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    Clinical Trial Results:
    A phase III, randomised, double-blind, parallel group study to evaluate efficacy and safety of linagliptin 5 mg compared to placebo, administered as oral fixed dose combinations with empagliflozin 10 mg or 25 mg for 24 weeks, in patients with type 2 diabetes mellitus and insufficient glycaemic control after 16 weeks treatment with empagliflozin 10 mg or 25 mg once daily on metformin background therapy.

    Summary
    EudraCT number
    		 2012-002271-34
    Trial protocol
    		 PT   DE   ES   IT  
    Global end of trial date
    30 Mar 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Apr 2016
    First version publication date
    09 Apr 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    1275.10
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01778049
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    173 Binger Strasse, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Apr 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Mar 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Mar 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this trial was to investigate the efficacy, safety, and tolerability of linagliptin 5 mg (lina 5) compared with placebo, each administered as add-on therapy to empagliflozin (25 mg [empa 25] or 10 mg [empa 10]) and metformin, over 24 weeks in patients with type 2 diabetes (T2DM), who had met the HbA1c inclusion criterion (HbA1c ≥7% and ≤10.5%) after 16 weeks of open-label (OL) treatment with empa 25 OL or empa 10 OL and metformin background treatment.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Feb 2013
    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: 131
    Country: Number of subjects enrolled
    Ukraine: 131
    Country: Number of subjects enrolled
    United States: 211
    Country: Number of subjects enrolled
    Argentina: 343
    Country: Number of subjects enrolled
    Australia: 27
    Country: Number of subjects enrolled
    Canada: 148
    Country: Number of subjects enrolled
    Germany: 111
    Country: Number of subjects enrolled
    Italy: 138
    Country: Number of subjects enrolled
    Portugal: 22
    Country: Number of subjects enrolled
    Russian Federation: 62
    Worldwide total number of subjects
    1324
    EEA total number of subjects
    402
    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)
    1023
    From 65 to 84 years
    298
    85 years and over
    3

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Subjects randomised to 16 week(wk) open-label (OL) treatment with either empagliflozin (empa) 25 or empa 10 treatment, thereafter subjects entered to 1 wk open label placebo (Plc) add-on period in order to complete further eligibility evaluations before being randomised into one of the 24 wk double-blind treatment groups.

    Pre-assignment
    Screening details
    		 This was a randomised, double-blind, multi-national, parallel group trial. In this trial the treatment effects of linagliptin (lina) 5 compared with Plc were analysed as add-on to either empa 25 or empa 10. All trial treatments were administered in addition to metformin background treatment.

    Period 1
    Period 1 title
    Open label treatment period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Trial medications during the initial 16 week treatment period and the placebo add-on period were open-label.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Empa 10 mg OL
    Arm description
    		 Subjects were orally administered once daily empa 10 mg film-coated (1 tablet) for 16 wk during OL treatment period, thereafter patients received once daily fixed dose combination (FDC) placebo (1 tablet) matching to FDC empa 10 mg/lina 5 mg in addition to empa 10 mg for one week during open label placebo add-on treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were orally administered once daily empagliflozin (empa) 10 mg film-coated tablet for 16 weeks during open-label treatment period.

    Investigational medicinal product name
    Placebo to linagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    After 16 weeks of open label treatment period, subjects were orally administered once daily placebo tablet matching to lina 5 mg (in combination with placebo to empa 10 mg, 1 FDC tablet) in addition to empa 10 mg for 1 week.

    Investigational medicinal product name
    Placebo to empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    After 16 week open label treatment, subjects were orally administered once daily placebo tablet matching to empa 10 mg ( in combination with placebo to linagliptin (lina) 5 mg, 1 FDC tablet) in addition to empa 10 mg for 1 week.

    Arm title
    		 Empa 25 mg OL
    Arm description
    		 Subjects were orally administered once daily empa 25 mg film-coated (1 tablet) for 16 week during OL treatment period, thereafter patients received once daily FDC placebo (1 tablet) matching to FDC empa 25 mg/lina 5 mg in addition to empa 25 mg for one week during open label placebo add-on treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were orally administered once daily empagliflozin (empa) 25 mg film-coated tablet for 16 weeks during open-label (OL) treatment period.

