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    Clinical Trial Results:
    An open-label, randomized, three-parallel-group study on pharmacodynamic effects of 8-week QD treatment with lixisenatide compared to liraglutide in patients with type 2 diabetes not adequately controlled with insulin glargine with or without metformin

    Summary
    EudraCT number
    		 2012-000027-40
    Trial protocol
    		 DE  
    Global end of trial date
    25 Jul 2013

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

    Trial information

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    Trial identification
    Sponsor protocol code
    PDY12625
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01596504
    WHO universal trial number (UTN)
    		 U1111-1124-1364
    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
    27 Aug 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Jul 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the effects of repeated subcutaneous (SC) doses of lixisenatide 20 microgram (mcg) once daily (QD) as compared to liraglutide 1.2 milligram (mg) QD or 1.8 mg QD in reducing post-prandial plasma glucose (PPG) assessed as area under the plasma glucose concentration- time curve (AUC) after a standardized breakfast at the end of an 8- week treatment period in subjects with type 2 diabetes mellitus (T2DM) not adequately controlled with insulin glargine (+/- metformin).
    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
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 May 2012
    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
    Germany: 142
    Worldwide total number of subjects
    142
    EEA total number of subjects
    142
    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)
    86
    From 65 to 84 years
    56
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 8 centres in Germany between 22 May 2012 to 25 July 2013.

    Pre-assignment
    Screening details
    		 A total of 236 subjects were screened and 142 subjects were randomized and treated.

    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 20 mcg
    Arm description
    		 Lixisenatide for 8 weeks (up to Day 57) and a maintenance dose of 20 mcg QD.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lixisenatide
    Investigational medicinal product code
    AVE0010
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Lixisenatide 10 mcg QD for 2 weeks followed by 20 mcg QD for 6 weeks (up to Day 57), to be self-administered with a pen-like injector (OptiClik®), under fasted conditions.

    Arm title
    		 Liraglutide 1.2 mg
    Arm description
    		 Liraglutide for 8 weeks (up to Day 57) and a maintenance dose of 1.2 mg QD.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Liraglutide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Liraglutide 0.6 mg QD for 1 week followed by 1.2 mg QD for 7 weeks (up to Day 57), to be self-administered using a prefilled pen (Victoza®), under fasted conditions.

    Arm title
    		 Liraglutide 1.8 mg
    Arm description
    		 Liraglutide for 8 weeks (up to Day 57) and a maintenance dose of 1.8 mg QD.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Liraglutide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Liraglutide 0.6 mg QD for 1 week followed by 1.2 mg QD for 1 week and then 1.8 QD mg for 6 weeks (up to Day 57), to be self-administered by using a prefilled pen (Victoza®) under fasted conditions.

    Number of subjects in period 1
    		Lixisenatide 20 mcg Liraglutide 1.2 mg Liraglutide 1.8 mg
    Started
    48
    47
    47
    Completed
    46
    44
    46
    Not completed
    2
    3
    1
         Consent withdrawn by subject
    1
    -
    -
         Adverse event
    1
    2
    1
         Subject's Private Reason
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lixisenatide 20 mcg
    Reporting group description
    		 Lixisenatide for 8 weeks (up to Day 57) and a maintenance dose of 20 mcg QD.

    Reporting group title
    Liraglutide 1.2 mg
    Reporting group description
    		 Liraglutide for 8 weeks (up to Day 57) and a maintenance dose of 1.2 mg QD.

    Reporting group title
    Liraglutide 1.8 mg
    Reporting group description
    		 Liraglutide for 8 weeks (up to Day 57) and a maintenance dose of 1.8 mg QD.

