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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, 2-Arm Parallel-Group, Multicenter, 24-Week Study Assessing the Safety and Efficacy of Lixisenatide in Older Patients with Type 2 Diabetes Inadequately Controlled on Their Current Diabetes Treatment Regimen

    Summary
    EudraCT number
    		 2012-003292-19
    Trial protocol
    		 GB   SE   ES   NO   DE   DK   BG  
    Global end of trial date
    19 Feb 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Mar 2016
    First version publication date
    20 Mar 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC12703
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01798706
    WHO universal trial number (UTN)
    		 U1111-1132-9156
    Other trial identifiers
    		 Study Name: GetGoal-O
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Mar 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Feb 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of lixisenatide versus placebo over a period of 24 weeks on glycemic control, as evaluated by HbA1c reduction, in older type 2 diabetes mellitus (T2DM) subjects who were inadequately controlled with their current anti-diabetic treatment regimen.
    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 a stable regimen of anti-diabetic background therapy for at least 3 months prior to screening, during the placebo run-in period and the 24-week treatment period. Allowed background anti-diabetic therapy included metformin, sulfonylurea (except glibenclamide >10mg, gliclazide >160mg), meglitinides (except repaglinide >6mg), pioglitazone and basal insulin. Insulin glargine, neutral protamine hagedorn (NPH) insulin, detemir, lente and ultralente were considered as basal insulin.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Jun 2013
    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
    Norway: 16
    Country: Number of subjects enrolled
    Poland: 11
    Country: Number of subjects enrolled
    Spain: 25
    Country: Number of subjects enrolled
    Sweden: 33
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    Bulgaria: 29
    Country: Number of subjects enrolled
    Denmark: 23
    Country: Number of subjects enrolled
    Germany: 29
    Country: Number of subjects enrolled
    Australia: 19
    Country: Number of subjects enrolled
    Canada: 23
    Country: Number of subjects enrolled
    Peru: 86
    Country: Number of subjects enrolled
    South Africa: 11
    Country: Number of subjects enrolled
    United States: 36
    Worldwide total number of subjects
    350
    EEA total number of subjects
    175
    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)
    0
    From 65 to 84 years
    344
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 73 centers in 13 countries between June 10, 2013 and February 19, 2015.

    Pre-assignment
    Screening details
    		 A total of 786 subjects were screened. 426 subjects underwent 4-week placebo run–in period. 436 subjects were screen failures and 76 subjects were run-in failures; the most frequent reason for screen and run-in failure was that glycosylated hemoglobin (HbA1c) criteria was not met at the end of run-in phase. A total of 350 subjects were randomized.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lixisenatide
    Arm description
    		 Lixisenatide 10 mcg once daily (QD) for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to Week 24.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lixisenatide
    Investigational medicinal product code
    AVE0010
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Lixisenatide was self-administered QD 30 to 60 minutes before breakfast in the morning. If the maintenance dose of 20 mcg was not tolerated, dose could be reduced to 10 mcg.

    Arm title
    		 Placebo
    Arm description
    		 Placebo matched to lixisenatide QD for 24 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo was self-administered QD 30 to 60 minutes before breakfast in the morning.

    Number of subjects in period 1
    		Lixisenatide Placebo
    Started
    176
    174
    Completed
    155
    153
    Not completed
    21
    21
         other than specified above
    5
    9
         Adverse event
    15
    10
         Poor compliance to protocol
    1
    -
         Lack of efficacy
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lixisenatide
    Reporting group description
    		 Lixisenatide 10 mcg once daily (QD) for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to Week 24.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to lixisenatide QD for 24 weeks.

