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    Clinical Trial Results:
    A Phase 3, Double-Blind, Placebo-Controlled, Randomized, Multicenter Study to Assess the Safety and Efficacy of Exenatide Once Weekly in Adolescents with Type 2 Diabetes

    Summary
    EudraCT number
    2015-000408-24
    Trial protocol
    HU   BG  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    18 Nov 2020
    First version publication date
    18 Nov 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D5551C00002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01554618
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Pepparedsleden 1, Mölndal, Sweden, SE-431 83
    Public contact
    Global Clinical Lead, AstraZeneca, +1 8772409479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca, +1 8772409479, information.center@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000689-PIP01-09
    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?
    Yes
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    06 May 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 May 2020
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect on glycemic control, as measured by glycosylated hemoglobin (HbA1c), of exenatide once weekly following 24 weeks of treatment compared with placebo in children and adolescents with type 2 diabetes mellitus. The Extended Safety Follow-up Period was continued for up to 3 years or until the increase in height between two 6 month interval visits was less than 5 millimeter (mm) (whichever came first). No study medication was administered during the Extended Safety Follow-up Period.
    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, applicable regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological Samples.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    12 May 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 1
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Israel: 7
    Country: Number of subjects enrolled
    Mexico: 15
    Country: Number of subjects enrolled
    United States: 53
    Country: Number of subjects enrolled
    Kuwait: 3
    Worldwide total number of subjects
    83
    EEA total number of subjects
    5
    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)
    4
    Adolescents (12-17 years)
    79
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study was conducted in adolescents (aged 10 to 17 years inclusive) with type 2 diabetes treated with diet and exercise alone or in combination with a stable dose of oral antidiabetic agents and/or insulin for at least 2 months prior to screening. 27 study centers in 6 countries randomized patients during the study.

    Pre-assignment
    Screening details
    Study had a screening period (5 weeks), controlled assessment period (24 weeks; patients randomized 5:2 to exenatide or placebo), open-label extension period (28 weeks) and post-treatment follow-up period (10 weeks). 84 patients were randomized but 1 due to clinical error and immediately discontinued, thus, 83 patients were included in the study.

    Period 1
    Period 1 title
    Randomized Through Start of Treatment
    Is this the baseline period?
    No
    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
    Patients randomized to the exenatide treatment group.
    Arm type
    Experimental

    Investigational medicinal product name
    Exenatide once weekly
    Investigational medicinal product code
    Other name
    EQW; BYDUREON™
    Pharmaceutical forms
    Powder and solvent for prolonged-release suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Period is prior to the start of treatment; no study medication administered.

    Arm title
    Placebo
    Arm description
    Patients randomized to the placebo treatment group.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Period is prior to the start of treatment; no study medication administered.

    Number of subjects in period 1
    Exenatide Placebo
    Started
    59
    24
    Completed
    58
    24
    Not completed
    1
    0
         Adverse event, non-fatal
    1
    -
    Period 2
    Period 2 title
    Controlled Assessment Period
    Is this the baseline period?
    Yes [1]
    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
    Patients received exenatide 2 milligrams (mg) subcutaneous (SC) injection once weekly for 24 weeks during the controlled assessment period.
    Arm type
    Experimental

    Investigational medicinal product name
    Exenatide once weekly
    Investigational medicinal product code
    Other name
    EQW; BYDUREON™
    Pharmaceutical forms
    Powder and solvent for prolonged-release suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Exenatide once weekly was administered by the caregiver (or the patient self-administered if the medically qualified site staff member assessed that this was appropriate) for 24 weeks using prefilled syringes or dual chamber pens (dual chamber pen was intended for use in all patients recruited from August 2018 onwards).

    Arm title
    Placebo
    Arm description
    Patients received placebo (matching with exenatide) SC injection once weekly for 24 weeks during the controlled assessment period.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo matching with exenatide once weekly was administered by the caregiver (or the patient self-administered if the medically qualified site staff member assessed that this was appropriate) for 24 weeks using prefilled syringes or dual chamber pens (dual chamber pen was intended for use in all patients recruited from August 2018 onwards).

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 presents data for all patients randomized until the start of treatment and Period 2 presents data for all patients who received study medication during the controlled assessment period. Baseline characteristics are based on patients who were randomized and who received at least one dose of the study medication; Period 2 is therefore the baseline period.
    Number of subjects in period 2 [2]
    Exenatide Placebo
    Started
    58
    24
    Completed
    50
    23
    Not completed
    8
    1
         Consent withdrawn by subject
    6
    -
         Lost to follow-up
    2
    1
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics are based on patients who were randomized and who received at least one dose of the study medication.
    Period 3
    Period 3 title
    Open-Label Extension Period
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Exenatide
    Arm description
    Patients received open-label exenatide 2 mg SC injection once weekly for 28 weeks during the extension period (from Week 25 to Week 52). Patients in this treatment group had previously received exenatide during the controlled assessment period.
    Arm type
    Experimental

    Investigational medicinal product name
    Exenatide once weekly
    Investigational medicinal product code
    Other name
    EQW; BYDUREON™
    Pharmaceutical forms
    Powder and solvent for prolonged-release suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Open-label exenatide once weekly was administered by the caregiver (or the patient self-administered if the medically qualified site staff member assessed that this was appropriate) for 28 weeks during the extension period using prefilled syringes or dual chamber pens (dual chamber pen was intended for use in all patients recruited from August 2018 onwards).

    Arm title
    Placebo to Exenatide
    Arm description
    Patients received open-label exenatide 2 mg SC injection once weekly for 28 weeks during the extension period (from Week 25 to Week 52). Patients in this treatment group had previously received placebo during the controlled assessment period.
    Arm type
    Experimental

    Investigational medicinal product name
    Exenatide once weekly
    Investigational medicinal product code
    Other name
    EQW; BYDUREON™
    Pharmaceutical forms
    Powder and solvent for prolonged-release suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Open-label exenatide once weekly was administered by the caregiver (or the patient self-administered if the medically qualified site staff member assessed that this was appropriate) for 28 weeks during the extension period using prefilled syringes or dual chamber pens (dual chamber pen was intended for use in all patients recruited from August 2018 onwards).

    Number of subjects in period 3 [3]
    Exenatide Placebo to Exenatide
    Started
    49
    23
    Completed
    46
    18
    Not completed
    3
    5
         Physician decision
    -
    1
         Consent withdrawn by subject
    2
    3
         Lost to follow-up
    1
    1
    Notes
    [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 1 patient who was noncompliant with study medication did not enter the open-label extension period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Exenatide
    Reporting group description
    Patients received exenatide 2 milligrams (mg) subcutaneous (SC) injection once weekly for 24 weeks during the controlled assessment period.

    Reporting group title
    Placebo
    Reporting group description
    Patients received placebo (matching with exenatide) SC injection once weekly for 24 weeks during the controlled assessment period.