    Reporting group values
    		 Lixisenatide 20 mcg Liraglutide 1.2 mg Liraglutide 1.8 mg Total
    Number of subjects
    		 48 47 47 142
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 33 29 24 86
        From 65-84 years
    		 15 18 23 56
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.6 ( 7.4 ) 61.4 ( 7.9 ) 62.6 ( 9.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 15 8 14 37
        Male
    		 33 39 33 105
    Race
    Units: Subjects
        Caucasian/White
    		 48 46 47 141
        Other
    		 0 1 0 1
    Metformin Use at Screening
    Units: Subjects
        Yes
    		 43 41 41 125
        No
    		 5 6 6 17
    Weight
    Units: kilogram (kg)
        arithmetic mean (standard deviation)
    		 90.56 ( 13.09 ) 91.62 ( 13.92 ) 92.92 ( 15.33 ) -
    Body Mass Index (BMI)
    Units: kilogram per square metre (kg/m^2)
        arithmetic mean (standard deviation)
    		 30.68 ( 4.34 ) 30.52 ( 4.01 ) 31.17 ( 4.34 ) -
    Glycosylated Haemoglobin (HbA1c) at Screening (Day -7)
    Units: percentage of haemoglobin
        arithmetic mean (standard deviation)
    		 7.22 ( 0.48 ) 7.19 ( 0.53 ) 7.33 ( 0.5 ) -
    Duration of Diabetes
    Units: years
        median (full range (min-max))
    		 11.41 (2.1 to 32.4) 10.51 (3.9 to 21.1) 12.53 (4 to 31.6) -
    Average Daily Insulin Glargine Dose at Baseline (Day -7)
    Units: units
        arithmetic mean (standard deviation)
    		 43.1 ( 19.1 ) 40.3 ( 18.1 ) 44.3 ( 16.1 ) -
    Plasma Glucose Corrected Area Under The Plasma Concentration-Time Curve From Time 0.5-4.5 Hours
    Number of subjects analysed for this parameter were 46, 43, and 45, respectively.
    Units: hour*millimole per litre (h*mmol/L)
        arithmetic mean (standard deviation)
    		 15.67 ( 6.71 ) 15.55 ( 5.55 ) 17.04 ( 5.73 ) -

    End points

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    End points reporting groups
    Reporting group title
    Lixisenatide 20 mcg
    Reporting group description
    		 Lixisenatide for 8 weeks (up to Day 57) and a maintenance dose of 20 mcg QD.

    Reporting group title
    Liraglutide 1.2 mg
    Reporting group description
    		 Liraglutide for 8 weeks (up to Day 57) and a maintenance dose of 1.2 mg QD.

    Reporting group title
    Liraglutide 1.8 mg
    Reporting group description
    		 Liraglutide for 8 weeks (up to Day 57) and a maintenance dose of 1.8 mg QD.

    Primary: Change From Baseline to Day 56 in Plasma Glucose Corrected Area Under The Plasma Concentration-Time Curve (AUC) From Time 0.5 Hours to 4.5 Hours

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    End point title
    		 Change From Baseline to Day 56 in Plasma Glucose Corrected Area Under The Plasma Concentration-Time Curve (AUC) From Time 0.5 Hours to 4.5 Hours
    End point description
    Plasma glucose was assessed using the Gluco-quant Glucose/hexokinase assay. The range of the method was 3 to 1000 milligram per decilitre (mg/dL) with 1 mg/dL as limit of detection (LOD). Calculation of the AUC was made on Day -3 (baseline) and on Day 56 using the linear trapezoidal rule from time of breakfast start (30 minutes after study drug administration [time: 0.5 hours]) to 4 hours after breakfast start (time: 4.5 hours) and corrected by subtracting pre-breakfast plasma glucose concentration (time: 0.5 hours). Analysis was carried out on pharmacodynamic (PD) population defined as all randomized subjects, who received at least one dose of lixisenatide 20 microgram (mcg), liraglutide 1.2 milligram (mg) or liraglutide 1.8 mg, and had both a baseline assessment and at least one post-baseline assessment of any primary or secondary PD variables.
    End point type
    Primary
    End point timeframe
    0.5 (8:00 clock time, prior to standardized breakfast), 0.67, 0.84, 1, 1.5, 2, 2.5, 3.5, 4.5 hours on Day -3 (baseline); 0.5 (prior to standardized breakfast), 0.67, 0.84, 1, 1.5, 2, 2.5, 3.5, 4.5 hours post study drug administration on Day 56
    End point values
    		 Lixisenatide 20 mcg Liraglutide 1.2 mg Liraglutide 1.8 mg
    Number of subjects analysed
    46
    43
    45
    Units: h*mmol/L
        least squares mean (standard error)
    -13.33 ( 1.11 )
    -7.32 ( 1.12 )
    -8.72 ( 1.16 )
    Statistical analysis title
    		 Lixisenatide vs Liraglutide 1.2 mg
    Statistical analysis description
    Analysis was performed using linear fixed effects model with treatment and stratification factors (HbA1c levels on Day -7 [<8% and >=8%], use of metformin at screening [yes or no]) and the study site as fixed effects and baseline plasma glucose AUC from 0.5 to 4.5 hours as covariate.
    Comparison groups
    Lixisenatide 20 mcg v Liraglutide 1.2 mg
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.0001
    Method
    		 Linear fixed effects model
    Parameter type
    		 Least squares mean difference
    Point estimate
    -6.01
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -7.77
         upper limit
    		 -
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.06
    Notes
    [1] - To address multiplicity issue and ensure overall 1-sided level of 5%, Hochberg method was used for testing procedure of comparison between lixisenatide vs liraglutide 1.2 mg or 1.8 mg. p-values were ordered (p1<=p2) and following rules were applied: 1)if p2<=0.05: lixisenatide was superior to liraglutide (both dose) 2)if p2>0.05 and p1<=0.025: lixisenatide was superior to dose of liraglutide associated with p1 3)if p2>0.05 and p1>0.025: no comparison was declared as statistically significant.
    Statistical analysis title
    		 Lixisenatide vs Liraglutide 1. 8 mg
    Statistical analysis description
    Analysis was performed using linear mixed effects model with treatment and stratification factors (HbA1c levels on Day -7 [<8% and >=8%], use of metformin at screening [yes or no]), and the study site as fixed effects and baseline plasma glucose AUC from 0.5 to 4.5 hours as covariate.
    Comparison groups
    Lixisenatide 20 mcg v Liraglutide 1.8 mg
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.0001
    Method
    		 Linear fixed effects model
    Parameter type
    		 Least squares mean difference
    Point estimate
    -4.61
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -6.34
         upper limit
    		 -
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.04
    Notes
    [2] - To address multiplicity issue and ensure overall 1-sided level of 5%, Hochberg method was used for testing procedure of comparison between lixisenatide vs liraglutide 1.2 mg or 1.8 mg. p-values were ordered (p1<=p2) and following rules were applied: 1)if p2<=0.05: lixisenatide was superior to liraglutide (both dose) 2)if p2>0.05 and p1<=0.025: lixisenatide was superior to dose of liraglutide associated with p1 3)if p2>0.05 and p1>0.025: no comparison was declared as statistically significant.

