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    Clinical Trial Results:
    A 24 week randomised, open label, 3 parallel-group comparison of once and twice daily biphasic insulin aspart (BIAsp) 30 plus sitagliptin and twice daily BIAsp 30, all in combination with metformin in insulin naïve type 2 diabetic subjects inadequately controlled on sitagliptin and metformin.

    Summary
    EudraCT number
    		 2011-004930-33
    Trial protocol
    		 GR   PT  
    Global end of trial date
    18 Oct 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Mar 2016
    First version publication date
    26 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BIASP-3963
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01519674
    WHO universal trial number (UTN)
    		 U1111-1125-0850
    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
    28 May 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Oct 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Oct 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy in terms of glycaemic control of biphasic insulin aspart 30 (BIAsp 30) twice daily + sitagliptin + metformin, BIAsp 30 twice daily + metformin and BIAsp 30 once daily + sitagliptin + metformin in subjects with type 2 diabetes inadequately controlled on sitagliptin and metformin (± other oral anti-diabetic drugs (OADs))
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (2008) and ICH Good Clinical Practice (1996).
    Background therapy
    		 Subjects on pre-trial metformin (1000 mg/day) (± additional OAD treatment) continued their medication. Subjects on pre-trial sitagliptin (100 mg/day) either continued or discontinued their sitagliptin treatment depending on the treatment group the subjects were randomised to.
    Evidence for comparator
    		 Not applicable.
    Actual start date of recruitment
    04 Jun 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 105
    Country: Number of subjects enrolled
    Australia: 34
    Country: Number of subjects enrolled
    Brazil: 73
    Country: Number of subjects enrolled
    India: 162
    Country: Number of subjects enrolled
    Malaysia: 26
    Country: Number of subjects enrolled
    Korea, Republic of: 51
    Country: Number of subjects enrolled
    Thailand: 22
    Country: Number of subjects enrolled
    Turkey: 35
    Country: Number of subjects enrolled
    Portugal: 22
    Country: Number of subjects enrolled
    Greece: 52
    Worldwide total number of subjects
    582
    EEA total number of subjects
    74
    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)
    484
    From 65 to 84 years
    98
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at 60 sites in 10 countries as follows: Argentina (6); Australia (2); Brazil (4); Greece (5); India (17); Malaysia (3); Portugal (6); Republic of Korea (7); Thailand (5); Turkey (5)

    Pre-assignment
    Screening details
    		 Subjects on pre-trial metformin (1000 mg/day) (± additional OAD treatment) continued their medication. Subjects on pre-trial sitagliptin (100 mg/day) either continued or discontinued their sitagliptin treatment depending on the treatment group the subjects were randomised to.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BID+Met
    Arm description
    		 Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, subcutaneously (under the skin) for 24 weeks. Subjects continued on their pre-trial metformin (1000 mg/day) treatment.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    NovoMix 30 FlexPen 100 U/mL suspension for injection in a prefilled pen (BIAsp-30).
    Investigational medicinal product code
    Other name
    INSULIN ASPART
    Pharmaceutical forms
    Suspension for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) treatment.

    Arm title
    		 BID+Sita+Met
    Arm description
    		 Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, subcutaneously under the skin) for 24 weeks. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    NovoMix 30 FlexPen 100 U/mL suspension for injection in a prefilled pen (BIAsp 30).
    Investigational medicinal product code
    Other name
    INSULIN ASPART
    Pharmaceutical forms
    Suspension for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.

    Arm title
    		 OD+Sita+Met
    Arm description
    		 Biphasic insulin aspart 30 (BIAsp 30) was injected once daily, subcutaneously (under the skin) for 24 weeks. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    NovoMix 30 FlexPen 100 U/mL suspension for injection in a prefilled pen (BIAsp 30).
    Investigational medicinal product code
    Other name
    INSULIN ASPART
    Pharmaceutical forms
    Suspension for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Biphasic insulin aspart 30 (BIAsp 30) was injected once daily, 12 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.

    Number of subjects in period 1
    		BID+Met BID+Sita+Met OD+Sita+Met
    Started
    194
    195
    193
    Completed
    173
    182
    181
    Not completed
    21
    13
    12
         Adverse event, non-fatal
    3
    3
    -
         Withdrawal criteria
    7
    2
    7
         Unclassified
    10
    4
    3
         Lack of efficacy
    1
    1
    1
         Protocol deviation
    -
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BID+Met
    Reporting group description
    		 Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, subcutaneously (under the skin) for 24 weeks. Subjects continued on their pre-trial metformin (1000 mg/day) treatment.

    Reporting group title
    BID+Sita+Met
    Reporting group description
    		 Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, subcutaneously under the skin) for 24 weeks. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.

    Reporting group title
    OD+Sita+Met
    Reporting group description
    		 Biphasic insulin aspart 30 (BIAsp 30) was injected once daily, subcutaneously (under the skin) for 24 weeks. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.

