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    Clinical Trial Results:
    A phase III randomized, double-blind, parallel group study to evaluate the efficacy and safety of once daily oral administration of linagliptin 5 mg/empagliflozin 25 mg and linagliptin 5 mg/empagliflozin 10 mg Fixed Dose Combination tablets compared with the individual components (linagliptin 5 mg, empagliflozin 25 mg, and empagliflozin 10 mg) for 52 weeks in treatment naïve and metformin treated patients with type 2 diabetes mellitus with insufficient glycaemic control.

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    2011-000383-10
    Trial protocol
    EE   ES   HU   SE   DK   IT   BG  
    Global end of trial date
    10 Sep 2013

    Results information
    Results version number
    v2(current)
    This version publication date
    23 Jul 2016
    First version publication date
    17 Apr 2015
    Other versions
    v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    Data correction due to system error in EudraCT- Results

    Trial information

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    Trial identification
    Sponsor protocol code
    1275.1
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01422876
    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 , +1 800-243-0127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim , +1 800-243-0127, 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
    07 Oct 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Sep 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Sep 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of the study is to investigate the efficacy, safety and tolerability of empagliflozin 25 mg/linagliptin 5 mg FDC qd and of empagliflozin 10 mg/linagliptin 5 mg FDC qd compared to the individual components (empagliflozin 25 mg, empagliflozin 10 mg, and linagliptin 5 mg) given for 52 weeks in treatment naïve and metformin treated patients with type 2 diabetes mellitus with insufficient glycaemic control.
    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.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    31 Aug 2011
    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
    Spain: 107
    Country: Number of subjects enrolled
    Sweden: 95
    Country: Number of subjects enrolled
    Taiwan: 56
    Country: Number of subjects enrolled
    United States: 1073
    Country: Number of subjects enrolled
    Argentina: 110
    Country: Number of subjects enrolled
    Australia: 27
    Country: Number of subjects enrolled
    Brazil: 38
    Country: Number of subjects enrolled
    Bulgaria: 15
    Country: Number of subjects enrolled
    Canada: 130
    Country: Number of subjects enrolled
    Colombia: 68
    Country: Number of subjects enrolled
    Denmark: 40
    Country: Number of subjects enrolled
    Estonia: 55
    Country: Number of subjects enrolled
    Hungary: 48
    Country: Number of subjects enrolled
    Italy: 26
    Country: Number of subjects enrolled
    Lebanon: 82
    Country: Number of subjects enrolled
    Malaysia: 23
    Country: Number of subjects enrolled
    Mexico: 79
    Country: Number of subjects enrolled
    Peru: 75
    Country: Number of subjects enrolled
    Philippines: 109
    Country: Number of subjects enrolled
    Poland: 26
    Country: Number of subjects enrolled
    Romania: 154
    Country: Number of subjects enrolled
    Russian Federation: 69
    Worldwide total number of subjects
    2505
    EEA total number of subjects
    566
    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)
    1957
    From 65 to 84 years
    543
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    Of the 1405 patients enrolled and randomized the data for 42 randomized patients were excluded from all analyses due to serious non-compliance. Therefore, 1363 patients were included in the analyses.

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Metformin Background: Empagliflozin 25 mg/linagliptin 5 mg
    Arm description
    Study population on a stable background of metformin defined as pre-treated with metformin (≥1500 mg/day or on the maximum tolerated dose or the maximum dose according to local label) unchanged for 12 weeks prior to randomisation. Test product: Empagliflozin/linagliptin FDC tablets dose: 25 mg/5 mg q.d. mode of admin.: Oral
    Arm type
    Experimental

    Investigational medicinal product name
    Empagliflozin + Linagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Empagliflozin/linagliptin Fixed Dose Combination (FDC) tablets, dose: 25 mg/5 mg q.d.

    Arm title
    Metformin Background: Empagliflozin 10 mg/linagliptin 5 mg
    Arm description
    Study population on a stable background of metformin defined as pre-treated with metformin (≥1500 mg/day or on the maximum tolerated dose or the maximum dose according to local label) unchanged for 12 weeks prior to randomisation. Test product: Empagliflozin/linagliptin FDC tablets dose: 10 mg/5 mg q.d. mode of admin.: Oral
    Arm type
    Experimental

    Investigational medicinal product name
    Empagliflozin + Linagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Empagliflozin/linagliptin Fixed Dose Combination (FDC) tablets, dose: 10 mg/5 mg q.d

    Arm title
    Metformin Background: Empagliflozin 25 mg
    Arm description
    Study population on a stable background of metformin defined as pre-treated with metformin (≥1500 mg/day or on the maximum tolerated dose or the maximum dose according to local label) unchanged for 12 weeks prior to randomisation. Reference therapy 1: Empagliflozin tablets dose: 25 mg q.d. mode of admin.: Oral
    Arm type
    Active comparator

    Investigational medicinal product name
    Empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Empagliflozin tablets 25 mg q.d.

    Arm title
    Metformin Background: Empagliflozin 10 mg
    Arm description
    Study population on a stable background of metformin defined as pre-treated with metformin (≥1500 mg/day or on the maximum tolerated dose or the maximum dose according to local label) unchanged for 12 weeks prior to randomisation. Reference therapy 1: Empagliflozin tablets dose: 10 mg q.d. mode of admin.: Oral
    Arm type
    Active comparator

    Investigational medicinal product name
    Empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Empagliflozin tablets 10 mg q.d.

    Arm title
    Metformin Background: Linagliptin 5 mg
    Arm description
    Study population on a stable background of metformin defined as pre-treated with metformin (≥1500 mg/day or on the maximum tolerated dose or the maximum dose according to local label) unchanged for 12 weeks prior to randomisation. Reference therapy 2: Linagliptin tablets dose: 5 mg q.d. mode of admin.: Oral
    Arm type
    Active comparator

    Investigational medicinal product name
    Linagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Linagliptin tablets 5 mg q.d.

    Arm title
    Treatment Naive: Empagliflozin 25 mg/linagliptin 5 mg
    Arm description
    Study population treatment naive defined as an absence of any oral antidiabetic therapy, GLP-1 analog or insulin for 12 weeks prior to randomisation. Test product: Empagliflozin/linagliptin FDC tablets dose: 25 mg/5 mg q.d. mode of admin.: Oral
    Arm type
    Experimental

    Investigational medicinal product name
    Empagliflozin + Linagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Empagliflozin/linagliptin FDC tablets, 25 mg/5 mg q.d.

    Arm title
    Treament Naive: Empagliflozin 10 mg/linagliptin 5 mg
    Arm description
    Study population treatment naive defined as an absence of any oral antidiabetic therapy, GLP-1 analog or insulin for 12 weeks prior to randomisation. Test product: Empagliflozin/linagliptin FDC tablets dose: 10 mg/5 mg q.d. mode of admin.: Oral
    Arm type
    Experimental

    Investigational medicinal product name
    Empagliflozin + Linagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Empagliflozin/linagliptin FDC tablets 10 mg/5 mg q.d.

    Arm title
    Treatment Naive: Empagliflozin 25 mg
    Arm description
    Study population treatment naive defined as an absence of any oral antidiabetic therapy, GLP-1 analog or insulin for 12 weeks prior to randomisation. Reference therapy 1: Empagliflozin tablets dose: 25 mg q.d. mode of admin.: Oral
    Arm type
    Active comparator

    Investigational medicinal product name
    Empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Empagliflozin tablets 25 mg q.d.

    Arm title
    Treatment Naive: Empagliflozin 10 mg
    Arm description
    Study population treatment naive defined as an absence of any oral antidiabetic therapy, GLP-1 analog or insulin for 12 weeks prior to randomisation. Reference therapy 1: Empagliflozin tablets dose: 10 mg q.d. mode of admin.: Oral
    Arm type
    Active comparator

    Investigational medicinal product name
    Empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Empagliflozin tablets 10 mg q.d.

    Arm title
    Treatment Naive: Linagliptin 5 mg
    Arm description
    Study population treatment naive defined as an absence of any oral antidiabetic therapy, GLP-1 analog or insulin for 12 weeks prior to randomisation. Reference therapy 2: Linagliptin tablets dose: 5 mg q.d. mode of admin.: Oral
    Arm type
    Active comparator

    Investigational medicinal product name
    Linagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Linagliptin tablets 5 mg q.d.