    Reporting group values
    Exenatide Placebo Total
    Number of subjects
    58 24 82
    Age Categorical
    Age group (years)
    Units: participants
        < 10
    0 0 0
        ≥ 10 to ≤ 12
    8 3 11
        ≥ 13 to ≤ 16
    36 12 48
        > 16
    14 9 23
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    14.9 ± 1.88 15.6 ± 1.66 -
    Sex: Female, Male
    Units: participants
        Female
    31 17 48
        Male
    27 7 34
    Race/Ethnicity, Customized
    Units: Subjects
        White
    23 12 35
        Black or African American
    17 8 25
        Asian
    2 1 3
        Native Hawaiian or Other Pacific Islander
    0 0 0
        American Indian or Alaska Native
    4 1 5
        Other
    12 2 14
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    25 8 33
        Not Hispanic or Latino
    29 13 42
        Unknown or Not Reported
    4 3 7
    Region of Enrollment
    Units: Subjects
        Bulgaria
    1 0 1
        Hungary
    3 1 4
        Israel
    4 3 7
        Mexico
    13 2 15
        United States
    35 17 52
        Kuwait
    2 1 3

    End points

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    End points reporting groups
    Reporting group title
    Exenatide
    Reporting group description
    Patients randomized to the exenatide treatment group.

    Reporting group title
    Placebo
    Reporting group description
    Patients randomized to the placebo treatment group.
    Reporting group title
    Exenatide
    Reporting group description
    Patients received exenatide 2 milligrams (mg) subcutaneous (SC) injection once weekly for 24 weeks during the controlled assessment period.

    Reporting group title
    Placebo
    Reporting group description
    Patients received placebo (matching with exenatide) SC injection once weekly for 24 weeks during the controlled assessment period.
    Reporting group title
    Exenatide
    Reporting group description
    Patients received open-label exenatide 2 mg SC injection once weekly for 28 weeks during the extension period (from Week 25 to Week 52). Patients in this treatment group had previously received exenatide during the controlled assessment period.

    Reporting group title
    Placebo to Exenatide
    Reporting group description
    Patients received open-label exenatide 2 mg SC injection once weekly for 28 weeks during the extension period (from Week 25 to Week 52). Patients in this treatment group had previously received placebo during the controlled assessment period.

    Subject analysis set title
    Controlled Assessment Period - Exenatide
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Patients received exenatide 2 mg SC injection once weekly for 24 weeks during the controlled assessment period.

    Subject analysis set title
    Controlled Assessment Period – Placebo
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Patients received placebo (matching with exenatide) SC injection once weekly for 24 weeks during the controlled assessment period.

    Subject analysis set title
    Treatment Period – Exenatide
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Patients received exenatide 2 mg SC injection once weekly for 24 weeks during the controlled assessment period and continued to receive exenatide 2 mg SC once weekly during the open-label extension period for a further 28 weeks (from Week 0 to Week 52 overall).

    Subject analysis set title
    Treatment Period - Placebo then Exenatide
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Patients received placebo (matching with exenatide) SC injection once weekly for 24 weeks during the controlled assessment period and then received exenatide 2 mg SC once weekly beginning at the start of the open-label extension period for 28 weeks (from Week 25 to Week 52).

    Primary: Change from Baseline in HbA1c to Week 24 (Controlled Assessment Period)

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    End point title
    Change from Baseline in HbA1c to Week 24 (Controlled Assessment Period)
    End point description
    Change from baseline in HbA1c (%) to Week 24 during the controlled assessment period is reported as adjusted least square (LS) mean values. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) on or prior to the first dose of randomized study medication. A mixed model with repeated measures (MMRM) analysis was performed, excluding data collected after initiation of rescue medication or premature discontinuation of study medication. The Evaluable Analysis Set consisted of all randomized patients who received at least 1 dose of randomized study medication and had at least 1 baseline and post-baseline HbA1c assessment.
    End point type
    Primary
    End point timeframe
    Baseline (Week 0) and Week 24
    End point values
    Controlled Assessment Period - Exenatide Controlled Assessment Period – Placebo
    Number of subjects analysed
    58
    24
    Units: percentage (% HbA1c)
        least squares mean (standard error)
    -0.36 ± 0.184
    0.49 ± 0.273
    Statistical analysis title
    Treatment difference in HbA1c at Week 24
    Statistical analysis description
    Adjusted LS mean and treatment group difference in the change from baseline at Week 24 were modeled using a MMRM including treatment group, region, visit, and treatment group by visit interaction, baseline HbA1c value (continuous) and baseline HbA1c by visit interaction as fixed effects, using an unstructured covariance matrix.
    Comparison groups
    Controlled Assessment Period - Exenatide v Controlled Assessment Period – Placebo
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.012
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -0.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.51
         upper limit
    -0.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.33
    Notes
    [1] - Exenatide versus Placebo

    Primary: Percentage of Patients with On-Treatment Adverse Events (AEs) up to Week 24 (Controlled Assessment Period)

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    End point title
    Percentage of Patients with On-Treatment Adverse Events (AEs) up to Week 24 (Controlled Assessment Period) [2]
    End point description
    A controlled assessment period AE was defined as an AE starting on or after day of first dose of study medication up to but not including Week 24 for patients entering the extension period. For patients not entering the extension period, the period was defined up to and including last dose of study medication + 7 days (+ 90 days for serious AEs [SAEs] and other clinically significant or related AEs). The Investigator assessed AEs for causal relationship to study drug medication. The Safety Analysis Set consisted of all patients who received at least 1 dose of study medication. One patient who was randomized to placebo received a dose of exenatide in error and was subsequently reassigned to the exenatide treatment group for analyses based on actual treatment (ie, for analyses based on the Safety Analysis Set).
    End point type
    Primary
    End point timeframe
    Day 1 (Week 0) up to Week 24, plus up to a maximum of 90 days follow up
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics were reported for this primary endpoint.
    End point values
    Controlled Assessment Period - Exenatide Controlled Assessment Period – Placebo
    Number of subjects analysed
    59
    23
    Units: percentage of participants
    number (not applicable)
        Any AE
    61.0
    73.9
        Any AE with outcome of death
    0
    0
        Any SAE
    3.4
    4.3
        Any AE leading to discontinuation of treatment
    0
    0
        Any AE leading to discontinuation from study
    0
    0
        Any AE related to treatment
    25.4
    21.7
    No statistical analyses for this end point

    Primary: Percentage of Patients Positive for Anti-Drug Antibodies (ADAs) to Exenatide up to Week 24