    Investigational medicinal product name
    Placebo to empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    After 16 week open label treatment period, subjects were orally administered once daily placebo tablet matching to empa 25 mg ( in combination with placebo to linagliptin (lina) 5 mg, 1 FDC tablet) in addition to empa 25 mg for 1 week.

    Investigational medicinal product name
    Placebo to linagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    After 16 week open label treatment period, subjects were orally administered once daily placebo tablet matching to lina 5 mg ( in combination with placebo to empa 25 mg, 1 FDC tablet) in addition to empa 25 mg for 1 week.

    Number of subjects in period 1
    		Empa 10 mg OL Empa 25 mg OL
    Started
    352
    354
    Completed
    256
    226
    Not completed
    96
    128
         Other reason not defined above
    77
    94
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    4
    10
         Adverse event, non-fatal
    5
    14
         Lost to follow-up
    4
    3
         Lack of efficacy
    1
    1
         Protocol deviation
    5
    5
    Period 2
    Period 2 title
    Double blind treatment period
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst
    Blinding implementation details
    Medications during the 24 week treatment period were administered double-blinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lina5 (E10)
    Arm description
    		 Subjects were orally administered FDC empa 10 mg/lina 5 mg (1 tablet) and placebo matching to empa 10 mg (1 tablet) for 24 weeks during the double-blind treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were orally administered once daily empa 10 mg tablet ( in combination with lina 5 mg, 1 FDC tablet) in addition to empa 10 mg for 24 weeks during the double-blind treatment period.

    Investigational medicinal product name
    linagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were orally administered once daily lina 5 mg tablet ( in combination with empa 10 mg, 1 FDC tablet) for 24 weeks during the double-blind treatment period.

    Investigational medicinal product name
    Placebo to empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were orally administered placebo matching to empa 10 mg for 24 weeks during the double-blind treatment period.

    Arm title
    		 Plc (E10)
    Arm description
    		 Subjects were orally administered empa 10 mg (1 tablet) and matching placebo to FDC empa 10 mg/lina 5 mg (1 tablet) for 24 weeks during the double-blind treatment period. Two subjects randomised to Plc (E10) were not treated. Although actual number of subjects started is 130, 128 were reported to ensure consistent reporting with baseline characteristics that includes only treated subjects.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were orally administered empa 10 mg for 24 weeks during the double-blind treatment period.

    Investigational medicinal product name
    Placebo to linagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were orally administered once daily placebo tablet matching to lina 5 mg ( in combination with placebo to empa 10 mg, 1 FDC tablet) for 24 weeks during the double-blind treatment period.

    Investigational medicinal product name
    Placebo to empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were orally administered once daily placebo tablet matching to empa 10 mg ( in combination with placebo to lina 5 mg, 1 FDC tablet) for 24 weeks during the double-blind treatment period.

    Arm title
    		 Lina5 (E25)
    Arm description
    		 Subjects were orally administered FDC empa 25 mg/lina 5 mg (1 tablet) and placebo matching to empa 25 mg (1 tablet) for 24 weeks during the double-blind treatment period. Two subjects randomised to Lina5 (E25) were not treated. Although actual number of subjects started is 114, 112 were reported to ensure consistent reporting with baseline characteristics that includes only treated subjects.
    Arm type
    		 Experimental

    Investigational medicinal product name
    empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were orally administered once daily empa 25 mg tablet ( in combination with lina 5 mg, 1 FDC tablet) in addition to empa 25 mg for 24 weeks during the double-blind treatment period.

    Investigational medicinal product name
    Placebo to empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were orally administered placebo matching to empa 25 mg for 24 weeks during the double-blind treatment period.

    Investigational medicinal product name
    linagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were orally administered once daily lina 5 mg tablet ( in combination with empa 25 mg, 1 FDC tablet) for 24 weeks during the double-blind treatment period.

    Arm title
    		 Plc (E25)
    Arm description
    		 Subjects were orally administered empa 25 mg (1 tablet) and matching placebo to FDC empa 25 mg/lina 5 mg (1 tablet) for 24 weeks during the double-blind treatment period.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were orally administered empa 25 mg for 24 weeks during the double-blind treatment period.