    Reporting group values
    		 BID+Met BID+Sita+Met OD+Sita+Met Total
    Number of subjects
    		 194 195 193 582
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.8 ± 9.5 56.3 ± 10.2 55.7 ± 10.4 -
    Gender categorical
    Units: Subjects
        Female
    		 83 101 97 281
        Male
    		 111 94 96 301
    Body weight
    Units: Kg
        arithmetic mean (standard deviation)
    		 79.4 ± 15.8 78.3 ± 16.1 77.5 ± 16.8 -
    Body Mass Index
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 29.3 ± 4.3 29.4 ± 4.5 29.4 ± 5 -
    Glycosylated haemoglobin (HbA1c)
    Units: Percentage (%)
        arithmetic mean (standard deviation)
    		 8.4 ± 0.8 8.4 ± 0.8 8.4 ± 0.8 -
    Fasting plasma glucose (FPG)
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 8.9 ± 2.2 9.3 ± 2.8 8.7 ± 2.7 -

    End points

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    End points reporting groups
    Reporting group title
    BID+Met
    Reporting group description
    		 Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, subcutaneously (under the skin) for 24 weeks. Subjects continued on their pre-trial metformin (1000 mg/day) treatment.

    Reporting group title
    BID+Sita+Met
    Reporting group description
    		 Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, subcutaneously under the skin) for 24 weeks. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.

    Reporting group title
    OD+Sita+Met
    Reporting group description
    		 Biphasic insulin aspart 30 (BIAsp 30) was injected once daily, subcutaneously (under the skin) for 24 weeks. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.

    Primary: Change From Baseline in HbA1c (Glycosylated Haemoglobin)

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    End point title
    		 Change From Baseline in HbA1c (Glycosylated Haemoglobin)
    End point description
    Mean change from baseline in HbA1c after 24 weeks of treatment.
    End point type
    Primary
    End point timeframe
    Week 0 to Week 24
    End point values
    		 BID+Met BID+Sita+Met OD+Sita+Met
    Number of subjects analysed
    183
    189
    187
    Units: percentage of glycosylated haemoglobin
        least squares mean (standard error)
    -1.27 ± 0.07
    -1.51 ± 0.07
    -1.15 ± 0.07
    Statistical analysis title
    		 Analysis 1 - BID + Met versus BID + Sita + Met
    Statistical analysis description
    Analysis method: The endpoint was analysed by means of a normal linear regression model with treatment (3 levels), stratum (2 levels: Previous use of OAD [other than sitaglitin and metformin] and no previous use of such OADs), region (3 levels: EU, Korea, and International Operations [the rest]), and baseline HbA1c as independent variables. LOCF was applied. From this model, the treatment difference 'BID+Met' vs 'BID+Sita+Met' was estimated.
    Comparison groups
    BID+Met v BID+Sita+Met
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.011
    Method
    		 Regression, Linear
    Parameter type
    		 Treatment difference
    Point estimate
    0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.06
         upper limit
    		 0.43
    Notes
    [1] - Test of no difference between the two treatments.
    Statistical analysis title
    		 Analysis 2 - BID + Met versus OD + Sita + Met
    Statistical analysis description
    Method: The endpoint was analysed by means of a normal linear regression model with treatment (3 levels), stratum (2 levels: Previous use of OAD [other than sitaglitin and metformin] and no previous use of such OADs), region (3 levels: EU, Korea, and International Operations [the rest]), and baseline HbA1c as independent variables. LOCF was applied. From this model, the treatment difference 'BID+Met' vs 'OD+Sita+Met' was estimated.
    Comparison groups
    BID+Met v OD+Sita+Met
    Number of subjects included in analysis
    370
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.231
    Method
    		 Regression, Linear
    Parameter type
    		 Treatment difference
    Point estimate
    -0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.07
    Notes
    [2] - Test of no difference between the two treatments.
    Statistical analysis title
    		 Analysis 3 - BID+Sita+Met versus OD + Sita + Met
    Statistical analysis description
    Method: The endpoint was analysed by means of a normal linear regression model with treatment (3 levels), stratum (2 levels: Previous use of OAD [other than sitaglitin and metformin] and no previous use of such OADs), region (3 levels: EU, Korea, and International Operations [the rest]), and baseline HbA1c as independent variables. LOCF was applied. From this model, the treatment difference 'BID+Sita+Met' vs 'OD+Sita+Met' was estimated.
    Comparison groups
    BID+Sita+Met v OD+Sita+Met
    Number of subjects included in analysis
    376
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 < 0.001
    Method
    		 Regression, Linear
    Parameter type
    		 Treatment difference
    Point estimate
    -0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.54
         upper limit
    		 -0.17
    Notes
    [3] - Test of no difference between the two treatments.