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    End point title
    Percentage of Patients Positive for Anti-Drug Antibodies (ADAs) to Exenatide up to Week 24 [3]
    End point description
    Percentage of patients positive for ADAs up to Week 24 is reported. Data were only available for the exenatide treatment group. Baseline was the antibody measurement at Week 0 (Day 1). A negative or missing antibody measurement was considered negative at baseline. High positive = antibody titers ≥625, including baseline assessment. Low positive = antibody titers <625, including baseline assessment. A patient was said to have treatment-emergent ADA positive at a visit if the antibody test was positive after first dose of exenatide following a negative or missing antibody measurement, or the titer increased by at least 1 titration category from a detectable measurement prior to first dose of randomized study medication. The Safety Analysis Set consisted of all patients who received at least 1 dose of study medication. Only patients receiving exenatide in the controlled assessment period were included in the analysis.
    End point type
    Primary
    End point timeframe
    Samples were collected on Day 1 (Week 0), Week 4, Week 8, Week 12 and Week 24
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics were reported for this primary endpoint.
    End point values
    Treatment Period – Exenatide
    Number of subjects analysed
    59
    Units: percentage of participants
    number (not applicable)
        Week 4: High Positive (n=55)
    16.4
        Week 4: Low Positive (n=55)
    29.1
        Week 4: Treatment-Emergent ADA Positive (n=55)
    43.6
        Week 8: High Positive (n=52)
    53.8
        Week 8: Low Positive (n=52)
    38.5
        Week 8: Treatment-Emergent ADA Positive (n=52)
    92.3
        Week 12: High Positive (n=51)
    58.8
        Week 12: Low Positive (n=51)
    37.3
        Week 12: Treatment-Emergent ADA Positive (n=51)
    96.1
        Week 24: High Positive (n=49)
    40.8
        Week 24: Low Positive (n=49)
    55.1
        Week 24: Treatment-Emergent ADA Positive (n=49)
    95.9
    No statistical analyses for this end point

    Secondary: Change from Baseline in Fasting Plasma Glucose (FPG) Concentration to Week 24 (Controlled Assessment Period)

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    End point title
    Change from Baseline in Fasting Plasma Glucose (FPG) Concentration to Week 24 (Controlled Assessment Period)
    End point description
    Change from baseline in FPG to Week 24 during the controlled assessment period is reported as adjusted LS mean values. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) on or prior to the first dose of randomized study medication. A MMRM analysis was performed, excluding data collected after initiation of rescue medication or after premature discontinuation of study medication. The Intent-to-Treat (ITT) Analysis Set consisted of all randomized patients who received at least 1 dose of randomized study medication.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Week 24
    End point values
    Controlled Assessment Period - Exenatide Controlled Assessment Period – Placebo
    Number of subjects analysed
    58
    24
    Units: milligrams per deciliter (mg/dL)
        least squares mean (standard error)
    -5.2 ± 7.65
    16.5 ± 11.32
    Statistical analysis title
    Treatment difference in FPG at Week 24
    Statistical analysis description
    Adjusted LS mean and treatment group difference in the change from baseline at Week 24 were modeled using a MMRM including treatment group, region, visit, and treatment group by visit interaction, baseline fasting plasma glucose value, screening HbA1c (< 9.0% or ≥ 9.0%), and baseline fasting plasma glucose by visit interaction as fixed effects, using an unstructured covariance matrix.
    Comparison groups
    Controlled Assessment Period - Exenatide v Controlled Assessment Period – Placebo
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    superiority [4]
    P-value
    = 0.119
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -21.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -49
         upper limit
    5.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    13.7
    Notes
    [4] - Exenatide versus Placebo

    Secondary: Change from Baseline in Body Weight to Week 24 (Controlled Assessment Period)

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    End point title
    Change from Baseline in Body Weight to Week 24 (Controlled Assessment Period)
    End point description
    Change from baseline in body weight to Week 24 during the controlled assessment period is reported as adjusted LS mean values. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) on or prior to the first dose of randomized study medication. A MMRM analysis was performed, excluding data collected after initiation of rescue medication or after premature discontinuation of study medication. The ITT Analysis Set consisted of all randomized patients who received at least 1 dose of randomized study medication.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Week 24
    End point values
    Controlled Assessment Period - Exenatide Controlled Assessment Period – Placebo
    Number of subjects analysed
    58
    24
    Units: kilogram (kg)
        least squares mean (standard error)
    -0.59 ± 0.665
    0.63 ± 0.982
    Statistical analysis title
    Treatment difference in body weight at Week 24
    Statistical analysis description
    Adjusted LS mean and treatment group difference in the change from baseline at Week 24 were modeled using a MMRM including treatment group, region, visit, and treatment group by visit interaction, baseline body weight, screening HbA1c (< 9.0% or ≥ 9.0%), and baseline body weight by visit interaction as fixed effects, using an unstructured covariance matrix.
    Comparison groups
    Controlled Assessment Period - Exenatide v Controlled Assessment Period – Placebo
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    = 0.307
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -1.22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.59
         upper limit
    1.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.189
    Notes
    [5] - Exenatide versus Placebo

    Secondary: Change from Baseline in Fasting Insulin to Week 24 (Controlled Assessment Period)

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    End point title
    Change from Baseline in Fasting Insulin to Week 24 (Controlled Assessment Period)
    End point description
    Change from baseline in fasting insulin to Week 24 during the controlled assessment period is reported as adjusted LS mean values. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) on or prior to the first dose of randomized study medication. A MMRM analysis was performed, excluding data collected after initiation of rescue medication or after premature discontinuation of study medication. The ITT Analysis Set consisted of all randomized patients who received at least 1 dose of randomized study medication.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Week 24
    End point values
    Controlled Assessment Period - Exenatide Controlled Assessment Period – Placebo
    Number of subjects analysed
    58
    24
    Units: picomoles per liter (pmol/L)
        least squares mean (standard error)
    79.6 ± 52.28
    -15.3 ± 78.49
    Statistical analysis title
    Treatment difference in fasting insulin at Week 24
    Statistical analysis description
    Adjusted LS mean and treatment group difference in the change from baseline at Week 24 were modeled using a MMRM including treatment group, region, visit, treatment group by visit interaction, baseline fasting insulin, screening HbA1c (< 9.0% or ≥ 9.0%), and baseline fasting insulin by visit interaction as fixed effects, using an unstructured covariance matrix.
    Comparison groups
    Controlled Assessment Period - Exenatide v Controlled Assessment Period – Placebo
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    P-value
    = 0.323
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    94.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -95.6
         upper limit
    285.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    95.26
    Notes
    [6] - Exenatide versus Placebo

    Secondary: Percentage of Patients Achieving HbA1c Goals of < 6.5%, ≤ 6.5%, and < 7.0% at Week 24 (Controlled Assessment Period)