    Investigational medicinal product name
    Placebo to linagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were orally administered once daily placebo tablet matching to lina 5 mg ( in combination with placebo to empa 25 mg, 1 FDC tablet) for 24 weeks during the double-blind treatment period.

    Investigational medicinal product name
    Placebo to empagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were orally administered once daily placebo tablet matching to empa 25 mg ( in combination with placebo to lina 5 mg, 1 FDC tablet) for 24 weeks during the double-blind treatment period.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: In this study, Period 1 evaluates open label treatment period which referred to as pre-treatment analysis , thus period 2 double blind treatment period was selected as a baseline period to define the baseline characteristics of this trial.
    Number of subjects in period 2 [2] [3]
    		Lina5 (E10) Plc (E10) Lina5 (E25) Plc (E25)
    Started
    126
    128
    112
    112
    Completed
    111
    118
    102
    105
    Not completed
    15
    10
    10
    7
         Other reason not defined above
    4
    2
    2
    1
         Consent withdrawn by subject
    1
    2
    -
    1
         Adverse event, non-fatal
    4
    5
    3
    2
         Lost to follow-up
    4
    1
    5
    2
         Protocol deviation
    2
    -
    -
    -
         Lack of efficacy
    -
    -
    -
    1
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics are based on the last measurement prior to the administration of any double-blind randomised study medication. In this study the term “baseline” was not used to refer to measurements prior to the administration of open-label medication. Such measurements were referred to as “pre-treatment".
    [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: This study was conducted in two phases, open label (OL) and double blind (DB) phase. Subjects received OL treatment for 16 weeks and thereafter patients entered a 1 week open-label placebo add-on period in order to complete further eligibility evaluations before being randomised into one of the 24 week DB treatment groups. The patients who were eligible were only randomised to DB treatemet period, thus the inconsistency within the number of subjects completed the preceding period is observed.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lina5 (E10)
    Reporting group description
    		 Subjects were orally administered FDC empa 10 mg/lina 5 mg (1 tablet) and placebo matching to empa 10 mg (1 tablet) for 24 weeks during the double-blind treatment period.

    Reporting group title
    Plc (E10)
    Reporting group description
    		 Subjects were orally administered empa 10 mg (1 tablet) and matching placebo to FDC empa 10 mg/lina 5 mg (1 tablet) for 24 weeks during the double-blind treatment period. Two subjects randomised to Plc (E10) were not treated. Although actual number of subjects started is 130, 128 were reported to ensure consistent reporting with baseline characteristics that includes only treated subjects.

    Reporting group title
    Lina5 (E25)
    Reporting group description
    		 Subjects were orally administered FDC empa 25 mg/lina 5 mg (1 tablet) and placebo matching to empa 25 mg (1 tablet) for 24 weeks during the double-blind treatment period. Two subjects randomised to Lina5 (E25) were not treated. Although actual number of subjects started is 114, 112 were reported to ensure consistent reporting with baseline characteristics that includes only treated subjects.

    Reporting group title
    Plc (E25)
    Reporting group description
    		 Subjects were orally administered empa 25 mg (1 tablet) and matching placebo to FDC empa 25 mg/lina 5 mg (1 tablet) for 24 weeks during the double-blind treatment period.

    Reporting group values
    		 Lina5 (E10) Plc (E10) Lina5 (E25) Plc (E25) Total
    Number of subjects
    		 126 128 112 112 478
    Age categorical
    Units: Subjects
    Age Continuous |
    The Treated set (TS) was used for the double-blind treatment period. The treated set (TS) consisted of all patients who were randomised and treated with at least one dose of study drug during the double-blind part of the trial. The TS was the basis of the safety analyses for the double-blind period.
    Units: years
        arithmetic mean (standard deviation)
    		 56.6 ( 9.5 ) 56.6 ( 9.5 ) 56.4 ( 9.9 ) 56.2 ( 10.7 ) -
    Gender, Male/Female
    Units: participants
        Female
    		 55 56 58 47 216
        Male
    		 71 72 54 65 262

    End points

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    End points reporting groups
    Reporting group title
    Empa 10 mg OL
    Reporting group description
    		 Subjects were orally administered once daily empa 10 mg film-coated (1 tablet) for 16 wk during OL treatment period, thereafter patients received once daily fixed dose combination (FDC) placebo (1 tablet) matching to FDC empa 10 mg/lina 5 mg in addition to empa 10 mg for one week during open label placebo add-on treatment period.

