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    Clinical Trial Results:
    A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel group, Phase 3 Trial to Evaluate the Safety and Efficacy of Once Weekly Exenatide Therapy Added to Titrated Basal Insulin Glargine Compared to Placebo Added to Titrated Basal Insulin Glargine in Patients with Type 2 Diabetes Who Have Inadequate Glycemic Control on Basal Insulin Glargine with or without Metformin

    Summary
    EudraCT number
    2014-003502-33
    Trial protocol
    SK   HU  
    Global end of trial date
    29 Aug 2016

    Results information
    Results version number
    v2(current)
    This version publication date
    02 Jan 2019
    First version publication date
    03 Sep 2017
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    D5553C00002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02229383
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Pepparedsleden 1, Mölndal, Sweden, SE-431 83
    Public contact
    Global Clinical Leader, AstraZeneca, 011 +1 302 885 1180, ClinicalTrialTransparency@astrazeneca.com
    Scientific contact
    Global Clinical Leader, AstraZeneca, 011 +1 302 885 1180, ClinicalTrialTransparency@astrazeneca.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
    29 Aug 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Aug 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Aug 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the change from baseline in hemoglobin A1c (HbA1c) achieved with exenatide once weekly (EQW) added to titrated basal insulin glargine to placebo added to titrated basal insulin glargine, with or without metformin, after 28 weeks of double-blind treatment.
    Protection of trial subjects
    This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Council for Harmonisation/Good Clinical Practice and applicable regulatory requirements and the AstraZeneca policy on Bioethics.
    Background therapy
    Insulin glargine titrated to achieve a target glucose of 4.0 to 5.5 millimoles per liter [72 to 99 milligram per deciliter (mg/dL)]; metformin as prescribed by the Investigator.
    Evidence for comparator
    -
    Actual start date of recruitment
    06 Sep 2014
    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
    Hungary: 59
    Country: Number of subjects enrolled
    Poland: 47
    Country: Number of subjects enrolled
    Romania: 45
    Country: Number of subjects enrolled
    Slovakia: 38
    Country: Number of subjects enrolled
    United States: 250
    Country: Number of subjects enrolled
    South Africa: 22
    Worldwide total number of subjects
    461
    EEA total number of subjects
    189
    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)
    353
    From 65 to 84 years
    108
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study was conducted in 107 centers globally between 06 September 2014 and 29 August 2016.

    Pre-assignment
    Screening details
    The study had a Screening Visit, an 8-week insulin dose optimization phase, followed by a 28-week randomized, double-blind treatment phase. A total of 464 participants were randomized and entered the double-blind Treatment Period. Of which, 3 participants from 1 center in the United States have been excluded from analyses.

    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, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Exenatide
    Arm description
    Exenatide 2 milligram (mg) 1 time per week + titrated basal insulin glargine with or without metformin.
    Arm type
    Experimental

    Investigational medicinal product name
    Exenatide
    Investigational medicinal product code
    Other name
    Bydureon
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    2 mg one time per week, injection

    Arm title
    Placebo
    Arm description
    Placebo (matching with exenatide) 1 time per week + titrated basal insulin glargine with or without metformin.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Matching with exenatide one time per week, injection

    Number of subjects in period 1
    Exenatide Placebo
    Started
    232
    229
    Received treatment
    231
    229
    Safety analysis set
    231
    229
    Intent-to-treat (ITT) analysis set
    230
    228
    Completed
    212
    207
    Not completed
    20
    22
         Did not receive treatment
    1
    -
         Adverse event, serious fatal
    -
    1
         Adverse event, non-fatal
    7
    4
         Unspecified
    3
    8
         Consent withdrawn by subject
    4
    6
         Lost to follow-up
    5
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Exenatide
    Reporting group description
    Exenatide 2 milligram (mg) 1 time per week + titrated basal insulin glargine with or without metformin.