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    End point title
    Percentage of Patients Achieving HbA1c Goals of < 6.5%, ≤ 6.5%, and < 7.0% at Week 24 (Controlled Assessment Period)
    End point description
    The percentage of patients achieving HbA1c goals of < 6.5%, ≤ 6.5%, and < 7.0% at Week 24 during the controlled assessment period is reported. A Cochran-Mantel-Haenszel (CMH) analysis was performed with missing data treated as non-responder, and excluding data collected after initiation of rescue medication or after premature discontinuation of study medication. The Evaluable Analysis Set consisted of all randomized patients who received at least 1 dose of randomized study medication and had at least 1 baseline and post-baseline HbA1c assessment. Only patients with data available were included in the analysis.
    End point type
    Secondary
    End point timeframe
    At Week 24
    End point values
    Controlled Assessment Period - Exenatide Controlled Assessment Period – Placebo
    Number of subjects analysed
    48
    22
    Units: percentage of participants
    number (confidence interval 95%)
        HbA1c <6 .5%
    19.0 (8.9 to 29.1)
    4.2 (0.0 to 12.2)
        HbA1c ≤ 6.5%
    19.0 (8.9 to 29.1)
    4.2 (0.0 to 12.2)
        HbA1c < 7.0%
    31.0 (19.1 to 42.9)
    8.3 (0.0 to 19.4)
    Statistical analysis title
    Treatment difference in HbA1c < 6.5% at Week 24
    Statistical analysis description
    Treatment group comparison was based on CMH test stratified by screening HbA1c (<9.0% or >=9.0%). P-value was from the general association statistic.
    Comparison groups
    Controlled Assessment Period - Exenatide v Controlled Assessment Period – Placebo
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 0.077
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference
    Point estimate
    14.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.9
         upper limit
    27.7
    Notes
    [7] - Exenatide versus Placebo. Difference was the risk difference of the 2 proportions.
    Statistical analysis title
    Treatment difference in HbA1c ≤ 6.5% at Week 24
    Statistical analysis description
    Treatment group comparison was based on CMH test stratified by screening HbA1c (<9.0% or >=9.0%). P-value was from the general association statistic.
    Comparison groups
    Controlled Assessment Period - Exenatide v Controlled Assessment Period – Placebo
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    superiority [8]
    P-value
    = 0.077
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference
    Point estimate
    14.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.9
         upper limit
    27.7
    Notes
    [8] - Exenatide versus Placebo. Difference was the risk difference of the 2 proportions.
    Statistical analysis title
    Treatment difference in HbA1c < 7.0% at Week 24
    Statistical analysis description
    Treatment group comparison was based on CMH test stratified by screening HbA1c (<9.0% or >=9.0%). P-value was from the general association statistic.
    Comparison groups
    Controlled Assessment Period - Exenatide v Controlled Assessment Period – Placebo
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    = 0.02
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Difference
    Point estimate
    22.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.5
         upper limit
    39
    Notes
    [9] - Exenatide versus Placebo. Difference was the risk difference of the 2 proportions.

    Secondary: Change from Baseline in Lipid Profiles to Week 24 (Controlled Assessment Period)

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    End point title
    Change from Baseline in Lipid Profiles to Week 24 (Controlled Assessment Period)
    End point description
    Change from baseline in lipid profiles to Week 24 during the controlled assessment period is reported as mean values (Standard International [SI] units). The following lipids were assessed: total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides. All lipids presented were taken in a fasted state. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) on or prior to the first dose of randomized study medication. Data collected after initiation of rescue medication or after premature discontinuation of study medication were excluded. The ITT Analysis Set consisted of all randomized patients who received at least 1 dose of randomized study medication. Only patients with data available were included in the analysis (n denotes number of patients analyzed for each parameter).
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Week 24
    End point values
    Controlled Assessment Period - Exenatide Controlled Assessment Period – Placebo
    Number of subjects analysed
    58
    24
    Units: millimoles per liter (mmol/L)
    arithmetic mean (standard deviation)
        Total Cholesterol (n=46, 21)
    -0.117 ± 0.7124
    -0.114 ± 0.5819
        HDL-C (n=46, 21)
    -0.035 ± 0.1950
    -0.047 ± 0.1039
        LDL-C (n=43, 20)
    -0.050 ± 0.5618
    -0.110 ± 0.5983
        Triglycerides (n=46, 21)
    -0.122 ± 1.0303
    0.094 ± 0.6626
    No statistical analyses for this end point

    Secondary: Change from Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) to Week 24 (Controlled Assessment Period)

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    End point title
    Change from Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) to Week 24 (Controlled Assessment Period)
    End point description
    Change from baseline in SBP and DBP to Week 24 during the controlled assessment period is reported as adjusted LS mean values. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) on or prior to the first dose of randomized study medication. A MMRM analysis was performed, excluding data collected after initiation of rescue medication or after premature discontinuation of study medication. The ITT Analysis Set consisted of all randomized patients who received at least 1 dose of randomized study medication.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Week 24
    End point values
    Controlled Assessment Period - Exenatide Controlled Assessment Period – Placebo
    Number of subjects analysed
    58
    24
    Units: millimeters mercury (mmHg)
    least squares mean (standard error)
        SBP
    -0.7 ± 1.48
    2.2 ± 2.15
        DBP
    0.2 ± 1.00
    -1.3 ± 1.45
    Statistical analysis title
    Treatment difference in SBP at Week 24
    Statistical analysis description
    Adjusted LS mean and treatment group difference in the change from baseline at Week 24 were modeled using a MMRM including treatment group, region, visit, treatment group by visit interaction, baseline SBP, screening HbA1c (< 9.0% or ≥ 9.0%), and baseline SBP by visit interaction as fixed effects, using an unstructured covariance matrix.
    Comparison groups
    Controlled Assessment Period - Exenatide v Controlled Assessment Period – Placebo
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    superiority [10]
    P-value
    = 0.284
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -2.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8
         upper limit
    2.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.61
    Notes
    [10] - Exenatide versus Placebo
    Statistical analysis title
    Treatment difference in DBP at Week 24
    Statistical analysis description
    Adjusted LS mean and treatment group difference in the change from baseline at Week 24 were modeled using a MMRM including treatment group, region, visit, treatment group by visit interaction, baseline DBP, screening HbA1c (< 9.0% or ≥ 9.0%), and baseline DBP by visit interaction as fixed effects, using an unstructured covariance matrix.
    Comparison groups
    Controlled Assessment Period - Exenatide v Controlled Assessment Period – Placebo
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    = 0.376
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    1.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2
         upper limit
    5.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.77
    Notes
    [11] - Exenatide versus Placebo

    Secondary: Number of Patients Needing Rescue Medication Due to Failure to Maintain Glycemic Control up to Week 24 (Controlled Assessment Period)

