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    Clinical Trial Results:
    The efficacy and safety of liraglutide as adjunct therapy to insulin in the treatment of type 1 diabetes. A 52-week randomised, treat-to-target, placebo-controlled, double-blinded, parallelgroup, multinational, multi-centre trial

    Summary
    EudraCT number
    		 2012-003580-21
    Trial protocol
    		 SE   FI   IE   NL   GB   NO   PL   BE  
    Global end of trial date
    04 Jun 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Jun 2016
    First version publication date
    08 Jun 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN9211-3919
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01836523
    WHO universal trial number (UTN)
    		 U1111-1133-0590
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaerd, Denmark, 2880
    Public contact
    Global Clinical Registry (GCR, 1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Global Clinical Registry (GCR, 1452), Novo Nordisk A/S, clinicaltrials@novonordisk.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
    10 Dec 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Jun 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To confirm the efficacy of liraglutide as adjunct to insulin treatment on glycaemic control, and to confirm the superiority of liraglutide treatment compared to placebo, both adjunct to insulin treatment, with regard to reduction in total daily insulin dose and body weight loss, after 52 weeks of treatment in subjects with established type 1 diabetes with inadequate glycaemic control.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (World Medical Association. Declaration of Helsinki. Ethical Principles for Medical Research Involving Human Subjects. 64th WMA General Assembly, Fortaleza. 1 Oct 2013. 2013) and ICH Good Clinical Practice (International Conference on Harmonisation. ICH Harmonised Tripartite Guideline. Good Clinical Practice. 01-May-1996) and 21 CFR 312.120 (Food and Drug Administration. FDA Code Federal Regulations. 21 CFR 312.120. Foreign clinical studies not conducted under an IND. 4 Jan 2008).
    Background therapy
    		 Subjects’ pre-trial insulin treatment was considered background medication.
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    25 Nov 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
    Australia: 51
    Country: Number of subjects enrolled
    Argentina: 73
    Country: Number of subjects enrolled
    Belgium: 33
    Country: Number of subjects enrolled
    Canada: 99
    Country: Number of subjects enrolled
    Finland: 49
    Country: Number of subjects enrolled
    France: 102
    Country: Number of subjects enrolled
    Germany: 88
    Country: Number of subjects enrolled
    Ireland: 31
    Country: Number of subjects enrolled
    Israel: 52
    Country: Number of subjects enrolled
    Netherlands: 37
    Country: Number of subjects enrolled
    Norway: 30
    Country: Number of subjects enrolled
    Poland: 60
    Country: Number of subjects enrolled
    Sweden: 42
    Country: Number of subjects enrolled
    Ukraine: 41
    Country: Number of subjects enrolled
    United Kingdom: 85
    Country: Number of subjects enrolled
    United States: 473
    Country: Number of subjects enrolled
    Russian Federation: 52
    Worldwide total number of subjects
    1398
    EEA total number of subjects
    557
    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)
    1321
    From 65 to 84 years
    77
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at 177 sites in 17 countries: Argentina: 6, Australia: 5, Belgium: 4, Canada: 14, Germany: 8, Finland: 6, France: 13, United Kingdom: 10, Ireland: 5, Israel: 6, Netherlands: 6, Norway: 5, Poland: 5, Russia: 5, Sweden: 4, Ukraine: 5, United States: 70.

    Pre-assignment
    Screening details
    		 Eligible subjects were randomised in a 3:3:3:1:1:1 manner to receive liraglutide (0.6 mg, 1.2 mg or 1.8 mg) or placebo (0.1 mL, 0.2 mL or 0.3 mL), both adjunct to insulin treatment.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Treatment allocation was blinded to all subjects, investigators and Novo Nordisk. The evaluations performed by the independent EAC and CMC committees were also based on blinded data.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Liraglutide 0.6 mg
    Arm description
    		 Subjects received liraglutide 0.6 mg once daily (OD) subcutaneously for 52 weeks in addition to their pre-trial insulin treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Liraglutide
    Investigational medicinal product code
    Other name
    Victoza®
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Liraglutide 0.6 mg, to be administered any time of the day and irrespective of meals. It was recommended that the time of injection was consistent throughout the trial.

    Arm title
    		 Liraglutide 1.2 mg
    Arm description
    		 Subjects received liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Liraglutide
    Investigational medicinal product code
    Other name
    Victoza®
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Liraglutide 1.2 mg, to be administered any time of the day and irrespective of meals. It was recommended that the time of injection was consistent throughout the trial.

    Arm title
    		 Liraglutide 1.8 mg
    Arm description
    		 Liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously for 2 weeks (weeks 2-4) followed by 1.8 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Liraglutide
    Investigational medicinal product code
    Other name
    Victoza®
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Liraglutide 1.8 mg, to be administered any time of the day and irrespective of meals. It was recommended that the time of injection was consistent throughout the trial.