    Reporting group title
    Placebo
    Reporting group description
    Placebo (matching with exenatide) 1 time per week + titrated basal insulin glargine with or without metformin.

    Reporting group values
    Exenatide Placebo Total
    Number of subjects
    232 229 461
    Age categorical
    Units: Subjects
        In Utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    182 171 353
        From 65-84 years
    50 58 108
        85 years and over
    0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    57.8 ± 9.01 57.6 ± 10.28 -
    Gender, Male/Female
    Units: Subjects
        Female
    119 122 241
        Male
    113 107 220
    Race, Customized
    Units: Subjects
        American Indian Or Alaska Native
    1 0 1
        Asian
    4 2 6
        Black Or African American
    19 28 47
        Native Hawaiian Or Other Pacific Islander
    1 0 1
        Other
    1 4 5
        White
    206 195 401

    End points

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    End points reporting groups
    Reporting group title
    Exenatide
    Reporting group description
    Exenatide 2 milligram (mg) 1 time per week + titrated basal insulin glargine with or without metformin.

    Reporting group title
    Placebo
    Reporting group description
    Placebo (matching with exenatide) 1 time per week + titrated basal insulin glargine with or without metformin.

    Primary: Change in HbA1c From Baseline to Week 28

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    End point title
    Change in HbA1c From Baseline to Week 28
    End point description
    To compare the change from baseline in HbA1c achieved with EQW added to titrated basal insulin glargine to placebo added to titrated basal insulin glargine, with or without metformin, after 28 weeks of double-blind treatment. The ITT analysis set included all randomized participants who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment. Only participants with data available for analysis are presented.
    End point type
    Primary
    End point timeframe
    Baseline to Week 28
    End point values
    Exenatide Placebo
    Number of subjects analysed
    205
    206
    Units: Percentage of HbA1c
        least squares mean (confidence interval 95%)
    -0.96 (-1.12 to -0.81)
    -0.22 (-0.38 to -0.07)
    Statistical analysis title
    Change in HbA1c - baseline to Week 28
    Statistical analysis description
    To compare the change from baseline in HbA1c achieved with EQW added to titrated basal insulin glargine to placebo added to titrated basal insulin glargine, with or without metformin, after 28 weeks of double-blind treatment.
    Comparison groups
    Exenatide v Placebo
    Number of subjects included in analysis
    411
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    < 0.001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.94
         upper limit
    -0.54
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.101
    Notes
    [1] - Treatment, region, baseline HbA1c (< or ≥ 9.0%), baseline sulphonylurea (SU)-use, week, treatment by week interaction as fixed factors; baseline value as covariate.

    Secondary: Change in Body Weight From Baseline to Week 28

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    End point title
    Change in Body Weight From Baseline to Week 28
    End point description
    To compare the change from baseline in body weight achieved with EQW added to titrated basal insulin glargine to placebo added to titrated basal insulin glargine, with or without metformin, after 28 weeks of double-blind treatment. The ITT analysis set included all randomized participants who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment. Only participants with data available for analysis are presented.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 28
    End point values
    Exenatide Placebo
    Number of subjects analysed
    205
    208
    Units: Kilogram
        least squares mean (confidence interval 95%)
    -1.04 (-1.54 to -0.53)
    0.48 (-0.02 to 0.98)
    Statistical analysis title
    Change in body weight - baseline to Week 28
    Statistical analysis description
    To compare the change from baseline in body weight achieved with EQW added to titrated basal insulin glargine to placebo added to titrated basal insulin glargine, with or without metformin, after 28 weeks of double-blind treatment.
    Comparison groups
    Exenatide v Placebo
    Number of subjects included in analysis
    413
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    < 0.001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.52
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.19
         upper limit
    -0.85
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.341
    Notes
    [2] - Treatment, region, baseline HbA1c (< or ≥ 9.0%), baseline SU-use, week, treatment by week interaction as fixed factors; baseline value as covariate.

