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    Clinical Trial Results:
    A Randomized, 30-Week, Active-controlled, Open-Label, 2-Treatment Arm, Parallel-group, Multicenter Study Comparing the Efficacy and Safety of the Insulin Glargine/Lixisenatide Fixed Ratio Combination to Insulin Glargine With or Without Metformin in Patients with Type 2 Diabetes Mellitus (T2DM)

    Summary
    EudraCT number
    		 2013-003132-79
    Trial protocol
    		 EE   SE   LT   CZ   NL   ES   HU   SK   DK  
    Global end of trial date
    09 Jul 2015

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

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC12405
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02058160
    WHO universal trial number (UTN)
    		 U1111-1148-4351
    Other trial identifiers
    		 Study Name: LixiLan-L
    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
    10 Aug 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jul 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 insulin glargine in glycated hemoglobin (HbA1c) change from baseline to Week 30.
    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
    		 If previously taken at a stable dose of at least 1500 mg/day or maximal tolerated dose for at least 3 months prior to screening, metformin as a background treatment was to be continued at a stable dose throughout the study unless prevented by a specific issue related to this treatment. Other oral antidiabetic treatment (OAD) if previously taken, were to be discontinued at start of run-in (6 weeks prior randomization).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Jan 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: 6
    Country: Number of subjects enrolled
    Canada: 22
    Country: Number of subjects enrolled
    Chile: 29
    Country: Number of subjects enrolled
    Mexico: 58
    Country: Number of subjects enrolled
    Romania: 42
    Country: Number of subjects enrolled
    Russian Federation: 101
    Country: Number of subjects enrolled
    Ukraine: 62
    Country: Number of subjects enrolled
    United States: 175
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Poland: 37
    Country: Number of subjects enrolled
    Slovakia: 40
    Country: Number of subjects enrolled
    Spain: 26
    Country: Number of subjects enrolled
    Sweden: 16
    Country: Number of subjects enrolled
    Czech Republic: 41
    Country: Number of subjects enrolled
    Denmark: 9
    Country: Number of subjects enrolled
    Estonia: 8
    Country: Number of subjects enrolled
    Hungary: 42
    Country: Number of subjects enrolled
    Lithuania: 19
    Worldwide total number of subjects
    736
    EEA total number of subjects
    283
    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)
    506
    From 65 to 84 years
    228
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 187 centers in 18 countries. A total of 1930 subjects were screened between January 27, 2014 and October 15, 2014. 912 subjects were not eligible for run-in phase mainly due to HbA1c value being out of the protocol-defined range.

    Pre-assignment
    Screening details
    		 After screening phase, 1018 subjects entered 6 week run–in phase, during which subjects were switched (if necessary) to insulin glargine; and dose was titrated/stabilized. Any OAD other than metformin were stopped. 282 subjects were run-in failures and 736 were randomized in 1:1 to FRC & insulin glargine 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
    		 Fixed Ratio Combination (FRC) of insulin glargine/lixisenatide once daily (QD) dose individually adjusted up to 30 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Insulin glargine (100 U/mL)/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
    FRC was self-administered QD in the morning within 1 hour before breakfast using one of the 2 available prefilled disposable SoloStar® pen-injectors: pen A or B, depending upon 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 doses from 10 U/5 mcg up to 40 U/20 mcg. 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 for administration doses from 30 U/10 mcg up to the maximal daily dose of 60 U/20 mcg. In order not to exceed the highest recommended initiation dose of 10 mcg for lixisenatide, the FRC was initiated at a dose of either 20 U/10mcg with Pen A or 30 U/10 mcg with Pen B, depending on subject’s dose on the day before randomization. The dose was kept stable for 2 weeks and then adjusted to reach and maintain fasting self-monitored plasma glucose (SMPG) of 80 mg/dL to 100 mg/dL (4.4 mmol/L to 5 mmol/L).

    Arm title
    		 Insulin Glargine
    Arm description
    		 Insulin glargine QD dose individually adjusted 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. The time of the injection was decided at the discretion of the subject and Investigator, at run-in start, and was to remain roughly the same throughout the study. The first dose after randomization was the same as the one administered on the day before randomization, and then dose was adjusted to reach and maintain fasting SMPG of 80 mg/dL to 100 mg/dL (4.4 mmol/L to 5.6 mmol/L).

