000 mg bid
    Reporting group description
    		 Oral administration of Empagliflozin 12.5 mg and Metformin 1000 mg twice daily (bid)

    Reporting group title
    Empagliflozin 12.5 mg bid+ Metformin 500 mg bid
    Reporting group description
    		 Oral administration of Empagliflozin 12.5 mg and Metformin 500 mg bid

    Reporting group title
    Empagliflozin 5 mg bid + Metformin 1000 mg bid
    Reporting group description
    		 Oral administration of Empagliflozin 5 mg and Metformin 1000 mg bid. Patient that was randomised to the Empagliflozin 5 mg bid + Metformin 1000 mg bid arm was not treated. Consequently, number of subjects that started is 172 but only 171 treated, thus reported.

    Reporting group title
    Empagliflozin 5 mg bid + Metformin 500 mg bid
    Reporting group description
    		 Oral administration of Empagliflozin 5 mg and Metformin 500 mg bid. Patient that was randomised to the Empagliflozin 5 mg bid + Metformin 500 mg bid arm was not treated. Consequently, number of subjects that started is 170 but only 169 treated, thus reported.

    Reporting group title
    Empagliflozin 25 mg qd
    Reporting group description
    		 Oral administration of Empagliflozin 25 mg once daily (qd). Patient that was randomised to the Empagliflozin 25 mg qd arm was not treated. Consequently, number of subjects that started is 168 but only 167 treated, thus reported.

    Reporting group title
    Empagliflozin 10 mg qd
    Reporting group description
    		 Oral administration of Empagliflozin 10 mg qd

    Reporting group title
    Metformin 1000 mg bid
    Reporting group description
    		 Oral administration of Metformin 1000 mg bid. Patient that was randomised to the Metformin 1000 mg bid arm was not treated. Consequently, number of subjects that started is 171 but only 170 treated, thus reported.

    Reporting group title
    Metformin 500 mg bid
    Reporting group description
    		 Oral administration of Metformin 500 mg bid

    Reporting group title
    Empagliflozin 12.5 mg bid + Metformin 1000 mg bid OL
    Reporting group description
    		 Oral administration of Empagliflozin 12.5 mg and Metformin 1000 mg bid in an open label (OL)

    Reporting group values
    		 Empagliflozin 12.5 mg bid+ Metformin 1000 mg bid Empagliflozin 12.5 mg bid+ Metformin 500 mg bid Empagliflozin 5 mg bid + Metformin 1000 mg bid Empagliflozin 5 mg bid + Metformin 500 mg bid Empagliflozin 25 mg qd Empagliflozin 10 mg qd Metformin 1000 mg bid Metformin 500 mg bid Empagliflozin 12.5 mg bid + Metformin 1000 mg bid OL Total
    Number of subjects
    		 170 170 171 169 167 172 170 171 53 1413
    Age categorical
    Units: Subjects
    Age Continuous |
    Treated set (TS): TS included all patients treated with at least 1 dose of randomised trial medication. Open label set (OL): included all patients that were not eligible to be randomised to double blind treatment due to HbA1c >10.0%
    Units: years
        arithmetic mean (standard deviation)
    		 53.6 ± 10.7 50.8 ± 10.6 52.4 ± 11.3 52.3 ± 11.5 53.3 ± 10.9 53.2 ± 10.6 52 ± 10.9 53.4 ± 10.8 50.3 ± 10 -
    Gender, Male/Female
    Units: participants
        Female
    		 81 61 70 67 83 72 76 83 12 605
        Male
    		 89 109 101 102 84 100 94 88 41 808

    End points

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    End points reporting groups
    Reporting group title
    Empagliflozin 12.5 mg bid+ Metformin 1000 mg bid
    Reporting group description
    		 Oral administration of Empagliflozin 12.5 mg and Metformin 1000 mg twice daily (bid)

    Reporting group title
    Empagliflozin 12.5 mg bid+ Metformin 500 mg bid
    Reporting group description
    		 Oral administration of Empagliflozin 12.5 mg and Metformin 500 mg bid

    Reporting group title
    Empagliflozin 5 mg bid + Metformin 1000 mg bid
    Reporting group description
    		 Oral administration of Empagliflozin 5 mg and Metformin 1000 mg bid. Patient that was randomised to the Empagliflozin 5 mg bid + Metformin 1000 mg bid arm was not treated. Consequently, number of subjects that started is 172 but only 171 treated, thus reported.

    Reporting group title
    Empagliflozin 5 mg bid + Metformin 500 mg bid
    Reporting group description
    		 Oral administration of Empagliflozin 5 mg and Metformin 500 mg bid. Patient that was randomised to the Empagliflozin 5 mg bid + Metformin 500 mg bid arm was not treated. Consequently, number of subjects that started is 170 but only 169 treated, thus reported.

    Reporting group title
    Empagliflozin 25 mg qd
    Reporting group description
    		 Oral administration of Empagliflozin 25 mg once daily (qd). Patient that was randomised to the Empagliflozin 25 mg qd arm was not treated. Consequently, number of subjects that started is 168 but only 167 treated, thus reported.