    Secondary: Responder for HbA1c, Proportion of Subjects Achieving Pre-defined HbA1c Targets (HbA1c < 7.0%)

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    End point title
    		 Responder for HbA1c, Proportion of Subjects Achieving Pre-defined HbA1c Targets (HbA1c < 7.0%)
    End point description
    Proportion of subjects achieving HbA1c below 7.0% after 24 weeks of treatment. Last observation carried forward (LOCF) has been applied.
    End point type
    Secondary
    End point timeframe
    After 24 weeks of treatment
    End point values
    		 BID+Met BID+Sita+Met OD+Sita+Met
    Number of subjects analysed
    194
    195
    193
    Units: Percentage
        number (not applicable)
    49.7
    59.8
    46.5
    Statistical analysis title
    		 Analysis 1 - BID + Met versus BID + Sita + Met
    Statistical analysis description
    The endpoint (achiever of HbA1c 7.0 % after 24 weeks of treatment [Y/N]) was analysed by means of a logistic regression model with treatment (3 levels), stratum (2 levels: Previous use of OAD [other than sitaglitin and metformin] and no previous use of such OADs), region (3 levels: EU, Korea, and International Operations [the rest]), and baseline HbA1c as independent variables. LOCF was applied. From this model, the treatment odds ratio 'BID+Met' vs 'BID+Sita+Met' was estimated.
    Comparison groups
    BID+Met v BID+Sita+Met
    Number of subjects included in analysis
    389
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.022
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 0.93
    Notes
    [4] - Test of no difference between the two treatments.
    Statistical analysis title
    		 Analysis 2 - BID + Met versus OD + Sita + Met
    Statistical analysis description
    The endpoint (achiever of HbA1c < 7.0 % after 24 weeks of treatment [Y/N]) was analysed by means of a logistic regression model with treatment (3 levels), stratum (2 levels: Previous use of OAD [other than sitaglitin and metformin] and no previous use of such OADs), region (3 levels: EU, Korea, and International Operations [the rest]), and baseline HbA1c as independent variables. LOCF was applied. From this model, the treatment odds ratio 'BID+Met' vs 'OD+Sita+Met' was estimated.
    Comparison groups
    OD+Sita+Met v BID+Met
    Number of subjects included in analysis
    387
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.618
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.71
    Notes
    [5] - Test of no difference between the two treatments.
    Statistical analysis title
    		 Analysis 3 - BID+Sita+Met versus OD + Sita + Met
    Statistical analysis description
    The endpoint (achiever of HbA1c < 7.0 % after 24 weeks of treatment [Y/N]) was analysed by means of a logistic regression model with treatment (3 levels), stratum (2 levels: Previous use of OAD [other than sitaglitin and metformin] and no previous use of such OADs), region (3 levels: EU, Korea, and International Operations [the rest]), and baseline HbA1c as independent variables. LOCF was applied. From this model, the treatment odds ratio 'BID+Sita+Met' vs 'OD+Sita+Met' was estimated.
    Comparison groups
    BID+Sita+Met v OD+Sita+Met
    Number of subjects included in analysis
    388
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.005
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.2
         upper limit
    		 2.85
    Notes
    [6] - Test of no difference between the two treatments.

    Secondary: Responder for HbA1c, Proportion of Subjects Achieving Pre-defined HbA1c Targets (HbA1c ≤ 6.5%)

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    End point title
    		 Responder for HbA1c, Proportion of Subjects Achieving Pre-defined HbA1c Targets (HbA1c ≤ 6.5%)
    End point description
    Proportion of subjects achieving HbA1c equal to or below 6.5% after 24 weeks of treatment. Last observation carried forward (LOCF) has been applied.
    End point type
    Secondary
    End point timeframe
    After 24 weeks of treatment
    End point values
    		 BID+Met BID+Sita+Met OD+Sita+Met
    Number of subjects analysed
    183
    189
    187
    Units: Percentage of subjects
        number (not applicable)
    30.6
    40.7
    25.1
    Statistical analysis title
    		 Analysis 1: BID+Met versus BID+Sita+Met
    Statistical analysis description
    The endpoint (achiever of HbA1c ≤ 6.5 % after 24 weeks of treatment [Y/N]) was analysed by means of a logistic regression model with treatment (3 levels), stratum (2 levels: Previous use of OAD [other than sitaglitin and metformin] and no previous use of such OADs), region (3 levels: EU, Korea, and International Operations [the rest]), and baseline HbA1c as independent variables. LOCF was applied. From this model, the treatment odds ratio 'BID+Met' vs 'BID+Sita+Met' was estimated.
    Comparison groups
    BID+Met v BID+Sita+Met
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.02
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 0.92
    Notes
    [7] - Test of no difference between the two treatments.
    Statistical analysis title
    		 Analysis 2: BID+Met versus OD+Sita+Met
    Statistical analysis description
    The endpoint (achiever of HbA1c ≤ 6.5 % after 24 weeks of treatment [Y/N]) was analysed by means of a logistic regression model with treatment (3 levels), stratum (2 levels: Previous use of OAD [other than sitaglitin and metformin] and no previous use of such OADs), region (3 levels: EU, Korea, and International Operations [the rest]), and baseline HbA1c as independent variables. LOCF was applied. From this model, the treatment odds ratio 'BID+Met' vs 'OD+Sita+Met' was estimated.
    Comparison groups
    BID+Met v OD+Sita+Met
    Number of subjects included in analysis
    370
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.286
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 2.07
    Notes
    [8] - Test of no difference between the two treatments.
    Statistical analysis title
    		 Analysis 3: BID+Sita+Met versus OD+Sita+Met
    Statistical analysis description
    The endpoint (achiever of HbA1c ≤ 6.5 % after 24 weeks of treatment [Y/N]) was analysed by means of a logistic regression model with treatment (3 levels), stratum (2 levels: Previous use of OAD [other than sitaglitin and metformin] and no previous use of such OADs), region (3 levels: EU, Korea, and International Operations [the rest]), and baseline HbA1c as independent variables. LOCF was applied. From this model, the treatment odds ratio 'BID+Sita+Met' vs 'OD+Sita+Met' was estimated.
    Comparison groups
    BID+Sita+Met v OD+Sita+Met
    Number of subjects included in analysis
    376
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.39
         upper limit
    		 3.47
    Notes
    [9] - Test of no difference between the two treatments.

