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    Clinical Trial Results:
    A Randomized, 30 Week, Active-controlled, Open-label, 3-Treatment Arm, Parallel-group Multicenter Study Comparing the Efficacy and Safety of Insulin Glargine/Lixisenatide Fixed Ratio Combination to Insulin Glargine Alone and to Lixisenatide Alone on Top of Metformin in Patients with Type 2 Diabetes Mellitus (T2DM)

    Summary
    EudraCT number
    		 2013-003131-30
    Trial protocol
    		 GB   DE   BE   IT   EE   SE   LT   LV   CZ   ES   HU   DK   FR  
    Global end of trial date
    17 Jun 2015

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

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC12404
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02058147
    WHO universal trial number (UTN)
    		 U1111-1148-4334
    Other trial identifiers
    		 Study Name: LixiLan-O
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.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
    12 Aug 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the superiority of the insulin glargine/lixisenatide fixed-ratio combination (FRC) to lixisenatide in glycosylated hemoglobin (HbA1c) change from baseline to Week 30, and to demonstrate the non-inferiority of the FRC to insulin glargine in HbA1c change from baseline to Week 30. If noninferiority was shown, statistical superiority of the FRC compared to insulin glargine on HbA1c change from baseline to Week 30 was to be tested according to the prespecified testing hierarchy.
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi­Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    		 Subjects were treated for at least 3 months prior to screening with metformin with or without a second oral anti-diabetic treatment (OAD). Subjects receiving metformin plus another OAD at screening had to stop the second OAD at the start of run-in (4 weeks prior randomization). For all subjects, the dose of metformin was optimized during run-in and had to be ≥1500 mg/day to allow randomization.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Feb 2014
    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
    Australia: 11
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    Chile: 45
    Country: Number of subjects enrolled
    United States: 362
    Country: Number of subjects enrolled
    Mexico: 72
    Country: Number of subjects enrolled
    Romania: 58
    Country: Number of subjects enrolled
    Russian Federation: 106
    Country: Number of subjects enrolled
    South Africa: 49
    Country: Number of subjects enrolled
    Ukraine: 59
    Country: Number of subjects enrolled
    Poland: 47
    Country: Number of subjects enrolled
    Spain: 47
    Country: Number of subjects enrolled
    Sweden: 19
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Czech Republic: 73
    Country: Number of subjects enrolled
    Denmark: 16
    Country: Number of subjects enrolled
    Estonia: 19
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 18
    Country: Number of subjects enrolled
    Hungary: 56
    Country: Number of subjects enrolled
    Italy: 26
    Country: Number of subjects enrolled
    Latvia: 27
    Country: Number of subjects enrolled
    Lithuania: 35
    Worldwide total number of subjects
    1170
    EEA total number of subjects
    455
    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)
    864
    From 65 to 84 years
    306
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 240 centers in 23 countries. A total of 2457 subjects were screened between February 12, 2014 and September 16, 2014. 978 subjects were not eligible for run-in mainly due to glycosylated hemoglobin (HbA1c) value at screening visit being out of the protocol defined range.

    Pre-assignment
    Screening details
    		 After 2 weeks screening period, 1479 subjects underwent 4­-week run–in period. 309 subjects were run-in failures. A total of 1170 subjects were randomized in 2:2:1 to insulin glargine/lixisenatide, insulin glargine and lixisenatide arms in open-label treatment period.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Insulin Glargine/Lixisenatide Fixed Ratio Combination
    Arm description
    		 Insulin glargine 10 U/ Lixisenatide 5 mcg fixed-ratio combination (FRC) once daily (QD) for first week post-randomization, followed by dose adjustment (avoiding hypoglycemia) to reach and maintain fasting self-monitored plasma glucose (SMPG) of 80 mg/dL to 100 mg/dL (4.4 mmol/L to 5.6 mmol/L) up to 30 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Insulin glargine/Lixisenatide
    Investigational medicinal product code
    HOE901/AVE0010
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Insulin glargine/Lixisenatide fixed ratio combination was self-administered QD in the morning within one hour before breakfast using one of the 2 available prefilled disposable SoloStar® pen-injectors: Pen A or B, depending upon the dose. Pen A contained 100 U/mL insulin glargine (Lantus, 100 U/mL) and 50 mcg/mL lixisenatide in a ratio of 2 U:1 mcg and was used for administration of doses from 10U/5mcg to 40U/20mcg. Pen B contained 100 U/mL insulin glargine (Lantus, 100 U/mL) and 33 mcg/mL lixisenatide in a ratio of 3 U:1 mcg and was used to administer doses above 30U/10 mcg up to the maximal daily dose of 60U/20 mcg.

    Arm title
    		 Insulin Glargine
    Arm description
    		 Insulin glargine 10 U QD for first week post-randomization, followed by dose adjustment (avoiding hypoglycemia) to reach and maintain fasting SMPG of 80 mg/dL to 100 mg/dL (4.4 mmol/L to 5.6 mmol/L) up to 30 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Insulin glargine
    Investigational medicinal product code
    HOE901
    Other name
    Lantus
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Insulin glargine (100 U/mL) was self-administered QD at approximately the same time every day.