    Number of subjects in period 1
    Metformin Background: Empagliflozin 25 mg/linagliptin 5 mg Metformin Background: Empagliflozin 10 mg/linagliptin 5 mg Metformin Background: Empagliflozin 25 mg Metformin Background: Empagliflozin 10 mg Metformin Background: Linagliptin 5 mg Treatment Naive: Empagliflozin 25 mg/linagliptin 5 mg Treament Naive: Empagliflozin 10 mg/linagliptin 5 mg Treatment Naive: Empagliflozin 25 mg Treatment Naive: Empagliflozin 10 mg Treatment Naive: Linagliptin 5 mg
    Started
    137
    136
    141
    140
    132
    137
    136
    135
    134
    135
    Week 24 (continuing trial medication)
    126
    129
    131
    124
    118
    125
    124
    121
    121
    123
    Week 52 (completed trial medication)
    121 [1]
    124 [2]
    125 [3]
    118 [4]
    113 [5]
    114 [6]
    116 [7]
    114
    110 [8]
    116 [9]
    Week 24 (remaining in the trial)
    131
    133
    136
    132
    125
    131
    130
    128
    128
    125
    Week 52 (completed trial)
    125
    126
    128
    122
    117
    120
    120
    112
    113
    118
    Completed
    125
    126
    128
    122
    117
    120
    120
    112
    113
    118
    Not completed
    12
    10
    13
    18
    15
    17
    16
    23
    21
    17
         Adverse event, serious fatal
    -
    1
    -
    1
    -
    -
    1
    3
    1
    -
         Consent withdrawn by subject
    9
    4
    6
    12
    7
    12
    10
    12
    13
    9
         Lost to follow-up
    3
    5
    7
    5
    8
    5
    5
    8
    7
    8
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This was a randomised, double-blind, multi-national, parallel-group comparison study. The number that completed are those patient who completd the trial. The patient could discontinue study medication while still in the trial. Thus this milestone represent the number of subjects who completed the trial medication Metformin Background: Empagliflozin 25 mg/linagliptin 5 mg at week 52 but not the trial.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This was a randomised, double-blind, multi-national, parallel-group comparison study. The number that completed are those patient who completd the trial. The patient could discontinue study medication while still in the trial. Thus this milestone represent the number of subjects who completed the trial medication Metformin Background: Empagliflozin 10 mg/linagliptin 5 mg at week 52 but not the trial.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This was a randomised, double-blind, multi-national, parallel-group comparison study. The number that completed are those patient who completd the trial. The patient could discontinue study medication while still in the trial. Thus this milestone represent the number of subjects who completed the trial medication Metformin Background: Empagliflozin 25 mg at week 52 but not the trial.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This was a randomised, double-blind, multi-national, parallel-group comparison study. The number that completed are those patient who completd the trial. The patient could discontinue study medication while still in the trial. Thus this milestone represent the number of subjects who completed the trial medication Metformin Background: Empagliflozin 10 mg at week 52 but not the trial.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This was a randomised, double-blind, multi-national, parallel-group comparison study. The number that completed are those patient who completd the trial. The patient could discontinue study medication while still in the trial. Thus this milestone represent the number of subjects who completed the trial medication Metformin Background: Linagliptin 5 mg at week 52 but not the trial.
    [6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This was a randomised, double-blind, multi-national, parallel-group comparison study. The number that completed are those patient who completd the trial. The patient could discontinue study medication while still in the trial. Thus this milestone represent the number of subjects who completed the trial medication Naive: Empagliflozin 25 mg/linagliptin 5 mg at week 52 but not the trial.
    [7] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This was a randomised, double-blind, multi-national, parallel-group comparison study. The number that completed are those patient who completd the trial. The patient could discontinue study medication while still in the trial. Thus this milestone represent the number of subjects who completed the trial medication Naive: Empagliflozin 10 mg/linagliptin 5 mg at week 52 but not the trial.
    [8] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This was a randomised, double-blind, multi-national, parallel-group comparison study. The number that completed are those patient who completd the trial. The patient could discontinue study medication while still in the trial. Thus this milestone represent the number of subjects who completed the trial medication Naive: Empagliflozin 10 mg at week 52 but not the trial.
    [9] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This was a randomised, double-blind, multi-national, parallel-group comparison study. The number that completed are those patient who completd the trial. The patient could discontinue study medication while still in the trial. Thus this milestone represent the number of subjects who completed the trial medication Naive: Linagliptin 5 mg at week 52 but not the trial.

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Metformin Background: Empagliflozin 25 mg/linagliptin 5 mg
    Reporting group description
    Study population on a stable background of metformin defined as pre-treated with metformin (≥1500 mg/day or on the maximum tolerated dose or the maximum dose according to local label) unchanged for 12 weeks prior to randomisation. Test product: Empagliflozin/linagliptin FDC tablets dose: 25 mg/5 mg q.d. mode of admin.: Oral

    Reporting group title
    Metformin Background: Empagliflozin 10 mg/linagliptin 5 mg
    Reporting group description
    Study population on a stable background of metformin defined as pre-treated with metformin (≥1500 mg/day or on the maximum tolerated dose or the maximum dose according to local label) unchanged for 12 weeks prior to randomisation. Test product: Empagliflozin/linagliptin FDC tablets dose: 10 mg/5 mg q.d. mode of admin.: Oral

    Reporting group title
    Metformin Background: Empagliflozin 25 mg
    Reporting group description
    Study population on a stable background of metformin defined as pre-treated with metformin (≥1500 mg/day or on the maximum tolerated dose or the maximum dose according to local label) unchanged for 12 weeks prior to randomisation. Reference therapy 1: Empagliflozin tablets dose: 25 mg q.d. mode of admin.: Oral

    Reporting group title
    Metformin Background: Empagliflozin 10 mg
    Reporting group description
    Study population on a stable background of metformin defined as pre-treated with metformin (≥1500 mg/day or on the maximum tolerated dose or the maximum dose according to local label) unchanged for 12 weeks prior to randomisation. Reference therapy 1: Empagliflozin tablets dose: 10 mg q.d. mode of admin.: Oral

    Reporting group title
    Metformin Background: Linagliptin 5 mg
    Reporting group description
    Study population on a stable background of metformin defined as pre-treated with metformin (≥1500 mg/day or on the maximum tolerated dose or the maximum dose according to local label) unchanged for 12 weeks prior to randomisation. Reference therapy 2: Linagliptin tablets dose: 5 mg q.d. mode of admin.: Oral

    Reporting group title
    Treatment Naive: Empagliflozin 25 mg/linagliptin 5 mg
    Reporting group description
    Study population treatment naive defined as an absence of any oral antidiabetic therapy, GLP-1 analog or insulin for 12 weeks prior to randomisation. Test product: Empagliflozin/linagliptin FDC tablets dose: 25 mg/5 mg q.d. mode of admin.: Oral

    Reporting group title
    Treament Naive: Empagliflozin 10 mg/linagliptin 5 mg
    Reporting group description
    Study population treatment naive defined as an absence of any oral antidiabetic therapy, GLP-1 analog or insulin for 12 weeks prior to randomisation. Test product: Empagliflozin/linagliptin FDC tablets dose: 10 mg/5 mg q.d. mode of admin.: Oral

    Reporting group title
    Treatment Naive: Empagliflozin 25 mg
    Reporting group description
    Study population treatment naive defined as an absence of any oral antidiabetic therapy, GLP-1 analog or insulin for 12 weeks prior to randomisation. Reference therapy 1: Empagliflozin tablets dose: 25 mg q.d. mode of admin.: Oral

    Reporting group title
    Treatment Naive: Empagliflozin 10 mg
    Reporting group description
    Study population treatment naive defined as an absence of any oral antidiabetic therapy, GLP-1 analog or insulin for 12 weeks prior to randomisation. Reference therapy 1: Empagliflozin tablets dose: 10 mg q.d. mode of admin.: Oral

    Reporting group title
    Treatment Naive: Linagliptin 5 mg
    Reporting group description
    Study population treatment naive defined as an absence of any oral antidiabetic therapy, GLP-1 analog or insulin for 12 weeks prior to randomisation. Reference therapy 2: Linagliptin tablets dose: 5 mg q.d. mode of admin.: Oral