    Secondary: Change From Baseline to Week 28 in 2-hour Postprandial Glucose (PPG) After a Standard Meal Tolerance Test (MTT)

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    End point title
    Change From Baseline to Week 28 in 2-hour Postprandial Glucose (PPG) After a Standard Meal Tolerance Test (MTT)
    End point description
    To compare the change from baseline in 2-hour PPG after a standard MTT achieved with EQW added to titrated basal insulin glargine to placebo added to titrated basal insulin glargine, with or without metformin, after 28 weeks of double-blind treatment. The ITT analysis set included all randomized participants who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment. Only participants with data available for analysis are presented.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 28
    End point values
    Exenatide Placebo
    Number of subjects analysed
    200
    204
    Units: mg/dL
        least squares mean (confidence interval 95%)
    -28.73 (-40.0 to -17.45)
    -0.96 (-12.41 to 10.48)
    Statistical analysis title
    Change in 2 hr PPG - baseline to Week 28
    Statistical analysis description
    To compare the change from baseline in 2-hour PPG after a standard MTT achieved with EQW added to titrated basal insulin glargine to placebo added to titrated basal insulin glargine, with or without metformin, after 28 weeks of double-blind treatment.
    Comparison groups
    Exenatide v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -27.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -39.07
         upper limit
    -16.45
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.754
    Notes
    [3] - Treatment, region, baseline HbA1c (< or ≥ 9.0%), baseline SU-use (yes vs. no) as fixed factors; baseline value as covariate.

    Secondary: Percentage of Participants Achieving HbA1c <7.0% at Week 28

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    End point title
    Percentage of Participants Achieving HbA1c <7.0% at Week 28
    End point description
    To compare the percentage of participants achieving HbA1c <7.0% between EQW added to titrated basal insulin glargine to placebo added to titrated basal insulin glargine, with or without metformin, after 28 weeks of double-blind treatment. The ITT analysis set included all randomized participants who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 28
    End point values
    Exenatide Placebo
    Number of subjects analysed
    230
    228
    Units: Percentage of participants
        number (confidence interval 95%)
    32.6 (26.6 to 38.7)
    7.0 (3.7 to 10.3)
    Statistical analysis title
    Percentage of participants achieving HbA1c <7%
    Statistical analysis description
    To compare the percentage of participants achieving HbA1c <7.0% between EQW added to titrated basal insulin glargine to placebo added to titrated basal insulin glargine, with or without metformin, after 28 weeks of double-blind treatment.
    Comparison groups
    Exenatide v Placebo
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    superiority [4]
    P-value
    < 0.001 [5]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [4] - Stratified by baseline HbA1c (<9.0% or ≥9.0%) and baseline SU-use (yes vs. no).
    [5] - Difference in percentages = 25.6

    Secondary: Change From Baseline to Week 28 in Daily Insulin Dose

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    End point title
    Change From Baseline to Week 28 in Daily Insulin Dose
    End point description
    To compare the change from baseline in daily insulin dose achieved with EQW added to titrated basal insulin glargine to placebo added to titrated basal insulin glargine, with or without metformin, after 28 weeks of double-blind treatment. The ITT analysis set included all randomized participants who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment. Only participants with data available for analysis are presented.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 28
    End point values
    Exenatide Placebo
    Number of subjects analysed
    209
    208
    Units: Units
        least squares mean (confidence interval 95%)
    1.6 (0.1 to 3.1)
    3.5 (2.0 to 5.1)
    Statistical analysis title
    Change in daily insulin dose - baseline to Week 28
    Statistical analysis description
    To compare the change from baseline in daily insulin dose achieved with EQW added to titrated basal insulin glargine to placebo added to titrated basal insulin glargine, with or without metformin, after 28 weeks of double-blind treatment.
    Comparison groups
    Exenatide v Placebo
    Number of subjects included in analysis
    417
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    P-value
    = 0.074
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.1
         upper limit
    0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.08
    Notes
    [6] - Treatment, region, baseline HbA1c (< or ≥ 9.0%), baseline SU-use, week, treatment by week interaction as fixed factors; baseline value as covariate.