    Arm title
    		 Lixisenatide
    Arm description
    		 Lixisenatide 10 mcg QD for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to 30 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Lixisenatide
    Investigational medicinal product code
    AVE0010
    Other name
    Lyxumia
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Lixisenatide was self-administered QD within 0 to 60 minutes before breakfast or evening meal. If the maintenance dose of 20 mcg was not tolerated, dose could be reduced to 10 mcg.

    Number of subjects in period 1
    		Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Started
    469
    467
    234
    Treated
    469
    467
    233
    Completed
    440
    440
    205
    Not completed
    29
    27
    29
         Randomized but not treated
    -
    -
    1
         Adverse event
    12
    9
    21
         Other than specified
    8
    9
    -
         Poor compliance to protocol
    8
    9
    4
         Lack of efficacy
    1
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Insulin Glargine/Lixisenatide Fixed Ratio Combination
    Reporting group description
    		 Insulin glargine 10 U/ Lixisenatide 5 mcg fixed-ratio combination (FRC) once daily (QD) for first week post-randomization, followed by dose adjustment (avoiding hypoglycemia) to reach and maintain fasting self-monitored plasma glucose (SMPG) of 80 mg/dL to 100 mg/dL (4.4 mmol/L to 5.6 mmol/L) up to 30 weeks.

    Reporting group title
    Insulin Glargine
    Reporting group description
    		 Insulin glargine 10 U QD for first week post-randomization, followed by dose adjustment (avoiding hypoglycemia) to reach and maintain fasting SMPG of 80 mg/dL to 100 mg/dL (4.4 mmol/L to 5.6 mmol/L) up to 30 weeks.

    Reporting group title
    Lixisenatide
    Reporting group description
    		 Lixisenatide 10 mcg QD for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to 30 weeks.

    Reporting group values
    		 Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide Total
    Number of subjects
    		 469 467 234 1170
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.2 ( 9.5 ) 58.3 ( 9.4 ) 58.7 ( 8.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 247 230 101 578
        Male
    		 222 237 133 592
    Race
    Units: Subjects
        Caucasian
    		 417 421 216 1054
        Black
    		 33 33 12 78
        Asian/Oriental
    		 8 7 3 18
        Other
    		 11 6 3 20
    Ethnicity
    Units: Subjects
        Hispanic
    		 85 87 51 223
        Not Hispanic
    		 384 380 183 947
    Second OAD use
    Units: Subjects
        Yes
    		 274 270 133 677
        No
    		 195 197 101 493
    Second OAD use at screening by class
    Units: Subjects
        Sulfonylurea
    		 259 249 123 631
        Glinide
    		 3 10 5 18
        Sodium-glucose cotransporter-2 inhibitor
    		 2 2 0 4
        Dipeptidyl peptidase-4 inhibitor
    		 12 11 5 28
        None
    		 193 195 101 489
    Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 31.64 ( 4.4 ) 31.66 ( 4.51 ) 31.99 ( 4.39 ) -
    Duration of Diabetes
    Units: years
        arithmetic mean (standard deviation)
    		 8.89 ( 5.51 ) 8.66 ( 5.59 ) 8.89 ( 6.26 ) -
    Daily dose of metformin
    Units: mg
        arithmetic mean (standard deviation)
    		 2246.1 ( 456.8 ) 2244.7 ( 444.7 ) 2267.3 ( 427.4 ) -
    HbA1c
    Units: percentage of HbA1c
        arithmetic mean (standard deviation)
    		 8.08 ( 0.71 ) 8.08 ( 0.69 ) 8.13 ( 0.72 ) -
    Fasting plasma glucose (FPG)
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 9.87 ( 2.35 ) 9.75 ( 2.32 ) 9.75 ( 2.19 ) -

    End points

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    End points reporting groups
    Reporting group title
    Insulin Glargine/Lixisenatide Fixed Ratio Combination
    Reporting group description
    		 Insulin glargine 10 U/ Lixisenatide 5 mcg fixed-ratio combination (FRC) once daily (QD) for first week post-randomization, followed by dose adjustment (avoiding hypoglycemia) to reach and maintain fasting self-monitored plasma glucose (SMPG) of 80 mg/dL to 100 mg/dL (4.4 mmol/L to 5.6 mmol/L) up to 30 weeks.

    Reporting group title
    Insulin Glargine
    Reporting group description
    		 Insulin glargine 10 U QD for first week post-randomization, followed by dose adjustment (avoiding hypoglycemia) to reach and maintain fasting SMPG of 80 mg/dL to 100 mg/dL (4.4 mmol/L to 5.6 mmol/L) up to 30 weeks.

    Reporting group title
    Lixisenatide
    Reporting group description
    		 Lixisenatide 10 mcg QD for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to 30 weeks.

