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    Clinical Trial Results:
    A Randomized, Open-Label, Active-Controlled, 3-Arm Parallel-Group, 26-Week Study Comparing the Efficacy and Safety of Lixisenatide to That of Insulin Glulisine Once Daily and Insulin Glulisine Three Times Daily in Patients With Type 2 Diabetes Insufficiently Controlled With Insulin Glargine With or Without Metformin

    Summary
    EudraCT number
    		 2012-004096-38
    Trial protocol
    		 CZ   GB   HU   ES   IT   DE   PL   EE   LV   LT  
    Global end of trial date
    03 Dec 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jul 2016
    First version publication date
    28 Jul 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    EFC12626
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01768559
    WHO universal trial number (UTN)
    		 U1111-1131-4936
    Other trial identifiers
    		 Study Name: GETGOAL DUO-2
    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
    16 Jan 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate in subjects with type 2 diabetes mellitus (T2DM) not adequately controlled on insulin glargine with or without metformin: The non-inferiority of lixisenatide versus insulin glulisine once daily (QD) (Basal Plus regimen) on glycated hemoglobin A1c (HbA1c) reduction at Week 26; The non-inferiority of lixisenatide versus insulin glulisine thrice daily (TID)(Basal Bolus regimen) on HbA1c reduction or superiority on body weight change at Week 26.
    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 Sanofi-Aventis 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 received insulin glargine throughout the study. During the run-in phase, the dose of insulin glargine was titrated every 3 days to maintain a fasting self-monitored plasma glucose (SMPG) between 80 and 100 mg/dL (4.4 and 5.6 mmol/L, respectively). After randomization, except during the 4 weeks following randomization where a stable dose should be maintained, the dose was adjusted weekly as necessary to maintain a fasting SMPG in the same range. Subjects who were receiving metformin prior to entering the study, continued to receive metformin at a dose of ≥1.5 g/day or at the maximal tolerated dose throughout the study, at a stable dose unless there was a specific safety issue related to this treatment.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Jan 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 27
    Country: Number of subjects enrolled
    Spain: 35
    Country: Number of subjects enrolled
    United Kingdom: 23
    Country: Number of subjects enrolled
    Czech Republic: 27
    Country: Number of subjects enrolled
    Estonia: 14
    Country: Number of subjects enrolled
    France: 28
    Country: Number of subjects enrolled
    Germany: 30
    Country: Number of subjects enrolled
    Hungary: 54
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    Latvia: 14
    Country: Number of subjects enrolled
    Lithuania: 15
    Country: Number of subjects enrolled
    Canada: 65
    Country: Number of subjects enrolled
    Chile: 50
    Country: Number of subjects enrolled
    Mexico: 100
    Country: Number of subjects enrolled
    Romania: 118
    Country: Number of subjects enrolled
    Russian Federation: 86
    Country: Number of subjects enrolled
    Ukraine: 54
    Country: Number of subjects enrolled
    United States: 138
    Worldwide total number of subjects
    894
    EEA total number of subjects
    401
    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)
    616
    From 65 to 84 years
    277
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 199 centers in 18 countries between January 08, 2013 and December 03, 2014.

    Pre-assignment
    Screening details
    		 A total of 2159 subjects were screened. Subjects underwent a 12 week run–in period with switch from other basal insulins to insulin glargine. 1265 subjects were screen failures/run-in failures; the most frequent reason for run-in failure was that HbA1C criteria were not met at the end of run-in phase. A total of 894 subjects were randomized.

    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
    		 Lixisenatide
    Arm description
    		 Lixisenatide 10 mcg QD subcutaneously for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to Week 26 on top of insulin glargine with or without metformin.
    Arm type
    		 Experimental

    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 by subcutaneous injection 30 to 60 minutes before breakfast or dinner using disposable pre-filled pen.

    Arm title
    		 Insulin Glulisine QD
    Arm description
    		 Insulin glulisine QD subcutaneously from randomization up to Week 26 on top of insulin glargine with or without metformin.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Insulin glulisine
    Investigational medicinal product code
    Other name
    Apidra®
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Insulin glulisine was administered QD within 15 minutes before breakfast or dinner. The initial dose was 3-5 units and then individually titrated to obtain the SMPG value >5.6 mmol/L (100 mg/dL) and ≤7.8 mmol/L (140 mg/dL) before lunch (if administered at breakfast) or at bedtime (if administered at dinner).