    Secondary: Percentage of Participants Achieving HbA1c <7.0% at Week 28, No Weight Gain at Week 28, and No Major Hypoglycemia Over 28 Weeks

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    End point title
    Percentage of Participants Achieving HbA1c <7.0% at Week 28, No Weight Gain at Week 28, and No Major Hypoglycemia Over 28 Weeks
    End point description
    To compare the percentage of participants achieving HbA1c <7.0% at Week 28, no weight gain at Week 28, and no major hypoglycemia over 28 weeks between EQW added to titrated basal insulin glargine to placebo added to titrated basal insulin glargine, with or without metformin. The ITT analysis set included all randomized participants who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 28
    End point values
    Exenatide Placebo
    Number of subjects analysed
    230
    228
    Units: Percentage of participants
        number (confidence interval 95%)
    22.2 (16.8 to 27.5)
    2.2 (0.3 to 4.1)
    Statistical analysis title
    HbA1c <7.0%, no weight gain or hypoglycemia
    Statistical analysis description
    To compare the percentage of participants achieving HbA1c <7.0% at Week 28, no weight gain at Week 28, and no major hypoglycemia over 28 weeks between EQW added to titrated basal insulin glargine to placebo added to titrated basal insulin glargine, with or without metformin.
    Comparison groups
    Exenatide v Placebo
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    < 0.001 [8]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [7] - Stratified by baseline HbA1c (<9.0% or ≥9.0%) and baseline SU-use (yes vs. no).
    [8] - Difference in percentages = 20.0

    Secondary: Change in Seated Systolic Blood Pressure (SBP) From Baseline to Week 28

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    End point title
    Change in Seated Systolic Blood Pressure (SBP) From Baseline to Week 28
    End point description
    To compare the change from baseline in seated SBP achieved with EQW added to titrated basal insulin glargine to placebo added to titrated basal insulin glargine, with or without metformin, after 28 weeks of double-blind treatment. The ITT analysis set included all randomized participants who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment. Only participants with data available for analysis are presented.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 28
    End point values
    Exenatide Placebo
    Number of subjects analysed
    208
    210
    Units: millimeter of mercury
        least squares mean (confidence interval 95%)
    -2.5 (-4.4 to -0.7)
    -0.7 (-2.6 to 1.1)
    Statistical analysis title
    Change in SBP - baseline to Week 28
    Statistical analysis description
    To compare the change from baseline in seated SBP achieved with EQW added to titrated basal insulin glargine to placebo added to titrated basal insulin glargine, with or without metformin, after 28 weeks of double-blind treatment.
    Comparison groups
    Exenatide v Placebo
    Number of subjects included in analysis
    418
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    = 0.11
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4
         upper limit
    0.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.13
    Notes
    [9] - Treatment, region, baseline HbA1c (< or ≥ 9.0%), baseline SU-use, week, treatment by week interaction as fixed factors; baseline value as covariate.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline (Day 1) up to Week 28
    Adverse event reporting additional description
    Safety analysis set included all participants who received at least 1 dose of randomized study medication. Total number of Deaths is reported for the overall study period, including the off-treatment period; Serious and Non-serious adverse event data is reported for the on-treatment period.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo (matching with exenatide) 1 time per week + titrated basal insulin glargine with or without metformin.

    Reporting group title
    Exenatide
    Reporting group description
    Exenatide 2 mg 1 time per week + titrated basal insulin glargine with or without metformin.

