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    Clinical Trial Results:
    A 24 week randomized, double-blind, placebo-controlled, parallel group, efficacy and safety trial of once daily linagliptin, 5 milligrams orally, as add on to basal insulin in elderly Type 2 Diabetes Mellitus patients with insufficient glycaemic control

    Summary
    EudraCT number
    		 2014-000904-88
    Trial protocol
    		 GR   ES   DK   GB   FI   DE   BE   IE  
    Global end of trial date
    25 Apr 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    01 Jun 2022
    First version publication date
    10 May 2018
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Correction to previously submitted information.

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    1218.149
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02240680
    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 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 May 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Apr 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the efficacy, safety, and tolerability of linagliptin 5 mg once daily compared with placebo as add-on therapy for 24 weeks to stable basal insulin treatment in elderly (≥60 years) patients with type 2 diabetes mellitus and insufficient glycaemic control.
    Protection of trial subjects
    Safety was to be ensured by monitoring the patients for AEs clinically, by laboratory testing, and by home blood glucose monitoring (HBGM). Patients who were not adequately controlled could have their permitted background medication adjusted or new antidiabetic medications introduced to ensure their safety. In case the patient developed any condition/disease or AE which did not allow – according to investigator’s judgement – the patient’s safe continuation of the trial, the patient was to be prematurely discontinued from the trial. Symptoms that could be attributed to hypoglycaemia were to be closely monitored during the trial. General risks associated with participating in this trial were related to trial-specific procedures such as blood sampling. The amount of blood taken during the whole course of the trial was considered to be of no or negligible risk to the patients. The trial design with a 1-week placebo run-in phase is a well-established design for trials in type 2 diabetes. Daily monitoring of blood glucose was performed by patients with the HBGM device and patients were to be discontinued if there was any indication that the patient was not stable enough. Thus the risk of the 1-week placebo treatment was minimal.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Oct 2014
    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
    Australia: 7
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Colombia: 12
    Country: Number of subjects enrolled
    Denmark: 31
    Country: Number of subjects enrolled
    Finland: 10
    Country: Number of subjects enrolled
    Germany: 15
    Country: Number of subjects enrolled
    Greece: 16
    Country: Number of subjects enrolled
    Ireland: 1
    Country: Number of subjects enrolled
    Japan: 108
    Country: Number of subjects enrolled
    Mexico: 33
    Country: Number of subjects enrolled
    New Zealand: 12
    Country: Number of subjects enrolled
    Poland: 31
    Country: Number of subjects enrolled
    Romania: 21
    Country: Number of subjects enrolled
    South Africa: 26
    Country: Number of subjects enrolled
    Spain: 56
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    United States: 133
    Worldwide total number of subjects
    525
    EEA total number of subjects
    194
    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)
    32
    From 65 to 84 years
    475
    85 years and over
    18

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was randomised, double blinded, placebo controlled, parallel study. Total 525 patients with type 2 diabetes mellitus (T2DM) and insufficient glycaemic control were screened. 302 patients were randomised into two groups. The trial was extended to 52 weeks for Japanese patients. 102 patients were identified and observed for the extended period.

    Pre-assignment
    Screening details
    		 All patients 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 to be randomised to trial treatment if any one of the specific entry criteria were violated.

    Period 1
    Period 1 title
    Overall Study (Up to 24 weeks)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer
    Blinding implementation details
    The randomised period of this trial was double blind, i.e. after randomisation neither the patient nor the investigator nor anyone involved in analysing trial data or with an interest in this double blind trial were aware of a treatment assignment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo (Up to 24 weeks)
    Arm description
    		 Patients were orally administered with Placebo tablets (matching Linagliptin) once daily up to 24 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral adminstration of placebo tablets (Matching Linagliptin) once daily up to 24 weeks.