    Arm title
    		 Insulin Glulisine TID
    Arm description
    		 Insulin Glulisine TID subcutaneously from randomization up to Week 26 on top of insulin glargine with or without metformin.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Insulin glulisine
    Investigational medicinal product code
    Other name
    Apidra®
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Insulin glulisine was administered TID within 15 minutes before each meal. The initial dose was 3-5 units for each meal and then individually titrated to obtain the SMPG value >5.6 mmol/L (100 mg/dL) and ≤7.8 mmol/L (140 mg/dL) before the next meal (for injections at breakfast or at lunch) or at bedtime (for injection at dinner).

    Number of subjects in period 1
    		Lixisenatide Insulin Glulisine QD Insulin Glulisine TID
    Started
    298
    298
    298
    Treated
    298
    298
    297
    Completed
    268
    281
    285
    Not completed
    30
    17
    13
         Randomized but not treated
    -
    -
    1
         Adverse event
    15
    2
    5
         Other than specified
    9
    8
    5
         Poor compliance to protocol
    -
    3
    2
         Lack of efficacy
    6
    4
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lixisenatide
    Reporting group description
    		 Lixisenatide 10 mcg QD subcutaneously for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to Week 26 on top of insulin glargine with or without metformin.

    Reporting group title
    Insulin Glulisine QD
    Reporting group description
    		 Insulin glulisine QD subcutaneously from randomization up to Week 26 on top of insulin glargine with or without metformin.

    Reporting group title
    Insulin Glulisine TID
    Reporting group description
    		 Insulin Glulisine TID subcutaneously from randomization up to Week 26 on top of insulin glargine with or without metformin.

    Reporting group values
    		 Lixisenatide Insulin Glulisine QD Insulin Glulisine TID Total
    Number of subjects
    		 298 298 298 894
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.8 ( 8.6 ) 60.2 ( 8.6 ) 59.4 ( 9.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 160 163 166 489
        Male
    		 138 135 132 405
    Race
    Units: Subjects
        Caucasian/White
    		 276 280 272 828
        Black
    		 13 11 12 36
        Asian/Oriental
    		 9 7 13 29
        Other
    		 0 0 1 1
    Ethnicity
    Units: Subjects
        Hispanic
    		 63 58 68 189
        Non-Hispanic
    		 235 240 230 705
    Metformin use at screening
    Units: Subjects
        Yes
    		 262 260 259 781
        No
    		 36 38 39 113
    Number of Subjects with Categorical Body Mass Index (BMI)
    Units: Subjects
        <30 kg/m^2
    		 97 118 97 312
        ≥30 kg/m^2
    		 201 180 200 581
        Subjects not analyzed for BMI
    		 0 0 1 1
    BMI
    893 subjects (298 in lixisenatide arm; 298 in Insulin Glulisine QD and 297 in Insulin Glulisine TID) were included for baseline BMI analysis.
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 32.27 ( 4.57 ) 31.86 ( 4.39 ) 32.5 ( 4.6 ) -
    Weight
    893 subjects (298 in lixisenatide arm; 298 in Insulin Glulisine QD and 297 in Insulin Glulisine TID) were included for baseline weight analysis.
    Units: kg
        arithmetic mean (standard deviation)
    		 90.06 ( 17.31 ) 88.45 ( 15.84 ) 90.08 ( 17.18 ) -
    HbA1c
    893 subjects (298 in lixisenatide arm; 298 in Insulin Glulisine QD and 297 in Insulin Glulisine TID) were included for HbA1c analysis.
    Units: Percentage of hemoglobin
        arithmetic mean (standard deviation)
    		 7.77 ( 0.55 ) 7.73 ( 0.59 ) 7.79 ( 0.6 ) -
    Fasting Plasma Glucose (FPG)
    893 subjects (298 in lixisenatide arm; 298 in Insulin Glulisine QD and 297 in Insulin Glulisine TID) were included for FPG analysis.
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 6.58 ( 1.82 ) 6.84 ( 1.98 ) 6.65 ( 1.89 ) -
    2-Hour Postprandial Plasma Glucose (PPG)
    258 subjects (79 in lixisenatide arm; 77 in Insulin Glulisine QD and 102 in Insulin Glulisine TID) were included for PPG analysis.
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 14.26 ( 3.55 ) 14.02 ( 3.59 ) 14.25 ( 3.35 ) -
    2-Hour Glucose Excursion
    243 subjects (73 in lixisenatide arm; 74 in Insulin Glulisine QD and 96 in Insulin Glulisine TID) were included for 2-hour glucose excursion analysis.
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 7.31 ( 3.19 ) 7.31 ( 3.63 ) 7.35 ( 3.34 ) -
    Average 7-Point SMPG
    877 subjects (292 in lixisenatide arm; 291 in Insulin Glulisine QD and 294 in Insulin Glulisine TID) were included for average 7-point SMPG analysis.
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 9.02 ( 1.75 ) 9.07 ( 1.74 ) 8.99 ( 1.57 ) -
    Insulin Glargine Dose
    893 subjects (298 in lixisenatide arm; 298 in Insulin Glulisine QD and 297 in Insulin Glulisine TID) were included for insulin glargine dose analysis.
    Units: Units (U)
        arithmetic mean (standard deviation)
    		 67.25 ( 31.95 ) 64.72 ( 32.07 ) 64.97 ( 26.9 ) -
    Duration of Diabetes
    Units: years
        arithmetic mean (standard deviation)
    		 11.89 ( 6.43 ) 12.33 ( 6.75 ) 12.41 ( 6.8 ) -