    Number of subjects in period 1
    		Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine
    Started
    367
    369
    Treated
    365
    365
    Completed
    336
    355
    Not completed
    31
    14
         Other than specified above
    12
    6
         Adverse events
    12
    3
         Randomized but not treated
    2
    4
         Poor compliance to protocol
    4
    1
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Insulin Glargine/Lixisenatide Fixed Ratio Combination
    Reporting group description
    		 Fixed Ratio Combination (FRC) of insulin glargine/lixisenatide once daily (QD) dose individually adjusted up to 30 weeks.

    Reporting group title
    Insulin Glargine
    Reporting group description
    		 Insulin glargine QD dose individually adjusted up to 30 weeks.

    Reporting group values
    		 Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine Total
    Number of subjects
    		 367 369 736
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.6 ( 9.4 ) 60.3 ( 8.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 202 190 392
        Male
    		 165 179 344
    Race
    Units: Subjects
        Caucasian
    		 337 338 675
        Black
    		 17 21 38
        Asian/Oriental
    		 12 8 20
        Other
    		 1 2 3
    Ethnicity
    Units: Subjects
        Hispanic
    		 66 66 132
        Not Hispanic
    		 301 303 604
    Oral Antidiabetic Drug (OAD) Use
    Units: Subjects
        Yes
    		 349 350 699
        No
    		 18 19 37
    OAD Use at Screening By Class
    Units: Subjects
        Metformin
    		 170 190 360
        Sulfonylurea
    		 16 14 30
        Sodiumglucose cotransporter-2 (SGLT-2) inhibitor
    		 0 1 1
        Dipeptidyl peptidase-4 (DPP-4) inhibitor
    		 2 4 6
        Glinide
    		 1 1 2
        Metformin + Sulfonylurea
    		 137 118 255
        Metformin + DPP-4 inhibitor
    		 20 18 38
        Metformin + Glinide
    		 2 3 5
        Sulfonylurea + DPP-4 inhibitor
    		 1 1 2
        None
    		 18 19 37
    Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 31.33 ( 4.25 ) 30.96 ( 4.15 ) -
    Duration of Diabetes
    (N = 367, 368)
    Units: years
        arithmetic mean (standard deviation)
    		 12.02 ( 6.64 ) 12.13 ( 6.85 ) -
    Daily Dose of Metformin
    (N = 329, 329)
    Units: mg
        arithmetic mean (standard deviation)
    		 2082.8 ( 499.2 ) 2042 ( 455.9 ) -
    HbA1c
    Units: Percentage of HbA1c
        arithmetic mean (standard deviation)
    		 8.07 ( 0.68 ) 8.08 ( 0.73 ) -
    Fasting Plasma Glucose (FPG)
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 7.34 ( 1.95 ) 7.36 ( 2.12 ) -

    End points

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    End points reporting groups
    Reporting group title
    Insulin Glargine/Lixisenatide Fixed Ratio Combination
    Reporting group description
    		 Fixed Ratio Combination (FRC) of insulin glargine/lixisenatide once daily (QD) dose individually adjusted up to 30 weeks.

    Reporting group title
    Insulin Glargine
    Reporting group description
    		 Insulin glargine QD dose individually adjusted 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
    Number of subjects analysed
    364
    364
    Units: Percentage of hemoglobin
        least squares mean (standard error)
    -1.13 ( 0.057 )
    -0.62 ( 0.055 )
    Statistical analysis title
    		 Insulin Glargine/Lixisenatide vs Insulin Glargine
    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 metformin use at screening, visits, treatment-by-visit interaction and country as fixed effects and baseline HbA1c value-by-visit interaction as covariates. A hierarchical testing procedure was used to control type I error and handle multiple endpoint analyses.
    Comparison groups
    Insulin Glargine/Lixisenatide Fixed Ratio Combination v Insulin Glargine
    Number of subjects included in analysis
    728
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.0001 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square (LS) Mean Difference
    Point estimate
    -0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.633
         upper limit
    		 -0.397
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.06
    Notes
    [1] - Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.
    [2] - Threshold for significance at 0.05 level.

    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 with no value for HbA1c 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
    Number of subjects analysed
    366
    365
    Units: Percentage of subjects
    number (not applicable)
        HbA1c <7.0%
    54.9
    29.6
        HbA1c ≤ 6.5%
    33.9
    14.2
    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 metformin 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
    731
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    25.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 18.94
         upper limit
    		 32.1
    Notes
    [3] - Threshold for significance at 0.05 level.
    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 metformin 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
    731
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    19.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 13.9
         upper limit
    		 25.62
    Notes
    [4] - Threshold for significance at 0.05 level.