    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
    Mean change from baseline in fasting plasma glucose (FPG) after 24 weeks of treatment.
    End point type
    Secondary
    End point timeframe
    Week 0 to Week 24
    End point values
    		 BID+Met BID+Sita+Met OD+Sita+Met
    Number of subjects analysed
    181
    188
    187
    Units: mmol/L
        least squares mean (standard error)
    -1.9 ± 0.14
    -2.03 ± 0.14
    -1.96 ± 0.14
    Statistical analysis title
    		 Analysis 1: BID+Met versus BID+Sita+Met
    Statistical analysis description
    The endpoint was analysed by means of a normal linear regression model with treatment (3 levels), stratum (2 levels: Previous use of OAD [other than sitaglitin and metformin] and no previous use of such OADs), region (3 levels: EU, Korea, and International Operations [the rest]), and baseline FPG as independent variables. LOCF was applied. From this model, the treatment difference 'BID+Met' vs 'BID+Sita+Met' was estimated.
    Comparison groups
    BID+Met v BID+Sita+Met
    Number of subjects included in analysis
    369
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 = 0.52
    Method
    		 Regression, Linear
    Parameter type
    		 Treatment difference
    Point estimate
    0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.26
         upper limit
    		 0.52
    Notes
    [10] - Test of no difference between the two treatments.
    Statistical analysis title
    		 Analysis 2 - BID+Met versus OD+Sita+Met
    Statistical analysis description
    The endpoint was analysed by means of a normal linear regression model with treatment (3 levels), stratum (2 levels: Previous use of OAD [other than sitaglitin and metformin] and no previous use of such OADs), region (3 levels: EU, Korea, and International Operations [the rest]), and baseline FPG as independent variables. LOCF was applied. From this model, the treatment difference 'BID+Met' vs 'OD+Sita+Met' was estimated.
    Comparison groups
    OD+Sita+Met v BID+Met
    Number of subjects included in analysis
    368
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.788
    Method
    		 Regression, Linear
    Parameter type
    		 Treatment difference
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.34
         upper limit
    		 0.45
    Notes
    [11] - Test of no difference between the two treatments.
    Statistical analysis title
    		 Analysis 3 - BID+Sita+Met versus OD+Sita+Met
    Statistical analysis description
    The endpoint was analysed by means of a normal linear regression model with treatment (3 levels), stratum (2 levels: Previous use of OAD [other than sitaglitin and metformin] and no previous use of such OADs), region (3 levels: EU, Korea, and International Operations [the rest]), and baseline FPG as independent variables. LOCF was applied. From this model, the treatment difference 'BID+Sita+Met' vs 'OD+Sita+Met' was estimated.
    Comparison groups
    BID+Sita+Met v OD+Sita+Met
    Number of subjects included in analysis
    375
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 0.708
    Method
    		 Regression, Linear
    Parameter type
    		 Treatment difference
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.46
         upper limit
    		 0.31
    Notes
    [12] - Test of no difference between the two treatments.