    Reporting group title
    Empa 25 mg OL
    Reporting group description
    		 Subjects were orally administered once daily empa 25 mg film-coated (1 tablet) for 16 week during OL treatment period, thereafter patients received once daily FDC placebo (1 tablet) matching to FDC empa 25 mg/lina 5 mg in addition to empa 25 mg for one week during open label placebo add-on treatment period.
    Reporting group title
    Lina5 (E10)
    Reporting group description
    		 Subjects were orally administered FDC empa 10 mg/lina 5 mg (1 tablet) and placebo matching to empa 10 mg (1 tablet) for 24 weeks during the double-blind treatment period.

    Reporting group title
    Plc (E10)
    Reporting group description
    		 Subjects were orally administered empa 10 mg (1 tablet) and matching placebo to FDC empa 10 mg/lina 5 mg (1 tablet) for 24 weeks during the double-blind treatment period. Two subjects randomised to Plc (E10) were not treated. Although actual number of subjects started is 130, 128 were reported to ensure consistent reporting with baseline characteristics that includes only treated subjects.

    Reporting group title
    Lina5 (E25)
    Reporting group description
    		 Subjects were orally administered FDC empa 25 mg/lina 5 mg (1 tablet) and placebo matching to empa 25 mg (1 tablet) for 24 weeks during the double-blind treatment period. Two subjects randomised to Lina5 (E25) were not treated. Although actual number of subjects started is 114, 112 were reported to ensure consistent reporting with baseline characteristics that includes only treated subjects.

    Reporting group title
    Plc (E25)
    Reporting group description
    		 Subjects were orally administered empa 25 mg (1 tablet) and matching placebo to FDC empa 25 mg/lina 5 mg (1 tablet) for 24 weeks during the double-blind treatment period.

    Primary: Change from baseline of HbA1c after 24 weeks of treatment

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    End point title
    		 Change from baseline of HbA1c after 24 weeks of treatment
    End point description
    Change from baseline in Glycated haemoglobin (HbA1c) [%] after 24 wk of treatment with double-blind trial medication, i.e. HbA1c change from baseline at week 24. The term "baseline" refers to the last measurement prior to the administration of any double-blind randomised study medication. It was not used to refer to measurements prior to the administration of open-label medication. Such measurements will be referred to as “pre-treatment". Observed Case (OC): This method analyse only available data that were observed while patients were on treatment, i.e., excluding the missing data. All values measured after rescue medication taken were set to missing. Full Analysis Set (FAS): Includes all patients in the Treated set who had a baseline HbA1c assessment and at least one on-treatment HbA1c assessment during the double-blind part of the trial.
    End point type
    Primary
    End point timeframe
    Baseline and 24 weeks
    End point values
    		 Lina5 (E10) Plc (E10) Lina5 (E25) Plc (E25)
    Number of subjects analysed
    111 [1]
    110 [2]
    98 [3]
    98 [4]
    Units: Percentage of HbA1c
        least squares mean (standard error)
    -0.53 ( 0.07 )
    -0.21 ( 0.07 )
    -0.58 ( 0.07 )
    -0.1 ( 0.07 )
    Notes
    [1] - FAS (OC)
    [2] - FAS (OC)
    [3] - FAS (OC)
    [4] - FAS (OC)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Superiority of lina 5 (E10) vs. Plc (E10): change in HbA1c using a restricted maximum likelihood (REML)- based mixed model repeated measures (MMRM) approach. The model includes baseline HbA1c as linear covariate & baseline estimated glomerula filtration rate (eGFR), geographical region, treatment, visit, visit by treatment interaction as fixed effects.
    Comparison groups
    Lina5 (E10) v Plc (E10)
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.0013
    Method
    		 Mixed Model Repeated Measure (MMRM)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.52
         upper limit
    		 -0.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1
    Notes
    [5] - The unstructured covariance structure has been used to fit the mixed model. Mean Difference (Final Values) is actually the adjusted mean difference calculated as Lina 5 (E10) minus Plc (E10) value.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Superiority of lina 5 (E25) vs.Plc (E25): change in HbA1c using a restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach. The model includes baseline HbA1c as linear covariate & baseline eGFR, geographical region, treatment, visit, visit by treatment interaction as fixed effects.
    Comparison groups
    Lina5 (E25) v Plc (E25)
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.66
         upper limit
    		 -0.28
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1
    Notes
    [6] - The unstructured covariance structure has been used to fit the mixed model. Mean Difference (Final Values) is actually the adjusted mean difference value calculated as Lina 5 (E25) minus Plc (E25).