    Reporting group title
    Empagliflozin 10 mg qd
    Reporting group description
    		 Oral administration of Empagliflozin 10 mg qd

    Reporting group title
    Metformin 1000 mg bid
    Reporting group description
    		 Oral administration of Metformin 1000 mg bid. Patient that was randomised to the Metformin 1000 mg bid arm was not treated. Consequently, number of subjects that started is 171 but only 170 treated, thus reported.

    Reporting group title
    Metformin 500 mg bid
    Reporting group description
    		 Oral administration of Metformin 500 mg bid

    Reporting group title
    Empagliflozin 12.5 mg bid + Metformin 1000 mg bid OL
    Reporting group description
    		 Oral administration of Empagliflozin 12.5 mg and Metformin 1000 mg bid in an open label (OL)

    Primary: HbA1c (Glycosylated Haemoglobin) Change From Baseline at Week 24

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    End point title
    		 HbA1c (Glycosylated Haemoglobin) Change From Baseline at Week 24 [1]
    End point description
    Change from baseline in HbA1c (%) after 24 weeks of treatment. “Baseline” refers to the last observation before the start of any randomised trial treatment medication. Means presented are the adjusted means. Full analysis set (FAS): FAS comprised all randomised patients treated with at least 1 dose of trial medication, with a baseline and at least 1 on-treatment HbA1c assessment. The FAS observed cases (OC) was used to evaluate primary endpoint, where only patients with available data were analysed.
    End point type
    Primary
    End point timeframe
    baseline and 24 weeks
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to the small number of patients entered to open label arm, the results for this arm were not included in primary analysis.
    End point values
    		 Empagliflozin 12.5 mg bid+ Metformin 1000 mg bid Empagliflozin 12.5 mg bid+ Metformin 500 mg bid Empagliflozin 5 mg bid + Metformin 1000 mg bid Empagliflozin 5 mg bid + Metformin 500 mg bid Empagliflozin 25 mg qd Empagliflozin 10 mg qd Metformin 1000 mg bid Metformin 500 mg bid
    Number of subjects analysed
    159 [2]
    149 [3]
    151 [4]
    153 [5]
    143 [6]
    156 [7]
    146 [8]
    142 [9]
    Units: percentage of HbA1c
        arithmetic mean (standard error)
    -2.08 ± 0.08
    -1.93 ± 0.08
    -2.07 ± 0.08
    -1.98 ± 0.08
    -1.36 ± 0.08
    -1.35 ± 0.08
    -1.75 ± 0.09
    -1.18 ± 0.08
    Notes
    [2] - FAS observed cases (OC). Only patients with available data were analysed.
    [3] - FAS observed cases (OC). Only patients with available data were analysed.
    [4] - FAS observed cases (OC). Only patients with available data were analysed.
    [5] - FAS observed cases (OC). Only patients with available data were analysed.
    [6] - FAS observed cases (OC). Only patients with available data were analysed.
    [7] - FAS observed cases (OC). Only patients with available data were analysed.
    [8] - FAS observed cases (OC). Only patients with available data were analysed.
    [9] - FAS observed cases (OC). Only patients with available data were analysed.
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of HbA1c (in units of %) after 24 weeks of double-blind treatment. 'Baseline HbA1c’:linear covariate;'treatment','baseline renal function','region','visit' & 'visit by treatment interaction':fixed effects.
    Comparison groups
    Empagliflozin 12.5 mg bid+ Metformin 1000 mg bid v Metformin 1000 mg bid
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0056 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean
    Point estimate
    -0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.56
         upper limit
    		 -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.12
    Notes
    [10] - Empagliflozin 12.5 mg bid+ Metformin 1000 mg bid minus Metformin 1000 mg bid
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of HbA1c (in units of %) after 24 weeks of double-blind treatment. 'Baseline HbA1c’:linear covariate;'treatment','baseline renal function','region','visit' & 'visit by treatment interaction':fixed effects.
    Comparison groups
    Empagliflozin 12.5 mg bid+ Metformin 1000 mg bid v Empagliflozin 25 mg qd
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [11]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean
    Point estimate
    -0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.95
         upper limit
    		 -0.48
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.12
    Notes
    [11] - Empagliflozin 12.5 mg bid+ Metformin 1000 mg bid minus Empagliflozin 25 mg qd
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of HbA1c (in units of %) after 24 weeks of double-blind treatment. 'Baseline HbA1c’:linear covariate;'treatment','baseline renal function','region','visit' & 'visit by treatment interaction':fixed effects.
    Comparison groups
    Empagliflozin 12.5 mg bid+ Metformin 500 mg bid v Metformin 500 mg bid
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [12]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted Mean
    Point estimate
    -0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.98
         upper limit
    		 -0.51
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.12
    Notes
    [12] - Empagliflozin 12.5 mg bid+ Metformin 500 mg bid minus Metformin 500 mg bid
    Statistical analysis title
    		 Statistical analysis 4
    Statistical analysis description
    Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of HbA1c (in units of %) after 24 weeks of double-blind treatment. 'Baseline HbA1c’:linear covariate;'treatment','baseline renal function','region','visit' & 'visit by treatment interaction':fixed effects.
    Comparison groups
    Empagliflozin 12.5 mg bid+ Metformin 500 mg bid v Empagliflozin 25 mg qd