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo (matched to liraglutide 0.6, 1.2 and 1.8 mg) OD subcutaneously as an add-on to their pre-trial insulin treatment. Placebo 0.1 mL (placebo matched to liraglutide 0.6 mg): Subjects received 0.1 mL liraglutide placebo for 52 weeks. Placebo 0.2 mL (placebo matched to liraglutide 1.2 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL up to week 52. Placebo 0.3 mL (placebo matched to liraglutide 1.8 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL for next 2 weeks and 0.3 mL up to week 52. All the 3 placebo doses were pooled for data analysis.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo (0.1 mL, 02 mL or 0.3 mL), to be administered any time of the day and irrespective of meals. It was recommended that the time of injection was consistent throughout the trial.

    Number of subjects in period 1
    		Liraglutide 0.6 mg Liraglutide 1.2 mg Liraglutide 1.8 mg Placebo
    Started
    351
    350
    349
    348
    Exposed
    350
    348
    347
    348
    Completed
    300
    265
    258
    274
    Not completed
    51
    85
    91
    74
         Adverse event, non-fatal
    15
    41
    49
    14
         Unclassified
    17
    28
    19
    29
         Protocol deviation
    6
    3
    2
    4
         Met Withdrawal Criteria
    13
    13
    21
    27

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Liraglutide 0.6 mg
    Reporting group description
    		 Subjects received liraglutide 0.6 mg once daily (OD) subcutaneously for 52 weeks in addition to their pre-trial insulin treatment.

    Reporting group title
    Liraglutide 1.2 mg
    Reporting group description
    		 Subjects received liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.

    Reporting group title
    Liraglutide 1.8 mg
    Reporting group description
    		 Liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously for 2 weeks (weeks 2-4) followed by 1.8 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo (matched to liraglutide 0.6, 1.2 and 1.8 mg) OD subcutaneously as an add-on to their pre-trial insulin treatment. Placebo 0.1 mL (placebo matched to liraglutide 0.6 mg): Subjects received 0.1 mL liraglutide placebo for 52 weeks. Placebo 0.2 mL (placebo matched to liraglutide 1.2 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL up to week 52. Placebo 0.3 mL (placebo matched to liraglutide 1.8 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL for next 2 weeks and 0.3 mL up to week 52. All the 3 placebo doses were pooled for data analysis.

    Reporting group values
    		 Liraglutide 0.6 mg Liraglutide 1.2 mg Liraglutide 1.8 mg Placebo Total
    Number of subjects
    		 351 350 349 348 1398
    Age categorical
    Units: Subjects
    Age Continuous
    Number of subjects analysed for this parameter=350 (liraglutide 0.6 mg), 346 (liraglutide 1.2 mg), 346 (liraglutide 1.8 mg) and 347 (placebo).
    Units: years
        arithmetic mean (standard deviation)
    		 43.6 ( 12.78 ) 43.9 ( 13.06 ) 43.7 ( 13.33 ) 43.4 ( 12.57 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 186 179 181 180 726
        Male
    		 164 167 165 167 663
        Data not used for this summary
    		 1 4 3 1 9
    Glycosylated haemoglobin (HbA1c)
    Number of subjects analysed for this parameter=350 (liraglutide 0.6 mg), 346 (liraglutide 1.2 mg), 346 (liraglutide 1.8 mg) and 347 (placebo).
    Units: percentage of glycosylated haemoglobin
        arithmetic mean (standard deviation)
    		 8.18 ( 0.738 ) 8.16 ( 0.779 ) 8.14 ( 0.74 ) 8.15 ( 0.728 ) -
    Body weight
    Number of subjects analysed for this parameter=350 (liraglutide 0.6 mg), 346 (liraglutide 1.2 mg), 346 (liraglutide 1.8 mg) and 347 (placebo).
    Units: kg
        arithmetic mean (standard deviation)
    		 86.54 ( 17.338 ) 85.39 ( 17.21 ) 86.27 ( 17.321 ) 86.41 ( 17.768 ) -
    Total daily actual insulin dose - continuous subcutaneous insulin infusion
    Total insulin daily dose of subjects who were on continuous subcutaneous insulin infusion treatment. Number of subjects analysed=69 (liraglutide 0.6 mg), 99 (liraglutide 1.2 mg), 113 (liraglutide 1.8 mg), 95 (Placebo).
    Units: units
        geometric mean (full range (min-max))
    		 52.97 (13.8 to 137.1) 50.73 (19.7 to 160.5) 50.46 (8.7 to 150.2) 49.18 (3.9 to 176.1) -
    Total daily actual insulin dose - multiple daily injections
    Total insulin daily dose of subjects who were on multiple daily insulin injection treatment. Number of subjects analysed=277 (liraglutide 0.6 mg), 242 (liraglutide 1.2 mg), 227 (liraglutide 1.8 mg), 250 (Placebo).
    Units: units
        geometric mean (full range (min-max))
    		 59.54 (22.9 to 181.6) 59.61 (16 to 282.5) 62.52 (16.4 to 271.3) 62.42 (20.3 to 230) -

    End points

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    End points reporting groups
    Reporting group title
    Liraglutide 0.6 mg
    Reporting group description
    		 Subjects received liraglutide 0.6 mg once daily (OD) subcutaneously for 52 weeks in addition to their pre-trial insulin treatment.