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The baseline characteristics represents the number of patients randomized and analyzed whereas the worldwide number represents the number of patients enrolled.
    Reporting group values
    Metformin Background: Empagliflozin 25 mg/linagliptin 5 mg Metformin Background: Empagliflozin 10 mg/linagliptin 5 mg Metformin Background: Empagliflozin 25 mg Metformin Background: Empagliflozin 10 mg Metformin Background: Linagliptin 5 mg Treatment Naive: Empagliflozin 25 mg/linagliptin 5 mg Treament Naive: Empagliflozin 10 mg/linagliptin 5 mg Treatment Naive: Empagliflozin 25 mg Treatment Naive: Empagliflozin 10 mg Treatment Naive: Linagliptin 5 mg Total
    Number of subjects
    137 136 141 140 132 137 136 135 134 135
    Age categorical
    Units: Subjects
    Age Continuous |
    Randomised set (RS) – including all patients from the screened set who were randomised to trial medication, regardless of whether any trial medication was taken.
    Units: years
        arithmetic mean (standard deviation)
    57.1 ± 10.2 56.2 ± 10.3 55.4 ± 10.1 55.9 ± 10.5 56.3 ± 9.9 54.3 ± 10 55.2 ± 9.7 55.7 ± 9.5 53.8 ± 10.4 53.7 ± 11.4 -
    Gender, Male/Female
    Units: participants
        Female
    64 52 75 59 65 65 62 57 70 60 620
        Male
    73 84 66 81 67 72 74 78 64 75 721

    End points

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    End points reporting groups
    Reporting group title
    Metformin Background: Empagliflozin 25 mg/linagliptin 5 mg
    Reporting group description
    Study population on a stable background of metformin defined as pre-treated with metformin (≥1500 mg/day or on the maximum tolerated dose or the maximum dose according to local label) unchanged for 12 weeks prior to randomisation. Test product: Empagliflozin/linagliptin FDC tablets dose: 25 mg/5 mg q.d. mode of admin.: Oral

    Reporting group title
    Metformin Background: Empagliflozin 10 mg/linagliptin 5 mg
    Reporting group description
    Study population on a stable background of metformin defined as pre-treated with metformin (≥1500 mg/day or on the maximum tolerated dose or the maximum dose according to local label) unchanged for 12 weeks prior to randomisation. Test product: Empagliflozin/linagliptin FDC tablets dose: 10 mg/5 mg q.d. mode of admin.: Oral

    Reporting group title
    Metformin Background: Empagliflozin 25 mg
    Reporting group description
    Study population on a stable background of metformin defined as pre-treated with metformin (≥1500 mg/day or on the maximum tolerated dose or the maximum dose according to local label) unchanged for 12 weeks prior to randomisation. Reference therapy 1: Empagliflozin tablets dose: 25 mg q.d. mode of admin.: Oral

    Reporting group title
    Metformin Background: Empagliflozin 10 mg
    Reporting group description
    Study population on a stable background of metformin defined as pre-treated with metformin (≥1500 mg/day or on the maximum tolerated dose or the maximum dose according to local label) unchanged for 12 weeks prior to randomisation. Reference therapy 1: Empagliflozin tablets dose: 10 mg q.d. mode of admin.: Oral

    Reporting group title
    Metformin Background: Linagliptin 5 mg
    Reporting group description
    Study population on a stable background of metformin defined as pre-treated with metformin (≥1500 mg/day or on the maximum tolerated dose or the maximum dose according to local label) unchanged for 12 weeks prior to randomisation. Reference therapy 2: Linagliptin tablets dose: 5 mg q.d. mode of admin.: Oral

    Reporting group title
    Treatment Naive: Empagliflozin 25 mg/linagliptin 5 mg
    Reporting group description
    Study population treatment naive defined as an absence of any oral antidiabetic therapy, GLP-1 analog or insulin for 12 weeks prior to randomisation. Test product: Empagliflozin/linagliptin FDC tablets dose: 25 mg/5 mg q.d. mode of admin.: Oral

    Reporting group title
    Treament Naive: Empagliflozin 10 mg/linagliptin 5 mg
    Reporting group description
    Study population treatment naive defined as an absence of any oral antidiabetic therapy, GLP-1 analog or insulin for 12 weeks prior to randomisation. Test product: Empagliflozin/linagliptin FDC tablets dose: 10 mg/5 mg q.d. mode of admin.: Oral

    Reporting group title
    Treatment Naive: Empagliflozin 25 mg
    Reporting group description
    Study population treatment naive defined as an absence of any oral antidiabetic therapy, GLP-1 analog or insulin for 12 weeks prior to randomisation. Reference therapy 1: Empagliflozin tablets dose: 25 mg q.d. mode of admin.: Oral

    Reporting group title
    Treatment Naive: Empagliflozin 10 mg
    Reporting group description
    Study population treatment naive defined as an absence of any oral antidiabetic therapy, GLP-1 analog or insulin for 12 weeks prior to randomisation. Reference therapy 1: Empagliflozin tablets dose: 10 mg q.d. mode of admin.: Oral

    Reporting group title
    Treatment Naive: Linagliptin 5 mg
    Reporting group description
    Study population treatment naive defined as an absence of any oral antidiabetic therapy, GLP-1 analog or insulin for 12 weeks prior to randomisation. Reference therapy 2: Linagliptin tablets dose: 5 mg q.d. mode of admin.: Oral

    Primary: Change from baseline in glycosylated hemoglobin (HbA1c) for Metformin Background patients

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    End point title
    Change from baseline in glycosylated hemoglobin (HbA1c) for Metformin Background patients [1]
    End point description
    Glycosylated hemoglobin (HbA1c) is a measurement of the percentage of hemoglobin that is glycated. The change from baseline in HbA1c is calculated as the week 24 HbA1c minus the baseline HbA1c. Since HbA1c is measured as a percentage the change from baseline is also a percentage. Full Analysis Set (FAS) with last observation carried forward (LOCF). FAS - all Metformin Background patients randomised and treated who had a baseline and at least 1 on treatment HbA1c value.
    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: Endpoints are presented separately for metformin patients versus treatment naive patients. Baseline charcteristics are presented for both groups combined.
    End point values
    Metformin Background: Empagliflozin 25 mg/linagliptin 5 mg Metformin Background: Empagliflozin 10 mg/linagliptin 5 mg Metformin Background: Empagliflozin 25 mg Metformin Background: Empagliflozin 10 mg Metformin Background: Linagliptin 5 mg
    Number of subjects analysed
    134 [2]
    135 [3]
    140 [4]
    137 [5]
    128 [6]
    Units: % change from baseline
        least squares mean (standard error)
    -1.19 ± 0.06
    -1.08 ± 0.06
    -0.62 ± 0.06
    -0.66 ± 0.06
    -0.7 ± 0.06
    Notes
    [2] - FAS (LOCF)
    [3] - FAS (LOCF)
    [4] - FAS (LOCF)
    [5] - FAS (LOCF)
    [6] - FAS (LOCF)
    Statistical analysis title
    Metformin: Empa/Lina 25/5 versus Empa 25
    Statistical analysis description
    Model for Week 24 includes baseline HbA1c (p<0.0001) as linear covariate(s) and baseline eGFR (MDRD) (p=0.0038), geographical region (p<0.0001), treatment (p<0.0001) as fixed effect(s). Treatment difference calculated as: Empa/Lina 25/5 minus Empa 25.
    Comparison groups
    Metformin Background: Empagliflozin 25 mg v Metformin Background: Empagliflozin 25 mg/linagliptin 5 mg
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.75
         upper limit
    -0.41
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.09
    Statistical analysis title
    Metformin: Empa/Lina 25/5 versus Lina 5
    Statistical analysis description
    Model for Week 24 includes baseline HbA1c (p<0.0001) as linear covariate(s) and baseline eGFR (MDRD) (p=0.0038), geographical region (p<0.0001), treatment (p<0.0001) as fixed effect(s). Treatment difference calculated as: Empa/Lina 25/5 minus Lina 5.
    Comparison groups
    Metformin Background: Linagliptin 5 mg v Metformin Background: Empagliflozin 25 mg/linagliptin 5 mg
    Number of subjects included in analysis
    262
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.67
         upper limit
    -0.32
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.09
    Statistical analysis title
    Metformin: Empa/Lina 10/5 versus Empa 10
    Statistical analysis description
    Model for Week 24 includes baseline HbA1c (p<0.0001) as linear covariate(s) and baseline eGFR (MDRD) (p=0.0038), geographical region (p<0.0001), treatment (p<0.0001) as fixed effect(s). Treatment difference calculated as: Empa/Lina 10/5 minus Empa 10.
    Comparison groups
    Metformin Background: Empagliflozin 10 mg v Metformin Background: Empagliflozin 10 mg/linagliptin 5 mg
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.59
         upper limit
    -0.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.09
    Statistical analysis title
    Metformin: Empa/Lina 10/5 versus Lina 5
    Statistical analysis description
    Model for Week 24 includes baseline HbA1c (p<0.0001) as linear covariate(s) and baseline eGFR (MDRD) (p=0.0038), geographical region (p<0.0001), treatment (p<0.0001) as fixed effect(s). Treatment difference calculated as: Empa/Lina 10/5 minus Lina 5.
    Comparison groups
    Metformin Background: Linagliptin 5 mg v Metformin Background: Empagliflozin 10 mg/linagliptin 5 mg
    Number of subjects included in analysis
    263
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.56
         upper limit
    -0.21
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.09