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [13]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean
    Point estimate
    -0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.81
         upper limit
    		 -0.34
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.12
    Notes
    [13] - Empagliflozin 12.5 mg bid+ Metformin 500 mg bid minus Empagliflozin 25 mg qd
    Statistical analysis title
    		 Statistical analysis 5
    Statistical analysis description
    Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of HbA1c (in units of %) after 24 weeks of double-blind treatment. 'Baseline HbA1c’:linear covariate;'treatment','baseline renal function','region','visit' & 'visit by treatment interaction':fixed effects.
    Comparison groups
    Empagliflozin 5 mg bid + Metformin 1000 mg bid v Metformin 1000 mg bid
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0062 [14]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean
    Point estimate
    -0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.56
         upper limit
    		 -0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.12
    Notes
    [14] - Empagliflozin 5 mg bid + Metformin 1000 mg bid minus Metformin 1000 mg bid
    Statistical analysis title
    		 Statistical analysis 6
    Statistical analysis description
    Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of HbA1c (in units of %) after 24 weeks of double-blind treatment. 'Baseline HbA1c’:linear covariate;'treatment','baseline renal function','region','visit' & 'visit by treatment interaction':fixed effects.
    Comparison groups
    Empagliflozin 5 mg bid + Metformin 1000 mg bid v Empagliflozin 10 mg qd
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [15]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted Mean
    Point estimate
    -0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.95
         upper limit
    		 -0.49
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.12
    Notes
    [15] - Empagliflozin 5 mg bid + Metformin 1000 mg bid minus Empagliflozin 10 mg qd
    Statistical analysis title
    		 Statistical analysis 7
    Statistical analysis description
    Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of HbA1c (in units of %) after 24 weeks of double-blind treatment. 'Baseline HbA1c’:linear covariate;'treatment','baseline renal function','region','visit' & 'visit by treatment interaction':fixed effects.
    Comparison groups
    Empagliflozin 5 mg bid + Metformin 500 mg bid v Metformin 500 mg bid
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [16]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted Mean
    Point estimate
    -0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.03
         upper limit
    		 -0.56
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.12
    Notes
    [16] - Empagliflozin 5 mg bid + Metformin 500 mg bid minus Metformin 500 mg bid
    Statistical analysis title
    		 Statistical analysis 8
    Statistical analysis description
    Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of HbA1c (in units of %) after 24 weeks of double-blind treatment. 'Baseline HbA1c’:linear covariate;'treatment','baseline renal function','region','visit' & 'visit by treatment interaction':fixed effects.
    Comparison groups
    Empagliflozin 5 mg bid + Metformin 500 mg bid v Empagliflozin 10 mg qd
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [17]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean
    Point estimate
    -0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.86
         upper limit
    		 -0.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.12
    Notes
    [17] - Empagliflozin 5 mg bid + Metformin 500 mg bid minus Empagliflozin 10 mg qd
    Statistical analysis title
    		 Statistical analysis 9
    Statistical analysis description
    Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of HbA1c (in units of %) after 24 weeks of double-blind treatment. 'Baseline HbA1c’:linear covariate;'treatment','baseline renal function','region','visit' & 'visit by treatment interaction':fixed effects.
    Comparison groups
    Empagliflozin 25 mg qd v Metformin 1000 mg bid
    Number of subjects included in analysis
    289
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [18]
    P-value
    		 = 0.6246 [19]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean
    Point estimate
    0.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.15
         upper limit
    		 0.62
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.12
    Notes
    [18] - The noninferiority of empagliflozin 10 mg qd against metformin 1000 mg bid were to be tested for HbA1c change from baseline to Week 24 at the level of α=0.025 (one-sided), through application of a non-inferiority margin of 0.35%.
    [19] - Empagliflozin 25 mg qd minus Metformin 1000 mg bid
    Statistical analysis title
    		 Statistical analysis 10
    Statistical analysis description
    Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of HbA1c (in units of %) after 24 weeks of double-blind treatment. 'Baseline HbA1c’:linear covariate;'treatment','baseline renal function','region','visit' & 'visit by treatment interaction':fixed effects.
    Comparison groups
    Empagliflozin 10 mg qd v Metformin 1000 mg bid
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [20]
    P-value
    		 = 0.6558 [21]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 0.63
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.12
    Notes
    [20] - The noninferiority of empagliflozin 10 mg qd against metformin 1000 mg bid were to be tested for HbA1c change from baseline to Week 24 at the level of α=0.025 (one-sided), through application of a non-inferiority margin of 0.35%.
    [21] - Empagliflozin 10 mg qd minus Metformin 1000 mg bid