    Reporting group title
    Liraglutide 1.2 mg
    Reporting group description
    		 Subjects received liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.

    Reporting group title
    Liraglutide 1.8 mg
    Reporting group description
    		 Liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously for 2 weeks (weeks 2-4) followed by 1.8 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo (matched to liraglutide 0.6, 1.2 and 1.8 mg) OD subcutaneously as an add-on to their pre-trial insulin treatment. Placebo 0.1 mL (placebo matched to liraglutide 0.6 mg): Subjects received 0.1 mL liraglutide placebo for 52 weeks. Placebo 0.2 mL (placebo matched to liraglutide 1.2 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL up to week 52. Placebo 0.3 mL (placebo matched to liraglutide 1.8 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL for next 2 weeks and 0.3 mL up to week 52. All the 3 placebo doses were pooled for data analysis.

    Primary: Change from baseline in HbA1c

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    End point title
    		 Change from baseline in HbA1c
    End point description
    Change from baseline in HbA1C at week 52. Missing values were handled by using a mixed model for repeated measurements (MMRM). Full analysis set (FAS) included all randomised subjects who received at least one dose and had any post-randomisation data. Five subjects, who started the study, were excluded because of no exposure to study drug and 4 subjects were excluded because of non-availability of post-baseline data. Number of subjects analysed=subjects with any post-baseline HbA1c data.
    End point type
    Primary
    End point timeframe
    After 52 weeks of treatment
    End point values
    		 Liraglutide 0.6 mg Liraglutide 1.2 mg Liraglutide 1.8 mg Placebo
    Number of subjects analysed
    334
    312
    305
    324
    Units: percentage of glycosylated haemoglobin
        arithmetic mean (standard deviation)
    -0.45 ( 0.741 )
    -0.5 ( 0.767 )
    -0.54 ( 0.729 )
    -0.34 ( 0.707 )
    Statistical analysis title
    		 Liraglutide 1.8 mg vs Placebo
    Statistical analysis description
    Analysis was performed using MMRMs where all post-baseline measurements for the specific variable from planned visits up to week 52 and obtained no later than 1 day after withdrawal from treatment were entered as the dependent variable, and visit, treatment, country and the stratification variable (4 levels: HbA1c < 8.5% and ≥8.5%, each intersected by BMI≤27 kg/m2 and >27 kg/m2) were included as fixed factors and the corresponding baseline value as covariate.
    Comparison groups
    Liraglutide 1.8 mg v Placebo
    Number of subjects included in analysis
    629
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.32
         upper limit
    		 -0.07
    Notes
    [1] - Non-inferiority was concluded if the upper bound of 95% confidence interval was <0.3.
    Statistical analysis title
    		 Liraglutide 1.2 mg vs Placebo
    Statistical analysis description
    Analysis was performed using MMRMs where all post-baseline measurements for the specific variable from planned visits up to week 52 and obtained no later than 1 day after withdrawal from treatment were entered as the dependent variable, and visit, treatment, country and the stratification variable (4 levels: HbA1c < 8.5% and ≥8.5%, each intersected by BMI≤27 kg/m2 and >27 kg/m2) were included as fixed factors and the corresponding baseline value as covariate.
    Comparison groups
    Liraglutide 1.2 mg v Placebo
    Number of subjects included in analysis
    636
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.27
         upper limit
    		 -0.03
    Notes
    [2] - Non-inferiority was concluded if the upper bound of 95% confidence interval was <0.3.
    Statistical analysis title
    		 Liraglutide 0.6 mg vs Placebo
    Statistical analysis description
    Analysis was performed using MMRMs where all post-baseline measurements for the specific variable from planned visits up to week 52 and obtained no later than 1 day after withdrawal from treatment were entered as the dependent variable, and visit, treatment, country and the stratification variable (4 levels: HbA1c < 8.5% and ≥8.5%, each intersected by BMI≤27 kg/m2 and >27 kg/m2) were included as fixed factors and the corresponding baseline value as covariate.
    Comparison groups
    Liraglutide 0.6 mg v Placebo
    Number of subjects included in analysis
    658
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.21
         upper limit
    		 0.03
    Notes
    [3] - Non-inferiority was concluded if the upper bound of 95% confidence interval was <0.3.

