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    Clinical Trial Results:
    Efficacy and safety of semaglutide once-weekly versus exenatide ER 2.0 mg once-weekly as add-on to 1-2 oral antidiabetic drugs (OADs) in subjects with type 2 diabetes

    Summary
    EudraCT number
    2012-004826-92
    Trial protocol
    IT   DE   NL   FI   GR   GB   HR  
    Global end of trial date
    13 Jul 2015

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

    Trial information

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    Trial identification
    Sponsor protocol code
    NN9535-3624
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01885208
    WHO universal trial number (UTN)
    U1111-1135-8647
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaerd, Denmark, 2880
    Public contact
    Global Clinical Registry (GCR,1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Global Clinical Registry (GCR,1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 May 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Jul 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effect of semaglutide 1.0 mg once-weekly versus exenatide extended release (ER) 2.0 mg once-weekly on glycaemic control after 56 weeks of treatment
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki, ICH Good Clinical Practice and FDA 21 CFR 312.50 and 56.
    Background therapy
    The following compounds (1-2 OADs) were considered as background medication: • Metformin • Thiazolidinedione (TZD) • Sulfonylureas (SU) Metformin: doses ≥ 1500 mg or maximum tolerated dose. TZD and SU: doses ≥ half of maximum dose allowed according to national label. Subjects upon inclusion continued pre-trial background medication throughout the entire trial. The background medication were maintained at the stable, pre-trial dose and frequency during the whole treatment period unless rescue medication was needed or if the subject had unacceptable hypoglycaemia on a background of SUs in which case the dose of SU was reduced.
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    02 Dec 2013
    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
    Serbia: 57
    Country: Number of subjects enrolled
    Argentina: 72
    Country: Number of subjects enrolled
    Switzerland: 19
    Country: Number of subjects enrolled
    United States: 313
    Country: Number of subjects enrolled
    Netherlands: 40
    Country: Number of subjects enrolled
    United Kingdom: 39
    Country: Number of subjects enrolled
    Croatia: 49
    Country: Number of subjects enrolled
    Finland: 23
    Country: Number of subjects enrolled
    France: 45
    Country: Number of subjects enrolled
    Germany: 54
    Country: Number of subjects enrolled
    Greece: 39
    Country: Number of subjects enrolled
    Italy: 59
    Worldwide total number of subjects
    809
    EEA total number of subjects
    348
    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)
    614
    From 65 to 84 years
    195
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The trial was conducted in 138 sites in 12 countries, Argentina: 4 sites; Croatia: 5 sites; Finland: 5 sites; France: 7 sites; Germany: 7 sites; Greece: 5 sites; Italy: 6 sites; Netherlands: 8 sites; Serbia: 5 sites; Switzerland: 5 sites; United Kingdom: 6 sites; and United States: 75 sites.

    Pre-assignment
    Screening details
    Not applicable

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Semaglutide 1.0 mg once-weekly
    Arm description
    Subjects randomised to semaglutide followed a fixed dose-escalation regimen, starting with once-weekly doses of 0.25 mg for 4 weeks, then escalated to doses of 0.5 mg once weekly for 4 weeks, and finally escalated to 1.0 mg once weekly (maximum dose). Doses were not changed during the trial after the maintenance dose was reached.
    Arm type
    Experimental

    Investigational medicinal product name
    Semaglutide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled injector
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Semaglutide 1.34 mg/mL, solution for injection, 1.5 mL pre-filled PDS290 pen-injector, one test pen per subject was given at the screening visit to ensure subject`s willingness and ability to self-inject. The test pen contained semaglutide placebo, solution for injection, 1.5 mL prefilled PDS290 pen-injector and was to be administered once. Subjects were instructed in administration of subcutaneous (s.c.) injection and the investigator documented whether direction for use (DFU) was given orally and/or in writing.

    Arm title
    Exenatide ER 2.0 mg once-weekly
    Arm description
    Subjects on exenatide ER 2.0 mg were treated with the same 2.0 mg dose throughout the trial.
    Arm type
    Active comparator

    Investigational medicinal product name
    Exenatide
    Investigational medicinal product code
    Other name
    Bydureon
    Pharmaceutical forms
    Powder and solvent for prolonged-release suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Exenatide ER (Bydureon®), one vial of 2 mg exenatide extended-release for injectable suspension for s.c. injection, one pre-filled syringe of 0.65 mL solvent, one vial connector, and two injection needles (one spare) were given at the screening visit. Subjects were instructed in administration of s.c. injection and the investigator documented whether DFU was given orally and/or in writing.