    Primary: Change in HbA1c From Baseline to Week 30

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    End point title
    		 Change in HbA1c From Baseline to Week 30
    End point description
    Change in HbA1c was calculated by subtracting baseline value from Week 30 value. Modified intent-to-treat (mITT) population: all randomized subjects who had both baseline and at least one post-baseline efficacy assessment. Here, number of subjects analyzed=subjects with baseline and at least one post-baseline HbA1c assessment during study period.
    End point type
    Primary
    End point timeframe
    Baseline, Week 30
    End point values
    		 Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Number of subjects analysed
    467
    464
    233
    Units: percentage of hemoglobin
        least squares mean (standard error)
    -1.63 ( 0.038 )
    -1.34 ( 0.039 )
    -0.85 ( 0.052 )
    Statistical analysis title
    		 Insulin Glargine/Lixisenatide vs Lixisenatide
    Statistical analysis description
    Analysis was performed using Mixed-effect model with repeated measures (MMRM) with treatment groups, randomization strata of Week ­-1 HbA1c (<8.0, ≥8.0%), randomization strata of second OAD use at screening, visit, treatment-by-visit interaction, and country as fixed effects and baseline HbA1c value-by-visit interaction as a covariate.
    Comparison groups
    Insulin Glargine/Lixisenatide Fixed Ratio Combination v Lixisenatide
    Number of subjects included in analysis
    700
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square (LS) Mean Difference
    Point estimate
    -0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.898
         upper limit
    		 -0.665
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.059
    Notes
    [1] - Threshold for significance ≤ 0.05.
    Statistical analysis title
    		 Insulin Glargine/Lixisenatide vs Insulin glargine
    Statistical analysis description
    Analysis was performed using MMRM model with treatment groups, randomization strata of Week ­-1 HbA1c (<8.0, ≥8.0%), randomization strata of second OAD use at screening, visit, treatment-by-visit interaction, and country as fixed effects and baseline HbA1c value-by-visit interaction as a covariate.
    Comparison groups
    Insulin Glargine/Lixisenatide Fixed Ratio Combination v Insulin Glargine
    Number of subjects included in analysis
    931
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.384
         upper limit
    		 -0.194
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.048
    Notes
    [2] - Predefined non-inferiority margin of 0.3%. Test of superiority of Insulin glargine/Lixisenatide FRC over Insulin glargine was also performed according to hierarchical testing procedure no. 6.

    Secondary: Percentage of Subjects with HbA1c <7.0% or ≤6.5% at Week 30

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    End point title
    		 Percentage of Subjects with HbA1c <7.0% or ≤6.5% at Week 30
    End point description
    mITT population. Subjects without Week 30 value for HbA1c were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    Week 30
    End point values
    		 Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Number of subjects analysed
    468
    466
    233
    Units: percentage of subjects
    number (not applicable)
        HbA1c <7.0%
    73.7
    59.4
    33
        HbA1c ≤6.5%
    55.8
    39.5
    19.3
    Statistical analysis title
    		 HbA1c <7.0%: FRC vs Lixisenatide
    Statistical analysis description
    Analysis was performed using Cochran-Mantel-Haenszel method stratified on randomization strata of Week -1 HbA1c (<8.0%, ≥8.0%) and randomization strata of second OAD use at screening. This analysis was out of testing order.
    Comparison groups
    Insulin Glargine/Lixisenatide Fixed Ratio Combination v Lixisenatide
    Number of subjects included in analysis
    701
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    40.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 33.63
         upper limit
    		 47.59
    Notes
    [3] - Threshold for significance ≤ 0.05.
    Statistical analysis title
    		 HbA1c ≤6.5%: FRC vs Lixisenatide
    Statistical analysis description
    Analysis was performed using Cochran-Mantel-Haenszel method stratified on randomization strata of Week -1 HbA1c (<8.0%, ≥8.0%) and randomization strata of second OAD use at screening. This analysis was out of testing order.
    Comparison groups
    Insulin Glargine/Lixisenatide Fixed Ratio Combination v Lixisenatide
    Number of subjects included in analysis
    701
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    36.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 29.81
         upper limit
    		 42.95
    Notes
    [4] - Threshold for significance ≤ 0.05.
    Statistical analysis title
    		 HbA1c <7.0%: FRC vs Insulin glargine
    Statistical analysis description
    Analysis was performed using Cochran-Mantel-Haenszel method stratified on randomization strata of Week -1 HbA1c (<8.0%, ≥8.0%) and randomization strata of second OAD use at screening. This analysis was out of testing order.
    Comparison groups
    Insulin Glargine/Lixisenatide Fixed Ratio Combination v Insulin Glargine
    Number of subjects included in analysis
    934
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [5]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    14.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.37
         upper limit
    		 20.25
    Notes
    [5] - Threshold for significance ≤ 0.05.
    Statistical analysis title
    		 HbA1c ≤6.5%: FRC vs Insulin glargine
    Statistical analysis description
    Analysis was performed using Cochran-Mantel-Haenszel method stratified on randomization strata of Week -1 HbA1c (<8.0%, ≥8.0%) and randomization strata of second OAD use at screening. This analysis was out of testing order.
    Comparison groups
    Insulin Glargine/Lixisenatide Fixed Ratio Combination v Insulin Glargine
    Number of subjects included in analysis
    934
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    16.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 10.13
         upper limit
    		 22.58
    Notes
    [6] - Threshold for significance ≤ 0.05.