    Primary: Change from baseline in glycosylated hemoglobin (HbA1c) for Treatment Naive patients

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    End point title
    Change from baseline in glycosylated hemoglobin (HbA1c) for Treatment Naive patients [7]
    End point description
    Glycosylated hemoglobin (HbA1c) is a measurement of the percentage of hemoglobin that is glycated. The change from baseline in HbA1c is calculated as the week 24 HbA1c minus the baseline HbA1c. Since HbA1c is measured as a percentage the change from baseline is also a percentage. Full Analysis Set (FAS) with last observation carried forward (LOCF). FAS - all treatment naive patients randomised and treated who had a baseline and at least 1 on treatment HbA1c value.
    End point type
    Primary
    End point timeframe
    Baseline and 24 weeks
    Notes
    [7] - 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: Endpoints are presented separately for metformin patients versus treatment naive patients. Baseline charcteristics are presented for both groups combined.
    End point values
    Treatment Naive: Empagliflozin 25 mg/linagliptin 5 mg Treament Naive: Empagliflozin 10 mg/linagliptin 5 mg Treatment Naive: Empagliflozin 25 mg Treatment Naive: Empagliflozin 10 mg Treatment Naive: Linagliptin 5 mg
    Number of subjects analysed
    134 [8]
    135 [9]
    133 [10]
    132 [11]
    133 [12]
    Units: % change from baseline
        least squares mean (standard error)
    -1.08 ± 0.07
    -1.24 ± 0.07
    -0.95 ± 0.07
    -0.83 ± 0.07
    -0.67 ± 0.07
    Notes
    [8] - FAS (LOCF)
    [9] - FAS (LOCF)
    [10] - FAS (LOCF)
    [11] - FAS (LOCF)
    [12] - FAS (LOCF)
    Statistical analysis title
    Naive: Empa/Lina 25/5 versus Empa 25
    Statistical analysis description
    Model for Week 24 includes baseline HbA1c (p<0.0001) as linear covariate(s) and baseline eGFR (MDRD) (p=0.8627), geographical region (p=0.0008), treatment (p<0.0001) as fixed effect(s). Treatment difference calculated as: Empa/Lina 25/5 minus Empa 25.
    Comparison groups
    Treatment Naive: Empagliflozin 25 mg/linagliptin 5 mg v Treatment Naive: Empagliflozin 25 mg
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1785
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.33
         upper limit
    0.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1
    Statistical analysis title
    Naive: Empa/Lina 10/5 versus Empa 10
    Statistical analysis description
    Model for Week 24 includes baseline HbA1c (p<0.0001) as linear covariate(s) and baseline eGFR (MDRD) (p=0.8627), geographical region (p=0.0008), treatment (p<0.0001) as fixed effect(s). Treatment difference calculated as: Empa/Lina 10/5 minus Empa 10.
    Comparison groups
    Treatment Naive: Empagliflozin 10 mg v Treament Naive: Empagliflozin 10 mg/linagliptin 5 mg
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.61
         upper limit
    -0.21
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1
    Statistical analysis title
    Naive: Empa/Lina 25/5 versus Lina 5
    Statistical analysis description
    Model for Week 24 includes baseline HbA1c (p<0.0001) as linear covariate(s) and baseline eGFR (MDRD) (p=0.8627), geographical region (p=0.0008), treatment (p<0.0001) as fixed effect(s). Treatment difference calculated as: Empa/Lina 25/5 minus Lina 5.
    Comparison groups
    Treatment Naive: Linagliptin 5 mg v Treatment Naive: Empagliflozin 25 mg/linagliptin 5 mg
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (net)
    Point estimate
    -0.41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.61
         upper limit
    -0.22
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1
    Statistical analysis title
    Naive: Empa/Lina 10/5 versus Lina 5
    Statistical analysis description
    Model for Week 24 includes baseline HbA1c (p<0.0001) as linear covariate(s) and baseline eGFR (MDRD) (p=0.8627), geographical region (p=0.0008), treatment (p<0.0001) as fixed effect(s). Treatment difference calculated as: Empa/Lina 25/5 minus Lina 5.
    Comparison groups
    Treament Naive: Empagliflozin 10 mg/linagliptin 5 mg v Treatment Naive: Linagliptin 5 mg
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.57
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.76
         upper limit
    -0.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1

    Secondary: Change from baseline in fasting plasma glucose at week 24 for Metformin Background patients

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    End point title
    Change from baseline in fasting plasma glucose at week 24 for Metformin Background patients [13]
    End point description
    Change from baseline in fasting plasma glucose at week 24 for Metformin Background patients. Full Analysis Set (FAS) with last observation carried forward (LOCF). FAS - all Metformin Background patients randomised and treated who had a baseline and at least 1 on treatment HbA1c value.
    End point type
    Secondary
    End point timeframe
    Baseline and 24 Weeks
    Notes
    [13] - 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: Endpoints are presented separately for metformin patients versus treatment naive patients. Baseline charcteristics are presented for both groups combined.
    End point values
    Metformin Background: Empagliflozin 25 mg/linagliptin 5 mg Metformin Background: Empagliflozin 10 mg/linagliptin 5 mg Metformin Background: Empagliflozin 25 mg Metformin Background: Empagliflozin 10 mg Metformin Background: Linagliptin 5 mg
    Number of subjects analysed
    133 [14]
    134 [15]
    139 [16]
    136 [17]
    127 [18]
    Units: mg/dL change from baseline
        least squares mean (standard error)
    -35.25 ± 2.53
    -32.18 ± 2.52
    -18.83 ± 2.47
    -20.84 ± 2.5
    -13.05 ± 2.59
    Notes
    [14] - FAS (LOCF)
    [15] - FAS (LOCF)
    [16] - FAS (LOCF)
    [17] - FAS (LOCF)
    [18] - FAS (LOCF)
    Statistical analysis title
    Metformin: Empa/Lina 25/5 versus Empa 25
    Statistical analysis description
    Model for Week 24 includes baseline fasting plasma glucose (p<0.0001), baseline HbA1c (p=0.6082) as linear covariate(s) and baseline eGFR (MDRD) (p=0.3685), geographical region (p=0.0104), treatment (p<0.0001) as fixed effect(s). Treatment difference calculated as: Empa/Lina 25/5 minus Empa 25.
    Comparison groups
    Metformin Background: Empagliflozin 25 mg v Metformin Background: Empagliflozin 25 mg/linagliptin 5 mg
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -16.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -23.37
         upper limit
    -9.48
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.54
    Statistical analysis title
    Metformin: Empa/Lina 25/5 versus Lina 5
    Statistical analysis description
    Model for Week 24 includes baseline fasting plasma glucose (p<0.0001), baseline HbA1c (p=0.6082) as linear covariate(s) and baseline eGFR (MDRD) (p=0.3685), geographical region (p=0.0104), treatment (p<0.0001) as fixed effect(s). Treatment difference calculated as: Empa/Lina 25/5 minus Lina 5.
    Comparison groups
    Metformin Background: Linagliptin 5 mg v Metformin Background: Empagliflozin 25 mg/linagliptin 5 mg
    Number of subjects included in analysis
    260
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -22.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -29.3
         upper limit
    -15.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.62
    Statistical analysis title
    Metformin: Empa/Lina 10/5 versus Empa 10
    Statistical analysis description
    Model for Week 24 includes baseline fasting plasma glucose (p<0.0001), baseline HbA1c (p=0.6082) as linear covariate(s) and baseline eGFR (MDRD) (p=0.3685), geographical region (p=0.0104), treatment (p<0.0001) as fixed effect(s). Treatment difference calculated as: Empa/Lina 10/5 minus Empa 10.
    Comparison groups
    Metformin Background: Empagliflozin 10 mg v Metformin Background: Empagliflozin 10 mg/linagliptin 5 mg
    Number of subjects included in analysis
    270
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0015
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -11.34
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -18.31
         upper limit
    -4.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.55
    Statistical analysis title
    Metformin: Empa/Lina 10/5 versus Lina 5
    Statistical analysis description
    Model for Week 24 includes baseline fasting plasma glucose (p<0.0001), baseline HbA1c (p=0.6082) as linear covariate(s) and baseline eGFR (MDRD) (p=0.3685), geographical region (p=0.0104), treatment (p<0.0001) as fixed effect(s). Treatment difference calculated as: Empa/Lina 10/5 minus Lina 5.
    Comparison groups
    Metformin Background: Linagliptin 5 mg v Metformin Background: Empagliflozin 10 mg/linagliptin 5 mg
    Number of subjects included in analysis
    261
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -19.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -26.21
         upper limit
    -12.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.61