    Secondary: Change From Baseline to Day 56 in Plasma Glucose Corrected AUC From Time 0.5 Hours to 5.5 Hours

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    End point title
    		 Change From Baseline to Day 56 in Plasma Glucose Corrected AUC From Time 0.5 Hours to 5.5 Hours
    End point description
    Plasma glucose was assessed using the Gluco-quant Glucose/hexokinase assay. The range of the method was 3 to 1000 mg/dL with 1 mg/dL as LOD. Calculation of the AUC was made on Day -3 (baseline) and on Day 56 using the linear trapezoidal rule from time of breakfast start (30 minutes after study drug administration [time: 0.5 hours]) to 5 hours after breakfast start (time: 5.5 hours) and corrected by subtracting pre-breakfast plasma glucose concentration (time: 0.5 hours). Analysis was carried out on PD population.
    End point type
    Secondary
    End point timeframe
    0.5 (8:00 clock time, prior to standardized breakfast), 0.67, 0.84, 1, 1.5, 2, 2.5, 3.5, 4.5, 5.5 hours on Day -3 (baseline); 0.5 (prior to standardized breakfast), 0.67, 0.84, 1, 1.5, 2, 2.5, 3.5, 4.5, 5.5 hours post study drug administration on Day 56
    End point values
    		 Lixisenatide 20 mcg Liraglutide 1.2 mg Liraglutide 1.8 mg
    Number of subjects analysed
    46
    43
    45
    Units: h*mmol/L
        least squares mean (standard error)
    -13.82 ( 1.19 )
    -9.09 ( 1.21 )
    -10.33 ( 1.25 )
    No statistical analyses for this end point

    Secondary: Number of Subjects With 2-Hour Postprandial Plasma Glucose <7.77 Millimole Per Litre (mmol/L) at Day 56

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    End point title
    		 Number of Subjects With 2-Hour Postprandial Plasma Glucose <7.77 Millimole Per Litre (mmol/L) at Day 56
    End point description
    Plasma glucose was assessed using the Gluco-quant Glucose/hexokinase assay. The range of the method was 3 to 1000 mg/dL with 1 mg/dL as LOD. The 2-hour PPG test measured blood glucose 2 hours after start of a standardized breakfast. Analysis was carried out on PD population.
    End point type
    Secondary
    End point timeframe
    Day 56
    End point values
    		 Lixisenatide 20 mcg Liraglutide 1.2 mg Liraglutide 1.8 mg
    Number of subjects analysed
    46
    44
    46
    Units: subjects
        number (not applicable)
    35
    13
    11
    No statistical analyses for this end point