    Secondary: FPG (Fasting Plasma Glucose) Change From Baseline at Week 24

    		 Close Top of page
    End point title
    		 FPG (Fasting Plasma Glucose) Change From Baseline at Week 24 [22]
    End point description
    Change from baseline in FPG (mg/dL) after 24 weeks of treatment. “Baseline” refers to the last observation before the start of any randomised trial treatment medication. Means presented are the adjusted means.
    End point type
    Secondary
    End point timeframe
    baseline and 24 weeks
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to the small number of patients entered to open label arm, the results for this arm were not included in primary analysis.
    End point values
    		 Empagliflozin 12.5 mg bid+ Metformin 1000 mg bid Empagliflozin 12.5 mg bid+ Metformin 500 mg bid Empagliflozin 5 mg bid + Metformin 1000 mg bid Empagliflozin 5 mg bid + Metformin 500 mg bid Empagliflozin 25 mg qd Empagliflozin 10 mg qd Metformin 1000 mg bid Metformin 500 mg bid
    Number of subjects analysed
    158 [23]
    146 [24]
    146 [25]
    153 [26]
    139 [27]
    154 [28]
    145 [29]
    139 [30]
    Units: mg/dL
        arithmetic mean (standard error)
    -51 ± 2.4
    -44 ± 2.4
    -47.8 ± 2.4
    -45.5 ± 2.4
    -28 ± 2.5
    -32.9 ± 2.4
    -32.1 ± 2.4
    -17.2 ± 2.5
    Notes
    [23] - FAS observed cases (OC). Only patients with available data were analysed.
    [24] - FAS observed cases (OC). Only patients with available data were analysed.
    [25] - FAS observed cases (OC). Only patients with available data were analysed.
    [26] - FAS observed cases (OC). Only patients with available data were analysed.
    [27] - FAS observed cases (OC). Only patients with available data were analysed.
    [28] - FAS observed cases (OC). Only patients with available data were analysed.
    [29] - FAS observed cases (OC). Only patients with available data were analysed.
    [30] - FAS observed cases (OC). Only patients with available data were analysed.
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of FPG after 24 weeks of double-blind treatment. 'Baseline HbA1c’:linear covariate;'treatment','baseline renal function', 'baseline fasting plasma glucose', 'region','visit' & 'visit by treatment interaction':fixed effects.
    Comparison groups
    Empagliflozin 12.5 mg bid+ Metformin 1000 mg bid v Metformin 1000 mg bid
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    		 other [31]
    P-value
    		 < 0.0001 [32]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean
    Point estimate
    -18.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.5
         upper limit
    		 -12.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.4
    Notes
    [31] - Since previous step in the hierarchical testing failed (primary measure analyses 9 and 10), the analyses for secondary measures of FPG andbody weight are considered exploratory and not confirmatory
    [32] - Empagliflozin 12.5 mg bid+ Metformin 1000 mg bid minus Metformin 1000 mg bid
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of FPG after 24 weeks of double-blind treatment. 'Baseline HbA1c’:linear covariate;'treatment','baseline renal function', 'baseline fasting plasma glucose','region','visit' & 'visit by treatment interaction':fixed effects.
    Comparison groups
    Empagliflozin 12.5 mg bid+ Metformin 1000 mg bid v Empagliflozin 25 mg qd
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    		 other [33]
    P-value
    		 < 0.0001 [34]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean
    Point estimate
    -23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -29.7
         upper limit
    		 -16.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.4
    Notes
    [33] - Since previous step in the hierarchical testing failed (primary measure analyses 9 and 10), the analyses for secondary measures of FPG andbody weight are considered exploratory and not confirmatory
    [34] - Empagliflozin 12.5 mg bid+ Metformin 1000 mg bid minus Empagliflozin 25 mg qd
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of FPG after 24 weeks of double-blind treatment. 'Baseline HbA1c’:linear covariate;'treatment','baseline renal function', 'baseline fasting plasma glucose','region','visit' & 'visit by treatment interaction':fixed effects.
    Comparison groups
    Empagliflozin 12.5 mg bid+ Metformin 500 mg bid v Metformin 500 mg bid
    Number of subjects included in analysis
    285
    Analysis specification
    Pre-specified
    Analysis type
    		 other [35]
    P-value
    		 < 0.0001 [36]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted Mean
    Point estimate
    -26.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -33.5
         upper limit
    		 -20
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.4
    Notes
    [35] - Since previous step in the hierarchical testing failed (primary measure analyses 9 and 10), the analyses for secondary measures of FPG and body weight are considered exploratory and not confirmatory
    [36] - Empagliflozin 12.5 mg bid+ Metformin 500 mg bid minus Metformin 500 mg bid
    Statistical analysis title
    		 Statistical analysis 4
    Statistical analysis description
    Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of FPG after 24 weeks of double-blind treatment. 'Baseline HbA1c’:linear covariate;'treatment','baseline renal function', 'baseline fasting plasma glucose','region','visit' & 'visit by treatment interaction':fixed effects.