    Secondary: Change from baseline in fasting plasma glucose at week 24 for Treatment Naive patients

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    End point title
    Change from baseline in fasting plasma glucose at week 24 for Treatment Naive patients [19]
    End point description
    Change from baseline in fasting plasma glucose at week 24 for Treatment Naive patients. Full Analysis Set (FAS) with last observation carried forward (LOCF). FAS - all treatment naive patients randomised and treated who had a baseline and at least 1 on treatment HbA1c value.
    End point type
    Secondary
    End point timeframe
    Baseline and 24 Weeks
    Notes
    [19] - 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: Endpoints are presented separately for metformin patients versus treatment naive patients. Baseline charcteristics are presented for both groups combined.
    End point values
    Treatment Naive: Empagliflozin 25 mg/linagliptin 5 mg Treament Naive: Empagliflozin 10 mg/linagliptin 5 mg Treatment Naive: Empagliflozin 25 mg Treatment Naive: Empagliflozin 10 mg Treatment Naive: Linagliptin 5 mg
    Number of subjects analysed
    134 [20]
    135 [21]
    133 [22]
    132 [23]
    133 [24]
    Units: mg/dL change from baseline
        least squares mean (standard error)
    -29.55 ± 2.67
    -28.21 ± 2.66
    -24.24 ± 2.68
    -22.39 ± 2.69
    -5.92 ± 2.68
    Notes
    [20] - FAS (LOCF)
    [21] - FAS (LOCF)
    [22] - FAS (LOCF)
    [23] - FAS (LOCF)
    [24] - FAS (LOCF)
    Statistical analysis title
    Naive: Empa/Lina 25/5 versus Empa 25
    Statistical analysis description
    Model for Week 24 includes baseline fasting plasma glucose (p<0.0001), baseline HbA1c (p=0.4591) as linear covariate(s) and baseline eGFR (MDRD) (p=0.7413), geographical region (p=0.1504), treatment (p<0.0001) as fixed effect(s). Treatment difference calculated as: Empa/Lina 25/5 minus Empa 25.
    Comparison groups
    Treatment Naive: Empagliflozin 25 mg/linagliptin 5 mg v Treatment Naive: Empagliflozin 25 mg
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1605
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -5.31
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.74
         upper limit
    2.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.78
    Statistical analysis title
    Naive: Empa/Lina 10/5 versus Empa 10
    Statistical analysis description
    Model for Week 24 includes baseline fasting plasma glucose (p<0.0001), baseline HbA1c (p=0.4591) as linear covariate(s) and baseline eGFR (MDRD) (p=0.7413), geographical region (p=0.1504), treatment (p<0.0001) as fixed effect(s). Treatment difference calculated as: Empa/Lina 10/5 minus Empa 10.
    Comparison groups
    Treatment Naive: Empagliflozin 10 mg v Treament Naive: Empagliflozin 10 mg/linagliptin 5 mg
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1246
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -5.82
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13.25
         upper limit
    1.61
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.78
    Statistical analysis title
    Naive: Empa/Lina 25/5 versus Lina 5
    Statistical analysis description
    Model for Week 24 includes baseline fasting plasma glucose (p<0.0001), baseline HbA1c (p=0.4591) as linear covariate(s) and baseline eGFR (MDRD) (p=0.7413), geographical region (p=0.1504), treatment (p<0.0001) as fixed effect(s). Treatment difference calculated as: Empa/Lina 25/5 minus Lina 5.
    Comparison groups
    Treatment Naive: Linagliptin 5 mg v Treatment Naive: Empagliflozin 25 mg/linagliptin 5 mg
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -23.63
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -31.06
         upper limit
    -16.21
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.78
    Statistical analysis title
    Naive: Empa/Lina 10/5 versus Lina 5
    Statistical analysis description
    Model for Week 24 includes baseline fasting plasma glucose (p<0.0001), baseline HbA1c (p=0.4591) as linear covariate(s) and baseline eGFR (MDRD) (p=0.7413), geographical region (p=0.1504), treatment (p<0.0001) as fixed effect(s). Treatment difference calculated as: Empa/Lina 10/5 minus Lina 5.
    Comparison groups
    Treatment Naive: Linagliptin 5 mg v Treament Naive: Empagliflozin 10 mg/linagliptin 5 mg
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -22.29
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -29.71
         upper limit
    -14.88
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.77

    Secondary: Change from baseline in body weight for Metformin Background patients

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    End point title
    Change from baseline in body weight for Metformin Background patients [25]
    End point description
    Change from baseline in body weight for Metformin Background patients. Full Analysis Set (FAS) with last observation carried forward (LOCF). FAS - all Metformin Background patients randomised and treated who had a baseline and at least 1 on treatment HbA1c value.
    End point type
    Secondary
    End point timeframe
    Baseline and 24 Weeks
    Notes
    [25] - 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: Endpoints are presented separately for metformin patients versus treatment naive patients. Baseline charcteristics are presented for both groups combined.
    End point values
    Metformin Background: Empagliflozin 25 mg/linagliptin 5 mg Metformin Background: Empagliflozin 10 mg/linagliptin 5 mg Metformin Background: Empagliflozin 25 mg Metformin Background: Empagliflozin 10 mg Metformin Background: Linagliptin 5 mg
    Number of subjects analysed
    134 [26]
    135 [27]
    140 [28]
    137 [29]
    128 [30]
    Units: kg change from baseline
        least squares mean (standard error)
    -2.99 ± 0.31
    -2.6 ± 0.3
    -3.18 ± 0.3
    -2.53 ± 0.3
    -0.69 ± 0.31
    Notes
    [26] - FAS (LOCF)
    [27] - FAS (LOCF)
    [28] - FAS (LOCF)
    [29] - FAS (LOCF)
    [30] - FAS (LOCF)
    Statistical analysis title
    Metformin: Empa/Lina 25/5 versus Empa 25
    Statistical analysis description
    Model for Week 24 includes baseline weight (p<0.0001), baseline HbA1c (p=0.1610) as linear covariate(s) and baseline eGFR (MDRD) (p=0.3685), geographical region (p=0.0162), treatment (p<0.0001) as fixed effect(s). Treatment difference calculated as: Empa/Lina 25/5 minus Empa 25.
    Comparison groups
    Metformin Background: Empagliflozin 25 mg v Metformin Background: Empagliflozin 25 mg/linagliptin 5 mg
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6604 [31]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    0.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.65
         upper limit
    1.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.43
    Notes
    [31] - Not an alpha protected test.
    Statistical analysis title
    Metformin: Empa/Lina 25/5 versus Lina 5
    Statistical analysis description
    Model for Week 24 includes baseline weight (p<0.0001), baseline HbA1c (p=0.1610) as linear covariate(s) and baseline eGFR (MDRD) (p=0.3685), geographical region (p=0.0162), treatment (p<0.0001) as fixed effect(s). Treatment difference calculated as: Empa/Lina 25/5 minus Lina 5.
    Comparison groups
    Metformin Background: Linagliptin 5 mg v Metformin Background: Empagliflozin 25 mg/linagliptin 5 mg
    Number of subjects included in analysis
    262
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -2.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.15
         upper limit
    -1.44
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.44
    Statistical analysis title
    Metformin: Empa/Lina 10/5 versus Empa 10
    Statistical analysis description
    Model for Week 24 includes baseline weight (p<0.0001), baseline HbA1c (p=0.1610) as linear covariate(s) and baseline eGFR (MDRD) (p=0.3685), geographical region (p=0.0162), treatment (p<0.0001) as fixed effect(s). Treatment difference calculated as: Empa/Lina 10/5 minus Empa 10.
    Comparison groups
    Metformin Background: Empagliflozin 10 mg v Metformin Background: Empagliflozin 10 mg/linagliptin 5 mg
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8757 [32]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.91
         upper limit
    0.77
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.43
    Notes
    [32] - Not an alpha protected test.
    Statistical analysis title
    Metformin: Empa/Lina 10/5 versus Lina 5
    Statistical analysis description
    Model for Week 24 includes baseline weight (p<0.0001), baseline HbA1c (p=0.1610) as linear covariate(s) and baseline eGFR (MDRD) (p=0.3685), geographical region (p=0.0162), treatment (p<0.0001) as fixed effect(s). Treatment difference calculated as: Empa/Lina 10/5 minus Lina 5.
    Comparison groups
    Metformin Background: Linagliptin 5 mg v Metformin Background: Empagliflozin 10 mg/linagliptin 5 mg
    Number of subjects included in analysis
    263
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -1.91
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.77
         upper limit
    -1.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.44