    Reporting group values
    		 Lixisenatide Placebo Total
    Number of subjects
    		 176 174 350
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 74 ± 4 74.4 ± 3.8 -
    Gender categorical
    Units: Subjects
        Female
    		 84 84 168
        Male
    		 92 90 182
    Race
    Units: Subjects
        Caucasian/white
    		 128 122 250
        Black
    		 3 0 3
        Asian/Oriental
    		 5 11 16
        Other
    		 40 41 81
    Ethnicity
    Units: Subjects
        Hispanic
    		 51 48 99
        Not Hispanic
    		 125 126 251
    Number of Subjects with Categorical BMI
    Units: Subjects
        <30
    		 102 96 198
        ≥30
    		 74 78 152
    Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 29.91 ± 3.7 30.09 ± 4.53 -
    Body Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 80.81 ± 14.54 80.08 ± 16.76 -
    Glycosylated Hemoglobin (HbA1c)
    Units: Percentage of HbA1c
        arithmetic mean (standard deviation)
    		 8.04 ± 0.72 8.05 ± 0.69 -
    Fasting Plasma Glucose (FPG)
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 8.83 ± 2.38 8.89 ± 2.26 -
    2-Hour Postprandial Plasma Glucose (PPG)
    347 subjects (174 in lixisenatide arm and 173 in placebo arm) were included for PPG analysis.
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 15.18 ± 3.78 14.87 ± 3.69 -
    Glucose Excursion
    345 subjects (173 in lixisenatide arm and 172 in placebo arm) were included for glucose excursion analysis.
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 6.51 ± 3.15 6.02 ± 3.17 -
    7-Point self-monitored plasma glucose (SMPG)
    333 subjects (171 in lixisenatide arm and 162 in placebo arm) were included for 7­point SMPG analysis.
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 9.79 ± 2.02 9.97 ± 1.98 -
    Duration of Diabetes
    Units: years
        arithmetic mean (standard deviation)
    		 13.63 ± 7.34 14.63 ± 7.87 -

    End points

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    End points reporting groups
    Reporting group title
    Lixisenatide
    Reporting group description
    		 Lixisenatide 10 mcg once daily (QD) for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to Week 24.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to lixisenatide QD for 24 weeks.

    Primary: Absolute Change in HbA1c From Baseline to Week 24

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    End point title
    		 Absolute Change in HbA1c From Baseline to Week 24
    End point description
    Change in HbA1c was calculated by subtracting baseline value from Week 24 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. Modified intent-to-treat (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 24
    End point values
    		 Lixisenatide Placebo
    Number of subjects analysed
    172
    172
    Units: percentage of hemoglobin
        least squares mean (standard error)
    -0.57 ± 0.075
    0.06 ± 0.072
    Statistical analysis title
    		 Lixisenatide vs Placebo
    Statistical analysis description
    Analysis was performed using analysis of covariance (ANCOVA) model with treatment groups, randomization strata of Week -1 HbA1c [<8.0, ≥8.0%], randomization strata of basal insulin use at screening, randomization strata of Week -1 glomerular filtration rate (eGFR) [ ≥30 to <60, ≥60 ml/min/1.73 m^2],and country as fixed effects and baseline HbA1c value as a covariate.
    Comparison groups
    Lixisenatide v Placebo
    Number of subjects included in analysis
    344
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 ANCOVA
    Parameter type
    		 Least Square (LS) Mean Difference
    Point estimate
    -0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.81
         upper limit
    		 -0.464
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.088
    Notes
    [1] - Threshold for significance at 0.05 level.

