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    Clinical Trial Results:
    DUAL™ III - GLP-1 switch: The efficacy of insulin degludec/liraglutide in controlling glycaemia in adults with type 2 diabetes inadequately controlled on GLP-1 receptor agonist and OAD therapy

    Summary
    EudraCT number
    2012-000209-63
    Trial protocol
    SK   HU  
    Global end of trial date
    11 Mar 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Mar 2016
    First version publication date
    28 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN9068-3851
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01676116
    WHO universal trial number (UTN)
    U1111-1127-1321
    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
    27 Aug 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Mar 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Mar 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To confirm superiority of insulin degludec/liraglutide versus unchanged glucagon-like peptide-1 (GLP-1) receptor agonist therapy in controlling glycaemia in insulin naïve subjects with type 2 diabetes mellitus (T2DM) inadequately controlled on GLP-1 receptor agonist therapy in combination with metformin±pioglitazone±sulphonylurea.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (59th WMA Assembly, October 2008) and ICH Good Clinical Practice (May 1996) and 21 CFR 312.120.
    Background therapy
    Subjects continued with the OADs Metformin, pioglitazone and sulphonylurea in stable pre-trial doses.
    Evidence for comparator
    Not applicable.
    Actual start date of recruitment
    29 Aug 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 41
    Country: Number of subjects enrolled
    United States: 262
    Country: Number of subjects enrolled
    Slovakia: 60
    Country: Number of subjects enrolled
    France: 40
    Country: Number of subjects enrolled
    Hungary: 35
    Worldwide total number of subjects
    438
    EEA total number of subjects
    135
    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)
    326
    From 65 to 84 years
    112
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The trial was conducted at 81 sites in 5 countries as follows: Australia: 5 sites; France: 7 sites; Hungary: 4 sites; Slovakia 6 sites; United States: 59 sites.

    Pre-assignment
    Screening details
    The duration of the screening period was 2-weeks. All subjects continued GLP-1 receptor agonist and metformin±pioglitazone±SU treatments in their pre-trial doses during the screening period.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Insulin degludec/liraglutide + OADs
    Arm description
    Subjects were treated with subcutaneous (under the skin) once daily (OD) insulin degludec/liraglutide. Insulin degludec/liraglutide was dosed on an individual basis. Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) treatment without changing the frequency or dose throughout the trial, unless there was a safety concern.
    Arm type
    Experimental

    Investigational medicinal product name
    Insulin degludec/liraglutide PDS290
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Insulin degludec/liraglutide in a fixed insulin degludec/liraglutide ratio of 100 units/3.6 mg per mL was supplied in a 3 mL prefilled PDS290 pen-injector. Insulin degludec/liraglutide was injected s.c. in the thigh, upper arm (deltoid region) or abdomen once daily preferably at the same time every day. The insulin degludec/liraglutide dosing unit is defined as a dose step, where 1 insulin degludec/liraglutide dose step consists of 1 unit insulin degludec and 0.036 mg liraglutide. Treatment with insulin degludec/liraglutide was initiated at 16 dose steps containing 16 units insulin degludec and 0.6 mg liraglutide. Adjustment of the insulin degludec/liraglutide dose performed twice weekly based on the mean of 3 preceding daily fasting SMPG values on 3 consecutive days. The maximum allowed dose was 50 dose steps (50 units insulin degludec/1.8 mg liraglutide).

    Arm title
    Liraglutide or exenatide + OADs
    Arm description
    Subjects continued on their pre-trial treatment with subcutaneous (under the skin) liraglutide (Victoza®) (GLP-1 receptor agonist) or exenatide (Byetta®) (GLP-1 receptor agonist) without changing the frequency or dose throughout the trial. Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) without changing the frequency or dose throughout the trial, unless there was a safety concern.
    Arm type
    Active comparator

    Investigational medicinal product name
    Liraglitide or Exenatide
    Investigational medicinal product code
    Other name
    Victoza or Byetta
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The subjects continued their pre-trial GLP-1 receptor agonist treatment either with liraglutide or exenatide with the dose and treatment schedule unchanged throughout the trial period. Subjects also continued with the OADs - metformin, pioglitazone and SU - in stable pre-trial doses (unless there was a safety concern).

    Number of subjects in period 1
    Insulin degludec/liraglutide + OADs Liraglutide or exenatide + OADs
    Started
    292
    146
    Completed
    276
    117
    Not completed
    16
    29
         Protocol deviation
    9
    3
         Other
    4
    10
         Adverse event, non-fatal
    1
    2
         Withdrawal criteria
    2
    14

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Insulin degludec/liraglutide + OADs
    Reporting group description
    Subjects were treated with subcutaneous (under the skin) once daily (OD) insulin degludec/liraglutide. Insulin degludec/liraglutide was dosed on an individual basis. Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) treatment without changing the frequency or dose throughout the trial, unless there was a safety concern.