    Comparison groups
    Empagliflozin 12.5 mg bid+ Metformin 500 mg bid v Empagliflozin 25 mg qd
    Number of subjects included in analysis
    285
    Analysis specification
    Pre-specified
    Analysis type
    		 other [37]
    P-value
    		 < 0.0001 [38]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean
    Point estimate
    -16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.8
         upper limit
    		 -9.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.4
    Notes
    [37] - Since previous step in the hierarchical testing failed (primary measure analyses 9 and 10), the analyses for secondary measures of FPG and body weight are considered exploratory and not confirmatory
    [38] - Empagliflozin 12.5 mg bid+ Metformin 500 mg bid minus Empagliflozin 25 mg qd
    Statistical analysis title
    		 Statistical analysis 5
    Statistical analysis description
    Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of FPG of double-blind treatment. 'Baseline HbA1c’:linear covariate;'treatment','baseline renal function', 'baseline fasting plasma glucose','region','visit' & 'visit by treatment interaction':fixed effects.
    Comparison groups
    Empagliflozin 5 mg bid + Metformin 1000 mg bid v Metformin 1000 mg bid
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 other [39]
    P-value
    		 < 0.0001 [40]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean
    Point estimate
    -15.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.3
         upper limit
    		 -8.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.4
    Notes
    [39] - Since previous step in the hierarchical testing failed (primary measure analyses 9 and 10), the analyses for secondary measures of FPG and body weight are considered exploratory and not confirmatory.
    [40] - Empagliflozin 5 mg bid + Metformin 1000 mg bid minus Metformin 1000 mg bid
    Statistical analysis title
    		 Statistical analysis 6
    Statistical analysis description
    Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of FPG after 24 weeks of double-blind treatment. 'Baseline HbA1c’:linear covariate;'treatment','baseline renal function', 'baseline fasting plasma glucose','region','visit' & 'visit by treatment interaction':fixed effects.
    Comparison groups
    Empagliflozin 5 mg bid + Metformin 1000 mg bid v Empagliflozin 10 mg qd
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    		 other [41]
    P-value
    		 < 0.0001 [42]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted Mean
    Point estimate
    -14.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.4
         upper limit
    		 -8.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.4
    Notes
    [41] - Since previous step in the hierarchical testing failed (primary measure analyses 9 and 10), the analyses for secondary measures of FPG and body weight are considered exploratory and not confirmatory
    [42] - Empagliflozin 5 mg bid + Metformin 1000 mg bid minus Empagliflozin 10 mg qd
    Statistical analysis title
    		 Statistical analysis 7
    Statistical analysis description
    Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of FPG after 24 weeks of double-blind treatment. 'Baseline HbA1c’:linear covariate;'treatment','baseline renal function', 'baseline fasting plasma glucose','region','visit' & 'visit by treatment interaction':fixed effects.
    Comparison groups
    Empagliflozin 5 mg bid + Metformin 500 mg bid v Metformin 500 mg bid
    Number of subjects included in analysis
    292
    Analysis specification
    Pre-specified
    Analysis type
    		 other [43]
    P-value
    		 < 0.0001 [44]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted Mean
    Point estimate
    -28.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -35
         upper limit
    		 -21.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.4
    Notes
    [43] - Since previous step in the hierarchical testing failed (primary measure analyses 9 and 10), the analyses for secondary measures of FPG and body weight are considered exploratory and not confirmatory
    [44] - Empagliflozin 5 mg bid + Metformin 500 mg bid minus Metformin 500 mg bid
    Statistical analysis title
    		 Statistical analysis 8
    Statistical analysis description
    Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of FPG after 24 weeks of double-blind treatment. 'Baseline HbA1c’:linear covariate;'treatment','baseline renal function', 'baseline fasting plasma glucose','region','visit' & 'visit by treatment interaction':fixed effects.
    Comparison groups
    Empagliflozin 5 mg bid + Metformin 500 mg bid v Empagliflozin 10 mg qd
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    		 other [45]
    P-value
    		 = 0.0002 [46]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean
    Point estimate
    -12.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.1
         upper limit
    		 -6
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.4
    Notes
    [45] - Since previous step in the hierarchical testing failed (primary measure analyses 9 and 10), the analyses for secondary measures of FPG and body weight are considered exploratory and not confirmatory
    [46] - Empagliflozin 5 mg bid + Metformin 500 mg bid minus Empagliflozin 10 mg qd