    Secondary: Prandial Plasma Glucose (PPG) Increments at Breakfast

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    End point title
    		 Prandial Plasma Glucose (PPG) Increments at Breakfast
    End point description
    Prandial plasma glucose increments at breakfast after 24 weeks of treatment.
    End point type
    Secondary
    End point timeframe
    After 24 weeks of treatment
    End point values
    		 BID+Met BID+Sita+Met OD+Sita+Met
    Number of subjects analysed
    184
    187
    184
    Units: mmol/L
        least squares mean (standard error)
    2.01 ± 0.19
    1.73 ± 0.19
    2.89 ± 0.19
    Statistical analysis title
    		 Analysis 1 - BID + Met versus BID + Sita + Met
    Statistical analysis description
    The endpoint was analysed by means of a normal linear regression model with treatment (3 levels), stratum (2 levels: Previous use of OAD [other than sitaglitin and metformin] and no previous use of such OADs), region (3 levels: EU, Korea, and International Operations [the rest]), and baseline PG increment at breakfast as independent variables. LOCF was applied. From this model, the treatment difference 'BID+Met' vs 'BID+Sita+Met' was estimated.
    Comparison groups
    BID+Met v BID+Sita+Met
    Number of subjects included in analysis
    371
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 = 0.291
    Method
    		 Regression, Linear
    Parameter type
    		 Treatment difference
    Point estimate
    0.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.24
         upper limit
    		 0.81
    Notes
    [13] - Test of no difference between the two treatments.
    Statistical analysis title
    		 Analysis 2 - BID + Met versus OD + Sita + Met
    Statistical analysis description
    The endpoint was analysed by means of a normal linear regression model with treatment (3 levels), stratum (2 levels: Previous use of OAD [other than sitaglitin and metformin] and no previous use of such OADs), region (3 levels: EU, Korea, and International Operations [the rest]), and baseline PG increment at breakfast as independent variables. LOCF was applied. From this model, the treatment difference 'BID+Met' vs 'OD+Sita+Met' was estimated.
    Comparison groups
    BID+Met v OD+Sita+Met
    Number of subjects included in analysis
    368
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 = 0.001
    Method
    		 Regression, Linear
    Parameter type
    		 Treatment difference
    Point estimate
    -0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.41
         upper limit
    		 -0.35
    Notes
    [14] - Test of no difference between the two treatments.
    Statistical analysis title
    		 Analysis 3-BID + Sita + Met versus OD + Sita + Met
    Statistical analysis description
    The endpoint was analysed by means of a normal linear regression model with treatment (3 levels), stratum (2 levels: Previous use of OAD [other than sitaglitin and metformin] and no previous use of such OADs), region (3 levels: EU, Korea, and International Operations [the rest]), and baseline PG increment at breakfast as independent variables. LOCF was applied. From this model, the treatment difference 'BID+Sita+Met' vs 'OD+Sita+Met' was estimated.
    Comparison groups
    BID+Sita+Met v OD+Sita+Met
    Number of subjects included in analysis
    371
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 < 0.001
    Method
    		 Regression, Linear
    Parameter type
    		 Treatment difference
    Point estimate
    -1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.69
         upper limit
    		 -0.64
    Notes
    [15] - Test of no difference between the two treatments.

    Secondary: Prandial Plasma Glucose (PPG) Increments at Lunch

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    End point title
    		 Prandial Plasma Glucose (PPG) Increments at Lunch
    End point description
    Prandial plasma glucose increments at lunch after 24 weeks of treatment.
    End point type
    Secondary
    End point timeframe
    After 24 weeks of treatment
    End point values
    		 BID+Met BID+Sita+Met OD+Sita+Met
    Number of subjects analysed
    180
    186
    182
    Units: mmol/L
        least squares mean (standard error)
    3.05 ± 0.22
    2.19 ± 0.21
    2.52 ± 0.21
    Statistical analysis title
    		 Analysis 1 - BID + Met versus BID + Sita + Met
    Statistical analysis description
    The endpoint was analysed by means of a normal linear regression model with treatment (3 levels), stratum (2 levels: Previous use of OAD [other than sitaglitin and metformin] and no previous use of such OADs), region (3 levels: EU, Korea, and International Operations [the rest]), and baseline PG increment at lunch as independent variables. LOCF was applied. From this model, the treatment difference 'BID+Met' vs 'BID+Sita+Met' was estimated.
    Comparison groups
    BID+Met v BID+Sita+Met
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 other [16]
    P-value
    		 = 0.005
    Method
    		 Regression, Linear
    Parameter type
    		 Treatment difference
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.26
         upper limit
    		 1.45
    Notes
    [16] - Test of no difference between the two treatments.
    Statistical analysis title
    		 Analysis 2 - BID + Met versus OD + Sita + Met
    Statistical analysis description
    The endpoint was analysed by means of a normal linear regression model with treatment (3 levels), stratum (2 levels: Previous use of OAD [other than sitaglitin and metformin] and no previous use of such OADs), region (3 levels: EU, Korea, and International Operations [the rest]), and baseline PG increment at lunch as independent variables. LOCF was applied. From this model, the treatment difference 'BID+Met' vs 'OD+Sita+Met' was estimated.
    Comparison groups
    BID+Met v OD+Sita+Met
    Number of subjects included in analysis
    362
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 = 0.085
    Method
    		 Regression, Linear
    Parameter type
    		 Treatment difference
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.07
         upper limit
    		 1.12
    Notes
    [17] - Test of no difference between the two treatments.
    Statistical analysis title
    		 Analysis 3 - BID + Sita + Met vs OD + Sita + Met
    Statistical analysis description
    The endpoint was analysed by means of a normal linear regression model with treatment (3 levels), stratum (2 levels: Previous use of OAD [other than sitaglitin and metformin] and no previous use of such OADs), region (3 levels: EU, Korea, and International Operations [the rest]), and baseline PG increment at lunch as independent variables. LOCF was applied. From this model, the treatment difference 'BID+Sita+Met' vs 'OD+Sita+Met' was estimated.
    Comparison groups
    OD+Sita+Met v BID+Sita+Met
    Number of subjects included in analysis
    368
    Analysis specification
    Pre-specified
    Analysis type
    		 other [18]
    P-value
    		 = 0.275
    Method
    		 Regression, Linear
    Parameter type
    		 Treatment difference
    Point estimate
    -0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.92
         upper limit
    		 0.26
    Notes
    [18] - Test of no difference between the two treatments.