    Reporting group title
    Liraglutide or exenatide + OADs
    Reporting group description
    Subjects continued on their pre-trial treatment with subcutaneous (under the skin) liraglutide (Victoza®) (GLP-1 receptor agonist) or exenatide (Byetta®) (GLP-1 receptor agonist) without changing the frequency or dose throughout the trial. Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) without changing the frequency or dose throughout the trial, unless there was a safety concern.

    Reporting group values
    Insulin degludec/liraglutide + OADs Liraglutide or exenatide + OADs Total
    Number of subjects
    292 146 438
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    58.3 ± 9.9 58.4 ± 8.8 -
    Gender categorical
    Units: Subjects
        Female
    139 75 214
        Male
    153 71 224
    HbA1c
    Units: percentage of glycated haemoglobin
        arithmetic mean (standard deviation)
    7.8 ± 0.6 7.7 ± 0.6 -
    Body weight
    Units: kg
        arithmetic mean (standard deviation)
    95.6 ± 16.6 95.5 ± 17.3 -
    Fasting plasma glucose
    Units: mmol/L
        arithmetic mean (standard deviation)
    9 ± 2.1 9.4 ± 2.3 -

    End points

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    End points reporting groups
    Reporting group title
    Insulin degludec/liraglutide + OADs
    Reporting group description
    Subjects were treated with subcutaneous (under the skin) once daily (OD) insulin degludec/liraglutide. Insulin degludec/liraglutide was dosed on an individual basis. Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) treatment without changing the frequency or dose throughout the trial, unless there was a safety concern.

    Reporting group title
    Liraglutide or exenatide + OADs
    Reporting group description
    Subjects continued on their pre-trial treatment with subcutaneous (under the skin) liraglutide (Victoza®) (GLP-1 receptor agonist) or exenatide (Byetta®) (GLP-1 receptor agonist) without changing the frequency or dose throughout the trial. Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) without changing the frequency or dose throughout the trial, unless there was a safety concern.

    Primary: Change in glycosylated haemoglobin (HbA1c) from baseline (randomisation, Visit 2).

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    End point title
    Change in glycosylated haemoglobin (HbA1c) from baseline (randomisation, Visit 2).
    End point description
    The mean change from baseline in HbA1c, after 26 weeks of treatment.
    End point type
    Primary
    End point timeframe
    After 26 weeks of treatment.
    End point values
    Insulin degludec/liraglutide + OADs Liraglutide or exenatide + OADs
    Number of subjects analysed
    292
    146
    Units: percentage of glycosylated haemoglobin
        least squares mean (standard error)
    -1.32 ± 0.05
    -0.37 ± 0.07
    Statistical analysis title
    Statistical Analysis
    Statistical analysis description
    The primary endpoint was analysed using an analysis of covariance (ANCOVA) model with treatment, pre-trial GLP-1 receptor agonist (Victoza® or Byetta®) and region as fixed factors and baseline HbA1c value as covariate.
    Comparison groups
    Insulin degludec/liraglutide + OADs v Liraglutide or exenatide + OADs
    Number of subjects included in analysis
    438
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Treatment Contrast
    Point estimate
    -0.94
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.11
         upper limit
    -0.78

    Secondary: Responders (Yes/No) achieving pre-defined target for HbA1c - HbA1c < 7.0% (53 mmol/mol).

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    End point title
    Responders (Yes/No) achieving pre-defined target for HbA1c - HbA1c < 7.0% (53 mmol/mol).
    End point description
    Proportion of subjects achieving HbA1c below 7.0% after 24 weeks of treatment.
    End point type
    Secondary
    End point timeframe
    After 26 weeks of treatment.
    End point values
    Insulin degludec/liraglutide + OADs Liraglutide or exenatide + OADs
    Number of subjects analysed
    292
    146
    Units: Percentage
        number (not applicable)
    75.3
    35.6
    No statistical analyses for this end point

    Secondary: Responders (Yes/No) achieving pre-defined target for HbA1c - HbA1c ≤ 6.5% (48 mmol/mol).

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    End point title
    Responders (Yes/No) achieving pre-defined target for HbA1c - HbA1c ≤ 6.5% (48 mmol/mol).
    End point description
    Proportion of responders achieving pre-defined target for HbA1c - HbA1c ≤ 6.5% (48 mmol/mol).
    End point type
    Secondary
    End point timeframe
    After 26 weeks of treatment
    End point values
    Insulin degludec/liraglutide + OADs Liraglutide or exenatide + OADs
    Number of subjects analysed
    292
    146
    Units: Percentage
        number (not applicable)
    63
    22.6
    No statistical analyses for this end point

    Secondary: Change from baseline in body weight.