    Secondary: Change from baseline in FPG (mmol/L) after 24 weeks

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    End point title
    		 Change from baseline in FPG (mmol/L) after 24 weeks
    End point description
    Change from baseline in fasting plasma glucose (FPG) (mmol/L) after 24 weeks of treatment with double-blind trial medication, i.e. FPG change from baseline at Week 24.
    End point type
    Secondary
    End point timeframe
    Baseline and 24 weeks
    End point values
    		 Lina5 (E10) Plc (E10) Lina5 (E25) Plc (E25)
    Number of subjects analysed
    108 [7]
    107 [8]
    93 [9]
    94 [10]
    Units: mmol/L
        least squares mean (standard error)
    -0.44 ( 0.18 )
    0.21 ( 0.18 )
    -0.68 ( 0.15 )
    -0.24 ( 0.15 )
    Notes
    [7] - FAS (OC)
    [8] - FAS (OC)
    [9] - FAS (OC)
    [10] - FAS (OC)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Superiority of lina5 (E10) vs. Plc (E10): change in FPG using a restricted maximum likelihood (REML)- based mixed model repeated measures (MMRM) approach. The model includes baseline HbA1c & baseline eGFR as linear covariates, geographical region, treatment, visit, visit by treatment interaction as fixed effects.
    Comparison groups
    Lina5 (E10) v Plc (E10)
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.0103
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.15
         upper limit
    		 -0.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.25
    Notes
    [11] - The unstructured covariance structure has been used to fit the mixed model. Mean Difference (Final Values) is actually the adjusted mean difference value calculated as Lina 5 (E10) minus Plc (E10).
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Superiority of lina5 (E25) vs. Plc (E25): change in FPG using a restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach. The model includes baseline HbA1c & baseline eGFR as linear covariates, geographical region, treatment, visit, visit by treatment interaction as fixed effects.
    Comparison groups
    Lina5 (E25) v Plc (E25)
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 0.0452
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.87
         upper limit
    		 -0.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.22
    Notes
    [12] - The unstructured covariance structure has been used to fit the mixed model. Mean Difference (Final Values) is actually the adjusted mean difference value calculated as Lina 5 (E25) minus Plc (E25).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first drug administration until 7 days after the last drug administration, up to 212 days (OL treatment period) and 205 days (double blind treatment period).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    empa 10 mg OL
    Reporting group description
    		 Subjects were orally administered once daily empa 10 mg film-coated (1 tablet) for 16 wk during OL treatment period, thereafter patients received once daily fixed dose combination (FDC) placebo (1 tablet) matching to FDC empa 10 mg/lina 5 mg in addition to empa 10 mg for one week during open label placebo add-on treatment period.

    Reporting group title
    empa 25 mg OL
    Reporting group description
    		 Subjects were orally administered once daily empa 25 mg film-coated (1 tablet) for 16 week during OL treatment period, thereafter patients received once daily FDC placebo (1 tablet) matching to FDC empa 25 mg/lina 5 mg in addition to empa 25 mg for one week during open label placebo add-on treatment period.

    Reporting group title
    Lina5 (E10)
    Reporting group description
    		 Subjects were orally administered FDC empa 10 mg/lina 5 mg (1 tablet) and placebo matching to empa 10 mg (1 tablet) for 24 weeks during the double-blind treatment period.