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    End point title
    Number of Patients Needing Rescue Medication Due to Failure to Maintain Glycemic Control up to Week 24 (Controlled Assessment Period)
    End point description
    Number of patients needing rescue medication at Week 24 and at each intermediate visit during the controlled assessment period is reported. Patients with a loss of glycemic control, defined as either an increase from baseline in HbA1c values by ≥ 1.0% at 2 consecutive clinic visits that were at least 1 month apart, or a fasting plasma glucose value ≥ 250 mg/dL or random blood glucose value > 300 mg/dL for 4 days during a 7 day period, received rescue medication. Data collected after premature discontinuation of study medication were excluded. The ITT Analysis Set consisted of all randomized patients who received at least 1 dose of randomized study medication. Only patients with data available were included in the analysis (n denotes number of patients analyzed at each time point).
    End point type
    Secondary
    End point timeframe
    At Week 4, Week 8, Week 12, Week 18 and Week 24
    End point values
    Controlled Assessment Period - Exenatide Controlled Assessment Period – Placebo
    Number of subjects analysed
    58
    24
    Units: participants
        Week 4 (n=57, 24)
    0
    0
        Week 8 (n=55, 24)
    0
    0
        Week 12 (n=51, 24)
    0
    0
        Week 18 (n=50, 24)
    1
    0
        Week 24 (n=49, 24)
    0
    0
    No statistical analyses for this end point

    Secondary: Change from Baseline in Homeostasis Model Assessments – Beta-Cell Function (HOMA-B) and Insulin Sensitivity (HOMA-S) to Week 24 (Controlled Assessment Period)

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    End point title
    Change from Baseline in Homeostasis Model Assessments – Beta-Cell Function (HOMA-B) and Insulin Sensitivity (HOMA-S) to Week 24 (Controlled Assessment Period)
    End point description
    Change from baseline in HOMA-B and HOMA-S in patients who were not taking insulin to Week 24 during the controlled assessment period is reported as adjusted LS mean values. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) on or prior to the first dose of randomized study medication. A MMRM analysis was performed, excluding data collected after initiation of rescue medication or after premature discontinuation of study medication. The ITT Analysis Set consisted of all randomized patients who received at least 1 dose of randomized study medication. Homeostasis model assessments were only performed in patients who were not taking insulin.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Week 24
    End point values
    Controlled Assessment Period - Exenatide Controlled Assessment Period – Placebo
    Number of subjects analysed
    14
    7
    Units: percentage (%HOMA-B and %HOMA-S)
    least squares mean (standard error)
        HOMA-B
    63.98 ± 39.552
    -26.39 ± 56.138
        HOMA-S
    0.62 ± 3.607
    7.37 ± 4.914
    Statistical analysis title
    Treatment difference in HOMA-B at Week 24
    Statistical analysis description
    Adjusted LS mean and treatment group difference in the change from baseline at Week 24 were modeled using a MMRM including treatment group, region, visit, treatment group by visit interaction, baseline HOMA-B, screening HbA1c (< 9.0% or ≥ 9.0%), and baseline HOMA-B by visit interaction as fixed effects, using an unstructured covariance matrix.
    Comparison groups
    Controlled Assessment Period - Exenatide v Controlled Assessment Period – Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    superiority [12]
    P-value
    = 0.211
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    90.37
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -57.27
         upper limit
    238
    Variability estimate
    Standard error of the mean
    Dispersion value
    69.207
    Notes
    [12] - Exenatide versus Placebo
    Statistical analysis title
    Treatment difference in HOMA-S at Week 24
    Statistical analysis description
    Adjusted LS mean and treatment group difference in the change from baseline at Week 24 were modeled using a MMRM including treatment group, region, visit, treatment group by visit interaction, baseline HOMA-S, screening HbA1c (< 9.0% or ≥ 9.0%), and baseline HOMA-S by visit interaction as fixed effects, using an unstructured covariance matrix.
    Comparison groups
    Controlled Assessment Period - Exenatide v Controlled Assessment Period – Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    superiority [13]
    P-value
    = 0.289
    Method
    Mixed models analysis
    Parameter type
    LS Mean Difference
    Point estimate
    -6.75
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -19.8
         upper limit
    6.29
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.173
    Notes
    [13] - Exenatide versus Placebo

    Secondary: Percentage of Patients Reporting AEs of Injection Site Reactions up to Week 24 (Controlled Assessment Period)

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    End point title
    Percentage of Patients Reporting AEs of Injection Site Reactions up to Week 24 (Controlled Assessment Period)
    End point description
    Percentage of patients reporting injection site reactions at Week 24 and at each intermediate visit during the controlled assessment period is reported. Injection site reactions were presented from the AE case report form (CRF), based on the “Injection site reactions” higher level term. A controlled assessment period AE was defined as an AE starting on or after day of first dose of study medication up to but not including Week 24 for patients entering the extension period. For patients not entering the extension period, the period was defined up to and including last dose of study medication + 7 days (+ 90 days for SAEs and other clinically significant or related AEs). The Safety Analysis Set consisted of all patients who received at least 1 dose of study medication. Only patients with data available were included in the analysis (n denotes number of patients analyzed at each time point).
    End point type
    Secondary
    End point timeframe
    At Week 4, Week 8, Week 12, Week 18 and Week 24
    End point values
    Controlled Assessment Period - Exenatide Controlled Assessment Period – Placebo
    Number of subjects analysed
    59
    23
    Units: percentage of participants
    number (not applicable)
        Week 4 (n=59, 23)
    8.5
    8.7
        Week 8 (n=57, 23)
    3.5
    4.3
        Week 12 (n=53, 23)
    1.9
    0
        Week 18 (n=51, 22)
    0
    0
        Week 24 (n=51, 22)
    0
    0
    No statistical analyses for this end point

    Secondary: Change from Baseline in HbA1c to Week 52 Among Patients who Received Open-Label Exenatide (Treatment Period)

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    End point title
    Change from Baseline in HbA1c to Week 52 Among Patients who Received Open-Label Exenatide (Treatment Period)
    End point description
    Change from baseline in HbA1c (%) to Week 52 among patients who received open-label exenatide during the treatment period is reported as mean values. The treatment period was defined as the controlled assessment period and extension period combined. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) on or prior to the first dose of randomized study medication. Data collected after initiation of rescue medication or after premature discontinuation of study medication were excluded. The Evaluable Analysis Set consisted of all randomized patients who received at least 1 dose of randomized study medication and had at least 1 baseline and post-baseline HbA1c assessment. Only patients with observed baseline and Week 52 values, and who received open-label exenatide were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Week 52
    End point values
    Treatment Period – Exenatide Treatment Period - Placebo then Exenatide
    Number of subjects analysed
    39
    17
    Units: percentage (% HbA1c)
        arithmetic mean (standard deviation)
    -0.10 ± 1.711
    0.53 ± 2.123
    No statistical analyses for this end point

    Secondary: Change from Baseline in FPG Concentration to Week 52 Among Patients who Received Open-Label Exenatide (Treatment Period)