    Secondary: Change in 2-Hour PPG from Baseline to Week 24

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    End point title
    		 Change in 2-Hour PPG from Baseline to Week 24
    End point description
    The 2-hour PPG test measured blood glucose 2 hours after eating a liquid standardized breakfast meal. Change in PPG was calculated by subtracting baseline value from Week 24 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 2-hour PPG assessment during on-treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Lixisenatide Placebo
    Number of subjects analysed
    147
    144
    Units: mmol/L
        least squares mean (standard error)
    -5.12 ± 0.392
    -0.07 ± 0.393
    Statistical analysis title
    		 Lixisenatide vs Placebo
    Statistical analysis description
    Analysis was performed using ANCOVA model with treatment groups, randomization strata of Week -1 HbA1c [<8.0, ≥8.0%], randomization strata of basal insulin use at screening, randomization strata of Week -1 eGFR [ ≥30 to <60, ≥60 ml/min/1.73 m^2], and country as fixed effects and baseline 2-hour PPG value as a covariate.
    Comparison groups
    Lixisenatide v Placebo
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.0001 [3]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -5.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.96
         upper limit
    		 -4.132
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.464
    Notes
    [2] - Hierarchical testing procedure was used to control type I error rate at 0.05. Testing was performed sequentially in order: 1. Change in PPG from Baseline to Week 24; 2. Change in Average 7-point SMPG from Baseline to Week 24; 3. Change in body weight from Baseline to Week 24; 4. Change in FPG from Baseline to Week 24; 5. Percentage of Subjects Requiring Rescue Therapy during 24-Week. Hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05.
    [3] - Threshold for significance at 0.05 level.

    Secondary: Change in Average 7-point SMPG Profiles from Baseline to Week 24

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    End point title
    		 Change in Average 7-point SMPG Profiles from Baseline to Week 24
    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 24 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 24
    End point values
    		 Lixisenatide Placebo
    Number of subjects analysed
    138
    125
    Units: mmol/L
        least squares mean (standard error)
    -1.15 ± 0.186
    -0.19 ± 0.189
    Statistical analysis title
    		 Lixisenatide vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using ANCOVA model with treatment groups, randomization strata of Week -1 HbA1c [<8.0, ≥8.0%], randomization strata of basal insulin use at screening, randomization strata of Week -1 eGFR [ ≥30 to <60, ≥60 ml/min/1.73 m^2], and country as fixed effects and baseline 7-point SMPG value as a covariate.
    Comparison groups
    Lixisenatide v Placebo
    Number of subjects included in analysis
    263
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [4]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.39
         upper limit
    		 -0.527
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.219
    Notes
    [4] - Threshold for significance at 0.05 level.

    Secondary: Change in Body Weight from Baseline to Week 24

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    End point title
    		 Change in Body Weight from Baseline to Week 24
    End point description
    Change in body weight was calculated by subtracting baseline value from Week 24 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. Missing data was imputed using LOCF. 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 24
    End point values
    		 Lixisenatide Placebo
    Number of subjects analysed
    174
    173
    Units: kg
        least squares mean (standard error)
    -1.47 ± 0.241
    -0.16 ± 0.228
    Statistical analysis title
    		 Lixisenatide vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using ANCOVA model with treatment groups, randomization strata of Week -1 HbA1c [<8.0, ≥8.0%], randomization strata of basal insulin use at screening, randomization strata of Week -1 eGFR [ ≥30 to <60, ≥60 ml/min/1.73 m^2],and country as fixed effects and baseline body weight value as a covariate.
    Comparison groups
    Lixisenatide v Placebo
    Number of subjects included in analysis
    347
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [5]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.862
         upper limit
    		 -0.769
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.278
    Notes
    [5] - Threshold for significance at 0.05 level.

    Secondary: Change in FPG from Baseline to Week 24

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    End point title
    		 Change in FPG from Baseline to Week 24
    End point description
    Change in FPG was calculated by subtracting baseline value from Week 24 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 24
    End point values
    		 Lixisenatide Placebo
    Number of subjects analysed
    171
    168
    Units: mmol/L
        least squares mean (standard error)
    -0.3 ± 0.224
    0.01 ± 0.218
    Statistical analysis title
    		 Lixisenatide vs Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant). Analysis was performed using ANCOVA model with treatment groups, randomization strata of Week -1 HbA1c [<8.0, ≥8.0%], randomization strata of basal insulin use at screening, randomization strata of Week -1 eGFR [ ≥30 to <60, ≥60 ml/min/1.73 m^2], and country as fixed effects and baseline FPG value as a covariate.
    Comparison groups
    Lixisenatide v Placebo
    Number of subjects included in analysis
    339
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2347 [6]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.828
         upper limit
    		 0.204
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.262
    Notes
    [6] - Threshold for significance at 0.05 level.