    End points

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    End points reporting groups
    Reporting group title
    Lixisenatide
    Reporting group description
    		 Lixisenatide 10 mcg QD subcutaneously for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to Week 26 on top of insulin glargine with or without metformin.

    Reporting group title
    Insulin Glulisine QD
    Reporting group description
    		 Insulin glulisine QD subcutaneously from randomization up to Week 26 on top of insulin glargine with or without metformin.

    Reporting group title
    Insulin Glulisine TID
    Reporting group description
    		 Insulin Glulisine TID subcutaneously from randomization up to Week 26 on top of insulin glargine with or without metformin.

    Subject analysis set title
    Insulin Glulisine QD
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Insulin glulisine QD subcutaneously from randomization up to Week 26 on top of insulin glargine with or without metformin. 4 subjects were randomized to Insulin glulisine TID group, but received insulin glulisine QD for more than 50% of treatment period. These subjects were included in QD arm for safety analysis.

    Subject analysis set title
    Insulin Glulisine TID
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Insulin Glulisine TID subcutaneously from randomization up to Week 26 on top of insulin glargine with or without metformin. 1 subject was randomized to Insulin glulisine QD group, but received insulin glulisine TID for more than 50% of treatment period. This subject was included in TID arm for safety analysis.

    Primary: Change in HbA1c From Baseline to Week 26

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    End point title
    		 Change in HbA1c From Baseline to Week 26
    End point description
    Change in HbA1C was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using last on-treatment observation carried forward (LOCF). On-treatment period for this efficacy variable was defined as the time from the first dose of study drug up to 14 days after the last dose of study drug. mITT population: all randomized subjects who received at least one dose of study drug; and had both baseline and at least one post-baseline efficacy assessment, irrespective of compliance with study protocol/procedures. Here, number of subjects analyzed=subjects with baseline and at least one post-baseline HbA1c assessment during on-treatment period.
    End point type
    Primary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Lixisenatide Insulin Glulisine QD Insulin Glulisine TID
    Number of subjects analysed
    292
    292
    295
    Units: Percentage of hemoglobin
        least squares mean (standard error)
    -0.63 ( 0.054 )
    -0.58 ( 0.054 )
    -0.84 ( 0.053 )
    Statistical analysis title
    		 Lixisenatide vs Insulin Glulisine QD
    Statistical analysis description
    Analysis was performed using analysis of covariance (ANCOVA) model with treatment groups, strata of Week -1 HbA1c (<8.0, ≥8.0%), randomization strata of metformin use, and country as fixed effects and baseline HbA1c value as a covariate. The non-inferiority was assessed using upper bound of 2-sided 95% CI.
    Comparison groups
    Lixisenatide v Insulin Glulisine QD
    Number of subjects included in analysis
    584
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    		 ANCOVA
    Parameter type
    		 Least Square (LS) Mean Difference
    Point estimate
    -0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.17
         upper limit
    		 0.064
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.059
    Notes
    [1] - Pre-specified non-inferiority margin of 0.4%
    Statistical analysis title
    		 Lixisenatide vs Insulin Glulisine TID
    Statistical analysis description
    Analysis was performed using ANCOVA model as described above. Hochberg procedure was used to control type 1 error at significance level = 0.025 (1-sided) for comparison between lixisenatide vs insulin glulisine TID in HbA1c and body weight. If both comparisons were met, then both would be declared significant. Otherwise, if only one was met, then the one met should be tested at α=0.0125 (1-sided).
    Comparison groups
    Lixisenatide v Insulin Glulisine TID
    Number of subjects included in analysis
    587
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.095
         upper limit
    		 0.328
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.059
    Notes
    [2] - Pre-specified non-inferiority margin of 0.4%