    Arm title
    		 Linagliptin 5 milligram (Up to 24 weeks)
    Arm description
    		 Patients were orally administered with Linagliptin 5 milligram film-coated tablets once daily up to 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Linagliptin 5 milligram
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral adminstation of Linagliptin 5 milligram film coated tablets once daily up to 24 weeks

    Number of subjects in period 1 [1]
    		Placebo (Up to 24 weeks) Linagliptin 5 milligram (Up to 24 weeks)
    Started
    151
    151
    Completed
    136
    143
    Not completed
    15
    8
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    3
    1
         Adverse event, non-fatal
    6
    5
         Other than specified
    1
    -
         Lost to follow-up
    1
    -
         Protocol deviation
    4
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Out of 525 enrolled subjects only 302 were randomized.
    Period 2
    Period 2 title
    Japanese Patients (Up to 52 weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer
    Blinding implementation details
    The randomised period of this trial was double-blind, i.e. after randomisation neither the patient nor the investigator nor anyone involved in analysing trial data or with an interest in this double-blind trial were aware of a treatment assignment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo (Up to 52 weeks)
    Arm description
    		 Only Japanese patients were orally administered with Placebo tablets (matching Linagliptin) once daily up to 52 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral adminstration of placebo tablets (Matching Linagliptin) once daily up to 52 weeks.

    Arm title
    		 Linagliptin 5 milligram (Up to 52 weeks)
    Arm description
    		 Only Japanese patients were orally administered with Linagliptin 5 milligram film-coated tablets once daily up to 52 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Linagliptin 5 milligram
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral adminstation of Linagliptin 5 milligram film coated tablets once daily up to 52 weeks.

    Number of subjects in period 2 [2]
    		Placebo (Up to 52 weeks) Linagliptin 5 milligram (Up to 52 weeks)
    Started
    50
    52
    Completed
    42
    45
    Not completed
    8
    7
         Consent withdrawn by subject
    1
    -
         Adverse event, non-fatal
    6
    7
         Protocol deviation
    1
    -
    Notes
    [2] - 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: Only the randomized Japanese patients were entered in this period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo (Up to 24 weeks)
    Reporting group description
    		 Patients were orally administered with Placebo tablets (matching Linagliptin) once daily up to 24 weeks

    Reporting group title
    Linagliptin 5 milligram (Up to 24 weeks)
    Reporting group description
    		 Patients were orally administered with Linagliptin 5 milligram film-coated tablets once daily up to 24 weeks.

    Reporting group values
    		 Placebo (Up to 24 weeks) Linagliptin 5 milligram (Up to 24 weeks) Total
    Number of subjects
    		 151 151 302
    Age categorical
    Units: Subjects
    Age Continuous
    Data of age collected for all included patients in the study.
    Units: Years
        arithmetic mean (standard deviation)
    		 72.5 ± 5.6 72.3 ± 5.1 -
    Sex: Female, Male
    Data of Gender collected of all patients included in the study.
    Units: Subjects
        Female
    		 60 59 119
        Male
    		 91 92 183
    Race (NIH/OMB)
    Data for Race of patients collected under protocol for all included patients in the study.
    Units: Subjects
        American Indian or Alaska Native
    		 7 4 11
        Asian
    		 52 52 104
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        Black or African American
    		 10 8 18
        White
    		 81 84 165
        More than one race
    		 1 2 3
        Unknown or Not Reported
    		 0 0 0
    Ethnicity (NIH/OMB)
    Data for Ethnicity of patients collected under protocol for all included patients in the study.
    Units: Subjects
        Hispanic or Latino
    		 19 15 34
        Not Hispanic or Latino
    		 132 136 268
        Unknown or Not Reported
    		 0 0 0
    Hemoglobin A1c (HbA1c) at baseline
    HbA1c values measured at baseline in percent. HbA1c is a form of hemoglobin, a blood pigment that carries oxygen, which is bound to glucose. The term HbA1c also refers to glycated hemoglobin. High levels of HbA1c (Normal range is less than 6%) indicate poorer control of diabetes than level in normal range.
    Units: Percentage (%) of HbA1c
        arithmetic mean (standard deviation)
    		 8.1 ± 0.7 8.2 ± 0.8 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo (Up to 24 weeks)
    Reporting group description
    		 Patients were orally administered with Placebo tablets (matching Linagliptin) once daily up to 24 weeks