    Secondary: Change From Baseline to Day 56 in Postprandial Plasma Glucose (PPG) Excursion

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    End point title
    		 Change From Baseline to Day 56 in Postprandial Plasma Glucose (PPG) Excursion
    End point description
    Plasma glucose was assessed using the Gluco-quant Glucose/hexokinase assay. The range of the method was 3 to 1000 mg/dL with 1 mg/dL as LOD. PPG excursion was determined on Day -3 (Baseline) and Day 56 as the maximum change in PPG from time of breakfast start (time: 0.5 hours) until 5 hours later (time: 5.5 hours) subtracted from pre-meal plasma concentration. Analysis was carried out on PD population.
    End point type
    Secondary
    End point timeframe
    0.67, 0.84, 1, 1.5, 2, 2.5, 3.5, 4.5, 5.5 hours on Day -3 (baseline); 0.67, 0.84, 1, 1.5, 2, 2.5, 3.5, 4.5, 5.5 hours post study drug administration on Day 56
    End point values
    		 Lixisenatide 20 mcg Liraglutide 1.2 mg Liraglutide 1.8 mg
    Number of subjects analysed
    46
    43
    45
    Units: mmol/L
        least squares mean (standard error)
    -3.26 ( 0.4 )
    -1.79 ( 0.4 )
    -2.5 ( 0.42 )
    No statistical analyses for this end point

    Secondary: Change From Baseline to Day 56 in Fasting Plasma Glucose (FPG)

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    End point title
    		 Change From Baseline to Day 56 in Fasting Plasma Glucose (FPG)
    End point description
    Plasma glucose was assessed using the Gluco-quant Glucose/hexokinase assay. The range of the method was 3-1000 mg/dL with 1 mg/dL as LOD. The value of FPG on Day -3 was the baseline. Analysis was carried out on PD population.
    End point type
    Secondary
    End point timeframe
    0.5 hour (prior to standardized breakfast) on Day -3; 0.5 hour (prior to standardized breakfast) on Day 56
    End point values
    		 Lixisenatide 20 mcg Liraglutide 1.2 mg Liraglutide 1.8 mg
    Number of subjects analysed
    45
    44
    45
    Units: mmol/L
        least squares mean (standard error)
    0.1 ( 0.22 )
    0.12 ( 0.22 )
    0.13 ( 0.23 )
    No statistical analyses for this end point

    Secondary: Change From Baseline to Day 56 in Average 7-Point Self-Monitored Plasma Glucose (SMPG)

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    End point title
    		 Change From Baseline to Day 56 in Average 7-Point Self-Monitored Plasma Glucose (SMPG)
    End point description
    Seven-point SMPG (before breakfast, 2 hours post breakfast, before lunch, 2 hours post lunch, before dinner, 2 hours post dinner, and at bedtime) was measured using Freestyle Precision glucometer and average of the 7 measurements was calculated. Analysis was carried out on PD population.
    End point type
    Secondary
    End point timeframe
    Before breakfast, 2 hours post breakfast, before lunch, 2 hours post lunch, before dinner, 2 hours post dinner, and at bedtime on Day -3 (Baseline) and  on Day 56.
    End point values
    		 Lixisenatide 20 mcg Liraglutide 1.2 mg Liraglutide 1.8 mg
    Number of subjects analysed
    46
    44
    46
    Units: mmol/L
        arithmetic mean (standard deviation)
    -0.69 ( 1.19 )
    -0.76 ( 1.23 )
    -1.2 ( 1.09 )
    No statistical analyses for this end point

    Secondary: Change From Baseline to Day 56 in Corrected C-Peptide AUC From Time 0.5 Hours to 5.5 Hours