    Primary: Change from baseline in body weight

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    End point title
    		 Change from baseline in body weight
    End point description
    Change from baseline in body weight at week 52. Missing values were handled by using a MMRM. Analysis was performed on full analysis set. Number of subjects analysed=subjects with any post-baseline body weight data.
    End point type
    Primary
    End point timeframe
    After 52 weeks of treatment
    End point values
    		 Liraglutide 0.6 mg Liraglutide 1.2 mg Liraglutide 1.8 mg Placebo
    Number of subjects analysed
    324
    300
    298
    311
    Units: kg
        arithmetic mean (standard deviation)
    -1.34 ( 4.183 )
    -2.73 ( 4.524 )
    -4.02 ( 4.873 )
    0.94 ( 3.828 )
    Statistical analysis title
    		 Liraglutide 1.8 mg vs Placebo
    Statistical analysis description
    Analysis was performed using MMRMs where all post-baseline measurements for the specific variable from planned visits up to week 52 and obtained no later than 1 day after withdrawal from treatment were entered as the dependent variable, and visit, treatment, country and the stratification variable (4 levels: HbA1c < 8.5% and ≥8.5%, each intersected by BMI≤27 kg/m2 and >27 kg/m2) were included as fixed factors and the corresponding baseline value as covariate.
    Comparison groups
    Liraglutide 1.8 mg v Placebo
    Number of subjects included in analysis
    609
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -4.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.65
         upper limit
    		 -4.16
    Statistical analysis title
    		 Liraglutide 1.2 mg vs Placebo
    Statistical analysis description
    Analysis was performed using MMRMs where all post-baseline measurements for the specific variable from planned visits up to week 52 and obtained no later than 7 days after withdrawal from treatment were entered as the dependent variable, and visit, treatment, country and the stratification variable (4 levels: HbA1c < 8.5% and ≥8.5%, each intersected by BMI≤27 kg/m2 and >27 kg/m2) were included as fixed factors and the corresponding baseline value as covariate.
    Comparison groups
    Liraglutide 1.2 mg v Placebo
    Number of subjects included in analysis
    611
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -3.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.29
         upper limit
    		 -2.81
    Statistical analysis title
    		 Liraglutide 0.6 mg vs Placebo
    Statistical analysis description
    Analysis was performed using MMRMs where all post-baseline measurements for the specific variable from planned visits up to week 52 and obtained no later than 7 days after withdrawal from treatment were entered as the dependent variable, and visit, treatment, country and the stratification variable (4 levels: HbA1c < 8.5% and ≥8.5%, each intersected by BMI≤27 kg/m2 and >27 kg/m2) were included as fixed factors and the corresponding baseline value as covariate.
    Comparison groups
    Liraglutide 0.6 mg v Placebo
    Number of subjects included in analysis
    635
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -2.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.91
         upper limit
    		 -1.47

    Primary: Change from baseline in total daily insulin dose

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    End point title
    		 Change from baseline in total daily insulin dose
    End point description
    Change from baseline in total daily insulin dose at week 52. Change from baseline was represented in terms of ratio to baseline for insulin dose i.e. Total daily insulin dose at week 52/total daily insulin dose at baseline. Missing values were handled by using a MMRM. Full analysis set. Number of subjects analysed=subjects with any post-baseline total insulin daily dose data.
    End point type
    Primary
    End point timeframe
    After 52 weeks of treatment
    End point values
    		 Liraglutide 0.6 mg Liraglutide 1.2 mg Liraglutide 1.8 mg Placebo
    Number of subjects analysed
    337
    328
    331
    341
    Units: ratio
        geometric mean (geometric coefficient of variation)
    1.04 ( 23.75 )
    0.98 ( 26.66 )
    0.95 ( 24.21 )
    1.04 ( 26.69 )
    Statistical analysis title
    		 Liraglutide 1.8 mg vs Placebo
    Statistical analysis description
    Analysis was done using MMRMs where all post-baseline measurements for specific variable from planned visits up to week 52 and obtained no later than 1 day after withdrawal from treatment were entered as dependent variable, and visit, treatment, country and stratification variable (4 levels: HbA1c < 8.5% and ≥8.5%, each intersected by BMI≤27 kg/m2 and >27 kg/m2) were included as fixed factors and the corresponding baseline value as covariate. The measurements were log-transformed before analysis
    Comparison groups
    Liraglutide 1.8 mg v Placebo
    Number of subjects included in analysis
    672
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment ratio
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 0.96
    Statistical analysis title
    		 Liraglutide 0.6 mg vs Placebo
    Statistical analysis description
    Analysis was done using MMRMs where all post-baseline measurements for specific variable from planned visits up to week 52 and obtained no later than 1 day after withdrawal from treatment were entered as dependent variable, and visit, treatment, country and stratification variable (4 levels: HbA1c < 8.5% and ≥8.5%, each intersected by BMI≤27 kg/m2 and >27 kg/m2) were included as fixed factors and the corresponding baseline value as covariate. The measurements were log-transformed before analysis
    Comparison groups
    Liraglutide 0.6 mg v Placebo
    Number of subjects included in analysis
    678
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9615
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment ratio
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 1.04
    Statistical analysis title
    		 Liraglutide 1.2 mg vs Placebo
    Statistical analysis description
    Analysis was done using MMRMs where all post-baseline measurements for specific variable from planned visits up to week 52 and obtained no later than 1 day after withdrawal from treatment were entered as dependent variable, and visit, treatment, country and stratification variable (4 levels: HbA1c < 8.5% and ≥8.5%, each intersected by BMI≤27 kg/m2 and >27 kg/m2) were included as fixed factors and the corresponding baseline value as covariate. The measurements were log-transformed before analysis
    Comparison groups
    Liraglutide 1.2 mg v Placebo
    Number of subjects included in analysis
    669
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0148
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment ratio
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 0.99