    Secondary: Change from baseline in body weight for Treatment Naive patients

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    End point title
    Change from baseline in body weight for Treatment Naive patients [33]
    End point description
    Change from baseline in body weight for Treatment Naive patients. Full Analysis Set (FAS) with last observation carried forward (LOCF). FAS - all treatment naive patients randomised and treated who had a baseline and at least 1 on treatment HbA1c value.
    End point type
    Secondary
    End point timeframe
    Baseline and 24 Weeks
    Notes
    [33] - 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: Endpoints are presented separately for metformin patients versus treatment naive patients. Baseline charcteristics are presented for both groups combined.
    End point values
    Treatment Naive: Empagliflozin 25 mg/linagliptin 5 mg Treament Naive: Empagliflozin 10 mg/linagliptin 5 mg Treatment Naive: Empagliflozin 25 mg Treatment Naive: Empagliflozin 10 mg Treatment Naive: Linagliptin 5 mg
    Number of subjects analysed
    134 [34]
    135 [35]
    133 [36]
    132 [37]
    133 [38]
    Units: kg change from baseline
        least squares mean (standard error)
    -2 ± 0.36
    -2.74 ± 0.36
    -2.13 ± 0.36
    -2.27 ± 0.37
    -0.78 ± 0.36
    Notes
    [34] - FAS (LOCF)
    [35] - FAS (LOCF)
    [36] - FAS (LOCF)
    [37] - FAS (LOCF)
    [38] - FAS (LOCF)
    Statistical analysis title
    Naive: Empa/Lina 25/5 versus Empa 25
    Statistical analysis description
    Model for Week 24 includes baseline weight (p<0.0001), baseline HbA1c (p=0.0023) as linear covariate(s) and baseline eGFR (MDRD) (p=0.0316), geographical region (p=0.0134), treatment (p=0.0031) as fixed effect(s). Treatment difference calculated as: Empa/Lina 25/5 minus Empa 25.
    Comparison groups
    Treatment Naive: Empagliflozin 25 mg v Treatment Naive: Empagliflozin 25 mg/linagliptin 5 mg
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.801 [39]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    0.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.88
         upper limit
    1.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.51
    Notes
    [39] - Not an alpha protected test.
    Statistical analysis title
    Naive: Empa/Lina 10/5 versus Empa 10
    Statistical analysis description
    Model for Week 24 includes baseline weight (p<0.0001), baseline HbA1c (p=0.0023) as linear covariate(s) and baseline eGFR (MDRD) (p=0.0316), geographical region (p=0.0134), treatment (p=0.0031) as fixed effect(s). Treatment difference calculated as: Empa/Lina 10/5 minus Empa 10.
    Comparison groups
    Treatment Naive: Empagliflozin 10 mg v Treament Naive: Empagliflozin 10 mg/linagliptin 5 mg
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3616 [40]
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.47
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.48
         upper limit
    0.54
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.51
    Notes
    [40] - Not an alpha protected test.
    Statistical analysis title
    Naive: Empa/Lina 25/5 versus Lina 5
    Statistical analysis description
    Model for Week 24 includes baseline weight (p<0.0001), baseline HbA1c (p=0.0023) as linear covariate(s) and baseline eGFR (MDRD) (p=0.0316), geographical region (p=0.0134), treatment (p=0.0031) as fixed effect(s). Treatment difference calculated as: Empa/Lina 25/5 minus Lina 5.
    Comparison groups
    Treatment Naive: Linagliptin 5 mg v Treatment Naive: Empagliflozin 25 mg/linagliptin 5 mg
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0178
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -1.22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.23
         upper limit
    -0.21
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.51
    Statistical analysis title
    Naive: Empa/Lina 10/5 versus Lina 5
    Statistical analysis description
    Model for Week 24 includes baseline weight (p<0.0001), baseline HbA1c (p=0.0023) as linear covariate(s) and baseline eGFR (MDRD) (p=0.0316), geographical region (p=0.0134), treatment (p=0.0031) as fixed effect(s). Treatment difference calculated as: Empa/Lina 10/5 minus Lina 5.
    Comparison groups
    Treatment Naive: Linagliptin 5 mg v Treament Naive: Empagliflozin 10 mg/linagliptin 5 mg
    Number of subjects included in analysis
    268
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -1.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.97
         upper limit
    -0.95
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.51

    Secondary: Occurrence of treat to target efficacy response for Metformin Background patients

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    End point title
    Occurrence of treat to target efficacy response for Metformin Background patients [41]
    End point description
    Occurrence of the treat-to-target efficacy response for Metformin Background patients measured as HbA1c < 7.0% after 24 weeks of treatment for patients with HbA1c >=7.0% at baseline. Full Analysis Set (FAS) with non-completers considered failures (NCF). FAS- Metformin background patients randomised and treated who had a baseline (HbA1c>= 7% at baseline are included) and at least 1 on treatment HbA1c value with NCF approach, in which missing data due to premature discontinuation of a patient were considered as failure.
    End point type
    Secondary
    End point timeframe
    24 Weeks
    Notes
    [41] - 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: Endpoints are presented separately for metformin patients versus treatment naive patients. Baseline charcteristics are presented for both groups combined.
    End point values
    Metformin Background: Empagliflozin 25 mg/linagliptin 5 mg Metformin Background: Empagliflozin 10 mg/linagliptin 5 mg Metformin Background: Empagliflozin 25 mg Metformin Background: Empagliflozin 10 mg Metformin Background: Linagliptin 5 mg
    Number of subjects analysed
    123 [42]
    128 [43]
    132 [44]
    125 [45]
    119 [46]
    Units: % of patients satisfying HbA1c <7.0%
        number (confidence interval 95%)
    61.8 (52.6 to 70.4)
    57.8 (48.8 to 66.5)
    32.6 (24.7 to 41.3)
    28 (20.3 to 36.7)
    36.1 (27.5 to 45.4)
    Notes
    [42] - FAS (NCF)
    [43] - FAS (NCF)
    [44] - FAS (NCF)
    [45] - FAS (NCF)
    [46] - FAS (NCF)
    Statistical analysis title
    Metformin: Empa/Lina 25/5 versus Empa 25
    Statistical analysis description
    Logistic regression includes treatment, baseline eGFR (MDRD), geographical region and baseline HbA1c. Odds ratio for Empa/Lina 25/5 versus Empa 25.
    Comparison groups
    Metformin Background: Empagliflozin 25 mg v Metformin Background: Empagliflozin 25 mg/linagliptin 5 mg
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    4.191
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.319
         upper limit
    7.573
    Statistical analysis title
    Metformin: Empa/Lina 10/5 versus Empa 10
    Statistical analysis description
    Logistic regression includes treatment, baseline eGFR (MDRD), geographical region and baseline HbA1c. Odds ratio for Empa/Lina 10/5 versus Empa 10
    Comparison groups
    Metformin Background: Empagliflozin 10 mg v Metformin Background: Empagliflozin 10 mg/linagliptin 5 mg
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    4.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.474
         upper limit
    8.184
    Statistical analysis title
    Metformin: Empa/Lina 25/5 versus Lina 5
    Statistical analysis description
    Logistic regression includes treatment, baseline eGFR (MDRD), geographical region and baseline HbA1c. Odds ratio for Empa/Lina 25/5 versus Lina 5.
    Comparison groups
    Metformin Background: Linagliptin 5 mg v Metformin Background: Empagliflozin 25 mg/linagliptin 5 mg
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.495
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.92
         upper limit
    6.363
    Statistical analysis title
    Metformin: Empa/Lina 10/5 versus Lina 5
    Statistical analysis description
    Logistic regression includes treatment, baseline eGFR (MDRD), geographical region and baseline HbA1c. Odds ratio for Empa/Lina 10/5 versus Lina 5.
    Comparison groups
    Metformin Background: Linagliptin 5 mg v Metformin Background: Empagliflozin 10 mg/linagliptin 5 mg
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0005
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.795
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.562
         upper limit
    5.001

    Secondary: Occurrence of treat to target efficacy response for Treatment Naive patients