    Reporting group title
    Linagliptin 5 milligram (Up to 24 weeks)
    Reporting group description
    		 Patients were orally administered with Linagliptin 5 milligram film-coated tablets once daily up to 24 weeks.
    Reporting group title
    Placebo (Up to 52 weeks)
    Reporting group description
    		 Only Japanese patients were orally administered with Placebo tablets (matching Linagliptin) once daily up to 52 weeks

    Reporting group title
    Linagliptin 5 milligram (Up to 52 weeks)
    Reporting group description
    		 Only Japanese patients were orally administered with Linagliptin 5 milligram film-coated tablets once daily up to 52 weeks

    Primary: Change from baseline in Hemoglobin A1c (HbA1c) after 24 weeks of treatment.

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    End point title
    		 Change from baseline in Hemoglobin A1c (HbA1c) after 24 weeks of treatment.
    End point description
    This outcome has measured difference between HbA1c values from baseline to 24 weeks post treatment. The term ‘baseline’ refers to the last observation prior to the administration of any randomised study medication. HbA1c is a form of hemoglobin, a blood pigment that carries oxygen, which is bound to glucose. The term HbA1c also refers to glycated hemoglobin. High levels of HbA1c (Normal range is less than 6%) indicate poorer control of diabetes than level in normal range. Population set used for analysis: Full analysis set observed cases (FAS (OC)): Includes all patients randomised in the Treated Set who had a baseline and at least one on-treatment HbA1c value. These analyses used available data as observed while patients were on treatment. All values collected after a patient started rescue medication were excluded from the analysis.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Placebo (Up to 24 weeks) Linagliptin 5 milligram (Up to 24 weeks)
    Number of subjects analysed
    113 [1]
    134 [2]
    Units: Percentage (%) of HbA1c
        least squares mean (standard error)
    -0.38 ± 0.07
    -1.01 ± 0.06
    Notes
    [1] - Full analysis set observed cases (FAS (OC))
    [2] - Full analysis set observed cases (FAS (OC))
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Mixed model repeated measures (MMRM) included treatment, week and interaction as fixed effects, baseline HbA1c, daily basal insulin dose as covariates
    Comparison groups
    Linagliptin 5 milligram (Up to 24 weeks) v Placebo (Up to 24 weeks)
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.81
         upper limit
    		 -0.46
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.09
    Notes
    [3] - MMRM including fixed effects treatment, week and treatment by week interaction linear covariates baseline HbA1c, baseline daily basal insulin and baseline HbA1c by week interaction and random effect for patient. Within−patient errors are modelled by unstructured covariance matrix. Adjusted mean is based on all patients in the model (not only patients with a baseline and week 24 measurement).

    Secondary: Percentage of patients experiencing at least one hypoglycaemia accompanied by a prespecified glucose value.