    Primary: Change in Body Weight From Baseline to Week 26

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    End point title
    		 Change in Body Weight From Baseline to Week 26
    End point description
    Change in body weight was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug up to 3 days after the last dose of study drug. mITT population. Here, number of subjects analyzed=subjects with baseline and at least one post-baseline body weight assessment during on-treatment period.
    End point type
    Primary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Lixisenatide Insulin Glulisine QD Insulin Glulisine TID
    Number of subjects analysed
    295
    295
    295
    Units: kg
        least squares mean (standard error)
    -0.63 ( 0.276 )
    1.03 ( 0.276 )
    1.37 ( 0.271 )
    Statistical analysis title
    		 Lixisenatide vs Insulin Glulisine TID
    Statistical analysis description
    Analysis was performed using ANCOVA model as described above. Hochberg procedure was used to control type 1 error at α = 0.025 (1-sided) for comparison between lixisenatide vs insulin glulisine TID in HbA1c and body weight . If both comparisons were met, then both would be declared significant. Otherwise, if only one was met, then the one met should be tested at α=0.0125 (1-sided).
    Comparison groups
    Lixisenatide v Insulin Glulisine TID
    Number of subjects included in analysis
    590
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.0001 [4]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.593
         upper limit
    		 -1.396
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.305
    Notes
    [3] - The superiority was assessed by comparing the P-value at significance level = 0.025 or 0.0125.
    [4] - Threshold for significance at 0.025 level.

    Secondary: Percentage of Subjects with HbA1c level <7% and ≤6.5% at Week 26

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    End point title
    		 Percentage of Subjects with HbA1c level <7% and ≤6.5% at Week 26
    End point description
    The on-treatment period for this efficacy variable was defined as the time from the first dose of study drug up to 14 days after the last dose of study drug. Missing data was imputed using LOCF. mITT population. Here, number of subjects analyzed=subjects with baseline and at least one post-baseline HbA1c assessment during on-treatment period.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 Lixisenatide Insulin Glulisine QD Insulin Glulisine TID
    Number of subjects analysed
    292
    292
    295
    Units: Percentage of subjects
    number (not applicable)
        HbA1c ≤6.5%
    20.5
    17.8
    30.8
        HbA1c <7.0%
    42.1
    38.4
    49.2
    No statistical analyses for this end point

    Secondary: Change in Body Weight from Baseline to Week 26- Lixisenatide arm versus Insulin Glulisine QD arm

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    End point title
    		 Change in Body Weight from Baseline to Week 26- Lixisenatide arm versus Insulin Glulisine QD arm
    End point description
    Change in body weight was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug up to 3 days after the last dose of study drug. mITT population. Here, number of subjects analyzed=subjects with baseline and at least one post-baseline body weight assessment during on-treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Lixisenatide Insulin Glulisine QD Insulin Glulisine TID
    Number of subjects analysed
    295
    295
    295
    Units: kg
        least squares mean (standard error)
    -0.63 ( 0.276 )
    1.03 ( 0.276 )
    1.37 ( 0.271 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with no Weight Gain at Week 26

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    End point title
    		 Percentage of Subjects with no Weight Gain at Week 26
    End point description
    The on-treatment period for this efficacy variable was the time from the first dose of study drug up to 3 days after the last dose of study drug. mITT population. Here, number of subjects analyzed=subjects with baseline and at least one post-baseline body weight assessment during on-treatment period.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 Lixisenatide Insulin Glulisine QD Insulin Glulisine TID
    Number of subjects analysed
    295
    295
    295
    Units: Percentage of subjects
        number (not applicable)
    64.7
    36.6
    30.5
    No statistical analyses for this end point

    Secondary: Change in Average 7-point SMPG Profiles from Baseline to Week 26

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    End point title
    		 Change in Average 7-point SMPG Profiles from Baseline to Week 26
    End point description
    Subjects recorded a 7-point plasma glucose profile measured before and 2 hours after each meal and at bedtime three times in a week before baseline, before visit Week 12 and before visit Week 26 and the average value across the profiles performed in the week a visit for the 7-time points was calculated. Change in average 7-point SMPG was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using LOCF. The on-treatment period for this efficacy variable was defined as the time from the first dose of study drug up to the day of last dose of study drug. mITT population. Here, number of subjects analyzed=subjects with baseline and at least one post-baseline 7-point SMPG assessment during on-treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Lixisenatide Insulin Glulisine QD Insulin Glulisine TID
    Number of subjects analysed
    270
    268
    278
    Units: mmol/L
        least squares mean (standard error)
    -0.784 ( 0.1141 )
    -0.782 ( 0.1133 )
    -1.053 ( 0.1105 )
    No statistical analyses for this end point