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    End point title
    Occurrence of treat to target efficacy response for Treatment Naive patients [47]
    End point description
    Occurrence of the treat-to-target efficacy response for Treatment Naive patients measured as HbA1c < 7.0% after 24 weeks of treatment for patients with HbA1c >=7.0% at baseline. Full Analysis Set (FAS) with non-completers considered failures (NCF). FAS-treatment naive patients randomised and treated who had a baseline (HbA1c>= 7% at baseline are included) and at least 1 on treatment HbA1c value with NCF approach, in which missing data due to premature discontinuation of a patient were considered as failure.
    End point type
    Secondary
    End point timeframe
    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: Endpoints are presented separately for metformin patients versus treatment naive patients. Baseline charcteristics are presented for both groups combined.
    End point values
    Treatment Naive: Empagliflozin 25 mg/linagliptin 5 mg Treament Naive: Empagliflozin 10 mg/linagliptin 5 mg Treatment Naive: Empagliflozin 25 mg Treatment Naive: Empagliflozin 10 mg Treatment Naive: Linagliptin 5 mg
    Number of subjects analysed
    121 [48]
    122 [49]
    118 [50]
    121 [51]
    127 [52]
    Units: % of patients satisfying HbA1c <7.0%
        number (confidence interval 95%)
    55.4 (46.1 to 64.4)
    62.3 (53.1 to 70.9)
    41.5 (32.5 to 51)
    38.8 (30.1 to 48.1)
    32.3 (24.3 to 41.2)
    Notes
    [48] - FAS (NCF)
    [49] - FAS (NCF)
    [50] - FAS (NCF)
    [51] - FAS (NCF)
    [52] - FAS (NCF)
    Statistical analysis title
    Naive: Empa/Lina 25/5 versus Empa 25
    Statistical analysis description
    Logistic regression includes treatment, baseline eGFR (MDRD), geographical region and baseline HbA1c. Odds ratio for Empa/Lina 25/5 versus Empa 25.
    Comparison groups
    Treatment Naive: Empagliflozin 25 mg v Treatment Naive: Empagliflozin 25 mg/linagliptin 5 mg
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0224
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.893
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.095
         upper limit
    3.274
    Statistical analysis title
    Naive: Empa/Lina 10/5 versus Empa 10
    Statistical analysis description
    Logistic regression includes treatment, baseline eGFR (MDRD), geographical region and baseline HbA1c. Odds ratio for Empa/Lina 10/5 versus Empa 10.
    Comparison groups
    Treatment Naive: Empagliflozin 10 mg v Treament Naive: Empagliflozin 10 mg/linagliptin 5 mg
    Number of subjects included in analysis
    243
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0001
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.961
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.697
         upper limit
    5.169
    Statistical analysis title
    Naive: Empa/Lina 25/5 versus Lina 5
    Statistical analysis description
    Logistic regression includes treatment, baseline eGFR (MDRD), geographical region and baseline HbA1c. Odds ratio for Empa/Lina 25/5 versus Lina 5.
    Comparison groups
    Treatment Naive: Linagliptin 5 mg v Treatment Naive: Empagliflozin 25 mg/linagliptin 5 mg
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.065
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.768
         upper limit
    5.314
    Statistical analysis title
    Naive: Empa/Lina 10/5 versus Lina 5
    Statistical analysis description
    Logistic regression includes treatment, baseline eGFR (MDRD), geographical region and baseline HbA1c. Odds ratio for Empa/Lina 10/5 versus Lina 5.
    Comparison groups
    Treatment Naive: Linagliptin 5 mg v Treament Naive: Empagliflozin 10 mg/linagliptin 5 mg
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    4.303
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.462
         upper limit
    7.522

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first trial medication intake until 7 days after last drug intake during the 52-week study period.
    Adverse event reporting additional description
    One patient was randomized to treatment with Empa/Lina 25/5 but was treated with Empa 10 from the start of trial for 6 weeks. For efficacy, the patient was analyzed as randomized (Empa/Lina 25/5) and for safety the patient was analyzed as first medication taken (Empa 10).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Empagliflozin 25 mg/Linagliptin 5 mg
    Reporting group description
    Test product: Empagliflozin/linagliptin FDC tablets dose: 25 mg/5 mg q.d. mode of admin.: Oral

    Reporting group title
    Empagliflozin 10 mg/Linagliptin 5 mg
    Reporting group description
    Test product: Empagliflozin/linagliptin FDC tablets dose: 10 mg/5 mg q.d. mode of admin.: Oral

    Reporting group title
    Empagliflozin 25 mg
    Reporting group description
    Reference therapy 1: Empagliflozin tablets dose: 25 mg q.d. mode of admin.: Oral

    Reporting group title
    Empagliflozin 10 mg
    Reporting group description
    Reference therapy 1: Empagliflozin tablets dose: 10 mg q.d. mode of admin.: Oral

    Reporting group title
    Linagliptin 5 mg
    Reporting group description
    Reference therapy 2: Linagliptin tablets dose: 5 mg q.d. mode of admin.: Oral