    Secondary: Number of treatment-emergent symptomatic hypoglycaemic episodes

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    End point title
    		 Number of treatment-emergent symptomatic hypoglycaemic episodes
    End point description
    This is a confirmatory secondary endpoint. Symptomatic hypoglycaemic episodes were defined as episodes that were: 1) Severe according to the American Diabetes Association (ADA) classification OR 2) Self-monitoring of plasma glucose value of < 3.1 mmol/L, with symptoms consistent with hypoglycaemia. ADA classification of severe hypoglycemia: An episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions. A treatment emergent episode is defined as an episode with onset date (or increase in severity) on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment. The safety analysis set included all randomised subjects exposed to at least one dose of liraglutide or placebo.
    End point type
    Secondary
    End point timeframe
    During 52 weeks of treatment
    End point values
    		 Liraglutide 0.6 mg Liraglutide 1.2 mg Liraglutide 1.8 mg Placebo
    Number of subjects analysed
    350
    348
    347
    348
    Units: episodes
    4954
    4602
    4614
    3654
    Statistical analysis title
    		 Liraglutide 1.8 mg vs Placebo
    Statistical analysis description
    The endpoint was analysed using a negative binomial regression model with a log-link function and the log of the time period in which an occurrence of a hypoglycaemic episode was considered treatment emergent as offset. The model included fixed factors (treatment, country, stratification group) and a covariate (baseline HbA1c). The actual number of subjects in this analysis was 693 instead of 695.
    Comparison groups
    Liraglutide 1.8 mg v Placebo
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0081
    Method
    		 Negative binomial regression
    Parameter type
    		 Rate ratio
    Point estimate
    1.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.07
         upper limit
    		 1.59
    Statistical analysis title
    		 Liraglutide 1.2 mg vs Placebo
    Statistical analysis description
    The endpoint was analysed using a negative binomial regression model with a log-link function and the log of the time period in which an occurrence of a hypoglycaemic episode was considered treatment emergent as offset. The model included fixed factors (treatment, country, stratification group) and a covariate (baseline HbA1c). The actual number of subjects in this analysis was 693 instead of 696.
    Comparison groups
    Liraglutide 1.2 mg v Placebo
    Number of subjects included in analysis
    696
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0219
    Method
    		 Negative binomial regression
    Parameter type
    		 Rate ratio
    Point estimate
    1.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.03
         upper limit
    		 1.55
    Statistical analysis title
    		 Liraglutide 0.6 mg vs Placebo
    Statistical analysis description
    The endpoint was analysed using a negative binomial regression model with a log-link function and the log of the time period in which an occurrence of a hypoglycaemic episode was considered treatment emergent as offset. The model included fixed factors (treatment, country, stratification group) and a covariate (baseline HbA1c). The actual number of subjects in this analysis was 697 instead of 698.
    Comparison groups
    Liraglutide 0.6 mg v Placebo
    Number of subjects included in analysis
    698
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1079
    Method
    		 Negative binomial regression
    Parameter type
    		 Rate ratio
    Point estimate
    1.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.97
         upper limit
    		 1.43

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 52 weeks
    Adverse event reporting additional description
    A treatment emergent adverse event is defined as an event with onset date (or increase in severity) on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    Liraglutide 0.6 mg
    Reporting group description
    		 Subjects received liraglutide 0.6 mg once daily (OD) subcutaneously for 52 weeks in addition to their pre-trial insulin treatment.

    Reporting group title
    Liraglutide 1.2 mg
    Reporting group description
    		 Subjects received liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.

    Reporting group title
    Liraglutide 1.8 mg
    Reporting group description
    		 Liraglutide 0.6 mg OD subcutaneously for 2 weeks followed by 1.2 mg OD subcutaneously for 2 weeks (weeks 2-4) followed by 1.8 mg OD subcutaneously up to week 52 in addition to their pre-trial insulin treatment.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo (matched to liraglutide 0.6, 1.2 and 1.8 mg) OD subcutaneously an add-on to their pre-trial insulin treatment. All the 3 placebo doses pooled together for data analysis. Placebo 0.1 mL (placebo matched to liraglutide 0.6 mg): Subjects received 0.1 mL liraglutide placebo for 52 weeks. Placebo 0.2 mL (placebo matched to liraglutide 1.2 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL up to week 52. Placebo 0.3 mL (placebo matched to liraglutide 1.8 mg): Subjects received 0.1 mL for 2 weeks followed by 0.2 mL for next 2 weeks and 0.3 mL up to week 52.