    Serious adverse events
    Placebo Exenatide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 229 (4.80%)
    11 / 231 (4.76%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 231 (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
    2 / 229 (0.87%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 229 (0.44%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 231 (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
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Acute stress disorder
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alcohol withdrawal syndrome
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal mass
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder neck obstruction
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Psoriasis
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 231 (0.43%)
         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
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 229 (0.87%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 229 (0.44%)
    1 / 231 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 231 (0.43%)
         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 / 229 (0.44%)
    0 / 231 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Exenatide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 229 (15.72%)
    40 / 231 (17.32%)
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    13 / 229 (5.68%)
    5 / 231 (2.16%)
         occurrences all number
    15
    6
    General disorders and administration site conditions
    Injection site nodule
         subjects affected / exposed
    1 / 229 (0.44%)
    12 / 231 (5.19%)
         occurrences all number
    1
    14
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    9 / 229 (3.93%)
    12 / 231 (5.19%)
         occurrences all number
    10
    13
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    15 / 229 (6.55%)
    18 / 231 (7.79%)
         occurrences all number
    21
    25

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Oct 2014
    Outcome measure of secondary objective was modified to specify “major” hypoglycemia. Insulin glargine, metformin, and rescue therapy would be sourced locally. Exclusion criterion #25 was included as inclusion criterion #9. Cut off for serum calcitonin concentration was decreased to 40 picogram per milliliter. Tobacco, caffeine, and strenuous exercise were added to list of restrictions 24 hours prior to each visit. Discontinuation procedures were amended to include a review when Investigator deemed it necessary to temporarily stop and re-start study medication. Discontinued participants were required to complete Follow-up visit (Visit 15), and who had symptoms of hypoglycemia were to record glucose measurements and episode details in participant diary. Study Plan updated to clarify when study diary was given out, procedures for collecting study diary, when study medication was dispensed and used/unused medication was collected. Text added to differentiate procedures for Early Termination and Rescue Visits, to indicate IVRS should be called on day of consent, to clarify that participants undergoing rescue therapy were to perform 6 point self-monitored blood glucose profile before returning for Rescue Visit, to indicate that staff monitored study medication administration at study visits, and to indicate when MTTs should be performed. Text regarding MTT updated to include instruction on MTT timing and for how MTT should have been performed. Blood pressure measurement instructions were modified. Investigators should contact medical monitor if a participant developed a liver function test abnormality. Hy’s Law text updated to state that cases meeting any of identification criteria required an unscheduled laboratory draw. Hypoglycemia assessment updated with criteria for classification. Sponsor should have been contacted regarding hypoglycemia events. Added use of SU as a stratification factor for exploratory analyses. Clarified assessment of causality for adverse events.
    20 Feb 2015
    The proportion of participants rescued or discontinued for lack of glycemic control at Week 28 was added as an exploratory outcome measure. Inclusion criterion #7 was clarified to state that participants may only take basal insulin glargine once daily. Exclusion criterion #32 was amended to include participation in an interventional clinical trial and to clarify that only administration of an investigational drug would have rendered a participant as ineligible. The Study Plan and Timing of Procedures was updated. This update clarified study visit windows, when used/unused study medication was to be collected, when training for study drug administration was to be received by the participant, and visits when rescue medication could have been dispensed. Review of potential cardiovascular (CV) event triggers was added to all visits where adverse events and concomitant medication were reviewed. Text was added to indicate that metformin should be taken with the next meal, and does not need to be taken at the study center, and that urine should be collected right before time 0 of the MTT. Text was added to indicate that study medication may be dispensed at a Rescue Visit. Text was added to clarify that potential CV event triggers would be reviewed at specified study visits. Text was added to indicate that urine was collected right before time 0 of the MTT. Text was amended to indicate that antibody results would be presented in the CSR. Text was added to clarify that the baseline physical examination data are collection at Visit 1. Text was added to clarify that there is no restriction on fathering children during the study. Text was added to describe the adjudication of CV events.

    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.
    Please note that the data from 4 subjects enrolled at one site were omitted due to potential scientific misconduct at that site. Study conclusions remain unchanged.
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