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    End point title
    Change from Baseline in FPG Concentration to Week 52 Among Patients who Received Open-Label Exenatide (Treatment Period)
    End point description
    Change from baseline in FPG to Week 52 among patients who received open-label exenatide during the treatment period is reported as mean values. The treatment period was defined as the controlled assessment period and extension period combined. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) on or prior to the first dose of randomized study medication. Data collected after initiation of rescue medication or after premature discontinuation of study medication were excluded. The ITT Analysis Set consisted of all randomized patients who received at least 1 dose of randomized study medication. Only patients with observed baseline and Week 52 values, and who received open-label exenatide were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Week 52
    End point values
    Treatment Period – Exenatide Treatment Period - Placebo then Exenatide
    Number of subjects analysed
    38
    16
    Units: mg/dL
        arithmetic mean (standard deviation)
    -1.8 ± 62.64
    10.6 ± 75.49
    No statistical analyses for this end point

    Secondary: Change from Baseline in Body Weight to Week 52 Among Patients who Received Open-Label Exenatide (Treatment Period)

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    End point title
    Change from Baseline in Body Weight to Week 52 Among Patients who Received Open-Label Exenatide (Treatment Period)
    End point description
    Change from baseline in body weight to Week 52 among patients who received open-label exenatide during the treatment period is reported as mean values. The treatment period was defined as the controlled assessment period and extension period combined. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) on or prior to the first dose of randomized study medication. Data collected after initiation of rescue medication or after premature discontinuation of study medication were excluded. The ITT Analysis Set consisted of all randomized patients who received at least 1 dose of randomized study medication. Only patients with observed baseline and Week 52 values, and who received open-label exenatide were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Week 52
    End point values
    Treatment Period – Exenatide Treatment Period - Placebo then Exenatide
    Number of subjects analysed
    39
    18
    Units: kg
        arithmetic mean (standard deviation)
    0.04 ± 6.088
    -0.04 ± 4.687
    No statistical analyses for this end point

    Secondary: Change from Baseline in Fasting Insulin to Week 52 Among Patients who Received Open-Label Exenatide (Treatment Period)

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    End point title
    Change from Baseline in Fasting Insulin to Week 52 Among Patients who Received Open-Label Exenatide (Treatment Period)
    End point description
    Change from baseline in fasting insulin to Week 52 among patients who received open-label exenatide during the treatment period is reported as mean values. The treatment period was defined as the controlled assessment period and extension period combined. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) on or prior to the first dose of randomized study medication. Data collected after initiation of rescue medication or after premature discontinuation of study medication were excluded. The ITT Analysis Set consisted of all randomized patients who received at least 1 dose of randomized study medication. Only patients with observed baseline and Week 52 values, and who received open-label exenatide were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Week 52
    End point values
    Treatment Period – Exenatide Treatment Period - Placebo then Exenatide
    Number of subjects analysed
    37
    16
    Units: pmol/L
        arithmetic mean (standard deviation)
    -32.4 ± 273.57
    121.5 ± 379.13
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving HbA1c Goals of < 6.5%, ≤ 6.5%, and < 7.0% to Week 52 Among Patients who Received Open-Label Exenatide (Treatment Period)

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    End point title
    Percentage of Participants Achieving HbA1c Goals of < 6.5%, ≤ 6.5%, and < 7.0% to Week 52 Among Patients who Received Open-Label Exenatide (Treatment Period)
    End point description
    The percentage of patients achieving HbA1c goals of < 6.5%, ≤ 6.5%, and < 7.0% at Week 52 among patients who received open-label exenatide during the treatment period is reported. The treatment period was defined as the controlled assessment period and extension period combined. Data collected after initiation of rescue medication or after premature discontinuation of study medication were excluded. The Evaluable Analysis Set consisted of all randomized patients who received at least 1 dose of randomized study medication and had at least 1 baseline and post-baseline HbA1c assessment. Only patients who received open-label exenatide and with data available were included in the analysis.
    End point type
    Secondary
    End point timeframe
    At Week 52
    End point values
    Treatment Period – Exenatide Treatment Period - Placebo then Exenatide
    Number of subjects analysed
    39
    17
    Units: percentage of participants
    number (not applicable)
        HbA1c < 6.5%
    30.8
    23.5
        HbA1c ≤ 6.5%
    30.8
    23.5
        HbA1c < 7.0%
    35.9
    29.4
    No statistical analyses for this end point

    Secondary: Change from Baseline in Lipids Profiles to Week 52 Among Patients who Received Open-Label Exenatide (Treatment Period)

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    End point title
    Change from Baseline in Lipids Profiles to Week 52 Among Patients who Received Open-Label Exenatide (Treatment Period)
    End point description
    Change from baseline in lipid profiles to Week 52 among patients who received open-label exenatide during the treatment period is reported as mean values (SI units). The treatment period was defined as the controlled assessment period and extension period combined. The following lipids were assessed: total cholesterol, HDL-C, LDL-C, and triglycerides. All lipids presented were taken in a fasted state. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) on or prior to the first dose of randomized study medication. Data collected after initiation of rescue medication or after premature discontinuation of study medication were excluded. The ITT Analysis Set consisted of all randomized patients who received at least 1 dose of randomized study medication. Only patients with observed baseline and Week 52 values, and who received open-label exenatide were included in the analysis (n denotes number of patients analyzed for each parameter).
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Week 52
    End point values
    Treatment Period – Exenatide Treatment Period - Placebo then Exenatide
    Number of subjects analysed
    37
    15
    Units: mmol/L
    arithmetic mean (standard deviation)
        Total Cholesterol (n=37, 15)
    -0.188 ± 0.4199
    -0.255 ± 0.9075
        HDL-C (n=37, 15)
    0.004 ± 0.1740
    -0.076 ± 0.2327
        LDL-C (n=33, 15)
    -0.175 ± 0.4025
    -0.152 ± 0.7682
        Triglycerides (n=37, 15)
    -0.155 ± 1.1108
    -0.043 ± 0.5971
    No statistical analyses for this end point

    Secondary: Change from Baseline in Blood Pressure (Systolic and Diastolic) to Week 52 Among Patients who Received Open-Label Exenatide (Treatment Period)

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    End point title
    Change from Baseline in Blood Pressure (Systolic and Diastolic) to Week 52 Among Patients who Received Open-Label Exenatide (Treatment Period)
    End point description
    Change from baseline in SBP and DBP to Week 52 among patients who received open-label exenatide during the treatment period is reported as mean values. The treatment period was defined as the controlled assessment period and extension period combined. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) on or prior to the first dose of randomized study medication. Data collected after initiation of rescue medication or after premature discontinuation of study medication were excluded. The ITT Analysis Set consisted of all randomized patients who received at least 1 dose of randomized study medication. Only patients with observed baseline and Week 52 values, and who received open-label exenatide were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Week 52
    End point values
    Treatment Period – Exenatide Treatment Period - Placebo then Exenatide
    Number of subjects analysed
    39
    18
    Units: mmHg
    arithmetic mean (standard deviation)
        SBP
    -0.7 ± 13.09
    -0.6 ± 8.73
        DBP
    1.1 ± 8.65
    -2.5 ± 10.65
    No statistical analyses for this end point