    Secondary: Percentage of Subjects Requiring Rescue Therapy during 24-Week Treatment Period

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    End point title
    		 Percentage of Subjects Requiring Rescue Therapy during 24-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. Threshold values - from baseline to Week 8: fasting SMPG/FPG >270 mg/dL (15.0 mmol/L), from Week 8 to Week 12: fasting SMPG/FPG >240 mg/dL (13.3 mmol/L), and from Week 12 to Week 24: fasting SMPG/FPG >200 mg/dL (11.1 mmol/L) or HbA1c >9%. mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 24
    End point values
    		 Lixisenatide Placebo
    Number of subjects analysed
    175
    173
    Units: percentage of subjects
        number (not applicable)
    2.9
    10.4
    No statistical analyses for this end point

    Secondary: Change in Plasma Glucose Excursions from Baseline to Week 24

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    End point title
    		 Change in Plasma Glucose Excursions from Baseline to Week 24
    End point description
    Plasma glucose excursion = 2-hour PPG minus plasma glucose 30 minutes prior to the liquid standardized breakfast meal test, before study drug administration. Change in plasma glucose excursions were calculated by subtracting baseline value from Week 24 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 plasma glucose excursion assessment during on-treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Lixisenatide Placebo
    Number of subjects analysed
    145
    143
    Units: mmol/L
        least squares mean (standard error)
    -4.71 ± 0.331
    -0.25 ± 0.331
    No statistical analyses for this end point

    Secondary: Change in Total Daily Basal Insulin Dose from Baseline to Week 24 (in Subjects who Took Basal Insulin as Background Therapy)

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    End point title
    		 Change in Total Daily Basal Insulin Dose from Baseline to Week 24 (in Subjects who Took Basal Insulin as Background Therapy)
    End point description
    Change in basal insulin dose was calculated by subtracting baseline value from Week 24 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 basal insulin dose assessment during on-treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Lixisenatide Placebo
    Number of subjects analysed
    54
    55
    Units: units
        least squares mean (standard error)
    -2.97 ± 1.145
    -1.3 ± 1.076
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Symptomatic and Severe Symptomatic Hypoglycemia

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    End point title
    		 Percentage of Subjects with Symptomatic and Severe Symptomatic Hypoglycemia
    End point description
    Symptomatic hypoglycemia was an event with clinical symptoms that were considered to result from a hypoglycemic episode with an accompanying plasma glucose less than 60 mg/dL (3.3 mmol/L) or associated with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration if no plasma glucose measurement was available. 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. Analysis was performed on safety population defined as all randomized subjects who received any amount of study drug.
    End point type
    Secondary
    End point timeframe
    First dose of study drug up to 3 days after the last dose administration (maximum of 171 days)
    End point values
    		 Lixisenatide Placebo
    Number of subjects analysed
    176
    174
    Units: percentage of subjects
    number (not applicable)
        Symptomatic hypoglycemia
    7.4
    5.7
        Severe symptomatic hypoglycemia
    0.57
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with HbA1c Reduction >0.5% at Week 24 and did not Experienced Documented (Plasma Glucose <60 mg/dL) Symptomatic Hypoglycemia

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    End point title
    		 Percentage of Subjects with HbA1c Reduction >0.5% at Week 24 and did not Experienced Documented (Plasma Glucose <60 mg/dL) Symptomatic Hypoglycemia
    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 24
    End point values
    		 Lixisenatide Placebo
    Number of subjects analysed
    172
    172
    Units: percentage of subjects
        number (not applicable)
    57.6
    21.5
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Gastrointestinal Disorders

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    End point title
    		 Percentage of Subjects with Gastrointestinal Disorders
    End point description
    Analysis was performed on safety population.
    End point type
    Secondary
    End point timeframe
    Up to Day 171
    End point values
    		 Lixisenatide Placebo
    Number of subjects analysed
    176
    174
    Units: percentage of subjects
        number (not applicable)
    40.3
    20.7
    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 171) regardless of seriousness or relationship to investigational Medicinal product (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).
    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 once daily (QD) for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to Week 24. (Median exposure: 169 days)