    Secondary: Change in FPG from Baseline to Week 26

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    End point title
    		 Change in FPG from Baseline to Week 26
    End point description
    Change in FPG was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using LOCF. The on-treatment period for this efficacy variable was the time from the first dose of study drug up to 1 day after the last dose of study drug. mITT population. Here, number of subjects analyzed=subjects with baseline and at least one post-baseline FPG assessment during on-treatment period
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Lixisenatide Insulin Glulisine QD Insulin Glulisine TID
    Number of subjects analysed
    295
    295
    294
    Units: mmol/L
        least squares mean (standard error)
    -0.23 ( 0.143 )
    -0.21 ( 0.142 )
    -0.06 ( 0.14 )
    No statistical analyses for this end point

    Secondary: Change in PPG from Baseline to Week 26 (in Subjects who had an Injection of Investigational Medicinal Product [IMP] Before Breakfast)

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    End point title
    		 Change in PPG from Baseline to Week 26 (in Subjects who had an Injection of Investigational Medicinal Product [IMP] Before Breakfast)
    End point description
    The 2-hour PPG test measured blood glucose 2 hours after eating a standardized meal. Change in PPG was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using LOCF. The on-treatment period for this efficacy variable was the time from the first dose of study drug up to the day of last dose of study drug. mITT population. Here, number of subjects analyzed=subjects with IMP injection before breakfast and baseline and at least one post-baseline 2-hour PPG assessment during on-treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Lixisenatide Insulin Glulisine QD Insulin Glulisine TID
    Number of subjects analysed
    69
    55
    68
    Units: mmol/L
        arithmetic mean (standard deviation)
    -3.93 ( 4.29 )
    -1.62 ( 4.01 )
    -1.87 ( 3.18 )
    No statistical analyses for this end point

    Secondary: Change in Glucose Excursions from Baseline to Week 26 (in Subjects who had an Injection of IMP Before Breakfast)

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    End point title
    		 Change in Glucose Excursions from Baseline to Week 26 (in Subjects who had an Injection of IMP Before Breakfast)
    End point description
    Glucose excursion = 2-hour PPG minus plasma glucose 30 minutes prior to the standardized meal test, before study drug administration. Change in glucose excursions was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using LOCF. The on-treatment period for this efficacy variable was the time from the first dose of study drug up to the day of last dose of study drug. mITT population. Here, number of subjects analyzed=subjects with IMP injection before breakfast and baseline and at least one post-baseline glucose excursion assessment during on-treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Lixisenatide Insulin Glulisine QD Insulin Glulisine TID
    Number of subjects analysed
    64
    53
    66
    Units: mmol/L
        arithmetic mean (standard deviation)
    -3.42 ( 4.13 )
    -1.59 ( 3.42 )
    -1.56 ( 2.52 )
    No statistical analyses for this end point

    Secondary: Change in Insulin Glargine Dose From Baseline to Week 26

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    End point title
    		 Change in Insulin Glargine Dose From Baseline to Week 26
    End point description
    Change in Insulin glargine dose was calculated by subtracting the baseline value from Week 26 value. Missing data was imputed using LOCF. The on-treatment period for this efficacy variable was the time from the first dose of study drug up to the day of last dose of study drug. mITT population. Here, number of subjects analyzed=subjects with baseline and at least one post-baseline insulin glargine dose assessment during on-treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 Lixisenatide Insulin Glulisine QD Insulin Glulisine TID
    Number of subjects analysed
    292
    294
    294
    Units: U
        least squares mean (standard error)
    0.7 ( 1.002 )
    -0.06 ( 0.999 )
    -3.13 ( 0.982 )
    No statistical analyses for this end point