    Serious adverse events
    		 Liraglutide 0.6 mg Liraglutide 1.2 mg Liraglutide 1.8 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    35 / 350 (10.00%)
    36 / 348 (10.34%)
    29 / 347 (8.36%)
    38 / 348 (10.92%)
         number of deaths (all causes)
    1
    1
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Haemangioma
         subjects affected / exposed
    1 / 350 (0.29%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    0 / 348 (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
    Haemangioma of bone
         subjects affected / exposed
    0 / 350 (0.00%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    0 / 348 (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
    Invasive lobular breast carcinoma
         subjects affected / exposed
    1 / 350 (0.29%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    0 / 348 (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
    Malignant melanoma
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    1 / 347 (0.29%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    1 / 350 (0.29%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    0 / 348 (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
    Peripheral vascular disorder
         subjects affected / exposed
    1 / 350 (0.29%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Popliteal artery entrapment syndrome
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         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
    Surgical and medical procedures
    Obesity surgery
         subjects affected / exposed
    1 / 350 (0.29%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    0 / 348 (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
    Toe amputation
         subjects affected / exposed
    1 / 350 (0.29%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    0 / 348 (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
    0 / 350 (0.00%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    0 / 348 (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
    Cyst
         subjects affected / exposed
    0 / 350 (0.00%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    0 / 348 (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
    Malaise
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         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
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 350 (0.00%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    0 / 348 (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
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    1 / 347 (0.29%)
    0 / 348 (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
    Dyspnoea
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         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
    Tonsillar inflammation
         subjects affected / exposed
    1 / 350 (0.29%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    0 / 348 (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
    Psychiatric disorders
    Alcoholism
         subjects affected / exposed
    1 / 350 (0.29%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    0 / 348 (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
    Completed suicide
         subjects affected / exposed
    1 / 350 (0.29%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression suicidal
         subjects affected / exposed
    1 / 350 (0.29%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    0 / 348 (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
    Panic attack
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         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
    Suicide attempt
         subjects affected / exposed
    1 / 350 (0.29%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Biopsy prostate
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    1 / 347 (0.29%)
    0 / 348 (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
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 350 (0.29%)
    0 / 348 (0.00%)
    1 / 347 (0.29%)
    0 / 348 (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
    Ankle fracture
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    1 / 347 (0.29%)
    0 / 348 (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
    Craniocerebral injury
         subjects affected / exposed
    0 / 350 (0.00%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    0 / 348 (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
    Fall
         subjects affected / exposed
    0 / 350 (0.00%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    0 / 348 (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
    Foot fracture
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    1 / 347 (0.29%)
    0 / 348 (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
    Ligament rupture
         subjects affected / exposed
    1 / 350 (0.29%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    0 / 348 (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
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         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
    Suture related complication
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         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
    Tibia fracture
         subjects affected / exposed
    1 / 350 (0.29%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    0 / 348 (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
    Congenital, familial and genetic disorders
    Melkersson-Rosenthal syndrome
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         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
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         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 / 1
    Angina pectoris
         subjects affected / exposed
    1 / 350 (0.29%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    0 / 348 (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 / 350 (0.29%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    0 / 348 (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
    Cardiac arrest
         subjects affected / exposed
    0 / 350 (0.00%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         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
    Coronary artery disease
         subjects affected / exposed
    0 / 350 (0.00%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    0 / 348 (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
    Myocardial infarction
         subjects affected / exposed
    0 / 350 (0.00%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    0 / 348 (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
    Myocarditis
         subjects affected / exposed
    0 / 350 (0.00%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    0 / 348 (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
    Nervous system disorders
    Cerebrospinal fluid leakage
         subjects affected / exposed
    0 / 350 (0.00%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    0 / 348 (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
    Hypoglycaemic seizure
         subjects affected / exposed
    1 / 350 (0.29%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemic unconsciousness
         subjects affected / exposed
    5 / 350 (1.43%)
    3 / 348 (0.86%)
    6 / 347 (1.73%)
    6 / 348 (1.72%)
         occurrences causally related to treatment / all
    4 / 5
    1 / 3
    3 / 7
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         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
    Transient ischaemic attack
         subjects affected / exposed
    0 / 350 (0.00%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    0 / 348 (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
         subjects affected / exposed
    0 / 350 (0.00%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    0 / 348 (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
    Vertigo positional
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         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
    Eye disorders
    Glaucoma
         subjects affected / exposed
    1 / 350 (0.29%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    0 / 348 (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
    Macular oedema
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    1 / 347 (0.29%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinopathy
         subjects affected / exposed
    0 / 350 (0.00%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    0 / 348 (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
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    0 / 350 (0.00%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    0 / 348 (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
    Dysphagia
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    1 / 347 (0.29%)
    0 / 348 (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
    Large intestine polyp
         subjects affected / exposed
    0 / 350 (0.00%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    0 / 348 (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
    Nausea
         subjects affected / exposed
    1 / 350 (0.29%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 350 (0.29%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    0 / 348 (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
    Rectal prolapse
         subjects affected / exposed
    1 / 350 (0.29%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    0 / 348 (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
    Vomiting
         subjects affected / exposed
    0 / 350 (0.00%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    0 / 348 (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
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 350 (0.00%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    0 / 348 (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
    Cholecystitis acute
         subjects affected / exposed
    1 / 350 (0.29%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    0 / 348 (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
    Cholelithiasis
         subjects affected / exposed
    0 / 350 (0.00%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    0 / 348 (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
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         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
    Urticaria
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         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
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         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
    Bladder prolapse