    Secondary: Change in Plasma Glucose Excursion from Baseline to Week 30

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    End point title
    		 Change in Plasma Glucose Excursion from Baseline to Week 30
    End point description
    Plasma glucose excursion = 2-hour postprandial plasma glucose (PPG) value minus plasma glucose value obtained 30 minutes prior to the start of meal and before investigational medicinal product (IMP) administration if IMP was injected before breakfast. Change in plasma glucose excursions were calculated by subtracting baseline value from Week 30 value. Missing data was imputed using last observation carried forward (LOCF). Here, number of subjects analyzed=subjects with baseline and at least one post-baseline plasma glucose excursion assessment during study period.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 30
    End point values
    		 Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Number of subjects analysed
    428
    425
    192
    Units: mmol/L
        least squares mean (standard error)
    -2.31 ( 0.154 )
    -0.18 ( 0.157 )
    -3.23 ( 0.216 )
    Statistical analysis title
    		 Insulin Glargine/Lixisenatide vs Insulin glargine
    Statistical analysis description
    Analysis was performed using analysis of covariance (ANCOVA) model with treatment groups, randomization strata of Week -­1 HbA1c (<8.0, ≥8.0%), randomization strata of second OAD use at screening, & country as fixed effects & baseline plasma glucose excursion value as a covariate. A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Here, it is test no. 1 of testing order.
    Comparison groups
    Insulin Glargine/Lixisenatide Fixed Ratio Combination v Insulin Glargine
    Number of subjects included in analysis
    853
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 < 0.0001 [8]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -2.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.498
         upper limit
    		 -1.77
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.185
    Notes
    [7] - Testing was performed in following order: 1. & 2. FRC v insulin glargine for both test of 2h-Glucose excursion; & body weight; 3. & 4. FRC vs lixisenatide for both FPG; & 7-point SMPG; 5. to 10. FRC vs insulin glargine for endpoints: subjects reached HbA1c<7% with no body weight gain; HbA1c (superiority); 7-point SMPG; subjects reached HbA1c<7% with no body weight gain & symptomatic hypoglycemia; insulin glargine dose; & FPG.
    [8] - Hierarchical testing sequence continued only when co-primary hypotheses (superiority of FRC to lixisenatide & non-inferiority of FRC to insulin glargine for HbA1c change from baseline) was statistically significant. Threshold for significance ≤ 0.05.

    Secondary: Change in Body Weight From Baseline to Week 30

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    End point title
    		 Change in Body Weight From Baseline to Week 30
    End point description
    Change in body weight was calculated by subtracting baseline value from Week 30 value. mITT population. Here, number of subjects analyzed=subjects with baseline and at least one post-baseline body weight assessment during study period.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 30
    End point values
    		 Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Number of subjects analysed
    467
    465
    233
    Units: kg
        least squares mean (standard error)
    -0.29 ( 0.182 )
    1.11 ( 0.183 )
    -2.3 ( 0.256 )
    Statistical analysis title
    		 Insulin Glargine/Lixisenatide vs Insulin glargine
    Statistical analysis description
    Testing according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant). Here, it is test no. 2 of testing order. Analysis was performed using MMRM model with treatment groups, randomization strata of Week ­-1 HbA1c (<8.0, ≥8.0%), randomization strata of second OAD use at screening, visit, treatment-by-visit interaction, and country as fixed effects and baseline body weight value-by-visit interaction as a covariate.
    Comparison groups
    Insulin Glargine/Lixisenatide Fixed Ratio Combination v Insulin Glargine
    Number of subjects included in analysis
    932
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [9]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.891
         upper limit
    		 -0.91
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.25
    Notes
    [9] - Threshold for significance ≤ 0.05.

    Secondary: Change in FPG From Baseline to Week 30

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    End point title
    		 Change in FPG From Baseline to Week 30
    End point description
    Change in FPG was calculated by subtracting baseline value from Week 30 value. mITT population. Here, number of subjects analyzed=subjects with baseline and at least one post-­baseline FPG assessment during study period.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 30
    End point values
    		 Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Number of subjects analysed
    465
    465
    232
    Units: mmol/L
        least squares mean (standard error)
    -3.46 ( 0.09 )
    -3.27 ( 0.091 )
    -1.5 ( 0.124 )
    Statistical analysis title
    		 Insulin Glargine/Lixisenatide vs Lixisenatide
    Statistical analysis description
    Testing according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant). Here, it is test no. 3 of testing order. Analysis was performed using MMRM model with treatment groups, randomization strata of Week -1 HbA1c (<8.0, ≥8.0%), randomization strata of second OAD use at screening, visit, treatment-by-visit interaction, and country as fixed effects and baseline FPG value-by-visit interaction as a covariate.
    Comparison groups
    Insulin Glargine/Lixisenatide Fixed Ratio Combination v Lixisenatide
    Number of subjects included in analysis
    697
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.246
         upper limit
    		 -1.682
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.144
    Notes
    [10] - Threshold for significance ≤ 0.05