    Secondary: Insulin Glulisine Dose at Week 26

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    End point title
    		 Insulin Glulisine Dose at Week 26 [5]
    End point description
    The on-treatment period for this efficacy variable was the time from the first dose of study drug up to the day of last dose of study drug. Missing data was imputed using LOCF. mITT population. Here, number of subjects analyzed=subjects with baseline and at least one post-baseline insulin glulisine dose assessment during on-treatment period.
    End point type
    Secondary
    End point timeframe
    Week 26
    Notes
    [5] - 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 Glulisine was administered.
    End point values
    		 Insulin Glulisine QD Insulin Glulisine TID
    Number of subjects analysed
    295
    293
    Units: U
        arithmetic mean (standard deviation)
    9.97 ( 7.8 )
    20.24 ( 13.04 )
    No statistical analyses for this end point

    Secondary: Total Insulin Dose at Week 26

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    End point title
    		 Total Insulin Dose at Week 26 [6]
    End point description
    The on-treatment period for this efficacy variable was the time from the first dose of study drug up to the day of last dose of study drug. Missing data was imputed using LOCF. mITT population. Here, number of subjects analyzed=subjects with baseline and at least one post-baseline total insulin dose assessment during on-treatment period.
    End point type
    Secondary
    End point timeframe
    Week 26
    Notes
    [6] - 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 of the arms in which Insulin Glulisine was administered, and therefore Total Insulin was derived by adding the Insuline Glulisine amount and Insulin Glargine amount.
    End point values
    		 Insulin Glulisine QD Insulin Glulisine TID
    Number of subjects analysed
    295
    294
    Units: U
        arithmetic mean (standard deviation)
    73.61 ( 39.13 )
    81.05 ( 33.55 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Documented Symptomatic and Severe Symptomatic Hypoglycemia

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    End point title
    		 Percentage of Subjects with Documented Symptomatic and Severe Symptomatic Hypoglycemia [7]
    End point description
    Documented symptomatic hypoglycemia was an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of <60 mg/dL (3.3 mmol/L). Severe symptomatic hypoglycemia was symptomatic hypoglycemia event in which the subject required the assistance of another person and was associated with either a plasma glucose level below 36 mg/dL (2.0 mmol/L) or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration, if no plasma glucose measurement was available. Safety population included all randomized subjects who were exposed to at least one dose of study drug, regardless of the amount of treatment administered.
    End point type
    Secondary
    End point timeframe
    First dose of study drug up to 3 days after the last dose administration (maximum of 185 days)
    Notes
    [7] - 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 statistics for safety set.
    End point values
    		 Lixisenatide Insulin Glulisine QD Insulin Glulisine TID
    Number of subjects analysed
    298
    301
    294
    Units: Percentage of subjects
    number (not applicable)
        Documented Symptomatic hypoglycemia
    31.5
    37.5
    44.6
        Severe symptomatic hypoglycemia
    0
    0.7
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects who Reached the Target of HbA1c <7% at Week 26 and did not Experienced Documented (Plasma Glucose <60 mg/dL) Symptomatic Hypoglycemia During 26-Week Treatment Period

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    End point title
    		 Percentage of Subjects who Reached the Target of HbA1c <7% at Week 26 and did not Experienced Documented (Plasma Glucose <60 mg/dL) Symptomatic Hypoglycemia During 26-Week Treatment Period
    End point description
    The on-treatment period for HbA1c assessment was defined as the time from the first dose of study drug up to 14 days after the last dose of study drug. The on-treatment period for symptomatic hypoglycemia assessment was defined as the time from the first dose of study drug up to 1 day after the last dose of study drug. mITT population. Subjects without any post-baseline on-treatment value for HbA1c were counted as non-responders if they experienced at least one symptomatic hypoglycemia. Otherwise, they were counted as missing.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 Lixisenatide Insulin Glulisine QD Insulin Glulisine TID
    Number of subjects analysed
    296
    293
    295
    Units: Percentage of subjects
        number (not applicable)
    29.4
    24.2
    26.1
    No statistical analyses for this end point

    Secondary: Percentage of Subjects who Reached the Target of HbA1c <7% and had no Weight Gain at Week 26

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    End point title
    		 Percentage of Subjects who Reached the Target of HbA1c <7% and had no Weight Gain at Week 26
    End point description
    The on-treatment period for HbA1c assessment was defined as the time from the first dose of study drug up to 14 days after the last dose of study drug. The on-treatment period for body weight assessment was defined as the time from the first dose of study drug up to 3 days after the last dose of study drug. mITT population. Subjects without post-baseline on-treatment values (for HbA1c and body weight) that were no more than 30 days apart were counted as non-responders if at least one of the components (HbA1c and/or body weight) was available and showed non-response. Otherwise, they were counted as missing data.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 Lixisenatide Insulin Glulisine QD Insulin Glulisine TID
    Number of subjects analysed
    295
    293
    295
    Units: Percentage of subjects
        number (not applicable)
    31.2
    16.7
    17.6
    No statistical analyses for this end point