    Secondary: Change in 2-hour Plasma Blood Glucose Excursion from Baseline to Week 30

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    End point title
    		 Change in 2-hour Plasma Blood Glucose Excursion from Baseline to Week 30
    End point description
    Plasma glucose excursion = 2-hour postprandial glucose (PPG) minus plasma glucose value obtained 30 minutes prior to the start of the 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. mITT population. Here, number of subjects analyzed=subjects with baseline and at least one post-baseline plasma glucose excursion assessment during study period. Missing data was imputed using last observation carried forward (LOCF).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 30
    End point values
    		 Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine
    Number of subjects analysed
    329
    336
    Units: mmol/L
        least squares mean (standard error)
    -3.9 ( 0.285 )
    -0.47 ( 0.274 )
    Statistical analysis title
    		 FRC vs Insulin Glargine
    Statistical analysis description
    Testing according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant). 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 metformin use at screening and country as fixed effects and baseline 2-hour plasma glucose excursion value as a covariate.
    Comparison groups
    Insulin Glargine/Lixisenatide Fixed Ratio Combination v Insulin Glargine
    Number of subjects included in analysis
    665
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [5]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -3.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.925
         upper limit
    		 -2.939
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.251
    Notes
    [5] - Threshold for significance at 0.05 level.

    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
    Number of subjects analysed
    365
    365
    Units: kg
        least squares mean (standard error)
    -0.67 ( 0.181 )
    0.7 ( 0.178 )
    Statistical analysis title
    		 FRC vs Insulin Glargine
    Statistical analysis description
    Testing according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant). Analysis was performed using MMRM model with treatment groups, randomization strata of Week -1 HbA1c (<8.0, ≥8.0%), randomization strata of metformin use at screening, scheduled visits, treatment-by-visit interaction and country as fixed effects and baseline body weight value-by-visit interaction as covariates.
    Comparison groups
    Insulin Glargine/Lixisenatide Fixed Ratio Combination v Insulin Glargine
    Number of subjects included in analysis
    730
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.808
         upper limit
    		 -0.93
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.224
    Notes
    [6] - Threshold for significance at 0.05 level.

    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
    Number of subjects analysed
    323
    320
    Units: mmol/L
        least squares mean (standard error)
    -1.5 ( 0.137 )
    -0.6 ( 0.13 )
    Statistical analysis title
    		 FRC vs Insulin Glargine
    Statistical analysis description
    Testing according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant). Analysis was performed using MMRM model with treatment groups, randomization strata of Week -1 HbA1c (<8.0, ≥8.0%), randomization strata of metformin use at screening, scheduled visits, treatment-by-visit interaction and country as fixed effects and baseline average SMPG value-by-visit interaction as covariates.
    Comparison groups
    Insulin Glargine/Lixisenatide Fixed Ratio Combination v Insulin Glargine
    Number of subjects included in analysis
    643
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [7]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.154
         upper limit
    		 -0.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.131
    Notes
    [7] - Threshold for significance at 0.05 level.

    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 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
    Number of subjects analysed
    366
    365
    Units: Percentage of subjects
        number (not applicable)
    34.2
    13.4
    Statistical analysis title
    		 FRC vs Insulin Glargine
    Statistical analysis description
    Testing according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant). Analysis was performed using Cochran-Mantel-Haenszel method stratified on randomization strata of Week-1 HbA1c (<8.0%, ≥8.0%) and randomization strata of metformin use at screening.
    Comparison groups
    Insulin Glargine/Lixisenatide Fixed Ratio Combination v Insulin Glargine
    Number of subjects included in analysis
    731
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [8]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference
    Point estimate
    20.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 14.98
         upper limit
    		 26.66
    Notes
    [8] - Threshold for significance at 0.05 level.

    Secondary: Change in Daily Insulin Glargine Dose From Baseline to Week 30

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    End point title
    		 Change in Daily Insulin Glargine Dose From Baseline to Week 30
    End point description
    mITT population. The analysis included scheduled measurements obtained up to the date of last injection of IMP. Here, number of subjects analyzed=subjects with insulin glargine dose 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
    Number of subjects analysed
    364
    365
    Units: Units (U)
        least squares mean (standard error)
    10.64 ( 0.601 )
    10.89 ( 0.587 )
    Statistical analysis title
    		 FRC vs Insulin Glargine
    Statistical analysis description
    Testing according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant). Analysis was performed using MMRM model with treatment groups, randomization strata of Week -1 HbA1c (<8.0, ≥8.0%), randomization strata of metformin use at screening, scheduled visits, treatment-by-visit interaction, and country as fixed effects, and baseline daily insulin glargine dose-by-visit interaction as a covariate.
    Comparison groups
    Insulin Glargine/Lixisenatide Fixed Ratio Combination v Insulin Glargine
    Number of subjects included in analysis
    729
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7362 [9]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.762
         upper limit
    		 1.246
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.766
    Notes
    [9] - Threshold for significance at 0.05 level.