    Secondary: Prandial Plasma Glucose (PPG) Increments at Dinner.

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    End point title
    		 Prandial Plasma Glucose (PPG) Increments at Dinner.
    End point description
    Prandial plasma glucose increments at dinner after 24 weeks of treatment.
    End point type
    Secondary
    End point timeframe
    After 24 weeks of treatment
    End point values
    		 BID+Met BID+Sita+Met OD+Sita+Met
    Number of subjects analysed
    178
    188
    184
    Units: mmol/L
        least squares mean (standard error)
    0.89 ± 0.21
    1.01 ± 0.2
    0.17 ± 0.21
    Statistical analysis title
    		 Analysis 1 - BID + Met versus BID + Sita + Met
    Statistical analysis description
    The endpoint was analysed by means of a normal linear regression model with treatment (3 levels), stratum (2 levels: Previous use of OAD [other than sitaglitin and metformin] and no previous use of such OADs), region (3 levels: EU, Korea, and International Operations [the rest]), and baseline PG increment at dinner as independent variables. LOCF was applied. From this model, the treatment difference 'BID+Met' vs 'BID+Sita+Met' was estimated.
    Comparison groups
    BID+Met v BID+Sita+Met
    Number of subjects included in analysis
    366
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 = 0.674
    Method
    		 Regression, Linear
    Parameter type
    		 Treatment difference
    Point estimate
    -0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 0.45
    Notes
    [19] - Test of no difference between the two treatments.
    Statistical analysis title
    		 Analysis 2 - BID + Met versus OD + Sita + Met
    Statistical analysis description
    The endpoint was analysed by means of a normal linear regression model with treatment (3 levels), stratum (2 levels: Previous use of OAD [other than sitaglitin and metformin] and no previous use of such OADs), region (3 levels: EU, Korea, and International Operations [the rest]), and baseline PG increment at dinner as independent variables. LOCF was applied. From this model, the treatment difference 'BID+Met' vs 'OD+Sita+Met' was estimated.
    Comparison groups
    OD+Sita+Met v BID+Met
    Number of subjects included in analysis
    362
    Analysis specification
    Pre-specified
    Analysis type
    		 other [20]
    P-value
    		 = 0.015
    Method
    		 Regression, Linear
    Parameter type
    		 Treatment difference
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.14
         upper limit
    		 1.3
    Notes
    [20] - Test of no difference between the two treatments.
    Statistical analysis title
    		 Analysis 3 -BID + Sita+ Met versus OD + Sita + Met
    Statistical analysis description
    The endpoint was analysed by means of a normal linear regression model with treatment (3 levels), stratum (2 levels: Previous use of OAD [other than sitaglitin and metformin] and no previous use of such OADs), region (3 levels: EU, Korea, and International Operations [the rest]), and baseline PG increment at dinner as independent variables. LOCF was applied. From this model, the treatment difference 'BID+Sita+Met' vs 'OD+Sita+Met' was estimated.
    Comparison groups
    BID+Sita+Met v OD+Sita+Met
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    		 other [21]
    P-value
    		 = 0.004
    Method
    		 Regression, Linear
    Parameter type
    		 Treatment difference
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.27
         upper limit
    		 1.41
    Notes
    [21] - Test of no difference between the two treatments.

    Secondary: Prandial Plasma Glucose (PPG) Overall Mean Increment.