    Secondary: Percentage of Subjects who Reached the Target of HbA1c <7%, had no Weight Gain at Week 26, and did not Experience Documented (Plasma Glucose <60 mg/dL) Symptomatic Hypoglycemia During 26-Week Treatment Period

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    End point title
    		 Percentage of Subjects who Reached the Target of HbA1c <7%, had no Weight Gain at Week 26, and did not Experience Documented (Plasma Glucose <60 mg/dL) Symptomatic Hypoglycemia During 26-Week Treatment Period
    End point description
    The on-treatment period for HbA1c assessment was defined as the time from the first dose of study drug up to 14 days after the last dose of study drug. The on-treatment period for body weight assessment was defined as the time from the first dose of study drug up to 3 days after the last dose of study drug. The on-treatment period for symptomatic hypoglycemia assessment was defined as the time from the first dose of study drug up to 1 day after the last dose of study drug. mITT population. Subjects without post-baseline on-treatment values (HbA1c and body weight) that were no more than 30 days apart were counted as non-responders if at least one of the components (HbA1c and/or body weight) was available and showed non-response, or if they experienced at least one documented symptomatic hypoglycemia during the on-treatment period. Otherwise, they were counted as missing data.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 Lixisenatide Insulin Glulisine QD Insulin Glulisine TID
    Number of subjects analysed
    297
    294
    295
    Units: Percentage of subjects
        number (not applicable)
    22.2
    9.2
    10.8
    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 (Day 185) regardless of seriousness or relationship to IMP.
    Adverse event reporting additional description
    Reported adverse events and deaths are treatment-emergent adverse events that is AEs that developed/worsened and death that occurred during the ‘on treatment period’ (time from the first dose of study drug up to 3 days after the last dose of study drug). Analysis was done on safety population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Lixisenatide
    Reporting group description
    		 Lixisenatide 10 mcg QD subcutaneously for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to Week 26 on top of insulin glargine with or without metformin (Median exposure of 182 days).

    Reporting group title
    Insulin Glulisine QD
    Reporting group description
    		 Insulin glulisine QD subcutaneously on top of insulin glargine with or without metformin (Median exposure of 182 days). 4 subjects were randomized to Insulin glulisine TID group, but received insulin glulisine QD for more than 50% of treatment period. These subjects were included in QD arm for safety analysis.

    Reporting group title
    Insulin Glulisine TID
    Reporting group description
    		 Insulin glulisine TID subcutaneously on top of insulin glargine with or without metformin (Median exposure of 182 days). 1 subject was randomized to Insulin glulisine QD group, but received insulin glulisine TID for more than 50% of treatment period. This subject was included in TID arm for safety analysis.