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    End point title
    		 Percentage of patients experiencing at least one hypoglycaemia accompanied by a prespecified glucose value.
    End point description
    Hypoglycaemia accompanied by a prespecified glucose value is defined as any investigator reported hypoglycaemia (event or AE) with a reported blood glucose level of less than 54 milligram/deciLitre (3.0 millimole/Litre) or any investigator reported symptomatic hypoglycaemic AE with a reported blood glucose level of less or equal 70 milligram/deciLitre (3.9millimole/Litre) or any severe hypoglycaemic AE. Severe hypoglycaemia is an event that requires the assistance of another person to actively administer carbohydrates or glucagon because the patient is unable to take the substance on his or her own. The confidence intervals mentioned in measure of dispersion are exact 95% confidence interval by Clopper and Pearson. The proportion of patients with at least one hypoglycaemia accompanied by a glucose value less than 54mg/dL alone has also represented separately according to American Diabetes Association definition of clinically significant hypoglycaemia.
    End point type
    Secondary
    End point timeframe
    24 Weeks
    End point values
    		 Placebo (Up to 24 weeks) Linagliptin 5 milligram (Up to 24 weeks)
    Number of subjects analysed
    147 [4]
    149 [5]
    Units: Percentage of patients (%)
    number (confidence interval 95%)
        Prespecified glucose value
    23.8 (17.2 to 31.5)
    30.9 (23.6 to 39.0)
        Glucose value <54 mg/dL
    15.0 (9.6 to 21.8)
    16.8 (11.2 to 23.8)
    Notes
    [4] - Full analysis set observed cases (FAS (OC))
    [5] - Full analysis set observed cases (FAS (OC))
    Statistical analysis title
    		 Statistical Analysis 2-Prespecified glucose value
    Statistical analysis description
    A logistic regression model with treatment as fixed effect and baseline HbA1c and baseline daily basal insulin dose as linear covariates was applied. The logistic regression analysis showed that patients treated with linagliptin and placebo were equally likely to observe occurrence of hypoglycaemia.The dispersion value standard error of the mean is actually standard error for odds ratio.
    Comparison groups
    Placebo (Up to 24 weeks) v Linagliptin 5 milligram (Up to 24 weeks)
    Number of subjects included in analysis
    296
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1594
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.464
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.861
         upper limit
    		 2.491
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.397
    Statistical analysis title
    		 Statistical Analysis 3- Glucose value < 54mg/dL
    Statistical analysis description
    A logistic regression model with treatment as fixed effect and baseline HbA1c and baseline daily basal insulin dose as linear covariates was applied. The logistic regression analysis showed that patients treated with linagliptin and placebo were equally likely to observe occurrence of hypoglycaemia.The dispersion value standard error of the mean is actually standard error for odds ratio.
    Comparison groups
    Placebo (Up to 24 weeks) v Linagliptin 5 milligram (Up to 24 weeks)
    Number of subjects included in analysis
    296
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.672
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.149
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.604
         upper limit
    		 2.188
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.377
    Notes
    [6] - The proportion of patients with at least one hypoglycaemia accompanied by a glucose value less than 54mg/dL alone has also represented separately according to American Diabetes Association definition of clinically significant hypoglycaemia.

    Secondary: Proportions of patients with HbA1c<8.0%

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    End point title
    		 Proportions of patients with HbA1c<8.0%
    End point description
    This is the proportion of patients with HbA1c on treatment <8.0% after 24 weeks of treatment. The confidence intervals mentioned in method of dispersion are exact 95% CI by Clopper and Pearson. Population set used for analysis: Full analysis set (Non-completers considered failure)(FAS (NCF)): Includes all patients randomised in the Treated Set who had a baseline and at least one on-treatment HbA1c value. This analyses regarded missing values for binary efficacy endpoints as failure.
    End point type
    Secondary
    End point timeframe
    24 Weeks
    End point values
    		 Placebo (Up to 24 weeks) Linagliptin 5 milligram (Up to 24 weeks)
    Number of subjects analysed
    87 [7]
    87 [8]
    Units: Percentage of patients (%)
        number (confidence interval 95%)
    40.2 (29.9 to 51.3)
    70.1 (59.4 to 79.5)
    Notes
    [7] - Full analysis set (Non-completers considered failure)(FAS (NCF))
    [8] - Full analysis set (Non-completers considered failure)(FAS (NCF))
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    A logistic regression model with treatment as fixed effect and baseline HbA1c and baseline daily basal insulin dose as linear covariates was applied. This analysis showed that patients teated with linagliptin were more likely to achieve these responses than in the placebo group.The dispersion value standard error of the mean is actually standard error for odds ratio.
    Comparison groups
    Placebo (Up to 24 weeks) v Linagliptin 5 milligram (Up to 24 weeks)
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.018
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.468
         upper limit
    		 10.206
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.818