         subjects affected / exposed
    1 / 350 (0.29%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    0 / 348 (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
    Nephrolithiasis
         subjects affected / exposed
    0 / 350 (0.00%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    0 / 348 (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
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         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
    Bursitis
         subjects affected / exposed
    1 / 350 (0.29%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    0 / 348 (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
    Dupuytren's contracture
         subjects affected / exposed
    0 / 350 (0.00%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    0 / 348 (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
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 350 (0.00%)
    1 / 348 (0.29%)
    1 / 347 (0.29%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint effusion
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    1 / 347 (0.29%)
    0 / 348 (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
    Musculoskeletal pain
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    1 / 347 (0.29%)
    0 / 348 (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
    Osteoarthritis
         subjects affected / exposed
    1 / 350 (0.29%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    0 / 348 (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
    Spinal column stenosis
         subjects affected / exposed
    0 / 350 (0.00%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    0 / 348 (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
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    1 / 347 (0.29%)
    0 / 348 (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
    Abscess limb
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    1 / 347 (0.29%)
    0 / 348 (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
    Appendicitis
         subjects affected / exposed
    0 / 350 (0.00%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    2 / 348 (0.57%)
         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
    Arthritis bacterial
         subjects affected / exposed
    1 / 350 (0.29%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    0 / 348 (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
    Arthritis infective
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    1 / 347 (0.29%)
    0 / 348 (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
    Cellulitis
         subjects affected / exposed
    0 / 350 (0.00%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    0 / 348 (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 / 350 (0.29%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    0 / 348 (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
    Gastroenteritis
         subjects affected / exposed
    1 / 350 (0.29%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    0 / 348 (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
    Herpes zoster
         subjects affected / exposed
    1 / 350 (0.29%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    0 / 348 (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
    Incision site infection
         subjects affected / exposed
    1 / 350 (0.29%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    0 / 348 (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
    Infectious mononucleosis
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         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
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    1 / 347 (0.29%)
    0 / 348 (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
    Otitis externa
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         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
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    1 / 347 (0.29%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pilonidal cyst
         subjects affected / exposed
    0 / 350 (0.00%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    0 / 348 (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
    Pneumonia
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         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
    Sepsis
         subjects affected / exposed
    0 / 350 (0.00%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    0 / 348 (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
    Subcutaneous abscess
         subjects affected / exposed
    0 / 350 (0.00%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    0 / 348 (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
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 350 (0.00%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    0 / 348 (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
    Urinary tract infection
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    3 / 347 (0.86%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         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
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 350 (0.00%)
    1 / 348 (0.29%)
    0 / 347 (0.00%)
    0 / 348 (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
    Diabetic ketoacidosis
         subjects affected / exposed
    3 / 350 (0.86%)
    1 / 348 (0.29%)
    3 / 347 (0.86%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    3 / 350 (0.86%)
    3 / 348 (0.86%)
    3 / 347 (0.86%)
    2 / 348 (0.57%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 4
    3 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    1 / 347 (0.29%)
    0 / 348 (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
    Hyperosmolar hyperglycaemic state
         subjects affected / exposed
    0 / 350 (0.00%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         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
    Hypoglycaemia
         subjects affected / exposed
    3 / 350 (0.86%)
    7 / 348 (2.01%)
    5 / 347 (1.44%)
    13 / 348 (3.74%)
         occurrences causally related to treatment / all
    3 / 4
    6 / 8
    3 / 5
    9 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 350 (0.29%)
    0 / 348 (0.00%)
    0 / 347 (0.00%)
    0 / 348 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Liraglutide 0.6 mg Liraglutide 1.2 mg Liraglutide 1.8 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    259 / 350 (74.00%)
    263 / 348 (75.57%)
    282 / 347 (81.27%)
    224 / 348 (64.37%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    56 / 350 (16.00%)
    46 / 348 (13.22%)
    49 / 347 (14.12%)
    40 / 348 (11.49%)
         occurrences all number
    78
    85
    119
    77
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    17 / 350 (4.86%)
    22 / 348 (6.32%)
    18 / 347 (5.19%)
    16 / 348 (4.60%)
         occurrences all number
    18
    24
    21
    18
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    20 / 350 (5.71%)
    16 / 348 (4.60%)
    29 / 347 (8.36%)
    8 / 348 (2.30%)
         occurrences all number
    32
    20
    41
    9
    Constipation
         subjects affected / exposed
    17 / 350 (4.86%)
    28 / 348 (8.05%)
    26 / 347 (7.49%)
    9 / 348 (2.59%)
         occurrences all number
    20
    30
    28
    11
    Diarrhoea
         subjects affected / exposed
    41 / 350 (11.71%)
    50 / 348 (14.37%)
    64 / 347 (18.44%)
    38 / 348 (10.92%)
         occurrences all number
    52
    69
    92
    50
    Dyspepsia
         subjects affected / exposed
    26 / 350 (7.43%)
    27 / 348 (7.76%)
    38 / 347 (10.95%)
    8 / 348 (2.30%)
         occurrences all number
    37
    41
    48
    8
    Nausea
         subjects affected / exposed
    112 / 350 (32.00%)
    141 / 348 (40.52%)
    172 / 347 (49.57%)
    42 / 348 (12.07%)
         occurrences all number
    146
    196
    271
    52
    Vomiting
         subjects affected / exposed
    24 / 350 (6.86%)
    44 / 348 (12.64%)
    64 / 347 (18.44%)
    21 / 348 (6.03%)
         occurrences all number
    26
    58
    106
    26
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    14 / 350 (4.00%)
    7 / 348 (2.01%)
    10 / 347 (2.88%)
    21 / 348 (6.03%)
         occurrences all number
    14
    8
    12
    24
    Oropharyngeal pain
         subjects affected / exposed
    15 / 350 (4.29%)
    22 / 348 (6.32%)
    28 / 347 (8.07%)
    13 / 348 (3.74%)
         occurrences all number
    17
    24
    32
    15
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    15 / 350 (4.29%)
    22 / 348 (6.32%)
    18 / 347 (5.19%)
    16 / 348 (4.60%)
         occurrences all number
    17
    24
    19
    16
    Infections and infestations
    Gastroenteritis viral
         subjects affected / exposed
    12 / 350 (3.43%)
    6 / 348 (1.72%)
    18 / 347 (5.19%)
    8 / 348 (2.30%)
         occurrences all number
    14
    6
    24
    10
    Gastroenteritis
         subjects affected / exposed
    21 / 350 (6.00%)
    15 / 348 (4.31%)
    29 / 347 (8.36%)
    15 / 348 (4.31%)
         occurrences all number
    25
    17
    32
    21
    Influenza
         subjects affected / exposed
    29 / 350 (8.29%)
    17 / 348 (4.89%)
    25 / 347 (7.20%)
    24 / 348 (6.90%)
         occurrences all number
    32
    26
    28
    30
    Nasopharyngitis
         subjects affected / exposed
    105 / 350 (30.00%)
    81 / 348 (23.28%)
    83 / 347 (23.92%)
    85 / 348 (24.43%)
         occurrences all number
    175
    124
    145
    130
    Sinusitis
         subjects affected / exposed
    24 / 350 (6.86%)
    17 / 348 (4.89%)
    16 / 347 (4.61%)
    21 / 348 (6.03%)
         occurrences all number
    35
    22
    21
    31
    Upper respiratory tract infection
         subjects affected / exposed
    33 / 350 (9.43%)
    23 / 348 (6.61%)
    43 / 347 (12.39%)
    40 / 348 (11.49%)
         occurrences all number
    37
    37
    59
    58
    Urinary tract infection
         subjects affected / exposed
    18 / 350 (5.14%)
    14 / 348 (4.02%)
    20 / 347 (5.76%)
    11 / 348 (3.16%)
         occurrences all number
    28
    21
    26
    15
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    31 / 350 (8.86%)
    43 / 348 (12.36%)
    64 / 347 (18.44%)
    6 / 348 (1.72%)
         occurrences all number
    32
    45
    70
    6
    Hyperglycaemia
         subjects affected / exposed
    17 / 350 (4.86%)
    17 / 348 (4.89%)
    22 / 347 (6.34%)
    17 / 348 (4.89%)
         occurrences all number
    29
    26
    38
    28
    Hypoglycaemia
         subjects affected / exposed
    26 / 350 (7.43%)
    13 / 348 (3.74%)
    20 / 347 (5.76%)
    24 / 348 (6.90%)
         occurrences all number
    32
    18
    37
    35