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to lixisenatide QD for 24 weeks. (Median exposure: 169 days)

    Serious adverse events
    		 Lixisenatide Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 176 (4.55%)
    10 / 174 (5.75%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lentigo Maligna
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip Fracture
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skull Fracture
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Compression Fracture
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic Intracranial Haemorrhage
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic Aneurysm
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypertensive Crisis
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 174 (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
    0 / 176 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina Unstable
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular Accident
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic Unconsciousness
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss Of Consciousness
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 174 (0.57%)
         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
    Fatigue
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain Lower
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal Failure Acute
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 174 (0.57%)
         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
    Systemic Lupus Erythematosus
         subjects affected / exposed
    1 / 176 (0.57%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 176 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    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
    		 Lixisenatide Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    89 / 176 (50.57%)
    58 / 174 (33.33%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 176 (5.68%)
    8 / 174 (4.60%)
         occurrences all number
    13
    10
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    19 / 176 (10.80%)
    13 / 174 (7.47%)
         occurrences all number
    28
    18
    Nausea
         subjects affected / exposed
    44 / 176 (25.00%)
    13 / 174 (7.47%)
         occurrences all number
    61
    15
    Vomiting
         subjects affected / exposed
    10 / 176 (5.68%)
    1 / 174 (0.57%)
         occurrences all number
    10
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    15 / 176 (8.52%)
    22 / 174 (12.64%)
         occurrences all number
    20
    29
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    30 / 176 (17.05%)
    18 / 174 (10.34%)
         occurrences all number
    69
    50

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jan 2013
    It included following changes: - The rescue medication was clarified as: only an increase by more than 20% in basal insulin for more than 7 days was considered a rescue therapy; - Pharmacokinetic (PK) sampling was clarified as: no pre-dose (before first study drug intake) PK assessment was needed for PK profile evaluation; - The cases of serious adverse events (SAEs) occurring after the end of the study period were clarified as: deaths post study (any deaths occurring after the end of the study judged by the Investigator as related to study drug).
    12 Mar 2014
    It included following changes: - A new safety committee, the Pancreatic Safety Assessment Committee (PSAC) was added to ensure the independent assessment of pancreatic event data; - Inclusion criteria was revised as: the current anti-diabetic regimen should be a pharmaceutical treatment. Subjects receiving only diet and lifestyle regimen were not eligible. - Stable dose of basal insulin was defined as a dose change during 3 months preceding screening visits, between -20% and +20% of the dose at Visit 1; - The discrepancy between exclusion criteria was corrected as: with a threshold of HbA1c > 7% required at visit 1 to enter the study; and basal insulin and sulfonyl urea adjustment in case of Hba1c ≥ 7%; - Correction in exclusion criteria: removal of the word single-blind since during run-in period only placebo was injected; - Regarding the final assessment before rescue therapy, removed the reference to Visit 22 to describe the final assessment visit before introducing the recue therapy; - Discrepancy between FPG values displayed in mg/dL and mmol/L were corrected; - Study drug dose adjustment was clarified: after Visit 13, the study drug dose should have been maintained at the 20 µg dose or to the 10 µg dose if the 20 µg dose could no longer be tolerated; - Correction of discrepancy regarding basal insulin and sulfonyl urea dose reduction that should occur the day before randomization and not the day of randomization; - Discrepancy regarding use of weight loss drugs was clarified: weight loss drugs were not allowed during the screening and double-blind treatment periods; - Re-screening was allowed only before entering the run-in period; - Alanine transaminase (ALT) increase was to be reported as an adverse events of special interest (AESI) with immediate notification to be in line with the updated requirements for safety information collection; Statistical analyses were corrected; - Creatinine clearance increase was clarified.

    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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