    Secondary: Proportion of patients with HbA1c on treatment <7.0%

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    End point title
    		 Proportion of patients with HbA1c on treatment <7.0%
    End point description
    This is the proportion of patients with HbA1c on treatment <7.0% after 24 weeks of treatment. The confidence intervals mentioned in method of dispersion are exact 95% CI by Clopper and Pearson. Population set used for analysis: Full analysis set (Non-completers considered failure)(FAS (NCF)): Includes all patients randomised in the Treated Set who had a baseline and at least one on-treatment HbA1c value. This analyses regarded missing values for binary efficacy endpoints as failure.
    End point type
    Secondary
    End point timeframe
    24 Weeks
    End point values
    		 Placebo (Up to 24 weeks) Linagliptin 5 milligram (Up to 24 weeks)
    Number of subjects analysed
    144 [9]
    143 [10]
    Units: Percentage of patients (%)
        number (confidence interval 95%)
    14.6 (9.3 to 21.4)
    37.8 (29.8 to 46.2)
    Notes
    [9] - Full analysis set (Non-completers considered failure)(FAS (NCF))
    [10] - Full analysis set (Non-completers considered failure)(FAS (NCF))
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    A logistic regression model with treatment as fixed effect and baseline HbA1c and baseline daily basal insulin dose as linear covariates was applied. This analysis showed that patients teated with linagliptin were more likely to achieve these responses than in the placebo group.The dispersion value standard error of the mean is actually standard error for odds ratio.
    Comparison groups
    Placebo (Up to 24 weeks) v Linagliptin 5 milligram (Up to 24 weeks)
    Number of subjects included in analysis
    287
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    4.689
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.485
         upper limit
    		 8.848
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.519

    Secondary: Proportion of patients with HbA1c lowering by at least 0.5%.

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    End point title
    		 Proportion of patients with HbA1c lowering by at least 0.5%.
    End point description
    The proportions of patients who attained lowering of HbA1c by ≥0.5% from baseline after 24 weeks of treatment were analysed. The confidence intervals mentioned in method of dispersion are exact 95% CI by Clopper and Pearson. Population set used for analysis: Full analysis set (Non-completers considered failure)(FAS (NCF)): Includes all patients randomised in the Treated Set who had a baseline and at least one on-treatment HbA1c value. This analyses regarded missing values for binary efficacy endpoints as failure.
    End point type
    Secondary
    End point timeframe
    24 Weeks
    End point values
    		 Placebo (Up to 24 weeks) Linagliptin 5 milligram (Up to 24 weeks)
    Number of subjects analysed
    55 [11]
    103 [12]
    Units: Percentage of patients (%)
        number (confidence interval 95%)
    37.4 (29.6 to 45.8)
    69.1 (61.0 to 76.4)
    Notes
    [11] - Full analysis set (Non-completers considered failure)(FAS (NCF))
    [12] - Full analysis set (Non-completers considered failure)(FAS (NCF))
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    A logistic regression model with treatment as fixed effect and baseline HbA1c and baseline daily basal insulin dose as linear covariates was applied. This analysis showed that patients teated with linagliptin were more likely to achieve these responses than in the placebo group.The dispersion value standard error of the mean is actually standard error for odds ratio.
    Comparison groups
    Placebo (Up to 24 weeks) v Linagliptin 5 milligram (Up to 24 weeks)
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.731
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.302
         upper limit
    		 6.048
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.92

    Secondary: Change from baseline in Fasting Plasma Glucose (FPG)