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    End point title
    		 Prandial Plasma Glucose (PPG) Overall Mean Increment.
    End point description
    The average over all three prandial plasma glucose increments (breakfast, lunch, dinner) after 24 weeks of treatment.
    End point type
    Secondary
    End point timeframe
    After 24 weeks of treatment
    End point values
    		 BID+Met BID+Sita+Met OD+Sita+Met
    Number of subjects analysed
    184
    188
    185
    Units: mmol/L
        least squares mean (standard error)
    1.97 ± 0.12
    1.66 ± 0.12
    1.88 ± 0.12
    Statistical analysis title
    		 Analysis 1 - BID + Met versus BID + Sita + Met
    Statistical analysis description
    The endpoint was analysed by means of a normal linear regression model with treatment (3 levels), stratum (2 levels: Previous use of OAD [other than sitaglitin and metformin] and no previous use of such OADs), region (3 levels: EU, Korea, and International Operations [the rest]), and baseline over all mean PPG increment as independent variables. LOCF was applied. From this model, the treatment difference 'BID+Met' vs 'BID+Sita+Met was estimated.
    Comparison groups
    BID+Met v BID+Sita+Met
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    		 other [22]
    P-value
    		 = 0.08
    Method
    		 Regression, Linear
    Parameter type
    		 Treatment difference
    Point estimate
    0.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.65
    Notes
    [22] - Test of no difference between the two treatments.
    Statistical analysis title
    		 Analysis 2 - BID + Met versus OD + Sita + Met
    Statistical analysis description
    The endpoint was analysed by means of a normal linear regression model with treatment (3 levels), stratum (2 levels: Previous use of OAD [other than sitaglitin and metformin] and no previous use of such OADs), region (3 levels: EU, Korea, and International Operations [the rest]), and baseline over all mean PPG increment as independent variables. LOCF was applied. From this model, the treatment difference 'BID+Met' vs 'OD+Sita+Met was estimated.
    Comparison groups
    BID+Met v OD+Sita+Met
    Number of subjects included in analysis
    369
    Analysis specification
    Pre-specified
    Analysis type
    		 other [23]
    P-value
    		 = 0.613
    Method
    		 Regression, Linear
    Parameter type
    		 Treatment difference
    Point estimate
    0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.26
         upper limit
    		 0.43
    Notes
    [23] - Test of no difference between the two treatments.
    Statistical analysis title
    		 Analysis 3-BID + Sita + Met versus OD + Sita + Met
    Statistical analysis description
    The endpoint was analysed by means of a normal linear regression model with treatment (3 levels), stratum (2 levels: Previous use of OAD [other than sitaglitin and metformin] and no previous use of such OADs), region (3 levels: EU, Korea, and International Operations [the rest]), and baseline over all mean PPG increment as independent variables. LOCF was applied. From this model, the treatment difference 'BID+Sita+Met' vs 'OD+Sita+Met' was estimated.
    Comparison groups
    BID+Sita+Met v OD+Sita+Met
    Number of subjects included in analysis
    373
    Analysis specification
    Pre-specified
    Analysis type
    		 other [24]
    P-value
    		 = 0.213
    Method
    		 Regression, Linear
    Parameter type
    		 Treatment difference
    Point estimate
    -0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.56
         upper limit
    		 0.13
    Notes
    [24] - Test of no difference between the two treatments.

    Secondary: Adverse Events (AEs)

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    End point title
    		 Adverse Events (AEs)
    End point description
    Rate of AEs per 100 years of patient exposure. An AE was defined as treatment emergent if the event had onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment.
    End point type
    Secondary
    End point timeframe
    Week 0 to Week 24
    End point values
    		 BID+Met BID+Sita+Met OD+Sita+Met
    Number of subjects analysed
    192
    193
    190
    Units: Events/100 years of patient exposure
        number (not applicable)
    262.2
    209.9
    281.2
    No statistical analyses for this end point

    Secondary: Number of Treatment Emergent Hypoglycaemic Episodes (Nocturnal and Day-time) Classified Both According to the American Diabetes Association (ADA) Definition and to an Additional Definition for Minor Episodes.

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    End point title
    		 Number of Treatment Emergent Hypoglycaemic Episodes (Nocturnal and Day-time) Classified Both According to the American Diabetes Association (ADA) Definition and to an Additional Definition for Minor Episodes.
    End point description
    Number of treatment emergent hypoglycaemic episodes. Treatment emergent hypoglycaemic episode: if the onset of the episode was on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment. Nocturnal: Time of onset between 00:01 and 05:59 a.m. (both included). Additional minor hypoglycaemic episode: symptomatic or asymptomatic hypoglycaemia with blood glucose (BG) values < 2.8 mmol/L (50 mg/dL) or plasma glucose (PG) < 3.1 mmol/L (56 mg/dL), and which was handled by the subject him/herself.
    End point type
    Secondary
    End point timeframe
    Week 0 to Week 24
    End point values
    		 BID+Met BID+Sita+Met OD+Sita+Met
    Number of subjects analysed
    192
    193
    190
    Units: Number of episodes
        All events
    600
    509
    320
        Diurnal
    515
    440
    249
        Nocturnal
    68
    54
    63
        Diurnal (additional minor)
    163
    112
    71
        Nocturnal (additional minor)
    21
    14
    23
    No statistical analyses for this end point

    Secondary: Change From Baseline in Patient Reported Outcome by Use of the Treatment Related Impact Measure - Diabetes.