    Number of subjects in period 1
    Semaglutide 1.0 mg once-weekly Exenatide ER 2.0 mg once-weekly
    Started
    404
    405
    Premature discontinuation of treatment
    82 [1]
    85 [2]
    Completed
    374
    369
    Not completed
    30
    36
         Not completed
             30
             36
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This number represents only those participants who prematurely discontinued the treatment. However, subjects who prematurely discontinued treatment were allowed to continue participation in the trial.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This number represents only those participants who prematurely discontinued the treatment. However, subjects who prematurely discontinued treatment were allowed to continue participation in the trial.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Semaglutide 1.0 mg once-weekly
    Reporting group description
    Subjects randomised to semaglutide followed a fixed dose-escalation regimen, starting with once-weekly doses of 0.25 mg for 4 weeks, then escalated to doses of 0.5 mg once weekly for 4 weeks, and finally escalated to 1.0 mg once weekly (maximum dose). Doses were not changed during the trial after the maintenance dose was reached.

    Reporting group title
    Exenatide ER 2.0 mg once-weekly
    Reporting group description
    Subjects on exenatide ER 2.0 mg were treated with the same 2.0 mg dose throughout the trial.

    Reporting group values
    Semaglutide 1.0 mg once-weekly Exenatide ER 2.0 mg once-weekly Total
    Number of subjects
    404 405 809
    Age categorical
    Units: Subjects
    Age continuous
    The number of subjects analysed in the semaglutide and exenatide arms was 404 and 405, respectively.
    Units: years
        arithmetic mean (standard deviation)
    56.4 ± 10.3 56.7 ± 11.1 -
    Gender categorical
    The number of subjects analysed in the semaglutide and exenatide arms was 404 and 405, respectively.
    Units: Subjects
        Female
    185 177 362
        Male
    219 228 447
    Glycated haemoglobin (HbA1c)
    The number of subjects analysed in the semaglutide and exenatide arms was 404 and 405, respectively.
    Units: Percantage of glycated haemoglobin
        arithmetic mean (standard deviation)
    8.36 ± 0.95 8.33 ± 0.96 -
    Body weight
    The number of subjects analysed in the semaglutide and exenatide arms was 404 and 405, respectively.
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    96.21 ± 22.5 95.37 ± 20.46 -
    Fasting Plasma Glucose
    The number of subjects analysed in the semaglutide and exenatide arms was 383 and 384, respectively.
    Units: mg/dL
        arithmetic mean (standard deviation)
    190.5 ± 48.06 187.5 ± 49.41 -
    Systolic blood pressure
    The number of subjects analysed in the semaglutide and exenatide arms was 404 and 404, respectively.
    Units: mm Hg
        arithmetic mean (standard deviation)
    133.35 ± 14.87 133.66 ± 14.25 -
    Diastolic blood pressure
    The number of subjects analysed in the semaglutide and exenatide arms was 404 and 404, respectively.
    Units: mm Hg
        arithmetic mean (standard deviation)
    80.23 ± 8.67 79.57 ± 8.8 -
    Patient-reported outcome: Diabetes Treatment Satisfaction Questionnaire (DTSQ)
    The result presented is the 'Treatment Satisfaction' summary score, which is the sum of 6 of the 8 items of the DTSQs questionnaire. The number of subjects analysed in the semaglutide and exenatide arms was 403 and 405, respectively.
    Units: Units on a scale
        arithmetic mean (standard deviation)
    27.35 ± 6.55 27.23 ± 6.62 -

    End points

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    End points reporting groups
    Reporting group title
    Semaglutide 1.0 mg once-weekly
    Reporting group description
    Subjects randomised to semaglutide followed a fixed dose-escalation regimen, starting with once-weekly doses of 0.25 mg for 4 weeks, then escalated to doses of 0.5 mg once weekly for 4 weeks, and finally escalated to 1.0 mg once weekly (maximum dose). Doses were not changed during the trial after the maintenance dose was reached.

    Reporting group title
    Exenatide ER 2.0 mg once-weekly
    Reporting group description
    Subjects on exenatide ER 2.0 mg were treated with the same 2.0 mg dose throughout the trial.