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    End point title
    Change from baseline in body weight.
    End point description
    Mean change in body weight after 26 weeks of treatment.
    End point type
    Secondary
    End point timeframe
    After 26 weeks of treatment.
    End point values
    Insulin degludec/liraglutide + OADs Liraglutide or exenatide + OADs
    Number of subjects analysed
    292
    146
    Units: Kilograms
        arithmetic mean (standard deviation)
    2 ± 3.9
    -0.8 ± 3
    No statistical analyses for this end point

    Secondary: Change from baseline in fasting plasma glucose (FPG).

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    End point title
    Change from baseline in fasting plasma glucose (FPG).
    End point description
    Mean change in fasting plasma glucose from baseline, after 26 weeks of treatment.
    End point type
    Secondary
    End point timeframe
    After 26 weeks of treatment.
    End point values
    Insulin degludec/liraglutide + OADs Liraglutide or exenatide + OADs
    Number of subjects analysed
    285
    145
    Units: mmol/L
        arithmetic mean (standard deviation)
    -2.98 ± 2.28
    -0.6 ± 2.74
    No statistical analyses for this end point

    Secondary: Number of treatment-emergent (confirmed) hypoglycaemic episodes.

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    End point title
    Number of treatment-emergent (confirmed) hypoglycaemic episodes.
    End point description
    Rate (event rate per 100 patient years of exposure) of treatment-emergent confirmed hypoglycaemic episodes. The pool of severe and minor hypoglycaemic episodes was referred to as confirmed hypoglycaemic episodes. Severe hypoglycaemia was categorised as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Minor hypoglycaemic episodes were defined as an episode with symptoms consistent with hypoglycaemia with confirmation by blood glucose <2.8 mmol/L (50 mg/dL) or PG <3.1 mmol/L (56 mg/dL), and which was handled by the subject himself/herself, or any asymptomatic blood glucose value <2.8 mmol/L (50 mg/dL) or PG value <3.1 mmol/L (56 mg/dL).
    End point type
    Secondary
    End point timeframe
    During 26 weeks of treatment.
    End point values
    Insulin degludec/liraglutide + OADs Liraglutide or exenatide + OADs
    Number of subjects analysed
    291
    145
    Units: Event Rate
        number (not applicable)
    281.7
    12.1
    No statistical analyses for this end point

    Secondary: Number of treatment-emergent adverse events (AEs)

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    End point title
    Number of treatment-emergent adverse events (AEs)
    End point description
    Rate (event rate per 100 exposure years) of treatment-emergent adverse events (an event that had onset date (or an increase in severity) on or after the first day of exposure to randomised treatment and no later than 7 days after the last day of randomised treatment) which occurred during the 26 weeks of treatment .
    End point type
    Secondary
    End point timeframe
    During 26 weeks of treatment.
    End point values
    Insulin degludec/liraglutide + OADs Liraglutide or exenatide + OADs
    Number of subjects analysed
    291
    145
    Units: Event rate
        number (not applicable)
    410.1
    364.3
    No statistical analyses for this end point

    Secondary: Change from baseline in patient reported outcomes (PROs):-Treatment related impact measure – diabetes (TRIM-D).

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    End point title
    Change from baseline in patient reported outcomes (PROs):-Treatment related impact measure – diabetes (TRIM-D).
    End point description
    The mean change from baseline on the ‘Treatment related impact measure for diabetes’ (TRIM-D), after 26 weeks of treatment. A higher score on the 1–5 point TRIM-D scale indicates a better health state (less negative impact). The mean change in scores for all the sub domains (treatment burden, daily life, diabetes management, compliance and psychological health) and total scores were analysed. Sub-domain scores were calculated by summing across items in the same domain and total score was calculated by adding scores from all the domains.
    End point type
    Secondary
    End point timeframe
    After 26 weeks of treatment.
    End point values
    Insulin degludec/liraglutide + OADs Liraglutide or exenatide + OADs
    Number of subjects analysed
    290
    146
    Units: Scores
    arithmetic mean (standard deviation)
        TRIM-D Treatment Burden Score
    10.8 ± 18.8
    5.7 ± 19.3
        TRIM-D Daily Life Score
    6.3 ± 18.4
    0.8 ± 18.2
        TRIM-D Diabetes Management Score
    10.9 ± 21.3
    4.1 ± 19.8
        TRIM-D Compliance Score
    8.9 ± 17.3
    4.3 ± 15.9
        TRIM-D Psychological Health Score
    7.3 ± 14.7
    1.4 ± 16.5
        TRIM-D Total Score
    8.7 ± 12
    3.1 ± 12.2
    No statistical analyses for this end point

    Secondary: Change from baseline in patient reported outcomes (PROs):-Diabetes treatment satisfaction questionnaire (DTSQ).