    Serious adverse events
    Empagliflozin 25 mg/Linagliptin 5 mg Empagliflozin 10 mg/Linagliptin 5 mg Empagliflozin 25 mg Empagliflozin 10 mg Linagliptin 5 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 273 (4.40%)
    16 / 272 (5.88%)
    19 / 276 (6.88%)
    16 / 275 (5.82%)
    10 / 267 (3.75%)
         number of deaths (all causes)
    0
    2
    3
    2
    0
         number of deaths resulting from adverse events
    0
    0
    1
    0
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 272 (0.37%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    1 / 276 (0.36%)
    0 / 275 (0.00%)
    0 / 267 (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
    Surgical and medical procedures
    Finger amputation
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    1 / 276 (0.36%)
    0 / 275 (0.00%)
    0 / 267 (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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenoid cystic carcinoma
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    1 / 275 (0.36%)
    0 / 267 (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
    Basal cell carcinoma
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 272 (0.00%)
    1 / 276 (0.36%)
    0 / 275 (0.00%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    0 / 267 (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
    Gastrointestinal carcinoma
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 272 (0.37%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    0 / 267 (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
    Clear cell renal cell carcinoma
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    0 / 267 (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
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 272 (0.37%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    0 / 267 (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
    Lung neoplasm
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    1 / 275 (0.36%)
    0 / 267 (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 / 1
    0 / 0
    Metastases to peritoneum
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    1 / 276 (0.36%)
    0 / 275 (0.00%)
    0 / 267 (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
    Non-small cell lung cancer metastatic
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    1 / 275 (0.36%)
    0 / 267 (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 / 1
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    1 / 276 (0.36%)
    0 / 275 (0.00%)
    0 / 267 (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
    Parathyroid tumour benign
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    1 / 276 (0.36%)
    0 / 275 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    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
    Prostate cancer
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    0 / 267 (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
    Renal cancer
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    0 / 267 (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
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    1 / 267 (0.37%)
         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
    Uterine leiomyoma
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    1 / 276 (0.36%)
    0 / 275 (0.00%)
    0 / 267 (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
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 273 (0.00%)
    2 / 272 (0.74%)
    1 / 276 (0.36%)
    1 / 275 (0.36%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 272 (0.37%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    0 / 267 (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
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    0 / 267 (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
    Mental status changes
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    0 / 267 (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
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    1 / 276 (0.36%)
    0 / 275 (0.00%)
    0 / 267 (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
    Postmenopausal haemorrhage
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    1 / 276 (0.36%)
    0 / 275 (0.00%)
    0 / 267 (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
    Rectocele
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    1 / 276 (0.36%)
    0 / 275 (0.00%)
    0 / 267 (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
    Injury, poisoning and procedural complications
    Chemical injury
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    1 / 275 (0.36%)
    0 / 267 (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
    Fibula fracture
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    1 / 276 (0.36%)
    0 / 275 (0.00%)
    0 / 267 (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
    Joint dislocation
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 272 (0.37%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    0 / 267 (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
    Lower limb fracture
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 272 (0.37%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    0 / 267 (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
    Rib fracture
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    1 / 276 (0.36%)
    0 / 275 (0.00%)
    0 / 267 (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
    Road traffic accident
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    1 / 275 (0.36%)
    0 / 267 (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 / 1
    0 / 0
    Seroma
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 272 (0.37%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    0 / 267 (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
    Tendon rupture
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    1 / 276 (0.36%)
    0 / 275 (0.00%)
    0 / 267 (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
    Investigations
    Troponin increased
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    1 / 275 (0.36%)
    0 / 267 (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
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    1 / 276 (0.36%)
    0 / 275 (0.00%)
    0 / 267 (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
    Angina pectoris
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    0 / 267 (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
    Angina unstable
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 272 (0.37%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    0 / 267 (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
    Coronary artery disease
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    1 / 275 (0.36%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive heart disease
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 272 (0.37%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    0 / 267 (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 / 1
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    1 / 275 (0.36%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 272 (0.37%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    0 / 267 (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
    Silent myocardial infarction
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    1 / 275 (0.36%)
    0 / 267 (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
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    1 / 275 (0.36%)
    0 / 267 (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
    Pulmonary embolism
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    1 / 275 (0.36%)
    0 / 267 (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
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    1 / 275 (0.36%)
    0 / 267 (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 / 1
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 272 (0.37%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    0 / 267 (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
    Cerebrovascular accident
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    1 / 267 (0.37%)
         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
    Dementia Alzheimer's type
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 272 (0.37%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    0 / 267 (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
    Encephalopathy
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    0 / 267 (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
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 272 (0.37%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    0 / 267 (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 / 1
    0 / 0
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    0 / 267 (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
    Syncope
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    1 / 276 (0.36%)
    0 / 275 (0.00%)
    0 / 267 (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
    Transient ischaemic attack
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    2 / 275 (0.73%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal adhesions
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    1 / 276 (0.36%)
    0 / 275 (0.00%)
    0 / 267 (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
    Abdominal pain
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 272 (0.37%)
    0 / 276 (0.00%)
    1 / 275 (0.36%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal strangulated hernia
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    1 / 276 (0.36%)
    0 / 275 (0.00%)
    0 / 267 (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
    Colitis ischaemic
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 272 (0.37%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    0 / 267 (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
    Intestinal perforation
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    1 / 275 (0.36%)
    0 / 267 (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
    Mechanical ileus
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    1 / 275 (0.36%)
    0 / 267 (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 chronic
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    1 / 267 (0.37%)
         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
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    1 / 275 (0.36%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    2 / 276 (0.72%)
    0 / 275 (0.00%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic mass
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    1 / 276 (0.36%)
    0 / 275 (0.00%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus bladder
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    0 / 267 (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
    Calculus ureteric
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    1 / 276 (0.36%)
    1 / 275 (0.36%)
    0 / 267 (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
    Hydronephrosis
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    1 / 276 (0.36%)
    0 / 275 (0.00%)
    0 / 267 (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
    Renal colic
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    1 / 275 (0.36%)
    0 / 267 (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
    Renal failure acute
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    1 / 267 (0.37%)
         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
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    1 / 275 (0.36%)
    0 / 267 (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
    Musculoskeletal and connective tissue disorders
    Myofascial pain syndrome
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 272 (0.37%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    0 / 267 (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
    Flank pain
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    0 / 267 (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
    Osteoarthritis
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 272 (0.37%)
    1 / 276 (0.36%)
    1 / 275 (0.36%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 272 (0.37%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    0 / 267 (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
    Metabolism and nutrition disorders
    Alkalosis
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    1 / 275 (0.36%)
    0 / 267 (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
    Dehydration
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    1 / 276 (0.36%)
    0 / 275 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    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
    Hyperglycaemia
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    1 / 275 (0.36%)
    0 / 267 (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
    Hypokalaemia
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    1 / 275 (0.36%)
    0 / 267 (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
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    1 / 267 (0.37%)
         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
    Cellulitis
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    0 / 267 (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
    Cystitis
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    1 / 276 (0.36%)
    0 / 275 (0.00%)
    0 / 267 (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
    Diverticulitis
         subjects affected / exposed
    0 / 273 (0.00%)
    1 / 272 (0.37%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    0 / 267 (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
    Encephalitis viral
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    0 / 267 (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
    Peritonitis
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    1 / 275 (0.36%)
    0 / 267 (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
    Meningitis tuberculous
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    1 / 276 (0.36%)
    0 / 275 (0.00%)
    0 / 267 (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 / 1
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    1 / 275 (0.36%)
    0 / 267 (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
    Pyelonephritis acute
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis chronic
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    1 / 276 (0.36%)
    0 / 275 (0.00%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 273 (0.37%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    0 / 275 (0.00%)
    0 / 267 (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
    Urinary tract infection
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    1 / 276 (0.36%)
    0 / 275 (0.00%)
    0 / 267 (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
    Urosepsis
         subjects affected / exposed
    0 / 273 (0.00%)
    0 / 272 (0.00%)
    0 / 276 (0.00%)
    1 / 275 (0.36%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    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
    Empagliflozin 25 mg/Linagliptin 5 mg Empagliflozin 10 mg/Linagliptin 5 mg Empagliflozin 25 mg Empagliflozin 10 mg Linagliptin 5 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    80 / 273 (29.30%)
    86 / 272 (31.62%)
    70 / 276 (25.36%)
    83 / 275 (30.18%)
    94 / 267 (35.21%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 273 (5.86%)
    15 / 272 (5.51%)
    13 / 276 (4.71%)
    19 / 275 (6.91%)
    24 / 267 (8.99%)
         occurrences all number
    18
    27
    18
    24
    28
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 273 (1.83%)
    14 / 272 (5.15%)
    13 / 276 (4.71%)
    10 / 275 (3.64%)
    12 / 267 (4.49%)
         occurrences all number
    6
    16
    17
    13
    12
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    8 / 273 (2.93%)
    8 / 272 (2.94%)
    12 / 276 (4.35%)
    12 / 275 (4.36%)
    24 / 267 (8.99%)
         occurrences all number
    8
    12
    17
    14
    28
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    18 / 273 (6.59%)
    16 / 272 (5.88%)
    10 / 276 (3.62%)
    16 / 275 (5.82%)
    20 / 267 (7.49%)
         occurrences all number
    19
    18
    13
    18
    29
    Upper respiratory tract infection
         subjects affected / exposed
    19 / 273 (6.96%)
    19 / 272 (6.99%)
    18 / 276 (6.52%)
    13 / 275 (4.73%)
    16 / 267 (5.99%)
         occurrences all number
    23
    23
    22
    15
    19
    Urinary tract infection
         subjects affected / exposed
    27 / 273 (9.89%)
    29 / 272 (10.66%)
    25 / 276 (9.06%)
    30 / 275 (10.91%)
    27 / 267 (10.11%)
         occurrences all number
    35
    38
    36
    34
    31

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jan 2012
    The amendment dated 27 Jan 2012 (approximately 5 months after trial initiation) introduced the following sponsor-initiated changes and clarifications after being approved by the IRB/IEC/CA: The protocol was revised to update the new co-ordinating investigator information in the trial. Increased number of entered patients: As per FDA request, the modified ITT population was to be used as the full analysis set, changed from the ITT population which included all randomised patients. The modified ITT population included all randomised patients who were treated with at least 1 dose of trial medication, had a baseline HbA1c measurement, and had at least 1 on-treatment HbA1c measurement. Considering the anticipated patient discontinuation in the trial before the first on-treatment HbA1c measurement, additional 30 patients were to be entered in the trial. The Screening study day in the flowchart was modified to clarify that the maximum time allowed from Visit 1 date to Visit 3 was 35 days. Description of DILI (drug-induced liver injury), definition of always serious AEs, and an appendix with further instruction on DILI handling were added in the protocol to fulfil the recommendation of the current FDA guidance. The CEC responsibility description was revised to clarify and reflect the current FDA guidance regarding evaluation of cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Known hypersensitivity or allergy to DPP4-inhibitors was added as exclusion criteria according to the FDA recommendation. A secondary analysis of the change from baseline in HbA1c after 24 weeks of treatment for the full analysis set including completers only was added according to FDA recommendation.
    11 Dec 2012
    The amendment dated 11 Dec 2012 (approximately 15.5 months after trial initiation) introduced the following sponsor-initiated changes and clarifications from logistical or administrative aspects which were implemented without the approval from IRB/IEC/CA: The other exploratory endpoint investigating the treat-to-target efficacy response of HbA1c <7.0% after 24 weeks of treatment was redefined as a key secondary endpoint. The endpoint was included into the confirmatory testing structure performed at 24 weeks. For the key secondary endpoint of change in body weight after 24 weeks of treatment, the comparison between the FDCs and empagliflozin was removed and redefined as other efficacy endpoint. Detailed information on DBL, treatment unblinding, and data planned to be analysed for the Week 24 confirmatory analysis were added to clarify that all confirmatory statistical analyses on the primary and key secondary endpoints were to be performed at Week 24. Laboratory tests were added and description for the clinical evaluation of liver injury was corrected to be consistent with the ISF DILI checklist and DILI laboratory kit.
    07 Jun 2013
    The amendment dated 07 Jun 2013 (approximately 1 year and 9 months after trial initiation) introduced the following sponsor-initiated changes and was implemented immediately in order to eliminate hazard and required IRB/IEC/CA to be notified of change with request for approval. Treatment discontinuation instructions were updated to include the criterion “if pancreatitis was suspected, the study treatment was to be stopped”. This amendment was introduced after the DBL of primary analysis on 20 Mar 2013; hence it was not included in the primary analysis report.

    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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