    Reporting group title
    Plc (E10)
    Reporting group description
    		 Subjects were orally administered empa 10 mg (1 tablet) and matching placebo to FDC empa 10 mg/lina 5 mg (1 tablet) for 24 weeks during the double-blind treatment period. Two subjects randomised to Plc (E10) were not treated. Although actual number of subjects started is 130, 128 were reported to ensure consistent reporting with baseline characteristics that includes only treated subjects.

    Reporting group title
    Lina5 (E25)
    Reporting group description
    		 Subjects were orally administered FDC empa 25 mg/lina 5 mg (1 tablet) and placebo matching to empa 25 mg (1 tablet) for 24 weeks during the double-blind treatment period. Two subjects randomised to Lina5 (E25) were not treated. Although actual number of subjects started is 114, 112 were reported to ensure consistent reporting with baseline characteristics that includes only treated subjects.

    Reporting group title
    Plc (E25)
    Reporting group description
    		 Subjects were orally administered empa 25 mg (1 tablet) and matching placebo to FDC empa 25 mg/lina 5 mg (1 tablet) for 24 weeks during the double-blind treatment period.

    Serious adverse events
    		 empa 10 mg OL empa 25 mg OL Lina5 (E10) Plc (E10) Lina5 (E25) Plc (E25)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 352 (3.41%)
    12 / 354 (3.39%)
    4 / 126 (3.17%)
    5 / 128 (3.91%)
    3 / 112 (2.68%)
    4 / 112 (3.57%)
         number of deaths (all causes)
    0
    1
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    0 / 352 (0.00%)
    1 / 354 (0.28%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostatic adenoma
         subjects affected / exposed
    1 / 352 (0.28%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Extremity necrosis
         subjects affected / exposed
    0 / 352 (0.00%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    1 / 352 (0.28%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Calcinosis
         subjects affected / exposed
    0 / 352 (0.00%)
    1 / 354 (0.28%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 352 (0.28%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 352 (0.00%)
    1 / 354 (0.28%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 352 (0.00%)
    0 / 354 (0.00%)
    1 / 126 (0.79%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    0 / 352 (0.00%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    1 / 128 (0.78%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    0 / 352 (0.00%)
    1 / 354 (0.28%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 352 (0.28%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal septum deviation
         subjects affected / exposed
    0 / 352 (0.00%)
    1 / 354 (0.28%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal turbinate hypertrophy
         subjects affected / exposed
    0 / 352 (0.00%)
    1 / 354 (0.28%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal lesion
         subjects affected / exposed
    0 / 352 (0.00%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    1 / 112 (0.89%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Amylase increased
         subjects affected / exposed
    1 / 352 (0.28%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 352 (0.28%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skull fractured base
         subjects affected / exposed
    1 / 352 (0.28%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    1 / 352 (0.28%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 352 (0.28%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 352 (0.00%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    1 / 112 (0.89%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 352 (0.00%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    1 / 128 (0.78%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 352 (0.28%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    1 / 128 (0.78%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 352 (0.28%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 352 (0.00%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    1 / 112 (0.89%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haematoma
         subjects affected / exposed
    1 / 352 (0.28%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 352 (0.28%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 352 (0.00%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    1 / 128 (0.78%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 352 (0.28%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Pancytopenia
         subjects affected / exposed
    0 / 352 (0.00%)
    1 / 354 (0.28%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diverticulum intestinal
         subjects affected / exposed
    0 / 352 (0.00%)
    1 / 354 (0.28%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 352 (0.00%)
    1 / 354 (0.28%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal polyp
         subjects affected / exposed
    0 / 352 (0.00%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    2 / 352 (0.57%)
    0 / 354 (0.00%)
    1 / 126 (0.79%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 352 (0.00%)
    1 / 354 (0.28%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 352 (0.00%)
    0 / 354 (0.00%)
    1 / 126 (0.79%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    2 / 352 (0.57%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    1 / 352 (0.28%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis bullous
         subjects affected / exposed
    0 / 352 (0.00%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    1 / 112 (0.89%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Dyshidrotic eczema
         subjects affected / exposed
    0 / 352 (0.00%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    1 / 112 (0.89%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 352 (0.00%)
    0 / 354 (0.00%)
    1 / 126 (0.79%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    0 / 352 (0.00%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    1 / 112 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 352 (0.00%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    1 / 128 (0.78%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 352 (0.00%)
    0 / 354 (0.00%)
    1 / 126 (0.79%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 352 (0.00%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    1 / 128 (0.78%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    0 / 352 (0.00%)
    1 / 354 (0.28%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 352 (0.00%)
    1 / 354 (0.28%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 352 (0.00%)
    1 / 354 (0.28%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infectious colitis
         subjects affected / exposed
    0 / 352 (0.00%)
    1 / 354 (0.28%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 352 (0.00%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    2 / 112 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 352 (0.00%)
    0 / 354 (0.00%)
    1 / 126 (0.79%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 352 (0.28%)
    0 / 354 (0.00%)
    0 / 126 (0.00%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 352 (0.00%)
    0 / 354 (0.00%)
    1 / 126 (0.79%)
    0 / 128 (0.00%)
    0 / 112 (0.00%)
    0 / 112 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 empa 10 mg OL empa 25 mg OL Lina5 (E10) Plc (E10) Lina5 (E25) Plc (E25)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    47 / 352 (13.35%)
    38 / 354 (10.73%)
    22 / 126 (17.46%)
    10 / 128 (7.81%)
    18 / 112 (16.07%)
    21 / 112 (18.75%)
    Investigations
    Lipase increased
         subjects affected / exposed
    15 / 352 (4.26%)
    10 / 354 (2.82%)
    4 / 126 (3.17%)
    1 / 128 (0.78%)
    7 / 112 (6.25%)
    7 / 112 (6.25%)
         occurrences all number
    15
    10
    4
    1
    7
    7
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    17 / 352 (4.83%)
    5 / 354 (1.41%)
    8 / 126 (6.35%)
    3 / 128 (2.34%)
    2 / 112 (1.79%)
    8 / 112 (7.14%)
         occurrences all number
    18
    5
    11
    3
    2
    8
    Urinary tract infection
         subjects affected / exposed
    16 / 352 (4.55%)
    23 / 354 (6.50%)
    10 / 126 (7.94%)
    6 / 128 (4.69%)
    11 / 112 (9.82%)
    7 / 112 (6.25%)
         occurrences all number
    17
    26
    13
    9
    14
    8