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    End point title
    		 Change From Baseline in Patient Reported Outcome by Use of the Treatment Related Impact Measure - Diabetes.
    End point description
    Change from baseline in 'total score' for Treatment Related Impact Measure - Diabetes (TRIM-D) after 24 wk of treatment. The TRIM-D 'total score' is reported on a 0 to 100 scale, where higher scores indicate greater satisfaction.
    End point type
    Secondary
    End point timeframe
    Week 0 to Week 24
    End point values
    		 BID+Met BID+Sita+Met OD+Sita+Met
    Number of subjects analysed
    178
    184
    183
    Units: Scores
        least squares mean (standard error)
    6.22 ± 0.82
    5.93 ± 0.81
    6.2 ± 0.81
    Statistical analysis title
    		 Analysis 1 - BID + Met versus BID + Sita + Met
    Statistical analysis description
    The endpoint was analysed by means of a normal linear regression model with treatment (3 levels), stratum (2 levels: Previous use of OAD [other than sitaglitin and metformin] and no previous use of such OADs), region (3 levels: EU, Korea, and International Operations [the rest]), and baseline TRIM-D 'total score' as independent variables. LOCF was applied. From this model, the treatment difference 'BID+Met' vs 'BID+Sita+Met' was estimated.
    Comparison groups
    BID+Met v BID+Sita+Met
    Number of subjects included in analysis
    362
    Analysis specification
    Pre-specified
    Analysis type
    		 other [25]
    P-value
    		 = 0.8
    Method
    		 Regression, Linear
    Parameter type
    		 Treatment difference
    Point estimate
    0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.97
         upper limit
    		 2.56
    Notes
    [25] - Test of no difference between the two treatments.
    Statistical analysis title
    		 Analysis 2 - BID + Met versus OD + Sita + Met
    Statistical analysis description
    The endpoint was analysed by means of a normal linear regression model with treatment (3 levels), stratum (2 levels: Previous use of OAD [other than sitaglitin and metformin] and no previous use of such OADs), region (3 levels: EU, Korea, and International Operations [the rest]), and baseline TRIM-D 'total score' as independent variables. LOCF was applied. From this model, the treatment difference 'BID+Met' vs 'OD+Sita+Met' was estimated.
    Comparison groups
    BID+Met v OD+Sita+Met
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    		 other [26]
    P-value
    		 = 0.989
    Method
    		 Regression, Linear
    Parameter type
    		 Treatment difference
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.26
         upper limit
    		 2.29
    Notes
    [26] - Test of no difference between the two treatments.
    Statistical analysis title
    		 Analysis 3-BID + Sita + Met versus OD + Sita + Met
    Statistical analysis description
    The endpoint was analysed by means of a normal linear regression model with treatment (3 levels), stratum (2 levels: Previous use of OAD [other than sitaglitin and metformin] and no previous use of such OADs), region (3 levels: EU, Korea, and International Operations [the rest]), and baseline TRIM-D 'total score' as independent variables. LOCF was applied. From this model, the treatment difference 'BID+Sita+Met' vs 'OD+Sita+Met' was estimated.
    Comparison groups
    OD+Sita+Met v BID+Met
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    		 other [27]
    P-value
    		 = 0.809
    Method
    		 Regression, Linear
    Parameter type
    		 Treatment difference
    Point estimate
    -0.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.52
         upper limit
    		 1.97
    Notes
    [27] - Test of no difference between the two treatments.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were captured the onset date on or after the first day of exposure to randomised treatment and no later than the last day of randomised treatment.
    Adverse event reporting additional description
    Safety analysis set included all subjects receiving at least one dose of the investigational product.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    BID+Met
    Reporting group description
    		 Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) treatment.

    Reporting group title
    BID+Sita+Met
    Reporting group description
    		 Biphasic insulin aspart 30 (BIAsp 30) was injected twice daily, 6 U before breakfast and 6 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.

    Reporting group title
    OD+Sita+Met
    Reporting group description
    		 Biphasic insulin aspart 30 (BIAsp 30) was injected once daily, 12 U before dinner (evening meal), subcutaneously (under the skin) for 24 weeks. Dosing of BIAsp 30 was adjusted individually according to the titration guideline and the subject's self-measured plasma glucose (SMPG) levels. Subjects continued on their pre-trial metformin (1000 mg/day) and sitagliptin (100 mg/day) treatments.

    Serious adverse events
    		 BID+Met BID+Sita+Met OD+Sita+Met
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 192 (3.65%)
    5 / 193 (2.59%)
    4 / 190 (2.11%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 193 (0.52%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thyroid cancer metastatic
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 193 (0.00%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Burns second degree
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 193 (0.00%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 193 (0.00%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 192 (0.00%)
    0 / 193 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemic unconsciousness
         subjects affected / exposed
    0 / 192 (0.00%)
    0 / 193 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VIIth nerve paralysis
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 193 (0.52%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 193 (0.00%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 192 (0.00%)
    0 / 193 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 193 (0.00%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 193 (0.52%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 192 (0.00%)
    0 / 193 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Liver abscess
         subjects affected / exposed
    1 / 192 (0.52%)
    0 / 193 (0.00%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 192 (0.00%)
    0 / 193 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 192 (0.00%)
    1 / 193 (0.52%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 192 (0.52%)
    1 / 193 (0.52%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 BID+Met BID+Sita+Met OD+Sita+Met
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 192 (15.63%)
    25 / 193 (12.95%)
    32 / 190 (16.84%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 192 (3.65%)
    11 / 193 (5.70%)
    8 / 190 (4.21%)
         occurrences all number
    11
    19
    15
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    8 / 192 (4.17%)
    1 / 193 (0.52%)
    10 / 190 (5.26%)
         occurrences all number
    10
    1
    10
    Infections and infestations
    Influenza
         subjects affected / exposed
    11 / 192 (5.73%)
    5 / 193 (2.59%)
    10 / 190 (5.26%)
         occurrences all number
    14
    6
    12
    Nasopharyngitis
         subjects affected / exposed
    9 / 192 (4.69%)
    11 / 193 (5.70%)
    8 / 190 (4.21%)
         occurrences all number
    9
    12
    9

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/25488587
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