    Secondary: Number of Patients Needing Rescue Medication Due to Failure to Maintain Glycemic Control up to Week 52 Among Patients who Received Open-Label Exenatide (Treatment Period)

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    End point title
    Number of Patients Needing Rescue Medication Due to Failure to Maintain Glycemic Control up to Week 52 Among Patients who Received Open-Label Exenatide (Treatment Period)
    End point description
    Number of patients needing rescue medication at Week 52 and at each intermediate visit during the treatment period is reported. The treatment period was defined as the controlled assessment period and extension period combined. Patients with a loss of glycemic control, defined as either an increase from baseline in HbA1c values by ≥ 1.0% at 2 consecutive clinic visits that were at least 1 month apart, or a fasting plasma glucose value ≥ 250 mg/dL or random blood glucose value > 300 mg/dL for 4 days during a 7 day period, received rescue medication. Data collected after premature discontinuation of study medication were excluded. The ITT Analysis Set consisted of all randomized patients who received at least 1 dose of randomized study medication. Only patients who received open-label exenatide and with data available were included in the analysis (n denotes number of patients analyzed at each time point).
    End point type
    Secondary
    End point timeframe
    At Week 4, Week 8, Week 12, Week 18, Week 24, Week 28, Week 40 and Week 52
    End point values
    Treatment Period – Exenatide Treatment Period - Placebo then Exenatide
    Number of subjects analysed
    49
    23
    Units: participants
        Week 4 (n=49, 23)
    0
    0
        Week 8 (n=49, 23)
    0
    0
        Week 12 (n=49, 23)
    0
    0
        Week 18 (n=49, 23)
    1
    0
        Week 24 (n=49, 23)
    0
    0
        Week 28 (n=49, 23)
    2
    1
        Week 40 (n=47, 20)
    2
    0
        Week 52 (n=45, 18)
    0
    0
    No statistical analyses for this end point

    Secondary: Change from Baseline in HOMA-B and HOMA-S to Week 52 Among Patients who Received Open-Label Exenatide (Treatment Period)

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    End point title
    Change from Baseline in HOMA-B and HOMA-S to Week 52 Among Patients who Received Open-Label Exenatide (Treatment Period)
    End point description
    Change from baseline in HOMA-B and HOMA-S to Week 52 among patients who received open-label exenatide during the treatment period is reported as mean values. The treatment period was defined as the controlled assessment period and extension period combined. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) on or prior to the first dose of randomized study medication. Data collected after initiation of rescue medication or after premature discontinuation of study medication were excluded. The ITT Analysis Set consisted of all randomized patients who received at least 1 dose of randomized study medication. Only patients with observed baseline and Week 52 values, and who received open-label exenatide were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Week 52
    End point values
    Treatment Period – Exenatide Treatment Period - Placebo then Exenatide
    Number of subjects analysed
    8
    5
    Units: percentage (%HOMA-B and %HOMA-S)
    arithmetic mean (standard deviation)
        HOMA-B
    -2.58 ± 130.435
    42.02 ± 183.869
        HOMA-S
    9.85 ± 12.366
    2.36 ± 7.631
    No statistical analyses for this end point

    Secondary: Percentage of Patients Reporting AEs of Injection Site Reactions up to Week 52 Among Patients who Received Open-Label Exenatide (Treatment Period)

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    End point title
    Percentage of Patients Reporting AEs of Injection Site Reactions up to Week 52 Among Patients who Received Open-Label Exenatide (Treatment Period)
    End point description
    Percentage of patients reporting injection site reactions at Week 52 and at each intermediate visit among patients who received open-label exenatide during the treatment period is reported. The treatment period was defined as the controlled assessment period and extension period combined. Injection site reactions were presented from the AE CRF, based on the “Injection site reactions” higher level term. An Extension Period AE was defined as an AE starting on or after day of first dose of open-label exenatide to last dose + 7 days (+ 90 days for SAEs and other clinically significant or related AEs). The Safety Analysis Set consisted of all patients who received at least 1 dose of study medication. Only patients with data available at each specified visit were included in the analysis (n denotes number of patients analyzed at each time point).
    End point type
    Secondary
    End point timeframe
    At Week 4, Week 8, Week 12, Week 18, Week 24, Week 28, Week 40 and Week 52
    End point values
    Treatment Period – Exenatide Treatment Period - Placebo then Exenatide
    Number of subjects analysed
    50
    22
    Units: percentage of participants
    number (not applicable)
        Week 4 (n=50, 22)
    10.0
    9.1
        Week 8 (n=50, 22)
    4.0
    4.5
        Week 12 (n=50, 22)
    2.0
    0
        Week 18 (n=50, 22)
    0
    0
        Week 24 (n=50, 22)
    0
    0
        Week 28 (n=50, 22)
    4.0
    0
        Week 40 (n=48, 19)
    0
    0
        Week 52 (n=46, 17)
    0
    0
    No statistical analyses for this end point

    Secondary: Plasma Exenatide Concentrations to Week 52 Among Patients who Received Open-Label Exenatide (Treatment Period)

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    End point title
    Plasma Exenatide Concentrations to Week 52 Among Patients who Received Open-Label Exenatide (Treatment Period)
    End point description
    Geometric mean plasma exenatide concentrations up to Week 52 during the treatment period are reported. The treatment period was defined as the controlled assessment period and extension period combined. Data were only available for the exenatide treatment group. Data collected after initiation of rescue medication were included. Data collected after discontinuation of study medication were excluded. The Pharmacokinetic (PK) Analysis Set consisted of all patients who received at least 1 dose of exenatide, for whom any postdose data were available and who did not deviate from the protocol in ways that would significantly affect the PK analyses. Only patients who received open-label exenatide and with data available were included in the analysis (n denotes number of patients analyzed at each time point). 99999 = Not calculated as below the lower limit of quantification.
    End point type
    Secondary
    End point timeframe
    Samples were collected on Day 1 (Week 0), Week 4, Week 8, Week 12, Week 24 and Week 52
    End point values
    Treatment Period – Exenatide
    Number of subjects analysed
    55
    Units: mmol/L
    geometric mean (geometric coefficient of variation)
        Baseline (n=54)
    99999 ± 99999
        Week 4 (n=54)
    41.51 ± 91.9
        Week 8 (n=49)
    130.60 ± 83.8
        Week 12 (n=44)
    163.58 ± 92.3
        Week 24 (n=33)
    140.81 ± 84.0
        Week 52 (n=28)
    88.88 ± 79.2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    After first dose of study medication in period through end of treatment in period +90 days for SAEs (or +7 days for non-serious AEs). Overall timeframe: up to maximum of ~37 weeks and 41 weeks for controlled assessment and extension periods, respectively.
    Adverse event reporting additional description
    The Safety Analysis Set consisted of all patients who received at least 1 dose of study medication. One patient who was randomized to placebo received a dose of exenatide in error and was subsequently reassigned to the exenatide treatment group for analyses based on actual treatment (ie, for analyses based on the Safety Analysis Set).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Controlled Assessment Period – Exenatide
    Reporting group description
    Patients received exenatide 2 mg SC injection once weekly for 24 weeks during the controlled assessment period.