    Secondary: Mean Change in 7-point SMPG Profile From Baseline to Week 30

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    End point title
    		 Mean Change in 7-point SMPG Profile From Baseline to Week 30
    End point description
    Subjects recorded a 7-­point plasma glucose profile measured before and 2 hours after each meal and at bedtime two times in a week before baseline, before visit Week 12 and before visit week 30 and the average value across the profiles performed in the week before a visit for the 7-­time points was calculated. Change in average 7-­point SMPG was calculated by subtracting baseline value from Week 30 value. mITT population. Here, number of subjects analyzed=subjects with baseline and at least one post­-baseline 7-­point SMPG assessment during study period.
    End point type
    Secondary
    End point timeframe
    Baseline , Week 30
    End point values
    		 Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Number of subjects analysed
    421
    411
    204
    Units: mmol/L
        least squares mean (standard error)
    -3.35 ( 0.081 )
    -2.66 ( 0.084 )
    -1.95 ( 0.111 )
    Statistical analysis title
    		 Insulin Glargine/Lixisenatide vs Lixisenatide
    Statistical analysis description
    Testing according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant). Here, it is test no. 4 of testing order. Analysis was performed using MMRM model with treatment groups, randomization strata of Week -1 HbA1c (<8.0, ≥8.0%), randomization strata of second OAD use at screening, visit, treatment-by-visit interaction, and country as fixed effects and baseline 7-point SMPG value-by-visit interaction as a covariate.
    Comparison groups
    Insulin Glargine/Lixisenatide Fixed Ratio Combination v Lixisenatide
    Number of subjects included in analysis
    625
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [11]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.645
         upper limit
    		 -1.158
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.124
    Notes
    [11] - Threshold for significance ≤ 0.05.
    Statistical analysis title
    		 Insulin Glargine/Lixisenatide vs Insulin Glargine
    Statistical analysis description
    Testing according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant). Here, it is test no. 7 of testing order. Analysis was performed using MMRM model with treatment groups, randomization strata of Week -1 HbA1c (<8.0, ≥8.0%), randomization strata of second OAD use at screening, visit, treatment-by-visit interaction, and country as fixed effects and baseline 7-point SMPG value-by-visit interaction, as a covariate.
    Comparison groups
    Insulin Glargine/Lixisenatide Fixed Ratio Combination v Insulin Glargine
    Number of subjects included in analysis
    832
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [12]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.892
         upper limit
    		 -0.495
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.101
    Notes
    [12] - Threshold for significance ≤ 0.05.

    Secondary: Percentage of Subjects Reaching HbA1c <7.0% With No Body Weight Gain at Week 30

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    End point title
    		 Percentage of Subjects Reaching HbA1c <7.0% With No Body Weight Gain at Week 30
    End point description
    mITT population. Subjects without any HbA1c and/or body weight value at Week 30 were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    Week 30
    End point values
    		 Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Number of subjects analysed
    468
    466
    233
    Units: Percentage of subjects
        number (not applicable)
    43.2
    25.1
    27.9
    Statistical analysis title
    		 Insulin Glargine/Lixisenatide vs Insulin glargine
    Statistical analysis description
    Testing according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant). Here, it is test no. 5 of testing order. Analysis was performed using Cochran-Mantel-Haenszel method stratified on randomization strata of Week-1 HbA1c (<8%, ≥8%) and randomization strata of second OAD use at screening.
    Comparison groups
    Insulin Glargine/Lixisenatide Fixed Ratio Combination v Insulin Glargine
    Number of subjects included in analysis
    934
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [13]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    18.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 12.15
         upper limit
    		 24.01
    Notes
    [13] - Threshold for significance ≤ 0.05.

    Secondary: Change in HbA1c From Baseline to Week 30 (Superiority of Insulin Glargine/Lixisenatide vs Insulin Glargine)

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    End point title
    		 Change in HbA1c From Baseline to Week 30 (Superiority of Insulin Glargine/Lixisenatide vs Insulin Glargine)
    End point description
    Change in HbA1c was calculated by subtracting baseline value from Week 30 value. mITT population. Here, number of subjects analyzed=subjects with baseline and at least one post-baseline HbA1c assessment during study period.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 30
    End point values
    		 Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Number of subjects analysed
    467
    464
    233
    Units: percentage of hemoglobin
        least squares mean (standard error)
    -1.63 ( 0.038 )
    -1.34 ( 0.039 )
    -0.85 ( 0.052 )
    Statistical analysis title
    		 Insulin Glargine/Lixisenatide vs Insulin Glargine
    Statistical analysis description
    Testing according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant). Here, it is test no. 6 of testing order. Analysis was performed using MMRM model with treatment groups, randomization strata of Week -1 HbA1c (<8.0, ≥8.0%), randomization strata of second OAD use at screening, visit, treatment-by-visit interaction, and country as fixed effects and baseline HbA1c value-by-visit interaction as a covariate.
    Comparison groups
    Insulin Glargine/Lixisenatide Fixed Ratio Combination v Insulin Glargine
    Number of subjects included in analysis
    931
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [14]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.384
         upper limit
    		 -0.194
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.048
    Notes
    [14] - Threshold for significance ≤ 0.05.

    Secondary: Percentage of Subjects Reaching HbA1c <7.0% With No Body Weight Gain at Week 30 and No Documented (Plasma Glucose [PG] ≤ 70 mg/dL [3.9 mmol/L]) Symptomatic Hypoglycemia During 30-Week Treatment Period

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    End point title
    		 Percentage of Subjects Reaching HbA1c <7.0% With No Body Weight Gain at Week 30 and No Documented (Plasma Glucose [PG] ≤ 70 mg/dL [3.9 mmol/L]) Symptomatic Hypoglycemia During 30-Week Treatment Period
    End point description
    Documented symptomatic hypoglycemia was an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of ≤70 mg/dL (3.9 mmol/L). mITT population. Subjects without any HbA1c and/or body weight value at Week 30 were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 30
    End point values
    		 Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Number of subjects analysed
    468
    466
    233
    Units: Percentage of subjects
        number (not applicable)
    31.8
    18.9
    26.2
    Statistical analysis title
    		 Insulin Glargine/Lixisenatide vs Insulin Glargine
    Statistical analysis description
    Testing according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant). Here, it is test no. 8 of testing order. Analysis was performed using Cochran-Mantel-Haenszel method stratified on randomization strata of Week-1 HbA1c (<8.0%, ≥8.0%) and randomization strata of second OAD use at screening.
    Comparison groups
    Insulin Glargine v Insulin Glargine/Lixisenatide Fixed Ratio Combination
    Number of subjects included in analysis
    934
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [15]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    12.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.5
         upper limit
    		 18.45
    Notes
    [15] - Threshold for significance ≤ 0.05.