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    End point title
    		 Change From Baseline to Day 56 in Corrected C-Peptide AUC From Time 0.5 Hours to 5.5 Hours
    End point description
    C-peptide was assessed using the Electro Chemiluminescence Immuno Assay.The range of the method was 0.2 to 25 nanogram per millilitre (ng/mL) and the LOD was 0.07 ng/mL. Measurement was done on Day -3 (Baseline) and Day 56 as the maximum change in C-peptide from time of breakfast start (time: 0.5 hours) until 5 hours later (time: 5.5 hours) subtracted from pre-meal plasma concentration. Analysis was carried out on PD population.
    End point type
    Secondary
    End point timeframe
    0.5 (8:00 clock time, prior to standardized breakfast), 0.67, 0.84, 1, 1.5, 2, 2.5, 3.5, 4.5, 5.5 hours on Day -3 (baseline); 0.5 (prior to standardized breakfast), 0.67, 0.84, 1, 1.5, 2, 2.5, 3.5, 4.5, 5.5 hours post study drug administration on Day 56
    End point values
    		 Lixisenatide 20 mcg Liraglutide 1.2 mg Liraglutide 1.8 mg
    Number of subjects analysed
    46
    43
    45
    Units: Hour*nanomole per Litre (h*nmol/L)
        least squares mean (standard error)
    -1.16 ( 0.37 )
    1.23 ( 0.37 )
    0.88 ( 0.39 )
    No statistical analyses for this end point

    Secondary: Change From Baseline to Day 56 in Corrected Glucagon AUC From Time 0.5 Hours to 5.5 Hours

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    End point title
    		 Change From Baseline to Day 56 in Corrected Glucagon AUC From Time 0.5 Hours to 5.5 Hours
    End point description
    Glucagon was assessed using the radioimmunoassay. The range of the method was 4.7 to 150 picomole per litre (pmol/L). Measurement was done on Day -3 (Baseline) and Day 56 as the maximum change in Glucagon from time of breakfast start (time: 0.5 hours) until 5 hours later (time: 5.5 hours) subtracted from pre-meal plasma concentration. Analysis was carried out on PD population.
    End point type
    Secondary
    End point timeframe
    0.5 (8:00 clock time, prior to standardized breakfast), 0.67, 0.84, 1, 1.5, 2, 2.5, 3.5, 4.5, 5.5 hours on Day -3 (baseline); 0.5 (prior to standardized breakfast), 0.67, 0.84, 1, 1.5, 2, 2.5, 3.5, 4.5, 5.5 hours post study drug administration on Day 56
    End point values
    		 Lixisenatide 20 mcg Liraglutide 1.2 mg Liraglutide 1.8 mg
    Number of subjects analysed
    46
    43
    45
    Units: Hour*nanogram per Litre (h*ng/L)
        least squares mean (standard error)
    -16.56 ( 19.43 )
    11.58 ( 19.86 )
    5.6 ( 20.3 )
    No statistical analyses for this end point

    Secondary: Change From Baseline to Day 56 in HbA1C

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    End point title
    		 Change From Baseline to Day 56 in HbA1C
    End point description
    HbA1C was assessed using the high-performance liquid chromatography method. Analysis was carried out on PD population
    End point type
    Secondary
    End point timeframe
    Pre-dose (Hour 0) on Day 1 (Baseline) and Day 56
    End point values
    		 Lixisenatide 20 mcg Liraglutide 1.2 mg Liraglutide 1.8 mg
    Number of subjects analysed
    46
    44
    46
    Units: percentage of haemoglobin
        least squares mean (standard error)
    -0.58 ( 0.06 )
    -0.66 ( 0.06 )
    -0.74 ( 0.06 )
    No statistical analyses for this end point

    Secondary: Change From Baseline to Day 56 in Average Daily Insulin Glargine Dose

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    End point title
    		 Change From Baseline to Day 56 in Average Daily Insulin Glargine Dose
    End point description
    Analysis was carried out on PD population.
    End point type
    Secondary
    End point timeframe
    Day -7 (Baseline), Day 56
    End point values
    		 Lixisenatide 20 mcg Liraglutide 1.2 mg Liraglutide 1.8 mg
    Number of subjects analysed
    46
    44
    46
    Units: units
        arithmetic mean (standard deviation)
    -4.7 ( 4.8 )
    -4.6 ( 6.8 )
    -4 ( 6.5 )
    No statistical analyses for this end point

    Secondary: Change From Baseline to Day 55 in Gastric Emptying Half Life (t1/2)