    Secondary: Body weight Change From Baseline at Week 24

    		 Close Top of page
    End point title
    		 Body weight Change From Baseline at Week 24 [47]
    End point description
    Change from baseline in body weight (kg) after 24 weeks of treatment. “Baseline” refers to the last observation before the start of any randomised trial treatment. medication. Means presented are the adjusted means.
    End point type
    Secondary
    End point timeframe
    baseline and 24 weeks
    Notes
    [47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Due to the small number of patients entered to open label arm, the results for this arm were not included in primary analysis.
    End point values
    		 Empagliflozin 12.5 mg bid+ Metformin 1000 mg bid Empagliflozin 12.5 mg bid+ Metformin 500 mg bid Empagliflozin 5 mg bid + Metformin 1000 mg bid Empagliflozin 5 mg bid + Metformin 500 mg bid Empagliflozin 25 mg qd Empagliflozin 10 mg qd Metformin 1000 mg bid Metformin 500 mg bid
    Number of subjects analysed
    160 [48]
    149 [49]
    150 [50]
    155 [51]
    143 [52]
    155 [53]
    148 [54]
    140 [55]
    Units: kg
        arithmetic mean (standard error)
    -3.78 ± 0.29
    -3.04 ± 0.3
    -3.48 ± 0.3
    -2.77 ± 0.3
    -2.38 ± 0.3
    -2.39 ± 0.29
    -1.27 ± 0.3
    -0.52 ± 0.3
    Notes
    [48] - FAS observed cases (OC). Only patients with available data were analysed.
    [49] - FAS observed cases (OC). Only patients with available data were analysed.
    [50] - FAS observed cases (OC). Only patients with available data were analysed.
    [51] - FAS observed cases (OC). Only patients with available data were analysed.
    [52] - FAS observed cases (OC). Only patients with available data were analysed.
    [53] - FAS observed cases (OC). Only patients with available data were analysed.
    [54] - FAS observed cases (OC). Only patients with available data were analysed.
    [55] - FAS observed cases (OC). Only patients with available data were analysed.
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of body weight after 24 weeks of double-blind treatment. 'Baseline HbA1c’:linear covariate;'treatment','baseline renal function','region','visit' & 'visit by treatment interaction':fixed effects.
    Comparison groups
    Empagliflozin 12.5 mg bid+ Metformin 1000 mg bid v Metformin 1000 mg bid
    Number of subjects included in analysis
    308
    Analysis specification
    Pre-specified
    Analysis type
    		 other [56]
    P-value
    		 < 0.0001 [57]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean
    Point estimate
    -2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.33
         upper limit
    		 -1.68
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.42
    Notes
    [56] - Since previous step in the hierarchical testing failed (primary measure analyses 9 and 10), the analyses for secondary measures of FPG and body weight are considered exploratory and not confirmatory
    [57] - Empagliflozin 12.5 mg bid+ Metformin 1000 mg bid minus Metformin 1000 mg bid
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of body weight after 24 weeks of double-blind treatment. 'Baseline HbA1c’:linear covariate;'treatment','baseline renal function','region','visit' & 'visit by treatment interaction':fixed effects.
    Comparison groups
    Empagliflozin 12.5 mg bid+ Metformin 500 mg bid v Metformin 500 mg bid
    Number of subjects included in analysis
    289
    Analysis specification
    Pre-specified
    Analysis type
    		 other [58]
    P-value
    		 < 0.0001 [59]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted Mean
    Point estimate
    -2.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.35
         upper limit
    		 -1.69
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.42
    Notes
    [58] - Since previous step in the hierarchical testing failed (primary measure analyses 9 and 10), the analyses for secondary measures of FPG and body weight are considered exploratory and not confirmatory
    [59] - Empagliflozin 12.5 mg bid+ Metformin 500 mg bid minus Metformin 500 mg bid
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of body weight after 24 weeks of double-blind treatment. 'Baseline HbA1c’:linear covariate;'treatment','baseline renal function','region','visit' & 'visit by treatment interaction':fixed effects.
    Comparison groups
    Empagliflozin 5 mg bid + Metformin 1000 mg bid v Metformin 1000 mg bid
    Number of subjects included in analysis
    298
    Analysis specification
    Pre-specified
    Analysis type
    		 other [60]
    P-value
    		 < 0.0001 [61]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted mean
    Point estimate
    -2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.03
         upper limit
    		 -1.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.42
    Notes
    [60] - Since previous step in the hierarchical testing failed (primary measure analyses 9 and 10), the analyses for secondary measures of FPG and body weight are considered exploratory and not confirmatory
    [61] - Empagliflozin 5 mg bid + Metformin 1000 mg bid minus Metformin 1000 mg bid
    Statistical analysis title
    		 Statistical analysis 4
    Statistical analysis description
    Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of body weight after 24 weeks of double-blind treatment. 'Baseline HbA1c’:linear covariate;'treatment','baseline renal function','region','visit' & 'visit by treatment interaction':fixed effects.
    Comparison groups
    Empagliflozin 5 mg bid + Metformin 500 mg bid v Metformin 500 mg bid
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other [62]
    P-value
    		 < 0.0001 [63]
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted Mean
    Point estimate
    -2.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.09
         upper limit
    		 -1.43
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.42
    Notes
    [62] - Since previous step in the hierarchical testing failed (primary measure analyses 9 and 10), the analyses for secondary measures of FPG and body weight are considered exploratory and not confirmatory
    [63] - Empagliflozin 5 mg bid + Metformin 500 mg bid minus Metformin 500 mg bid

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Adverse events with an onset after the first dose of randomised trial medication up to a period of 7 days after the last dose (Up to 237 days)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Empagliflozin 10 mg qd
    Reporting group description
    		 Oral administration of Empagliflozin 10 mg qd

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

    Reporting group title
    Empagliflozin 5 mg bid + Metformin 500 mg bid
    Reporting group description
    		 Oral administration of Empagliflozin 5 mg and Metformin 500 mg bid

    Reporting group title
    Empagliflozin 5 mg bid + Metformin 1000 mg bid
    Reporting group description
    		 Oral administration of Empagliflozin 5 mg and Metformin 1000 mg bid

    Reporting group title
    Empagliflozin 12.5 mg bid+ Metformin 500 mg bid
    Reporting group description
    		 Oral administration of Empagliflozin 12.5 mg and Metformin 500 mg bid