    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 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
    Number of subjects analysed
    366
    365
    Units: Percentage of subjects
        number (not applicable)
    19.9
    9
    No statistical analyses for this end point

    Secondary: Change in Fasting Plasma Glucose (FPG) From Baseline to Week 30

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    End point title
    		 Change in Fasting Plasma Glucose (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
    Number of subjects analysed
    364
    364
    Units: mmol/L
        least squares mean (standard error)
    -0.35 ( 0.142 )
    -0.46 ( 0.138 )
    No statistical analyses for this end point

    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
    Change in PPG 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 PPG assessment during study period. Missing data was imputed using LOCF.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 30
    End point values
    		 Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine
    Number of subjects analysed
    332
    340
    Units: mmol/L
        least squares mean (standard error)
    -4.72 ( 0.322 )
    -1.39 ( 0.31 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Reaching HbA1c <7.0% 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% 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). mITT population. Subjects with no value for HbA1c 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
    Number of subjects analysed
    366
    365
    Units: Percentage of subjects
        number (not applicable)
    31.7
    18.6
    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) were 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
    Number of subjects analysed
    366
    365
    Units: Percentage of subjects
        number (not applicable)
    2.7
    6
    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 [FRC], 210 days [Insulin glargine])
    End point values
    		 Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine
    Number of subjects analysed
    365
    365
    Units: Events per subject-year
        number (not applicable)
    3.03
    4.22
    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 [FRC], 210 days [Insulin glargine])
    End point values
    		 Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine
    Number of subjects analysed
    365
    365
    Units: Percentage of subjects
        number (not applicable)
    40
    42.5
    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 for 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 [FRC], 210 days [Insulin glargine])
    End point values
    		 Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine
    Number of subjects analysed
    365
    365
    Units: Percentage of subjects
        number (not applicable)
    1.1
    0.3
    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-emergent period’ (time from first injection of open-label IMP up to 3 days after the last injection of IMP. Analysis was performed on safety population.
    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
    		 Fixed Ratio Combination (FRC) of Insulin glargine /lixisenatide QD dose individually adjusted up to 30 weeks (median exposure: 211 days).

    Reporting group title
    Insulin Glargine
    Reporting group description
    		 Insulin glargine QD dose individually adjusted up to 30 weeks (median exposure: 210 days).

    Serious adverse events
    		 Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 365 (5.48%)
    18 / 365 (4.93%)
         number of deaths (all causes)
    1
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign Breast Neoplasm
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign Gastric Neoplasm
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast Cancer
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder Cancer
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Kaposi's Sarcoma
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous Cell Carcinoma Of The Tongue
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest Discomfort
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    0 / 365 (0.00%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign Prostatic Hyperplasia
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Meniscus Injury
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scar
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural Haematoma
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    2 / 365 (0.55%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina Unstable
         subjects affected / exposed
    2 / 365 (0.55%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis Coronary Artery
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary Failure
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial Infarction
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular Tachycardia
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Hypoglycaemic Seizure
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic Unconsciousness
         subjects affected / exposed
    2 / 365 (0.55%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Glaucoma
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis Acute
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis Chronic
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal Impairment
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral Disc Protrusion
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendonitis
         subjects affected / exposed
    1 / 365 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Osteomyelitis
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 365 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Wound Infection
         subjects affected / exposed
    0 / 365 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    2 / 365 (0.55%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Insulin Glargine/Lixisenatide Fixed Ratio Combination Insulin Glargine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    81 / 365 (22.19%)
    42 / 365 (11.51%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    21 / 365 (5.75%)
    10 / 365 (2.74%)
         occurrences all number
    32
    11
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    38 / 365 (10.41%)
    2 / 365 (0.55%)
         occurrences all number
    44
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    32 / 365 (8.77%)
    32 / 365 (8.77%)
         occurrences all number
    35
    36

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Jul 2014
    - Exclusion criterion was modified to limit exclusion to subjects who used insulin products other than basal insulin within 1 year prior to screening and to clarify the duration of short-term treatment. - Monitoring and evaluating of device/pen-related events was added. - Changes to collection of pharmacokinetic (PK) and antibody sampling were made. - The calculated creatinine clearance categories at screening used for the description of demographic and baseline characteristics were changed. - Contraceptive methods allowed for women of childbearing potential were clarified. - The statistical method used for the efficacy analyses was changed.

    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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