    Secondary: Average Daily Insulin Glargine Dose at Week 30

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    End point title
    		 Average Daily Insulin Glargine Dose at Week 30 [16]
    End point description
    mITT population. The analysis included scheduled measurements obtained up to the date of last injection of the IMP, including those obtained after introduction of rescue therapy. Here, number of subjects analyzed=subjects with insulin glargine dose assessment during study period.
    End point type
    Secondary
    End point timeframe
    Week 30
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is reporting results only for the arms in which Insulin glargine was administered.
    End point values
    		 Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine
    Number of subjects analysed
    467
    463
    Units: Units (U)
        least squares mean (standard error)
    39.77 ( 0.699 )
    40.46 ( 0.701 )
    Statistical analysis title
    		 Insulin Glargine/Lixisenatide vs Insulin Glargine
    Statistical analysis description
    Testing according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant). Here, it is test no. 9 of testing order. Analysis was performed using MMRM model with treatment groups, randomization strata of Week-1 HbA1c (<8.0, ≥8.0%), randomization strata of second OAD use at screening, visit, treatment-by-visit interaction, and country as fixed effects.
    Comparison groups
    Insulin Glargine/Lixisenatide Fixed Ratio Combination v Insulin Glargine
    Number of subjects included in analysis
    930
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4857 [17]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.632
         upper limit
    		 1.252
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.99
    Notes
    [17] - Threshold for significance ≤ 0.05.

    Secondary: Change in 2-Hour PPG From Baseline to Week 30

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    End point title
    		 Change in 2-Hour PPG From Baseline to Week 30
    End point description
    The 2-hour PPG test measured blood glucose 2 hours after eating a liquid standardized breakfast meal. Change in PPG was calculated by subtracting baseline value from Week 30 value. Missing data was imputed using LOCF. mITT population. Here, number of subjects analyzed=subjects with baseline and at least one post-baseline 2¬hour PPG assessment during study period.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 30
    End point values
    		 Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Number of subjects analysed
    430
    430
    196
    Units: mmol/L
        least squares mean (standard error)
    -5.68 ( 0.176 )
    -3.31 ( 0.178 )
    -4.58 ( 0.245 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Reaching HbA1c <7.0% at Week 30 With No Documented Symptomatic Hypoglycemia (PG ≤ 70 mg/dL [3.9 mmol/L]) During 30-Week Treatment Period

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    End point title
    		 Percentage of Subjects Reaching HbA1c <7.0% at Week 30 With No Documented Symptomatic Hypoglycemia (PG ≤ 70 mg/dL [3.9 mmol/L]) During 30-Week Treatment Period
    End point description
    Documented symptomatic hypoglycemia was an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of ≤70 mg/dL (3.9 mmol/L). The analysis included all HbA1c measurements at week 30, including those obtained after the IMP discontinuation or the introduction of rescue medication. mITT population. Subjects without Week 30 value for HbA1c were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 30
    End point values
    		 Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Number of subjects analysed
    468
    466
    233
    Units: Percentage of subjects
        number (not applicable)
    53.6
    44.4
    30.5
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Requiring Rescue Therapy During 30-Week Treatment Period

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    End point title
    		 Percentage of Subjects Requiring Rescue Therapy During 30-Week Treatment Period
    End point description
    Routine fasting SMPG and central laboratory FPG (and HbA1c after Week 12) values were used to determine the requirement of rescue medication. If fasting SMPG value exceeded the specified limit for 3 consecutive days, the central laboratory FPG (and HbA1c after Week 12) was performed. mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 30
    End point values
    		 Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Number of subjects analysed
    468
    466
    233
    Units: Percentage of subjects
        number (not applicable)
    3.6
    3.4
    12.4
    No statistical analyses for this end point

    Secondary: Number of Documented Symptomatic Hypoglycemia Events per Subject-Year

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    End point title
    		 Number of Documented Symptomatic Hypoglycemia Events per Subject-Year
    End point description
    Documented symptomatic hypoglycemia was an event during which symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of ≤ 70 mg/dL (3.9 mmol/L). Analysis was performed on safety population defined as all randomized subjects who received at least one dose of IMP regardless of the amount of treatment administered.
    End point type
    Secondary
    End point timeframe
    First dose of study drug up to 1 day after the last dose administration (median treatment exposure: 211 days)
    End point values
    		 Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Number of subjects analysed
    469
    467
    233
    Units: Events per subject-year
        number (not applicable)
    1.44
    1.22
    0.34
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Documented Symptomatic Hypoglycemia

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    End point title
    		 Percentage of Subjects With Documented Symptomatic Hypoglycemia
    End point description
    Documented symptomatic hypoglycemia was an event during which symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of ≤ 70 mg/dL (3.9 mmol/L). Analysis was performed on safety population.
    End point type
    Secondary
    End point timeframe
    First dose of study drug up to 1 day after the last dose administration (median treatment exposure 211 days)
    End point values
    		 Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Number of subjects analysed
    469
    467
    233
    Units: Percentage of Subjects
        number (not applicable)
    25.6
    23.6
    6.4
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Severe Symptomatic Hypoglycemia