    Reporting group title
    Empagliflozin 12.5 mg bid+ Metformin 1000 mg bid
    Reporting group description
    		 Oral administration of Empagliflozin 12.5 mg and Metformin 1000 mg twice daily (bid)

    Reporting group title
    Metformin 500 mg bid
    Reporting group description
    		 Oral administration of Metformin 500 mg bid

    Reporting group title
    Metformin 1000 mg bid
    Reporting group description
    		 Oral administration of Metformin 1000 mg bid

    Reporting group title
    Empagliflozin 12.5 mg bid+ Metformin 1000 mg bid OL
    Reporting group description
    		 Oral administration of Empagliflozin 12.5 mg and Metformin 1000 mg twice daily (bid) in an open label (OL)

    Serious adverse events
    		 Empagliflozin 10 mg qd Empagliflozin 25 mg qd Empagliflozin 5 mg bid + Metformin 500 mg bid Empagliflozin 5 mg bid + Metformin 1000 mg bid Empagliflozin 12.5 mg bid+ Metformin 500 mg bid Empagliflozin 12.5 mg bid+ Metformin 1000 mg bid Metformin 500 mg bid Metformin 1000 mg bid Empagliflozin 12.5 mg bid+ Metformin 1000 mg bid OL
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 172 (0.58%)
    3 / 167 (1.80%)
    2 / 169 (1.18%)
    3 / 171 (1.75%)
    6 / 170 (3.53%)
    2 / 170 (1.18%)
    3 / 171 (1.75%)
    3 / 170 (1.76%)
    2 / 53 (3.77%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 171 (0.00%)
    1 / 170 (0.59%)
    0 / 170 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    1 / 170 (0.59%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 170 (0.00%)
    0 / 171 (0.00%)
    1 / 170 (0.59%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 169 (0.59%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 170 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 170 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    1 / 169 (0.59%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 170 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 171 (0.00%)
    1 / 170 (0.59%)
    0 / 170 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    1 / 171 (0.58%)
    0 / 170 (0.00%)
    0 / 170 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    1 / 171 (0.58%)
    0 / 170 (0.00%)
    0 / 170 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 170 (0.00%)
    1 / 171 (0.58%)
    0 / 170 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 170 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia paroxysmal
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 171 (0.00%)
    1 / 170 (0.59%)
    0 / 170 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    1 / 170 (0.59%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 170 (0.00%)
    0 / 171 (0.00%)
    1 / 170 (0.59%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    1 / 171 (0.58%)
    0 / 170 (0.00%)
    0 / 170 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 171 (0.00%)
    1 / 170 (0.59%)
    0 / 170 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 170 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 170 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    0 / 171 (0.00%)
    1 / 170 (0.59%)
    0 / 170 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 171 (0.00%)
    1 / 170 (0.59%)
    0 / 170 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 170 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 171 (0.00%)
    1 / 170 (0.59%)
    0 / 170 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 170 (0.00%)
    1 / 171 (0.58%)
    0 / 170 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes simplex encephalitis
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 170 (0.00%)
    1 / 171 (0.58%)
    0 / 170 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal abscess
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 171 (0.00%)
    1 / 170 (0.59%)
    0 / 170 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 170 (0.00%)
    0 / 171 (0.00%)
    1 / 170 (0.59%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 172 (0.00%)
    0 / 167 (0.00%)
    0 / 169 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    0 / 170 (0.00%)
    0 / 171 (0.00%)
    0 / 170 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Empagliflozin 10 mg qd Empagliflozin 25 mg qd Empagliflozin 5 mg bid + Metformin 500 mg bid Empagliflozin 5 mg bid + Metformin 1000 mg bid Empagliflozin 12.5 mg bid+ Metformin 500 mg bid Empagliflozin 12.5 mg bid+ Metformin 1000 mg bid Metformin 500 mg bid Metformin 1000 mg bid Empagliflozin 12.5 mg bid+ Metformin 1000 mg bid OL
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 172 (20.93%)
    41 / 167 (24.55%)
    42 / 169 (24.85%)
    35 / 171 (20.47%)
    40 / 170 (23.53%)
    48 / 170 (28.24%)
    38 / 171 (22.22%)
    53 / 170 (31.18%)
    16 / 53 (30.19%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 172 (2.33%)
    3 / 167 (1.80%)
    5 / 169 (2.96%)
    4 / 171 (2.34%)
    9 / 170 (5.29%)
    6 / 170 (3.53%)
    7 / 171 (4.09%)
    4 / 170 (2.35%)
    3 / 53 (5.66%)
         occurrences all number
    4
    4
    5
    4
    9
    6
    7
    7
    4
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 172 (1.16%)