    Primary: Change in HbA1c

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    End point title
    Change in HbA1c
    End point description
    Change in HbA1c from baseline to week 56. The full analysis set (FAS) included all randomised subjects who had received at least one dose of randomised semaglutide 1.0 mg or exenatide ER 2.0 mg.
    End point type
    Primary
    End point timeframe
    From baseline to week 56
    End point values
    Semaglutide 1.0 mg once-weekly Exenatide ER 2.0 mg once-weekly
    Number of subjects analysed
    404
    405
    Units: Percentage of glycated haemoglobin
        least squares mean (standard error)
    -1.54 ± 0.06
    -0.92 ± 0.06
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    The post-baseline responses were analysed using a mixed model for repeated measurements with treatment and country as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 1.0 mg once-weekly v Exenatide ER 2.0 mg once-weekly
    Number of subjects included in analysis
    809
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    -0.62
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.8
         upper limit
    -0.44
    Notes
    [1] - Non-inferiority was concluded if the upper limit of the two-sided 95% confidence interval for the estimated treatment difference between semaglutide 1.0 mg and exenatide ER 2.0 mg was below the pre-specified non-inferiority margin (0.3 %).
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    The post-baseline responses were analysed using a mixed model for repeated measurements with treatment and country as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 1.0 mg once-weekly v Exenatide ER 2.0 mg once-weekly
    Number of subjects included in analysis
    809
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    -0.62
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.8
         upper limit
    -0.44
    Notes
    [2] - Superiority was concluded if the upper limit of the two-sided 95% confidence interval for the estimated treatment difference between semaglutide 1.0 mg and exenatide ER 2.0 mg was below the pre-specified superiority margin (0 %).

    Secondary: Change in body weight

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    End point title
    Change in body weight
    End point description
    The full analysis set (FAS) included all randomised subjects who had received at least one dose of randomised semaglutide 1.0 mg or exenatide ER 2.0 mg.
    End point type
    Secondary
    End point timeframe
    From baseline to week 56
    End point values
    Semaglutide 1.0 mg once-weekly Exenatide ER 2.0 mg once-weekly
    Number of subjects analysed
    404
    405
    Units: kilograms
        least squares mean (standard error)
    -5.63 ± 0.29
    -1.85 ± 0.29
    No statistical analyses for this end point

    Secondary: Change in fasting plasma glucose (FPG)

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    End point title
    Change in fasting plasma glucose (FPG)
    End point description
    The full analysis set (FAS) included all randomised subjects who had received at least one dose of randomised semaglutide 1.0 mg or exenatide ER 2.0 mg.
    End point type
    Secondary
    End point timeframe
    From baseline to week 56
    End point values
    Semaglutide 1.0 mg once-weekly Exenatide ER 2.0 mg once-weekly
    Number of subjects analysed
    404
    405
    Units: mg/dL
        least squares mean (standard error)
    -51.22 ± 2.36
    -36.1 ± 2.45
    No statistical analyses for this end point

    Secondary: Change in diastolic blood pressure

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    End point title
    Change in diastolic blood pressure
    End point description
    The full analysis set (FAS) included all randomised subjects who had received at least one dose of randomised semaglutide 1.0 mg or exenatide ER 2.0 mg.
    End point type
    Secondary
    End point timeframe
    From baseline to week 56
    End point values
    Semaglutide 1.0 mg once-weekly Exenatide ER 2.0 mg once-weekly
    Number of subjects analysed
    404
    405
    Units: mm Hg
        least squares mean (standard error)
    -1 ± 0.45
    -0.1 ± 0.46
    No statistical analyses for this end point

    Secondary: Change in systolic blood pressure

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    End point title
    Change in systolic blood pressure
    End point description
    The full analysis set (FAS) included all randomised subjects who had received at least one dose of randomised semaglutide 1.0 mg or exenatide ER 2.0 mg.
    End point type
    Secondary
    End point timeframe
    From baseline to week 56
    End point values
    Semaglutide 1.0 mg once-weekly Exenatide ER 2.0 mg once-weekly
    Number of subjects analysed
    404
    405
    Units: mm Hg
        least squares mean (standard error)
    -4.6 ± 0.68
    -2.23 ± 0.7
    No statistical analyses for this end point

    Secondary: Change in Patient reported outcome (PRO) questionnaire Diabetes Treatment Satisfaction Questionnaire status (DTSQs)

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    End point title
    Change in Patient reported outcome (PRO) questionnaire Diabetes Treatment Satisfaction Questionnaire status (DTSQs)
    End point description
    The DTSQs questionnaire was used to assess subjects’ treatment satisfaction. This questionnaire contained 8 components and evaluated the diabetes treatment (including insulin, tablets and/or diet) in terms of convenience, flexibility and general feelings regarding towards the treatment. The result presented is the 'Treatment Satisfaction' summary score, which is the sum of 6 of the 8 items of the DTSQs questionnaire. The full analysis set (FAS) included all randomised subjects who had received at least one dose of randomised semaglutide 1.0 mg or exenatide ER 2.0 mg.
    End point type
    Secondary
    End point timeframe
    From baseline to week 56
    End point values
    Semaglutide 1.0 mg once-weekly Exenatide ER 2.0 mg once-weekly
    Number of subjects analysed
    404
    405
    Units: Units on a scale
        least squares mean (standard error)
    4.98 ± 0.26
    3.96 ± 0.27
    No statistical analyses for this end point