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    End point title
    		 Change From Baseline to Day 55 in Gastric Emptying Half Life (t1/2)
    End point description
    Gastric emptying was measured using 13C-octanoic acid breath test by isotope-selective non-dispersive infrared spectrometry. Analysis was carried out on PD population.
    End point type
    Secondary
    End point timeframe
    0 (7:30 clock time, prior to standardized breakfast), 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 hours on Day -4 (baseline) and on Day 55
    End point values
    		 Lixisenatide 20 mcg Liraglutide 1.2 mg Liraglutide 1.8 mg
    Number of subjects analysed
    46
    44
    46
    Units: minutes (min)
        least squares mean (standard error)
    453.56 ( 58.24 )
    175.31 ( 58.49 )
    130.49 ( 60.27 )
    No statistical analyses for this end point

    Secondary: Change From Baseline to Day 55 in Gastric Emptying Coefficient

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    End point title
    		 Change From Baseline to Day 55 in Gastric Emptying Coefficient
    End point description
    Gastric emptying was measured using 13C-octanoic acid breath test by isotope-selective non-dispersive infrared spectrometry. Gastric emptying coefficient was derived from a mathematical formula that describes the gastric-emptying rate and gives an overall index of gastric emptying. Analysis was carried out on PD population.
    End point type
    Secondary
    End point timeframe
    0 (7:30 clock time, prior to standardized breakfast), 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 hours on Day -4 (baseline) and on Day 55
    End point values
    		 Lixisenatide 20 mcg Liraglutide 1.2 mg Liraglutide 1.8 mg
    Number of subjects analysed
    46
    44
    46
    Units: coefficient (unit-less)
        arithmetic mean (standard deviation)
    -0.33 ( 1.09 )
    -0.34 ( 0.53 )
    -0.28 ( 0.52 )
    No statistical analyses for this end point

    Secondary: Change From Baseline to Day 57/58 in 24-Hour Mean Heart Rate

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    End point title
    		 Change From Baseline to Day 57/58 in 24-Hour Mean Heart Rate
    End point description
    The baseline value was the 24-hour mean on Day -2/-1 determined as overall, night- and day-time mean. Measurements were made every 15 minutes from 07:00 to 23:00 (daytime) and every 30 minutes from 23:00 to 07:00 (nighttime) at baseline and Day 57/58. Measurements were obtained after 10 minutes in the supine resting position. Analysis was carried out on PD population.
    End point type
    Secondary
    End point timeframe
    Every 15 minutes from 07:00 clock time to 23:00 clock time (daytime) and every 30 minutes from 23:00 clock time to 07:00 clock time (nighttime) on Day -2/-1 (Baseline) and Day 57/58
    End point values
    		 Lixisenatide 20 mcg Liraglutide 1.2 mg Liraglutide 1.8 mg
    Number of subjects analysed
    42
    43
    44
    Units: beats per minute (bpm)
        least squares mean (standard error)
    3.34 ( 1.33 )
    9.33 ( 1.24 )
    9.17 ( 1.31 )
    No statistical analyses for this end point

    Secondary: Change From Baseline to Day 57/58 in 24-Hour Mean Systolic Blood Pressure and Diastolic Blood Pressure

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    End point title
    		 Change From Baseline to Day 57/58 in 24-Hour Mean Systolic Blood Pressure and Diastolic Blood Pressure
    End point description
    The baseline value was the 24-hour means on Day -2/-1 determined as overall, night- and day-time mean. Measurements were made every 15 minutes from 07:00 to 23:00 (day time) and every 30 minutes from 23:00 to 07:00 (night time) at baseline and at Day 57/58. Measurements were obtained after 10 minutes in the supine resting position. Analysis was carried out on PD population.
    End point type
    Secondary
    End point timeframe
    Every 15 minutes from 07:00 clock time to 23:00 clock time (daytime) and every 30 minutes from 23:00 clock time to 07:00 clock time (nighttime) on Day -2/-1 (Baseline) and Day 57/58
    End point values
    		 Lixisenatide 20 mcg Liraglutide 1.2 mg Liraglutide 1.8 mg
    Number of subjects analysed
    42
    43
    44
    Units: millimetre of mercury (mmHg)
    arithmetic mean (standard deviation)
        24-Hour Mean Systolic Blood Pressure
    0.4 ( 6.4 )
    -0.5 ( 7.1 )
    -2.5 ( 7.7 )
        24-Hour Mean Diastolic Blood Pressure
    0.8 ( 4.1 )
    2.4 ( 4.7 )
    1.6 ( 4.7 )
    No statistical analyses for this end point