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Jun 2013
    Stopping of trial treatment in case of changes in metformin background treatment or with suspected pancreatitis (included in the linagliptin labelling) were added as discontinuation criteria. Minor corrections and clarifications for consistency within the CTP and within the development program were introduced.
    27 Nov 2013
    Based upon comments in an advice letter received from health authority on 24 Apr 2013 the primary analysis model was changed from ANCOVA (LOCF) to MMRM (OC). According to published literature, MMRM analysis appears to be a superior approach for controlling Type I error rates and minimizing bias as compared to single imputation approaches such as LOCF ANCOVA analysis particularly in the presence of missing completely at random or missing at random data [R10-5462]. The MMRM approach included treatment, baseline renal function, region, visit, and visit-by-treatment interaction as fixed effects, and HbA1c baseline as linear covariate. An unstructured covariance structure was used to model the within-patient errors. Subsequent changes to the sensitivity analyses of the primary endpoint included the analysis of the primary endpoint using an ANCOVA model. The analysis of the key secondary endpoint and the subgroup analyses were updated accordingly. For consistency with the TSAP, the planned analyses were updated by adding definitions of the different analysis sets (SCR, OLS, and OLFAS). The description of the trial objective and the trial design was amended to clarify the use of FDCs of empagliflozin and linagliptin. External independent committees were set-up for the adjudication of safety relevant events (pancreatic events, hepatic events, cancer assessments). To match new requirement for public disclosure AEs, hypoglycaemic events, AESIs and cardiovascular events were part of the safety assessment without being classified as further endpoints [001-MCS-40-106_RD-03]. Processes for expedited AE reporting were updated and clarified. Administration of herbal/nutritional supplements/medication that interfered with the investigational products was included as a reason for patient withdrawal. Administrative changes including updates and clarifications on AE reporting requirements including the definition of the REP, minor corrections and further clarifications were introduced.
    11 Jun 2014
    This revision of the CTP involved only minor administrative aspects and clarifications and did not require IRB/IEC approval.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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