    Serious adverse events
    		 Lixisenatide Insulin Glulisine QD Insulin Glulisine TID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 298 (3.69%)
    11 / 301 (3.65%)
    14 / 294 (4.76%)
         number of deaths (all causes)
    1
    0
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal Cell Carcinoma
         subjects affected / exposed
    0 / 298 (0.00%)
    0 / 301 (0.00%)
    1 / 294 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Invasive Ductal Breast Carcinoma
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 301 (0.00%)
    1 / 294 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasm Malignant
         subjects affected / exposed
    0 / 298 (0.00%)
    0 / 301 (0.00%)
    1 / 294 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatic Carcinoma Metastatic
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 301 (0.00%)
    0 / 294 (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
    Uterine Cancer
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 301 (0.00%)
    0 / 294 (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
    Accidental Overdose
         subjects affected / exposed
    0 / 298 (0.00%)
    2 / 301 (0.66%)
    1 / 294 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ankle Fracture
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 301 (0.33%)
    0 / 294 (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
    Incisional Hernia
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 301 (0.33%)
    0 / 294 (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
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 298 (0.00%)
    0 / 301 (0.00%)
    1 / 294 (0.34%)
         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 disorders
    Angina Pectoris
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 301 (0.00%)
    1 / 294 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina Unstable
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 301 (0.33%)
    0 / 294 (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
    Atrial Fibrillation
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 301 (0.33%)
    0 / 294 (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
    Atrioventricular Block Complete
         subjects affected / exposed
    0 / 298 (0.00%)
    0 / 301 (0.00%)
    1 / 294 (0.34%)
         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 Chronic
         subjects affected / exposed
    0 / 298 (0.00%)
    0 / 301 (0.00%)
    1 / 294 (0.34%)
         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 Congestive
         subjects affected / exposed
    0 / 298 (0.00%)
    0 / 301 (0.00%)
    1 / 294 (0.34%)
         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 / 298 (0.00%)
    1 / 301 (0.33%)
    0 / 294 (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
    Myocardial Ischaemia
         subjects affected / exposed
    0 / 298 (0.00%)
    0 / 301 (0.00%)
    1 / 294 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular Accident
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 301 (0.00%)
    2 / 294 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemic Unconsciousness
         subjects affected / exposed
    0 / 298 (0.00%)
    2 / 301 (0.66%)
    0 / 294 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuritis Cranial
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 301 (0.33%)
    0 / 294 (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
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 301 (0.00%)
    0 / 294 (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
    Epigastric Discomfort
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 301 (0.00%)
    0 / 294 (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
    Gastric Ulcer Haemorrhage
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 301 (0.00%)
    0 / 294 (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
    Hepatic Mass
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 301 (0.00%)
    0 / 294 (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
    Diabetic Bullosis
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 301 (0.00%)
    0 / 294 (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 Ulcer Haemorrhage
         subjects affected / exposed
    0 / 298 (0.00%)
    0 / 301 (0.00%)
    1 / 294 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Renal and urinary disorders
    Renal Failure
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 301 (0.00%)
    0 / 294 (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
    Renal Failure Acute
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 301 (0.00%)
    0 / 294 (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
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 301 (0.33%)
    1 / 294 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 301 (0.00%)
    0 / 294 (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
    Penile Infection
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 301 (0.00%)
    0 / 294 (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
    Septic Arthritis Staphylococcal
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 301 (0.00%)
    0 / 294 (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
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 301 (0.00%)
    0 / 294 (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
    Dehydration
         subjects affected / exposed
    1 / 298 (0.34%)
    1 / 301 (0.33%)
    0 / 294 (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
    Hypoglycaemia
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 301 (0.33%)
    0 / 294 (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
    		 Lixisenatide Insulin Glulisine QD Insulin Glulisine TID
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    183 / 298 (61.41%)
    186 / 301 (61.79%)
    195 / 294 (66.33%)
    Investigations
    Blood Glucose Decreased
         subjects affected / exposed
    60 / 298 (20.13%)
    67 / 301 (22.26%)
    82 / 294 (27.89%)
         occurrences all number
    153
    254
    344
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    0 / 298 (0.00%)
    12 / 301 (3.99%)
    20 / 294 (6.80%)
         occurrences all number
    0
    15
    21
    Nervous system disorders
    Headache
         subjects affected / exposed
    20 / 298 (6.71%)
    8 / 301 (2.66%)
    12 / 294 (4.08%)
         occurrences all number
    22
    15
    14
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    20 / 298 (6.71%)
    10 / 301 (3.32%)
    4 / 294 (1.36%)
         occurrences all number
    21
    12
    4
    Nausea
         subjects affected / exposed
    75 / 298 (25.17%)
    5 / 301 (1.66%)
    3 / 294 (1.02%)
         occurrences all number
    97
    6
    3
    Vomiting
         subjects affected / exposed
    26 / 298 (8.72%)
    5 / 301 (1.66%)
    6 / 294 (2.04%)
         occurrences all number
    40
    6
    6
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    14 / 298 (4.70%)
    21 / 301 (6.98%)
    18 / 294 (6.12%)
         occurrences all number
    16
    23
    18
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    107 / 298 (35.91%)
    140 / 301 (46.51%)
    154 / 294 (52.38%)
         occurrences all number
    455
    630
    844

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Sep 2013
    It included following changes: - Revised inclusion/exclusion criteria as follows: Glinides were added as allowed previous oral antidiabetic medication within 3 months before the study entry; Previous use of glucagon-like peptide 1 (GLP-1) receptor agonist (except lixisenatide) was changed from forbidden to allowed, provided that GLP-1 receptor agonist treatment was stopped for other reason than safety/tolerability issue or lack of efficacy - A new safety committee was added, the pancreatic safety assessment committee (PSAC), to ensure the independent assessment of pancreatic event data by external experts. The PSAC reviewed pancreatic events reported on a specific adverse event form. -Clarified that alanine aminotransferase (ALT) increase was to be reported as an adverse event of special interest (AESI) with immediate notification to be in line with the updated requirements for safety information collection.

    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/27222510
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