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    End point title
    		 Percentage of Subjects With Severe Symptomatic Hypoglycemia
    End point description
    Severe symptomatic hypoglycemia was an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Plasma glucose measurements might not have been available during such an event, but neurological recovery attributable to the restoration of plasma glucose to normal was considered sufficient evidence that the event had been induced by a low plasma glucose concentration. Severe symptomatic hypoglycemia included all episodes in which neurological impairment was severe enough to prevent self-treatment, and which were thus thought to place subjects at risk of injury to themselves or others. Analysis was performed on safety population.
    End point type
    Secondary
    End point timeframe
    First dose of study drug up to 1 day after the last dose administration (median treatment exposure: 211 days)
    End point values
    		 Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Lixisenatide
    Number of subjects analysed
    469
    467
    233
    Units: Percentage of subjects
        number (not applicable)
    0
    0.2
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Week 30) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported AEs and deaths are treatment-emergent that is AEs that developed/worsened and deaths that occurred during 'on-treatment period’ (time from first injection of open-label IMP up to 3 days [1 day for symptomatic hypoglycemia] after the last injection of IMP regardless of the introduction of rescue therapy).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Insulin Glargine/Lixisenatide Fixed Ratio Combination
    Reporting group description
    		 Insulin glargine 10 U/ Lixisenatide 5 mcg fixed-ratio combination (FRC) once daily (QD) for first week post-randomization, followed by dose adjustment (avoiding hypoglycemia) to reach and maintain fasting SMPG of 80 mg/dL to 100 mg/dL (4.4 mmol/L to 5.6 mmol/L) up to 30 weeks (median exposure: 211 days).

    Reporting group title
    Lixisenatide
    Reporting group description
    		 Lixisenatide 10 mcg QD for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to Week 30 (median exposure: 211 days).

    Reporting group title
    Insulin Glargine
    Reporting group description
    		 Insulin glargine 10 U QD for first week post-randomization, followed by dose adjustment (avoiding hypoglycemia) to reach and maintain fasting SMPG of 80 mg/dL to 100 mg/dL (4.4 mmol/L to 5.6 mmol/L) up to 30 weeks (median exposure: 211 days).