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Apr 2013
    1) Correcting a discrepancy between the wording of the key exclusion criteria in the summary section and the exclusion criteria stated in the protocol so the text is in alignment. 2) The model for calculating within-subject variability in self-measured fasting plasma glucose for insulin dose titration was simplified to employ a fewer number of parameters. 3) A discrepancy in the wording of the MESI regarding administration of an accidental overdose in the protocol and Appendix were corrected.
    26 Feb 2014
    1) Further instruction/clarification was added to ensure that the insulin dose was reduced correctly when trial drug was started. 2) Endpoints of hypoglycaemia were slightly revised. The endpoint hypoglycaemia with concurrent presence of both hypoglycaemic symptoms and low glucose value was added. 3) Severe hypoglycaemic events were to undergo independent review to evaluate if the event was a severe hypoglycaemic event. It was decided to follow the same set-up and present the severe hypoglycaemic events to the EAC as described in the current protocol for other MESI requiring event adjudication. 4) Statistical consideration was updated in regards to the definition of the hypoglycaemic events. A figure illustrating the updated ADA definition of hypoglycaemic events was included. 5) An Investigator Portal was used to exchange documents between Novo Nordisk and the sites. Text regarding the Investigator Portal was added to provide clarification for sites. 6) Changes in the protocol were made for clarification and consistency purposes. The rationale for adjudicating the MESIs Fatal. Acute Coronory Syndrome and Cerebrovascular events was updated to clarify that this was performed in all Novo Nordisk trials with Victoza®.

    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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