    Reporting group title
    Controlled Assessment Period – Placebo
    Reporting group description
    Patients received placebo (matching with exenatide) SC injection once weekly for 24 weeks during the controlled assessment period.

    Reporting group title
    Extension Period - Exenatide
    Reporting group description
    Patients received open-label exenatide 2 mg SC injection once weekly for 28 weeks during the extension period. Patients in this treatment group had previously received exenatide during the controlled assessment period.

    Reporting group title
    Extension Period – Placebo to Exenatide
    Reporting group description
    Patients received open-label exenatide 2 mg SC injection once weekly for 28 weeks during the extension period. Patients in this treatment group had previously received placebo during the controlled assessment period.

    Serious adverse events
    Controlled Assessment Period – Exenatide Controlled Assessment Period – Placebo Extension Period - Exenatide Extension Period – Placebo to Exenatide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 59 (3.39%)
    1 / 23 (4.35%)
    3 / 50 (6.00%)
    1 / 22 (4.55%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Psychiatric disorders
    Major depression
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 23 (0.00%)
    0 / 50 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 23 (0.00%)
    1 / 50 (2.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 23 (0.00%)
    1 / 50 (2.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Irritable bowel syndrome
         subjects affected / exposed
    0 / 59 (0.00%)
    1 / 23 (4.35%)
    0 / 50 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 23 (0.00%)
    0 / 50 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 23 (0.00%)
    1 / 50 (2.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 59 (0.00%)
    0 / 23 (0.00%)
    1 / 50 (2.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Controlled Assessment Period – Exenatide Controlled Assessment Period – Placebo Extension Period - Exenatide Extension Period – Placebo to Exenatide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 59 (42.37%)
    10 / 23 (43.48%)
    10 / 50 (20.00%)
    4 / 22 (18.18%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 59 (6.78%)
    1 / 23 (4.35%)
    0 / 50 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    5
    1
    0
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 59 (6.78%)
    2 / 23 (8.70%)
    2 / 50 (4.00%)
    1 / 22 (4.55%)
         occurrences all number
    5
    3
    2
    1
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    3 / 59 (5.08%)
    1 / 23 (4.35%)
    0 / 50 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 59 (3.39%)
    3 / 23 (13.04%)
    1 / 50 (2.00%)
    0 / 22 (0.00%)
         occurrences all number
    5
    3
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 23 (0.00%)
    1 / 50 (2.00%)
    0 / 22 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    5 / 59 (8.47%)
    1 / 23 (4.35%)
    1 / 50 (2.00%)
    0 / 22 (0.00%)
         occurrences all number
    5
    1
    1
    0
    Nausea
         subjects affected / exposed
    4 / 59 (6.78%)
    1 / 23 (4.35%)
    0 / 50 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    4
    1
    0
    1
    Vomiting
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 23 (0.00%)
    2 / 50 (4.00%)
    0 / 22 (0.00%)
         occurrences all number
    3
    0
    2
    0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 23 (0.00%)
    0 / 50 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 59 (1.69%)
    1 / 23 (4.35%)
    0 / 50 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    2
    1
    0
    2
    Hypoglycaemia
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 23 (0.00%)
    1 / 50 (2.00%)
    0 / 22 (0.00%)
         occurrences all number
    4
    0
    2
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 59 (6.78%)
    2 / 23 (8.70%)
    1 / 50 (2.00%)
    1 / 22 (4.55%)
         occurrences all number
    5
    3
    1
    2
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 59 (10.17%)
    0 / 23 (0.00%)
    2 / 50 (4.00%)
    0 / 22 (0.00%)
         occurrences all number
    6
    0
    2
    0
    Urinary tract infection
         subjects affected / exposed
    3 / 59 (5.08%)
    2 / 23 (8.70%)
    0 / 50 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    4
    2
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 May 2011
    - Inclusion criterion updated to specify that patients aged 10 to 17, inclusive, at Screening visit were eligible to participate in the study. - Study plan and procedures updated to include assessment of study medication compliance. - Additional guidance provided for rescue treatment following the loss of glycemic control.
    20 Jun 2012
    - Study design amended to include extended safety follow-up period. - Primary, secondary and safety objectives and corresponding endpoints updated. Exploratory safety endpoints added. - Descriptions of the analysis methods for the study endpoints also updated. - An inclusion criterion and an exclusion criterion were updated and another exclusion criterion was removed. - Additional information provided regarding dispensing of study medication. - Randomization strata updated to include country. - Procedures for rescue treatment updated. - Certain screening procedures revised. - For the controlled assessment period, certain laboratory assessments were amended and guidance for returning used/unused medication was updated. - For the open-label extension period, certain laboratory assessments were amended. - For study termination/early termination, a procedure was added requiring patients to fast overnight and certain laboratory assessments were amended. - Ethical safety considerations updated. - Blood glucose threshold for determination of hypoglycemia event updated. - Total blood draw volume increased. - Description of analysis populations updated.
    09 Apr 2015
    - Information was transferred into AstraZeneca format, including transferal of the mixed meal substudy addenda. - Study population description expanded to specify both children and adolescents. The study objectives, plan, and an inclusion criterion were updated to reflect this. - Study duration and plan updated as follows: controlled assessment period updated to 24 weeks, open-label extension period updated to 28 weeks, and 10-week post-treatment follow-up period added. - Observation periods for variables related to the primary and secondary objectives updated to align with the revised study plan. - Procedures for rescue treatment updated. - Updates/additions for 4 inclusion criteria and 3 exclusion criteria. - Procedures for patient enrollment and randomization, and for handling patients incorrectly enrolled or randomized in the study, and blinding/unblinding procedures were updated and expanded. - Dosing guidance generalized to remove specific reference to abdomen for route of injection. - Guidance for the concomitant use of insulin, as well as other medications, updated. - Text added to clarify treatment compliance procedures. - Text added to clarify the procedures for discontinuing from study medication, and withdrawing from the study. - Visit schedule and procedures were updated to reflect the updated study duration/plan. - Collection of safety variables updated. - Analysis sets expanded to include Per Protocol population. - Interim analysis details, including the timing of the analysis, were updated. - The study sample size was adjusted. - Study plan and procedures modified to include injection site reaction assessments. - Safety assessments related to markers of bone turnover updated from deoxypyridinoline to N telopeptide. - Formulation of study medication updated to include a dual chamber pen. Instructions for study medication administration were clarified. - Procedures regarding paternal exposure were removed.

    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.
    Indicated as interim analysis to allow submission of results while trial is ongoing, but all reported endpoint data is considered the final analysis. Due to limited sample size, statistical inference for HOMA-B and HOMA-S is difficult to interpret.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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