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    End point title
    		 Change from baseline in Fasting Plasma Glucose (FPG)
    End point description
    This outcome has measured difference between FPG values from baseline to 24 weeks post treatment. The term ‘baseline’ refers to the last observation prior to the administration of any randomised study medication. Population set used for analysis: Full analysis set observed cases (FAS (OC)): Includes all patients randomised in the Treated Set who had a baseline and at least one on-treatment HbA1c value. These analyses used available data as observed while patients were on treatment. All values collected after a patient started rescue medication were excluded from the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Placebo (Up to 24 weeks) Linagliptin 5 milligram (Up to 24 weeks)
    Number of subjects analysed
    110 [13]
    134 [14]
    Units: milligram/decilitre
        least squares mean (standard error)
    0.2 ± 3.6
    -11.3 ± 3.3
    Notes
    [13] - Full analysis set observed cases (FAS (OC))
    [14] - Full analysis set observed cases (FAS (OC))
    Statistical analysis title
    		 Statistical Analysis 7
    Statistical analysis description
    Adjusted mean of all differences between HbA1c at baseline and after 24 weeks. It is based on all patients in the model (not only patients with a baseline and week 24 measurement).
    Comparison groups
    Placebo (Up to 24 weeks) v Linagliptin 5 milligram (Up to 24 weeks)
    Number of subjects included in analysis
    244
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.0178
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -11.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21
         upper limit
    		 -2
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.8
    Notes
    [15] - MMRM including fixed effects treatment, week and treatment by week interaction, linear covariates baseline HbA1c, baseline daily basal insulin, baseline FPG and baseline FPG by week interaction and random effect for patient. Within−patient errors are modelled by unstructured covariance matrix. Adjusted mean is based on all patients in the model (not only patients with a baseline and week 24 measurement).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first drug administration up to 24 weeks, until 7 days after last drug administration for overall population. And from first drug administration up to 52 weeks, until 7 days after last drug administration for Japanese population.
    Adverse event reporting additional description
    An AE was defined as any untoward medical occurrence, including an exacerbation of a preexisting condition, in a patient in a clinical investigation who received a pharmaceutical product. A treated set (TS) was used for AE analysis. TS includes patients who were dispensed study medication and taken at least one dose of investigational treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Placebo (Up to 24 weeks)
    Reporting group description
    		 Patients were orally administered with Placebo tablets (matching Linagliptin) once daily up to 24 weeks

    Reporting group title
    Linagliptin 5 mg (Up to 24 weeks)
    Reporting group description
    		 Patients were orally administered with Linagliptin 5 mg film-coated tablets once daily up to 24 weeks.

    Reporting group title
    Placebo (Up to 52 weeks)
    Reporting group description
    		 Japanese patients were orally administered with Placebo tablets (matching Linagliptin) once daily up to 52 weeks

    Reporting group title
    Linagliptin 5mg (Up to 52 weeks)
    Reporting group description
    		 Japanese patients were orally administered with Linagliptin 5 mg film-coated tablets once daily up to 52 weeks.