    Serious adverse events
    		 Insulin Glargine/Lixisenatide Fixed Ratio Combination Lixisenatide Insulin Glargine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 469 (3.84%)
    9 / 233 (3.86%)
    19 / 467 (4.07%)
         number of deaths (all causes)
    1
    1
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung Cancer Metastatic
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 233 (0.00%)
    0 / 467 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Lung Neoplasm Malignant
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 233 (0.43%)
    0 / 467 (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
    Metastases To Liver
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 233 (0.43%)
    0 / 467 (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
    Pancreatic Carcinoma
         subjects affected / exposed
    0 / 469 (0.00%)
    0 / 233 (0.00%)
    1 / 467 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate Cancer Recurrent
         subjects affected / exposed
    0 / 469 (0.00%)
    0 / 233 (0.00%)
    1 / 467 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous Cell Carcinoma Of Skin
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 233 (0.00%)
    0 / 467 (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
    Squamous Cell Carcinoma Of The Oral Cavity
         subjects affected / exposed
    0 / 469 (0.00%)
    0 / 233 (0.00%)
    1 / 467 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Thyroid Adenoma
         subjects affected / exposed
    0 / 469 (0.00%)
    0 / 233 (0.00%)
    1 / 467 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 233 (0.00%)
    1 / 467 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 233 (0.43%)
    0 / 467 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    0 / 469 (0.00%)
    0 / 233 (0.00%)
    1 / 467 (0.21%)
         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
    Anaphylactic Reaction
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 233 (0.43%)
    0 / 467 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Acquired Phimosis
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 233 (0.00%)
    0 / 467 (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
    Cervical Dysplasia
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 233 (0.00%)
    0 / 467 (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
    Metrorrhagia
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 233 (0.00%)
    0 / 467 (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
    Respiratory, thoracic and mediastinal disorders
    Acute Pulmonary Oedema
         subjects affected / exposed
    0 / 469 (0.00%)
    0 / 233 (0.00%)
    1 / 467 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    0 / 469 (0.00%)
    0 / 233 (0.00%)
    1 / 467 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 469 (0.00%)
    0 / 233 (0.00%)
    1 / 467 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 233 (0.43%)
    0 / 467 (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
    Investigations
    Electrocardiogram St-T Segment Abnormal
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 233 (0.00%)
    0 / 467 (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
    Lipase Increased
         subjects affected / exposed
    0 / 469 (0.00%)
    0 / 233 (0.00%)
    1 / 467 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Comminuted Fracture
         subjects affected / exposed
    0 / 469 (0.00%)
    0 / 233 (0.00%)
    1 / 467 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tendon Rupture
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 233 (0.00%)
    0 / 467 (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
    Toxicity To Various Agents
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 233 (0.43%)
    0 / 467 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    0 / 469 (0.00%)
    0 / 233 (0.00%)
    1 / 467 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiac Failure Acute
         subjects affected / exposed
    0 / 469 (0.00%)
    0 / 233 (0.00%)
    1 / 467 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiac Failure Chronic
         subjects affected / exposed
    0 / 469 (0.00%)
    0 / 233 (0.00%)
    1 / 467 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 233 (0.00%)
    1 / 467 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Coronary Artery Disease
         subjects affected / exposed
    0 / 469 (0.00%)
    0 / 233 (0.00%)
    1 / 467 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    0 / 469 (0.00%)
    0 / 233 (0.00%)
    1 / 467 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 233 (0.00%)
    0 / 467 (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
    Lacunar Infarction
         subjects affected / exposed
    0 / 469 (0.00%)
    0 / 233 (0.00%)
    1 / 467 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 233 (0.43%)
    0 / 467 (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
    Transient Ischaemic Attack
         subjects affected / exposed
    1 / 469 (0.21%)
    1 / 233 (0.43%)
    0 / 467 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Pancytopenia
         subjects affected / exposed
    0 / 469 (0.00%)
    0 / 233 (0.00%)
    1 / 467 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Oesophagitis
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 233 (0.00%)
    0 / 467 (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
    Hepatobiliary disorders
    Cholecystitis Chronic
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 233 (0.00%)
    0 / 467 (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
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 233 (0.00%)
    0 / 467 (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
    Urticaria
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 233 (0.00%)
    0 / 467 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 233 (0.43%)
    0 / 467 (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
    Bladder Prolapse
         subjects affected / exposed
    0 / 469 (0.00%)
    0 / 233 (0.00%)
    1 / 467 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Calculus Urinary
         subjects affected / exposed
    0 / 469 (0.00%)
    0 / 233 (0.00%)
    1 / 467 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 469 (0.00%)
    0 / 233 (0.00%)
    1 / 467 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal Colic
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 233 (0.00%)
    0 / 467 (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
    Costochondritis
         subjects affected / exposed
    0 / 469 (0.00%)
    0 / 233 (0.00%)
    1 / 467 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal Osteoarthritis
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 233 (0.43%)
    0 / 467 (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
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 469 (0.00%)
    0 / 233 (0.00%)
    1 / 467 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 469 (0.21%)
    1 / 233 (0.43%)
    0 / 467 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile Infection
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 233 (0.00%)
    0 / 467 (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
    Meningitis Staphylococcal
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 233 (0.43%)
    0 / 467 (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
    Pneumonia
         subjects affected / exposed
    0 / 469 (0.00%)
    0 / 233 (0.00%)
    1 / 467 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis Acute
         subjects affected / exposed
    0 / 469 (0.00%)
    0 / 233 (0.00%)
    1 / 467 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    2 / 469 (0.43%)
    0 / 233 (0.00%)
    0 / 467 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 469 (0.00%)
    0 / 233 (0.00%)
    1 / 467 (0.21%)
         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
    Diabetes Mellitus Inadequate Control
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 233 (0.43%)
    0 / 467 (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
    Metabolic Acidosis
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 233 (0.43%)
    0 / 467 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         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
    		 Insulin Glargine/Lixisenatide Fixed Ratio Combination Lixisenatide Insulin Glargine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    138 / 469 (29.42%)
    98 / 233 (42.06%)
    85 / 467 (18.20%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    24 / 469 (5.12%)
    18 / 233 (7.73%)
    15 / 467 (3.21%)
         occurrences all number
    28
    22
    16
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    42 / 469 (8.96%)
    21 / 233 (9.01%)
    20 / 467 (4.28%)
         occurrences all number
    54
    26
    26
    Nausea
         subjects affected / exposed
    45 / 469 (9.59%)
    56 / 233 (24.03%)
    17 / 467 (3.64%)
         occurrences all number
    63
    76
    17
    Vomiting
         subjects affected / exposed
    15 / 469 (3.20%)
    15 / 233 (6.44%)
    7 / 467 (1.50%)
         occurrences all number
    18
    19
    9
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    26 / 469 (5.54%)
    15 / 233 (6.44%)
    25 / 467 (5.35%)
         occurrences all number
    33
    18
    27
    Upper Respiratory Tract Infection
         subjects affected / exposed
    33 / 469 (7.04%)
    12 / 233 (5.15%)
    23 / 467 (4.93%)
         occurrences all number
    38
    13
    25

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Jul 2014
    Following changes were made: •Inclusion criterion was modified to allow enrollment of subjects with prior metformin and Dipeptidyl peptidase-4 (DPP-4) inhibitor treatment. •Monitoring and evaluating of device/pen-related events was added. •Changes to collection of pharmacokinetic (PK) and antibody sampling were made. PK assessments in the lixisenatide group were only to be done in subjects who injected IMP in the morning. Blood samples for PK and antibody analyses were to be analyzed before initiating rescue therapy. Blood samples for antibody analyses had to be collected and assessed at Week 30 for subjects who permanently discontinued IMP and stayed in the study. •Calculated creatinine clearance categories at screening used for the description of demographic and baseline characteristics were changed to be consistent with the draft Food and Drugs Administration (FDA) guideline for Industry. •Contraceptive methods allowed for women of childbearing potential were clarified following a request from the Danish Health Authority for subjects from Denmark. •Primary efficacy analyses were to be performed using assessment collected during the study instead of during the on-treatment period •The step-down testing procedure for efficacy endpoints was updated •Analyses of pancreatitis and pancreatic neoplasm positively adjudicated by pancreatic safety assessment committee (PSAC) were added.

    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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