    Secondary: Change From Baseline to Day 57 in Body Weight

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    End point title
    		 Change From Baseline to Day 57 in Body Weight
    End point description
    Analysis was carried out on PD population.
    End point type
    Secondary
    End point timeframe
    0.5 hours prior to standardized breakfast (7:30 clock time) on Day -1 (Baseline); 0.5 hours prior to study drug administration on Day 57
    End point values
    		 Lixisenatide 20 mcg Liraglutide 1.2 mg Liraglutide 1.8 mg
    Number of subjects analysed
    46
    44
    46
    Units: kilogram
        least squares mean (standard error)
    -1.61 ( 0.47 )
    -1.78 ( 0.48 )
    -2.42 ( 0.49 )
    No statistical analyses for this end point

    Secondary: Change From Baseline to Day 57 in Waist Circumference

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    End point title
    		 Change From Baseline to Day 57 in Waist Circumference
    End point description
    Analysis was carried out on PD population.
    End point type
    Secondary
    End point timeframe
    0.5 hours prior to standardized breakfast (7:30 clock time) on Day -1 (Baseline); 0.5 hours prior to IMP administration on Day 57
    End point values
    		 Lixisenatide 20 mcg Liraglutide 1.2 mg Liraglutide 1.8 mg
    Number of subjects analysed
    46
    43
    46
    Units: centimetre
        arithmetic mean (standard deviation)
    -1.4 ( 4.66 )
    -1.93 ( 3.59 )
    -2.12 ( 4.95 )
    No statistical analyses for this end point

    Secondary: Change From Baseline to Day 56 in The Cumulative Score Mean on The Appetite Perception Using a Visual Analogue Scale After Standardized Solid Breakfast

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    End point title
    		 Change From Baseline to Day 56 in The Cumulative Score Mean on The Appetite Perception Using a Visual Analogue Scale After Standardized Solid Breakfast
    End point description
    Visual Analogue Scale, 100 millimetre (mm) in length with words anchored at each end, expressing the most positive and the most negative rating, was used to assess hunger, satiety, fullness and prospective food consumption. Analysis was carried out on PD population.
    End point type
    Secondary
    End point timeframe
    0.5 (8:00 clock time, prior to standardized breakfast), 1.5, 2.5, 3.5, 4.5, 5.5 hours on Day -3; 0 (prior to standardized breakfast), 1.5, 2.5, 3.5, 4.5, 5.5 hours post study drug administration on Day 56
    End point values
    		 Lixisenatide 20 mcg Liraglutide 1.2 mg Liraglutide 1.8 mg
    Number of subjects analysed
    46
    44
    46
    Units: millimeter(s)
    arithmetic mean (standard deviation)
        How hungry do you feel?
    -3.7 ( 16.4 )
    -3.1 ( 16.8 )
    -1 ( 14.6 )
        How satisfied do you feel?
    4.5 ( 15.8 )
    8.9 ( 13.2 )
    3.6 ( 11 )
        How full do you feel?
    4.9 ( 17 )
    9.3 ( 15.6 )
    6.4 ( 13.8 )
        How much do you think you can eat?
    -6.4 ( 16.1 )
    -4.5 ( 15.7 )
    -7.2 ( 12 )
    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 end of study regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported adverse events are treatment-emergent adverse events that developed/worsened during the ‘on treatment period’ (the time from the first drug injection [included] up to 3 days after the last injection of drug administration [included]).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Lixisenatide 20 mcg
    Reporting group description
    		 Lixisenatide for 8 weeks (up to Day 57) and a maintenance dose of 20 mcg QD.

    Reporting group title
    Liraglutide 1.2 mg
    Reporting group description
    		 Liraglutide for 8 weeks (up to Day 57) and a maintenance dose of 1.2 mg QD.

    Reporting group title
    Liraglutide 1.8 mg
    Reporting group description
    		 Liraglutide for 8 weeks (up to Day 57) and a maintenance dose of 1.8 mg QD.