    Secondary: Subjects who achieve HbA1c ≤6.5% (48 mmol/mol) American Association of Clinical Endocrinologists (AACE) target (yes/no)

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    End point title
    Subjects who achieve HbA1c ≤6.5% (48 mmol/mol) American Association of Clinical Endocrinologists (AACE) target (yes/no)
    End point description
    The endpoint considered HbA1c ≤6.5% (48 mmol/mol) as per the AACE (American Association of Clinical Endocrinologists) target. The full analysis set (FAS) included all randomised subjects who had received at least one dose of randomised semaglutide 1.0 mg or exenatide ER 2.0 mg.
    End point type
    Secondary
    End point timeframe
    After 56 weeks' treatment
    End point values
    Semaglutide 1.0 mg once-weekly Exenatide ER 2.0 mg once-weekly
    Number of subjects analysed
    404
    405
    Units: Subjects
        Yes
    190
    89
        No
    214
    316
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First day of exposure to trial product and until week 61
    Adverse event reporting additional description
    The 'on-treatment' overview includes treatment-emergent adverse events with onset at or after the date of the first trial product dose and before or at the date of the last trial product dose plus 5 weeks plus the 7 days visit window for the end-of-treatment follow-up visit (=42 days).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    exenatide ER 2.0 mg
    Reporting group description
    Subjects on exenatide ER 2.0 mg were treated with the same dose throughout the trial.

    Reporting group title
    semaglutide 1.0 mg
    Reporting group description
    Subjects randomised to semaglutide followed a fixed dose-escalation regimen, starting with doses of 0.25 mg for 4 weeks, then escalated to doses of 0.5 mg for 4 weeks, and finally escalated to 1.0 mg (maximum dose). Doses were not changed during the trial after the maintenance dose was reached.

    Serious adverse events
    exenatide ER 2.0 mg semaglutide 1.0 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    24 / 405 (5.93%)
    38 / 404 (9.41%)
         number of deaths (all causes)
    0
    2
         number of deaths resulting from adverse events
    0
    0
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac ablation
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary arterial stent insertion
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery bypass
         subjects affected / exposed
    0 / 405 (0.00%)
    2 / 404 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus removal
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         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)
    Benign renal neoplasm
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 405 (0.25%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Castleman's disease
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial adenocarcinoma
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial cancer stage I
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Follicular thyroid cancer
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Invasive lobular breast carcinoma
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Prostate cancer
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical failure
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Spinal compression fracture
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    HIV test positive
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 405 (0.74%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery insufficiency
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (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
    Aphasia
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 405 (0.25%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 405 (0.00%)
    3 / 404 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Glycosuria
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 405 (0.00%)
    2 / 404 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal disorder
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendonitis
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertebral foraminal stenosis
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 405 (0.25%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 405 (0.49%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 405 (0.25%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 404 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 404 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    exenatide ER 2.0 mg semaglutide 1.0 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    187 / 405 (46.17%)
    194 / 404 (48.02%)
    Investigations
    Lipase increased
         subjects affected / exposed
    49 / 405 (12.10%)
    41 / 404 (10.15%)
         occurrences all number
    64
    51
    Nervous system disorders
    Headache
         subjects affected / exposed
    39 / 405 (9.63%)
    38 / 404 (9.41%)
         occurrences all number
    65
    81
    General disorders and administration site conditions
    Injection site nodule
         subjects affected / exposed
    49 / 405 (12.10%)
    0 / 404 (0.00%)
         occurrences all number
    55
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    21 / 405 (5.19%)
    26 / 404 (6.44%)
         occurrences all number
    26
    28
    Diarrhoea
         subjects affected / exposed
    34 / 405 (8.40%)
    46 / 404 (11.39%)
         occurrences all number
    58
    86
    Dyspepsia
         subjects affected / exposed
    19 / 405 (4.69%)
    27 / 404 (6.68%)
         occurrences all number
    23
    33
    Nausea
         subjects affected / exposed
    48 / 405 (11.85%)
    90 / 404 (22.28%)
         occurrences all number
    70
    159
    Vomiting
         subjects affected / exposed
    25 / 405 (6.17%)
    29 / 404 (7.18%)
         occurrences all number
    40
    37
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    21 / 405 (5.19%)
    32 / 404 (7.92%)
         occurrences all number
    24
    34
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    38 / 405 (9.38%)
    39 / 404 (9.65%)
         occurrences all number
    51
    46

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Mar 2014
    Update of the hypoglycaemic definition and endpoint in this connection, rescue medication criteria, statistical analysis and other minor corrections.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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