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    End point title
    Change from baseline in patient reported outcomes (PROs):-Diabetes treatment satisfaction questionnaire (DTSQ).
    End point description
    Mean change in diabetes treatment satisfaction questionnaire (DTSQs) scores from baseline. Higher total score on a 0–6 point scale indicates a general higher treatment satisfaction (items 1, 4, 5, 6, 7 and 8), whereas higher score on perceived frequency of hyperglycaemia (item 2) and perceived frequency of hypoglycaemia (item 3) indicate that blood glucose levels are out of the target range.
    End point type
    Secondary
    End point timeframe
    After 26 weeks of treatment.
    End point values
    Insulin degludec/liraglutide + OADs Liraglutide or exenatide + OADs
    Number of subjects analysed
    290
    146
    Units: Score
    arithmetic mean (standard deviation)
        Treatment satisfaction scale total
    3.1 ± 5.6
    1.1 ± 5
        Hyperglycaemia
    -1.8 ± 2
    -0.6 ± 2
        Hypoglycaemia
    0.2 ± 1.7
    -0.1 ± 1.5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events from the first trial-related activity after the subject had signed the informed consent until the end of the post-treatment follow-up period are reported.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Liraglutide or exenatide + OADs
    Reporting group description
    Subjects continued on their pre-trial treatment with subcutaneous (under the skin) liraglutide (Victoza®) (GLP-1 receptor agonist) or exenatide (Byetta®) (GLP-1 receptor agonist) without changing the frequency or dose throughout the trial. Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) without changing the frequency or dose throughout the trial, unless there was a safety concern.

    Reporting group title
    Insulin degludec/liraglutide +OADs
    Reporting group description
    Subjects were treated with subcutaneous (under the skin) once daily (OD) insulin degludec/liraglutide. Insulin degludec/liraglutide was dosed on an individual basis. Subjects also continued their pre-trial OADs (metformin±pioglitazone±SU) treatment without changing the frequency or dose throughout the trial, unless there was a safety concern.

    Serious adverse events
    Liraglutide or exenatide + OADs Insulin degludec/liraglutide +OADs
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 145 (2.07%)
    9 / 291 (3.09%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Foot fracture
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 291 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 291 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral artery thrombosis
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 291 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Thrombectomy
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 291 (0.34%)
         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)
    Pituitary tumour
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 291 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 291 (0.34%)
         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
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 291 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Lacunar infarction
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 291 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 291 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 291 (0.34%)
         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
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 291 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 291 (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 / 145 (0.00%)
    1 / 291 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Spinal pain
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 291 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 291 (0.34%)
         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
    Liraglutide or exenatide + OADs Insulin degludec/liraglutide +OADs
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 145 (26.90%)
    88 / 291 (30.24%)
    Investigations
    Lipase increased
         subjects affected / exposed
    7 / 145 (4.83%)
    29 / 291 (9.97%)
         occurrences all number
    8
    31
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 145 (6.21%)
    27 / 291 (9.28%)
         occurrences all number
    14
    31
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    8 / 145 (5.52%)
    13 / 291 (4.47%)
         occurrences all number
    9
    18
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    19 / 145 (13.10%)
    26 / 291 (8.93%)
         occurrences all number
    20
    31
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 145 (5.52%)
    18 / 291 (6.19%)
         occurrences all number
    9
    18

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Feb 2013
    The global amendment included: a) Changes in the pre-trial medication from GLP-1 and metformin therapy to allow GLP-1 in combination with OADs (metformin±pioglitazone±SU) due to recruitment facilitation and reflection of current diabetic patient population on GLP-1 receptor agonists. b) Changes to the endpoints and statistical sections as described in Section 9.8.2 of this CTR. c) Update of withdrawal criterion no. 1. Updates of the list of participating countries (Hungary added), recruitment timelines, blood volume to be drawn, protocol title, version and date of all appendices. d) Update of the following MESI’s based on the learning’s from previous insulin degludec/liraglutide trials: – Acute coronary syndrome (myocardial infarction [MI] or hospitalisation for unstable angina), incl. AMI caused by stent thrombosis: The wording “, incl. AMI caused by stent thrombosis” was deleted, as this information was already provided under Definitions in Appendix D. – Hospitalisation for cardiac arrhythmia: The word “hospitalisation” was removed, as reporting of hospitalisation for cardiac arrhythmia was not always applicable. Cardiac arrhythmia was still to be reported as a MESI. – Elevated lipase and/or amylase: Confirmatory testing removed. The single elevation >3xUNR of lipase/amylase was to be reported as a MESI. – Elevated calcitonin: Protocol text clarified and aligned to match Appendix D of the protocol. e) Removal of the initial aim to recruit approximately 50% of each type of GLP-1 receptor agonist. f) Update of the ICF regarding blood to be drawn and increased heart rate according to the recent investigator’s brochure for liraglutide.

    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.
    Not applicable
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