    Serious adverse events
    		 Lixisenatide 20 mcg Liraglutide 1.2 mg Liraglutide 1.8 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Cardiac disorders
    Coronary Artery Disease
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 47 (0.00%)
    0 / 47 (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
    Myocardial Infarction
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 47 (2.13%)
    0 / 47 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Lixisenatide 20 mcg Liraglutide 1.2 mg Liraglutide 1.8 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 48 (54.17%)
    27 / 47 (57.45%)
    27 / 47 (57.45%)
    Nervous system disorders
    Dizziness Postural
         subjects affected / exposed
    3 / 48 (6.25%)
    1 / 47 (2.13%)
    0 / 47 (0.00%)
         occurrences all number
    3
    1
    0
    Headache
         subjects affected / exposed
    4 / 48 (8.33%)
    5 / 47 (10.64%)
    8 / 47 (17.02%)
         occurrences all number
    5
    5
    9
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 48 (6.25%)
    1 / 47 (2.13%)
    4 / 47 (8.51%)
         occurrences all number
    4
    1
    4
    Malaise
         subjects affected / exposed
    3 / 48 (6.25%)
    0 / 47 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    3
    0
    1
    Gastrointestinal disorders
    Abdominal Distension
         subjects affected / exposed
    3 / 48 (6.25%)
    7 / 47 (14.89%)
    4 / 47 (8.51%)
         occurrences all number
    4
    9
    4
    Abdominal Pain
         subjects affected / exposed
    2 / 48 (4.17%)
    3 / 47 (6.38%)
    1 / 47 (2.13%)
         occurrences all number
    2
    4
    1
    Abdominal Pain Upper
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 47 (0.00%)
    5 / 47 (10.64%)
         occurrences all number
    1
    0
    5
    Constipation
         subjects affected / exposed
    0 / 48 (0.00%)
    5 / 47 (10.64%)
    3 / 47 (6.38%)
         occurrences all number
    0
    6
    3
    Diarrhoea
         subjects affected / exposed
    3 / 48 (6.25%)
    4 / 47 (8.51%)
    5 / 47 (10.64%)
         occurrences all number
    3
    6
    7
    Dyspepsia
         subjects affected / exposed
    3 / 48 (6.25%)
    3 / 47 (6.38%)
    4 / 47 (8.51%)
         occurrences all number
    3
    6
    5
    Flatulence
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 47 (0.00%)
    4 / 47 (8.51%)
         occurrences all number
    3
    0
    4
    Nausea
         subjects affected / exposed
    9 / 48 (18.75%)
    8 / 47 (17.02%)
    11 / 47 (23.40%)
         occurrences all number
    11
    9
    14
    Vomiting
         subjects affected / exposed
    5 / 48 (10.42%)
    2 / 47 (4.26%)
    5 / 47 (10.64%)
         occurrences all number
    9
    2
    5
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 47 (0.00%)
    3 / 47 (6.38%)
         occurrences all number
    0
    0
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 48 (12.50%)
    10 / 47 (21.28%)
    5 / 47 (10.64%)
         occurrences all number
    6
    12
    5
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    9 / 48 (18.75%)
    9 / 47 (19.15%)
    13 / 47 (27.66%)
         occurrences all number
    9
    9
    15

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Sep 2012
    - Change in the Inclusion/Exclusion criteria: Subjects were eligible to enter in the screening phase with a stable dose of Neutral Protamine Hagedorn (NPH) or insulin glargine of at least 10 International units per day (IU/Day) (for at least 2 months prior to screening) instead of 20 units per day, alone or combined with a stable dose of metformin with or without Dipeptidyl peptidase (DPP)-IV inhibitor or sulfonylurea. Subjects receiving NPH or insulin glargine with metformin combined with DPP-IV inhibitors or sulfonylurea were eligible to enter in the screening phase provided that the run-in period will last 12 fixed weeks and subjects who received liraglutide 3 months prior to the time of screening were eligible. Inclusion of subjects who had received liraglutide provided that liraglutide treatment was stopped at least 3 months before the time of the screening for other reason than safety/tolerability issue or lack of efficacy. - Change in the run-in period: Either the run-in period was to be extended up to 12 weeks, if needed, in subjects treated with an initial therapy with NPH or insulin glargine of at least 10 IU/Day with or without metformin alone; or the run-in period was to be fixed to 12 weeks for subjects treated with an initial therapy with NPH or insulin glargine with metformin combined with DPP-4 inhibitor or sulfonylurea. This period was needed for reaching an appropriate baseline glycemic control after stopping DPP-4 inhibitor or sulfonylurea. - Change in the study/period flow charts and duration of participation: The changes in the run-in period with additional visits was to be included in the change in the study/period flow charts. The maximum duration of participation per subject was 23 weeks and one day +/- 2 days. Reporting timelines of SAE by the investigator have been changed from "within 1 working day" to "within 24 hours" following the European Commission (EC) guidance 2011/C 172/01 (dated 11 June 2011).

    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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