    6 / 167 (3.59%)
    9 / 169 (5.33%)
    5 / 171 (2.92%)
    6 / 170 (3.53%)
    12 / 170 (7.06%)
    6 / 171 (3.51%)
    24 / 170 (14.12%)
    4 / 53 (7.55%)
         occurrences all number
    2
    7
    12
    6
    14
    13
    6
    29
    6
    Gastritis
         subjects affected / exposed
    0 / 172 (0.00%)
    2 / 167 (1.20%)
    1 / 169 (0.59%)
    2 / 171 (1.17%)
    1 / 170 (0.59%)
    0 / 170 (0.00%)
    2 / 171 (1.17%)
    4 / 170 (2.35%)
    3 / 53 (5.66%)
         occurrences all number
    0
    2
    1
    2
    1
    0
    2
    4
    3
    Nausea
         subjects affected / exposed
    1 / 172 (0.58%)
    1 / 167 (0.60%)
    5 / 169 (2.96%)
    5 / 171 (2.92%)
    4 / 170 (2.35%)
    6 / 170 (3.53%)
    1 / 171 (0.58%)
    3 / 170 (1.76%)
    3 / 53 (5.66%)
         occurrences all number
    1
    1
    5
    5
    4
    6
    1
    4
    3
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 172 (2.91%)
    7 / 167 (4.19%)
    4 / 169 (2.37%)
    8 / 171 (4.68%)
    5 / 170 (2.94%)
    4 / 170 (2.35%)
    10 / 171 (5.85%)
    5 / 170 (2.94%)
    3 / 53 (5.66%)
         occurrences all number
    5
    8
    4
    11
    8
    4
    11
    7
    3
    Urinary tract infection
         subjects affected / exposed
    12 / 172 (6.98%)
    13 / 167 (7.78%)
    9 / 169 (5.33%)
    12 / 171 (7.02%)
    17 / 170 (10.00%)
    18 / 170 (10.59%)
    12 / 171 (7.02%)
    14 / 170 (8.24%)
    0 / 53 (0.00%)
         occurrences all number
    16
    15
    11
    14
    19
    20
    13
    16
    0
    Metabolism and nutrition disorders
    Dyslipidaemia
         subjects affected / exposed
    15 / 172 (8.72%)
    11 / 167 (6.59%)
    15 / 169 (8.88%)
    8 / 171 (4.68%)
    6 / 170 (3.53%)
    8 / 170 (4.71%)
    7 / 171 (4.09%)
    8 / 170 (4.71%)
    2 / 53 (3.77%)
         occurrences all number
    15
    11
    15
    8
    6
    8
    8
    8
    2
    Hypoglycaemia
         subjects affected / exposed
    2 / 172 (1.16%)
    1 / 167 (0.60%)
    0 / 169 (0.00%)
    1 / 171 (0.58%)
    4 / 170 (2.35%)
    4 / 170 (2.35%)
    0 / 171 (0.00%)
    2 / 170 (1.18%)
    3 / 53 (5.66%)
         occurrences all number
    2
    1
    0
    1
    5
    6
    0
    2
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Dec 2012
    The first amendment introduced a change in inclusion criterion no. 3. In the original version of the CTP, patients were to have an HbA1c value of ≥ 7.0% and ≤ 10% (≥53.0 mmol/mol and ≤85.8 mmol/mol) at Visit 1 (screening) to be eligible for randomised treatment and patients with HbA1dc >12% were eligible for OL arm. The values were changed to HbA1c ≥ 7.5% and ≤ 12.0% (≥ 58.5 mmol/mol and ≤ 107.7 mmol/mol) at Visit 1 (screening). This change was introduced to investigate the potential of empagliflozin treatment for reducing higher HbA1c values in a randomised set-up rather than in an open label group. As a consequence, patients were no longer to be recruited in the open-label group after the introduction of this amendment. Subsequently, the planned total number of patients was changed from from 1424 to 1344. However, patients who had already entered the open-label treatment group based on the original inclusion criteria had the option to continue in the trial and complete their assigned treatment. The ANCOVA (LOCF) analysis used for the main analysis of the primary and key secondary endpoints was replaced by an MMRM (OC) model following an FDA request (also see Section 9.7.1.1). The last paragraph in Section 5.4.2 of the CTP (Physical examiniation and ECG) was deleted, because after the finalisation of the CTP it was decided that ECGs will not be stored by the vendor. A clarification was added that pulse rate (PR) should be measured during second blood pressure (BP) measurement when automated BP devices were used.
    06 Mar 2014
    An additional study objective was added, namely to investigate the efficacy of empagliflozin 10 mg qd and 25 mg qd compared with metformin 1000 mg bid. The following tests were added in the null and alternative hypotheses section:  non-inferiority testing of empagliflozin 25mg qd vs. metformin 1000 mg bid followed by non-inferiority testing of empagliflozin 10mg qd vs. metformin 1000 mg bid,  superiority testing of empagliflozin 25mg qd vs. metformin 1000 mg bid followed by superiority testing of empagliflozin 10mg qd vs. metformin 1000 mg bid: The power calculation for non-inferiority tests was also added. A new process was implemented for the further evaluation and assessment of hepatic events and cases of cancer. The timing for submitting SAE forms was changed from ‘within 24 hours or the next business day whichever is shorter’ to ‘within 24 hours of awareness’ to comply with new company standards for AE reporting. The Cockcroft-Gault formula for calculating creatinine clearance was corrected. The description of the open-label set (OLS) was added, as it was previously missing.

    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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