    Serious adverse events
    		 Placebo (Up to 24 weeks) Linagliptin 5 mg (Up to 24 weeks) Placebo (Up to 52 weeks) Linagliptin 5mg (Up to 52 weeks)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 151 (13.91%)
    19 / 151 (12.58%)
    7 / 50 (14.00%)
    13 / 52 (25.00%)
         number of deaths (all causes)
    0
    2
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 151 (0.66%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colorectal cancer
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 151 (0.66%)
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enchondromatosis
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 151 (0.00%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 151 (0.00%)
    0 / 151 (0.00%)
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 151 (0.00%)
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 151 (0.66%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 151 (0.00%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intermittent claudication
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 151 (0.00%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 151 (0.00%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 151 (0.66%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 151 (0.66%)
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 151 (0.00%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 151 (1.32%)
    0 / 151 (0.00%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 151 (0.00%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Lipase increased
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 151 (0.00%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 151 (0.66%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 151 (0.00%)
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 151 (0.00%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 151 (0.00%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 151 (0.00%)
    0 / 151 (0.00%)
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 151 (0.00%)
    0 / 151 (0.00%)
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 151 (0.00%)
    0 / 151 (0.00%)
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 151 (0.66%)
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 151 (0.66%)
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 151 (0.00%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 151 (0.00%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 151 (0.66%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 151 (0.00%)
    2 / 151 (1.32%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 151 (0.66%)
    2 / 151 (1.32%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    2 / 151 (1.32%)
    0 / 151 (0.00%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 151 (0.66%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Nervous system disorders
    Brain stem infarction
         subjects affected / exposed
    1 / 151 (0.66%)
    1 / 151 (0.66%)
    1 / 50 (2.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral arteriosclerosis
         subjects affected / exposed
    0 / 151 (0.00%)
    0 / 151 (0.00%)
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 151 (0.00%)
    0 / 151 (0.00%)
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 151 (0.00%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    0 / 151 (0.00%)
    0 / 151 (0.00%)
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 151 (0.66%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 151 (0.00%)
    0 / 151 (0.00%)
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 151 (0.66%)
    0 / 50 (0.00%)
    2 / 52 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic retinopathy
         subjects affected / exposed
    0 / 151 (0.00%)
    2 / 151 (1.32%)
    0 / 50 (0.00%)
    2 / 52 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 151 (0.66%)
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 151 (0.00%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 151 (0.00%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 151 (0.00%)
    0 / 151 (0.00%)
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 151 (0.66%)
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 151 (0.00%)
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 151 (0.00%)
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 151 (0.00%)
    2 / 151 (1.32%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 151 (0.66%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 151 (0.66%)
    0 / 50 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 151 (0.66%)
    2 / 151 (1.32%)
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 151 (0.66%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 151 (0.00%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 151 (0.00%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 151 (0.66%)
    0 / 151 (0.00%)
    1 / 50 (2.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 151 (0.66%)
    0 / 50 (0.00%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 151 (0.00%)
    1 / 151 (0.66%)
    1 / 50 (2.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo (Up to 24 weeks) Linagliptin 5 mg (Up to 24 weeks) Placebo (Up to 52 weeks) Linagliptin 5mg (Up to 52 weeks)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    58 / 151 (38.41%)
    72 / 151 (47.68%)
    19 / 50 (38.00%)
    37 / 52 (71.15%)
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 151 (0.66%)
    2 / 151 (1.32%)
    0 / 50 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    1
    2
    0
    3
    Large intestine polyp
         subjects affected / exposed
    0 / 151 (0.00%)
    2 / 151 (1.32%)
    0 / 50 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    0
    2
    0
    3
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 151 (0.66%)
    3 / 151 (1.99%)
    0 / 50 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    1
    3
    0
    3
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    6 / 151 (3.97%)
    5 / 151 (3.31%)
    3 / 50 (6.00%)
    2 / 52 (3.85%)
         occurrences all number
    6
    5
    3
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    4 / 151 (2.65%)
    7 / 151 (4.64%)
    0 / 50 (0.00%)
    5 / 52 (9.62%)
         occurrences all number
    4
    9
    0
    6
    Urinary tract infection
         subjects affected / exposed
    9 / 151 (5.96%)
    10 / 151 (6.62%)
    1 / 50 (2.00%)
    1 / 52 (1.92%)
         occurrences all number
    11
    11
    1
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    8 / 151 (5.30%)
    11 / 151 (7.28%)
    3 / 50 (6.00%)
    11 / 52 (21.15%)
         occurrences all number
    9
    12
    4
    16
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    38 / 151 (25.17%)
    51 / 151 (33.77%)
    14 / 50 (28.00%)
    20 / 52 (38.46%)
         occurrences all number
    162
    142
    107
    58

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Oct 2015
    The amendment was implemented after approval by the IEC/IRB/competent authority. The main changes introduced by the amendment were: *There was a change in Coordinating Investigator *The inclusion criteria were modified to allow patients from 60 years old (lower age limit) and with a lower HbA1c limit of 7.0% to be eligible for the trial *There was a change in the secondary endpoint regarding the proportion of patients with HbA1c <7.5% at the end of the trial – this was changed to HbA1c <7.0% *The key secondary endpoint was designated as a secondary endpoint *The sample size was reduced to 300 patients, with 100 randomised patients required in Japan *Exclusion criteria no. 1 was clarified for dementia scores excluding patients from undergoing further additional assessment, thereby excluding these patients from participation clarify the Saint Louis University Mental Status Examination scores for mild neurocognitive disorder *Exclusion criteria no. 4 was modified to add STEMI and/or unstable angina pectoris *Exclusion criteria no.10 was modified to add meglitinides and bromocriptine *The permitted antidiabetic therapy that was to be considered rescue therapy was clarified *The definition of hypoglycaemia as ≤70 mg/dL was clarified *The process for AESIs was updated and clarified *It was clarified that the results of pharmacogenetic sampling would be reported separately from the main clinical trial 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.
    For patients in Japan, a local protocol amendment was introduced, and according to it the study was extended to 52 weeks for Japanese population only.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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